Sean P. Cosgriff, PharmD, BCOP

Early Treatment and Diagnosis

Dr. Ascensão. An area that is becoming very important is identifying and separating smoldering multiple myeloma (SMM) from multiple myeloma (MM) and determining when to start treatment. At the Washington DC VAMC (DCVAMC) we started early on bisphosphonates and thalidomide without much benefit, but perhaps we were treating the wrong disease.

Dr. Mehta. Identifying patients as early as possible is often the best way to start. Treating early disease is easier than treating late disease, and it avoids all the complications. The problem is we don’t want to treat too many people because some of the people with SMM will never develop overt MM and, therefore, may not need treatment. We don’t have benign treatment yet. Whatever treatment we decide to use is going to carry adverse effects and toxicity.

So the trick is identifying those patients with SMM who are likely to progress in a finite period and, therefore, can be helped by treating early to avoid the complications of late diagnosis. We know that early treatment for patients with high-risk SMM helps. In a report from Lancet Oncology, early treatment with lenalidomide and dexamethasone reduces time to progression.¹ There are other reports that treating early reduces time to progression.

So how do we identify those patients who are going to progress? We have a few clues. We know that patients who have a myeloma spike of > 1.5 g/dL are more likely to progress than others…The more discordant the / ratio from 1:1, the higher the risk for progression. And if that ratio is 1:100 or more, that would be a risk factor for progression.

We know from the work of Mayo Clinic researchers that if there are ≥ 60% of plasma cells in the bone marrow then it is a risk factor for progression. And we know from early studies that magnetic resonance imaging (MRI) detection of bone lesions, even long before they become detectable by X-ray, also is a risk factor for rapid development to myeloma.

...Methods such as genotyping, which we do here at the University of Arkansas for Medical Sciences, even in patients with MGUS (monoclonal gammopathy of undetermined significance), can identify high-risk patients, but that is not the standard of care yet. But it may become the standard of care in the days to come.

Another thing to think about for MGUS patients: Are there ways to identify what causes MGUS patients to evolve to SMM and then to overt myeloma, and to develop means of interrupting the progression cascade? There have been clinical trials on treatments (eg, bisphosphonates, thalidomide, aspirin, and cyclooxygenase inhibitors), but we haven’t found any safe, good treatment to prevent progression yet. With better technologies, we may be able to do that.

Dr. Ascensão. At the DCVAMC often we receive consults for a patient who had a little anemia, diabetes, renal disease, and the serum protein electrophoresis reveals a very small peak. How often should you follow patients? Do you do a complete workup the moment you see an MGUS or do you wait until they reach SMM?

Dr. Mehta. I don’t think every patient needs a complete workup. If you have obviously identifiable reasons for the anemia or the renal failure, then it’s less likely to be suspicious for myeloma. But patients with M spikes > 1 g/dL deserve a workup with a bone marrow aspirate and biopsy and at least bone X-rays, although MRIs would be even better.

I would differentiate based on the amount of M protein. Higher M protein patients deserve to have at least a bone marrow aspirate and bone study. Patients
with M protein > 1g/dL deserve to be seen every 3 to 4 months. I see patients with tiny little peaks every 6 months. And then, after 1 or 2 years, I turn over their care to the primary care doctor to follow. If we had research protocols to look at those patients and find the methods for progression, which I had at one point, then of course, we could see them more often and try to unravel the mystery.

Use of Imaging

Dr. Ascensão. That’s pretty close to what we do at DCVAMC. What do you think is the role for a bone survey as opposed to MRIs and positron emission tomography (PET) scans in this setting?

Dr. Mehta. In the real world X-rays are more accessible and much less expensive. So for the patient with very low risk who doesn’t have any complaints and
who has a low M spike, I think a bone survey is adequate. But you need about 30% to 40% bone destruction before you’re going to find anything on the X-ray.
MRIs are much more sensitive, plus they tell you about bone marrow involvement, but that should be reserved for the patient who has symptoms or a high
M protein. At Central Arkansas Veterans Healthcare System we simply can’t get PET scans for myeloma patients. At the myeloma center across the street from us, PET scans are used for routine evaluations.

Dr. Chauncey. I agree with Dr. Mehta. At VA Puget Sound Healthcare System (VAPSHCS) there isn’t a problem getting PET scans, but we probably get far fewer
scans than Arkansas. I still like the skeletal survey because it directs you where to look for potential pathologic fracture. It’s definitely not as sensitive as the dedicated myeloma MRI, but it’s a lot easier to get at VAPSHCS, especially as a screening tool.

Dr. Ascensão. Right, I believe there are some issues about the number of osteolytic lesions that may drive diagnosis.

Dr. Mehta. For patients with high M protein, I always request MRI. But the correlation is poorer in patients who have lower M protein. I try to limit it to the patients who have symptoms or high M protein, but I don’t have any evidence-based data to prove that’s the right way.

Dr. Ascensão. If you were going to start treatment of SMM that you believe is evolving to a more regular myeloma, do you do anything different than you would for any of the patients that you have identified as having active myeloma? Do you have different protocols for those patients as opposed to patients who present de novo with active myeloma?

Dr. Mehta. Those patients should be treated with the same drugs, an IMiD and a steroid. And the question is plus or minus a proteasome inhibitor. Studies have shown that an IMiD with a steroid gets much better results than using observation alone. Whether you would get even better results with the proteasome inhibitor remains to be seen. Maybe we can do that study.

Dr. Chauncey. We strive to identify high-risk SMM patients and treat them accordingly. Alternatively, physicians are pulling the trigger for therapy earlier and earlier and when they come for transplant with a diagnosis of MM, it is critical to review the initial diagnostic information. Most transplant centers have experience with this phenomena and know that they don’t want to transplant a non-high-risk SMM or any MGUS. However, by the time the patient is referred for transplantation, the initial clinical data are sometimes obscured or inaccessible.

Dr. Ascensão. We also look into the bone bearing areas, which allows us to make sure that if the patient has hip problems, we can work on how to approach them, whether we want to radiate those patients to prevent fractures.

Use of Bisphosphonates

Dr. Cosgriff. Myeloma metastasizes to bone, and it is one of the common sites of metastatic disease. It poses some interesting complications, whether it is from hypercalcemia due to metastatic sites, or pain syndromes. Bisphosphonates are indicated for myeloma, and they have been for years. Interestingly, unlike some of the other disease, the use of bisphosphonates induces apoptosis in myeloma. So we have seen some disease control with these agents.

The 2 bisphosphonates that are available for use are pamidronate and zoledronic acid. At the VA Portland Health Care System (VAPORHCS), we have been
using pamidronate exclusively for individuals with myeloma. There was a 2003 paper that evaluated the use of bisphosphonates for skeletal-related events in myeloma and in patients with metastatic breast cancer.2 In the subset analysis of myeloma patients with the bisphosphonates, there was no difference between pamidronate and zoledronic acid.

At the time, zoledronic acid was significantly more expensive than pamidronate, and so VAPORHCS opted to use pamidronate as a cost-saving measure. But there are the other reasons for picking pamidronate: Zoledronic acid has some dose recommendations and guidelines for individuals with renal failure, which is often a significant problem in patients with myeloma as well. To get around dose adjustments that need to be made for zoledronic acid, VAPORHCS switched to pamidronate, which is looser with the recommendations on renal failure.

Earlier use criteria, like the National Comprehensive Cancer Network guidelines, stated that if the renal failure was due to the disease itself and not some other outlying factor, a full 90-mg dose of pamidronate could still be used. That comment has since been removed. We still pay attention to it and reduce pamidronate dosing to 60 mg for patients with renal failure.

The prices for zoledronic acid have dropped significantly since it became a generic. The nice thing about zoledronic acid is that it has a short infusion time of 15 minutes. As chair space becomes a problem—VAPHCS has significant issues with that—zoledronic acid looks more and more attractive. The FDA label states that pamidronate should be infused over 4 hours, but VAPHCS typically has been infusing it for 3 hours.

It should be noted that denosumab (XGEVA), a monoclonal antibody that also is targeted for hypercalcemia, has been specifically excluded for myeloma. It
has no FDA indication for myeloma. It does have an indication for hypercalcemia. Whether or not you can state that the patient with myeloma is hypercalcemic, and that’s the reason you want to use it, it starts crossing into some gray area. The drug is still significantly more expensive and it seems to have similar efficacy rates compared with both pamidronate and zoledronic acid, so VAPHCS limits its use to individuals who would otherwise be contraindicated to zoledronic acid or pamidronate due to renal failure.

Dr. Ascensão. How often do you give it, every month, every 3 months?

Dr. Cosgriff. Currently, VAPORHCS is giving bisphosphonates every month whether in the chemotherapy unit or in the short stay unit. We are starting to reevaluate that. I have heard some emerging data that suggest we can use it once a quarter and get the same results. Those data are still emerging. It would be nice to be able to reduce the infusion frequency. But bisphosphonates adhere to bone and get incorporated into the bone matrix and stay there for an extended period of time, upwards of 6 months to a year, as with zoledronic acid.

Osteonecrosis

Dr. Ascensão. Do you require dental clearance prior to first dose?

Dr. Cosgriff. Bisphosphonates have a warning for 2% incidence of osteonecrosis of the jaw. Risk factors for the development of osteonecrosis of the jaw include poor dentition or major dental work, like extractions and illfitting dentures but not necessarily root canals. Ill-fitting dentures tend to rub on the gums and irritate the bone layer underneath. It’s the irritation of the bone that’s the biggest risk factor for osteonecrosis of the jaw.

We require that patients see the dentist because we’ve had individuals develop osteonecrosis eventhough we thought they had good dentition. If a patient is seeing a dentist outside of the VA system, we ask them to notify their dentist that they’re receiving bisphosphonates. Because of the risk and because we’ve had some individuals with good dentition develop it, VAPORHCS requires all patients, particularly those who are receiving zoledronic acid, to have dental evaluations. Denosumab also has a listed 2% incidence of osteonecrosis of the jaw, so those individuals also need to be evaluated by our dental service.

Dr. Ascensão. The DCVAMC has the same problem. I have a patient that presented primarily with a plasmacytoma, and we tried to get him to see the dentist. The dentist said, ‘You’ve got to get your teeth pulled.’ The patient has tried to see outside dentists and is finding all kinds of excuses because he would like to have implants.

Dr. Cosgriff. Anytime that you somehow damage or irritate that bone, that becomes a risk factor for the development of osteonecrosis. And for those individuals, we delay the bisphosphonate. If they’re having pain syndrome, we try to support them with opiates. We would love to be able to use nonsteroidal anti-inflammatory drugs—they have really good efficacy against bone pain—but renal function and renal failures prevent the use of those in a majority of patients. We start bisphosphonates as soon as dental clears them.

Dr. Mehta. Isn’t there a contraindication for denosumab and some evidence that it may worsen MM outcomes?

Dr. Cosgriff. When the drug first came on the market, it specifically stated in the package insert that it is not to be used in MM (it doesn’t state it specifically anymore). There is a thought that maybe some underlying mechanism exists that might stimulate some of the myeloma problems, which is why I get a little concerned when people say, “Well, I’m using it for hypercalcemia, I’m not using it to treat or to prevent a skeletal-related event in patients with myeloma.” That becomes a gray area and in that type of situation, I would recommend treating the hypercalcemia with a single dose and then switching the
patient to a bisphosphonate.

Dr. Mehta. And of course, bisphosphonates also lower calcium. They can be used to treat hypercalcemia.

Dr. Cosgriff. Yes. Zoledronic acid does have limitations in renal failure, though pamidronate doesn’t have quite the same limitations. The VAPORHCS tries to
use exclusively for hypercalcemia as well. The data show that when using zoledronic acid compared with pamidronate, you end up with the same outcomes as far as hypercalcemia. The zoledronic acid onset of action is a little faster, around 12 to 24 hours vs 48 to 72 hours with pamidronate, but you can get around that by using calcitonin over a short period; 48 hours is typically the maximum efficacy for calcitonin in treating hypercalcemia. So we use pamidronate in place of that, supplementing with calcitonin.

The result is that at 7 days, pamidronate and zoledronic acid show the same efficacy rates for treating hypercalcemia. But the renal function sometimes prevents us from doing that. Denosumab does become an option for hypercalcemia, but again, I caution against its use for treating hypercalcemia in patients with myeloma due to the risk of advancing the myeloma.

Bone Marrow Transplant

Dr. Ascensão. Do you transplant for 1 or 2 bone marrows? What’s the best maintenance regimen postallograft, and when do you start? Do you use lenalidomide the first month of the transplant or do you wait until day 100?

Dr. Chauncey. From my perspective, hematopoietic stem cell transplantation has never really lost prominence. It is true that the concept of marrow transplantation for MM has been around for more than 20 years for those patients with first best response (Note that I’ll use best response rather than first remission). The concept was developed in an era when we had much less effective therapy, and in comparative trials, progressionfree survival was consistently superior and occasionally, overall survival was better with transplantation. As treatments got better, responses got better, and there were regular questions as to whether we still needed transplantation. But the data show that as responses got better, the progression-free survivals continued to improve, and transplantation still adds something to initial therapy.

Probably the most current data are from the Dana Farber- IFM trial for which Nikhil Munshi, MD, is an investigator. The trial includes induction with lenalidomide/bortezomib/dexamethasone, which is one of the more aggressive induction regimens. When upfront transplant vs delayed transplant are compared, it seems the preliminary data still favor having an upfront transplant after initial induction therapy.

The consensus is that autologous transplantation adds to the better response that we see with better induction therapy. Overall survival has become a less accessible endpoint since the initial trials, and that’s really a consequence of having better salvage therapy, and the confounding effects of subsequent treatments. We have so many options for salvage therapy that it’s now very hard to look at overall survival as an endpoint in trials of initial therapy.

A sometimes contentious question when it comes to payers, and less so in the VA, is how many transplants to do as part of initial therapy? Little Rock and the French did some of the pioneering work on tandem transplants. The BMT CTN 0702–StaMINA trial looks at this directly, and is mature and should be presented soon [Editorial Note: Preliminary results were presented at the American Society of Hematology meeting on December 6, 2016].

The approach at VAPSHCS and most other transplant centers has typically been to harvest a sufficient quantity of peripheral blood stem cells to do 2 transplants. If less than a very good partial response is achieved after the first transplant, then we do a second transplant in tandem fashion.

One exception would be for plasma cell leukemia, which is very aggressive. In that case, we would routinely perform tandem transplantation. We are unlikely to ever have a randomized trial that compares 1 vs 2 transplants in that particular setting.

Another question is whether a second autologous transplantation can be useful in a nontandem fashion, and there is a large amount of retrospective data about its use as salvage treatment. In eras when there were not as many effective therapies, salvage autologous transplant was more attractive. As new therapies came along, its use has somewhat waned, but there’s been renewed interest because dose-intensive melphalan with autologous rescue is relatively safe and not cross-resistant to other therapies. It also offers the option of a drug holiday after the transplant, whereas salvage drug therapy is typically continuous.

There is no universal agreement on nontandem second transplantation, there are no consistent algorithms to say when it is appropriate, but it’s worth discussing with the transplant programs, especially if there is a lot of toxicity with current salvage therapy.

The last question is the role of allogeneic transplantation, and while I’m generally a proponent of allogeneic transplantation for many diseases, in spite of some really significant efforts, the majority of allogeneic data for MM has not been very positive. The large BMT-CTN 0102 trial compared tandem autologous transplant at first response to a single autologous transplantation followed by reduced-intensity autologous transplantation from a matched sibling. This study was limited in part by enrollment bias, but the published results did not favor an allogeneic approach.³ Although there was less relapse in the allogeneic setting, the mortality of allogeneic transplant was not overcome by the decrease in relapse. Neither progression-free or overall survivals at 3 years were better in the allogeneic group.

Despite small studies showing feasibility and promising results, it’s currently very hard to advocate for allogeneic transplantation in MM. There are certainly centers that continue to have their own approach, with some in the U.S. that are pioneering tweaks on allogeneic regimens and graft engineering, but the data are typically small and anecdotal. That doesn’t mean that there won’t ultimately be a better way to do allogeneic transplantation in MM, but rather that we don’t currently know the best way to approach this strategy.

Next Steps in Myeloma Treatment

Dr. Ascensão. There are some people who are now starting to talk about a cure for myeloma. I’m not sure we’re there yet. Certainly, it’s a chronic disease that, if we can take care of the complications and maybe by starting treatment early. I’m not sure Agent Orange-exposed patients do better or worse. That’s something that needs to be researched if we can find a way to compare within this group and within the type of treatment that patients get.

Is it reasonable to start looking for minimal residual disease in cells? Should we shoot for the best response? I think one of the points that Dr. Chauncey made a number of times, and I agree, is that our patient population may not be able to tolerate some of the more aggressive therapies. Perhaps we need to find a slightly different version of this algorithm for VA patients.

Dr. Chauncey. There’s a diverse biology for both veterans and nonveterans alike. There are patients for whom a deeper response will lead to longer remission and better survival, and there are others whose disease will smolder with a lower tumor burden and not progress quickly. A lot of the early gene expression profiling data on this comes from Little Rock. Unfortunately, determination of an individual’s biology is not readily accessible in the clinic, and we are typically unable to clearly define each patient’s inherent disease biology.

Dr. Mehta. We just don’t have the answers as to exactly what to do with the information that we get except watch more closely and treat a little bit earlier. We don’t even know the significance of minimal residue disease and how often to test for it and if it correlates truly with longer-term survival. These are great research questions. We need to accumulate the data and try to analyze it. We need to participate in the big data programs.

Dr. Ascensão. The other thing, of course, is now we have new immunotherapy approaches beyond transplant, which includes some of the checkpoint inhibitors and there’s some exciting data coming out. So I think the future looks good.

We all are committed to treating our patients, our veterans, to the best of our abilities. And I think the VA has done a very good job in allowing us to do this for our patients and allowing us to provide the best treatments available out there.

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Early Treatment and Diagnosis

Dr. Ascensão. An area that is becoming very important is identifying and separating smoldering multiple myeloma (SMM) from multiple myeloma (MM) and determining when to start treatment. At the Washington DC VAMC (DCVAMC) we started early on bisphosphonates and thalidomide without much benefit, but perhaps we were treating the wrong disease.

Dr. Mehta. Identifying patients as early as possible is often the best way to start. Treating early disease is easier than treating late disease, and it avoids all the complications. The problem is we don’t want to treat too many people because some of the people with SMM will never develop overt MM and, therefore, may not need treatment. We don’t have benign treatment yet. Whatever treatment we decide to use is going to carry adverse effects and toxicity.

So the trick is identifying those patients with SMM who are likely to progress in a finite period and, therefore, can be helped by treating early to avoid the complications of late diagnosis. We know that early treatment for patients with high-risk SMM helps. In a report from Lancet Oncology, early treatment with lenalidomide and dexamethasone reduces time to progression.¹ There are other reports that treating early reduces time to progression.

So how do we identify those patients who are going to progress? We have a few clues. We know that patients who have a myeloma spike of > 1.5 g/dL are more likely to progress than others…The more discordant the / ratio from 1:1, the higher the risk for progression. And if that ratio is 1:100 or more, that would be a risk factor for progression.

We know from the work of Mayo Clinic researchers that if there are ≥ 60% of plasma cells in the bone marrow then it is a risk factor for progression. And we know from early studies that magnetic resonance imaging (MRI) detection of bone lesions, even long before they become detectable by X-ray, also is a risk factor for rapid development to myeloma.

...Methods such as genotyping, which we do here at the University of Arkansas for Medical Sciences, even in patients with MGUS (monoclonal gammopathy of undetermined significance), can identify high-risk patients, but that is not the standard of care yet. But it may become the standard of care in the days to come.

Another thing to think about for MGUS patients: Are there ways to identify what causes MGUS patients to evolve to SMM and then to overt myeloma, and to develop means of interrupting the progression cascade? There have been clinical trials on treatments (eg, bisphosphonates, thalidomide, aspirin, and cyclooxygenase inhibitors), but we haven’t found any safe, good treatment to prevent progression yet. With better technologies, we may be able to do that.

Dr. Ascensão. At the DCVAMC often we receive consults for a patient who had a little anemia, diabetes, renal disease, and the serum protein electrophoresis reveals a very small peak. How often should you follow patients? Do you do a complete workup the moment you see an MGUS or do you wait until they reach SMM?

Dr. Mehta. I don’t think every patient needs a complete workup. If you have obviously identifiable reasons for the anemia or the renal failure, then it’s less likely to be suspicious for myeloma. But patients with M spikes > 1 g/dL deserve a workup with a bone marrow aspirate and biopsy and at least bone X-rays, although MRIs would be even better.

I would differentiate based on the amount of M protein. Higher M protein patients deserve to have at least a bone marrow aspirate and bone study. Patients
with M protein > 1g/dL deserve to be seen every 3 to 4 months. I see patients with tiny little peaks every 6 months. And then, after 1 or 2 years, I turn over their care to the primary care doctor to follow. If we had research protocols to look at those patients and find the methods for progression, which I had at one point, then of course, we could see them more often and try to unravel the mystery.

Use of Imaging

Dr. Ascensão. That’s pretty close to what we do at DCVAMC. What do you think is the role for a bone survey as opposed to MRIs and positron emission tomography (PET) scans in this setting?

Dr. Mehta. In the real world X-rays are more accessible and much less expensive. So for the patient with very low risk who doesn’t have any complaints and
who has a low M spike, I think a bone survey is adequate. But you need about 30% to 40% bone destruction before you’re going to find anything on the X-ray.
MRIs are much more sensitive, plus they tell you about bone marrow involvement, but that should be reserved for the patient who has symptoms or a high
M protein. At Central Arkansas Veterans Healthcare System we simply can’t get PET scans for myeloma patients. At the myeloma center across the street from us, PET scans are used for routine evaluations.

Dr. Chauncey. I agree with Dr. Mehta. At VA Puget Sound Healthcare System (VAPSHCS) there isn’t a problem getting PET scans, but we probably get far fewer
scans than Arkansas. I still like the skeletal survey because it directs you where to look for potential pathologic fracture. It’s definitely not as sensitive as the dedicated myeloma MRI, but it’s a lot easier to get at VAPSHCS, especially as a screening tool.

Dr. Ascensão. Right, I believe there are some issues about the number of osteolytic lesions that may drive diagnosis.

Dr. Mehta. For patients with high M protein, I always request MRI. But the correlation is poorer in patients who have lower M protein. I try to limit it to the patients who have symptoms or high M protein, but I don’t have any evidence-based data to prove that’s the right way.

Dr. Ascensão. If you were going to start treatment of SMM that you believe is evolving to a more regular myeloma, do you do anything different than you would for any of the patients that you have identified as having active myeloma? Do you have different protocols for those patients as opposed to patients who present de novo with active myeloma?

Dr. Mehta. Those patients should be treated with the same drugs, an IMiD and a steroid. And the question is plus or minus a proteasome inhibitor. Studies have shown that an IMiD with a steroid gets much better results than using observation alone. Whether you would get even better results with the proteasome inhibitor remains to be seen. Maybe we can do that study.

Dr. Chauncey. We strive to identify high-risk SMM patients and treat them accordingly. Alternatively, physicians are pulling the trigger for therapy earlier and earlier and when they come for transplant with a diagnosis of MM, it is critical to review the initial diagnostic information. Most transplant centers have experience with this phenomena and know that they don’t want to transplant a non-high-risk SMM or any MGUS. However, by the time the patient is referred for transplantation, the initial clinical data are sometimes obscured or inaccessible.

Dr. Ascensão. We also look into the bone bearing areas, which allows us to make sure that if the patient has hip problems, we can work on how to approach them, whether we want to radiate those patients to prevent fractures.

Use of Bisphosphonates

Dr. Cosgriff. Myeloma metastasizes to bone, and it is one of the common sites of metastatic disease. It poses some interesting complications, whether it is from hypercalcemia due to metastatic sites, or pain syndromes. Bisphosphonates are indicated for myeloma, and they have been for years. Interestingly, unlike some of the other disease, the use of bisphosphonates induces apoptosis in myeloma. So we have seen some disease control with these agents.

The 2 bisphosphonates that are available for use are pamidronate and zoledronic acid. At the VA Portland Health Care System (VAPORHCS), we have been
using pamidronate exclusively for individuals with myeloma. There was a 2003 paper that evaluated the use of bisphosphonates for skeletal-related events in myeloma and in patients with metastatic breast cancer.2 In the subset analysis of myeloma patients with the bisphosphonates, there was no difference between pamidronate and zoledronic acid.

At the time, zoledronic acid was significantly more expensive than pamidronate, and so VAPORHCS opted to use pamidronate as a cost-saving measure. But there are the other reasons for picking pamidronate: Zoledronic acid has some dose recommendations and guidelines for individuals with renal failure, which is often a significant problem in patients with myeloma as well. To get around dose adjustments that need to be made for zoledronic acid, VAPORHCS switched to pamidronate, which is looser with the recommendations on renal failure.

Earlier use criteria, like the National Comprehensive Cancer Network guidelines, stated that if the renal failure was due to the disease itself and not some other outlying factor, a full 90-mg dose of pamidronate could still be used. That comment has since been removed. We still pay attention to it and reduce pamidronate dosing to 60 mg for patients with renal failure.

The prices for zoledronic acid have dropped significantly since it became a generic. The nice thing about zoledronic acid is that it has a short infusion time of 15 minutes. As chair space becomes a problem—VAPHCS has significant issues with that—zoledronic acid looks more and more attractive. The FDA label states that pamidronate should be infused over 4 hours, but VAPHCS typically has been infusing it for 3 hours.

It should be noted that denosumab (XGEVA), a monoclonal antibody that also is targeted for hypercalcemia, has been specifically excluded for myeloma. It
has no FDA indication for myeloma. It does have an indication for hypercalcemia. Whether or not you can state that the patient with myeloma is hypercalcemic, and that’s the reason you want to use it, it starts crossing into some gray area. The drug is still significantly more expensive and it seems to have similar efficacy rates compared with both pamidronate and zoledronic acid, so VAPHCS limits its use to individuals who would otherwise be contraindicated to zoledronic acid or pamidronate due to renal failure.

Dr. Ascensão. How often do you give it, every month, every 3 months?

Dr. Cosgriff. Currently, VAPORHCS is giving bisphosphonates every month whether in the chemotherapy unit or in the short stay unit. We are starting to reevaluate that. I have heard some emerging data that suggest we can use it once a quarter and get the same results. Those data are still emerging. It would be nice to be able to reduce the infusion frequency. But bisphosphonates adhere to bone and get incorporated into the bone matrix and stay there for an extended period of time, upwards of 6 months to a year, as with zoledronic acid.

Osteonecrosis

Dr. Ascensão. Do you require dental clearance prior to first dose?

Dr. Cosgriff. Bisphosphonates have a warning for 2% incidence of osteonecrosis of the jaw. Risk factors for the development of osteonecrosis of the jaw include poor dentition or major dental work, like extractions and illfitting dentures but not necessarily root canals. Ill-fitting dentures tend to rub on the gums and irritate the bone layer underneath. It’s the irritation of the bone that’s the biggest risk factor for osteonecrosis of the jaw.

We require that patients see the dentist because we’ve had individuals develop osteonecrosis eventhough we thought they had good dentition. If a patient is seeing a dentist outside of the VA system, we ask them to notify their dentist that they’re receiving bisphosphonates. Because of the risk and because we’ve had some individuals with good dentition develop it, VAPORHCS requires all patients, particularly those who are receiving zoledronic acid, to have dental evaluations. Denosumab also has a listed 2% incidence of osteonecrosis of the jaw, so those individuals also need to be evaluated by our dental service.

Dr. Ascensão. The DCVAMC has the same problem. I have a patient that presented primarily with a plasmacytoma, and we tried to get him to see the dentist. The dentist said, ‘You’ve got to get your teeth pulled.’ The patient has tried to see outside dentists and is finding all kinds of excuses because he would like to have implants.

Dr. Cosgriff. Anytime that you somehow damage or irritate that bone, that becomes a risk factor for the development of osteonecrosis. And for those individuals, we delay the bisphosphonate. If they’re having pain syndrome, we try to support them with opiates. We would love to be able to use nonsteroidal anti-inflammatory drugs—they have really good efficacy against bone pain—but renal function and renal failures prevent the use of those in a majority of patients. We start bisphosphonates as soon as dental clears them.

Dr. Mehta. Isn’t there a contraindication for denosumab and some evidence that it may worsen MM outcomes?

Dr. Cosgriff. When the drug first came on the market, it specifically stated in the package insert that it is not to be used in MM (it doesn’t state it specifically anymore). There is a thought that maybe some underlying mechanism exists that might stimulate some of the myeloma problems, which is why I get a little concerned when people say, “Well, I’m using it for hypercalcemia, I’m not using it to treat or to prevent a skeletal-related event in patients with myeloma.” That becomes a gray area and in that type of situation, I would recommend treating the hypercalcemia with a single dose and then switching the
patient to a bisphosphonate.

Dr. Mehta. And of course, bisphosphonates also lower calcium. They can be used to treat hypercalcemia.

Dr. Cosgriff. Yes. Zoledronic acid does have limitations in renal failure, though pamidronate doesn’t have quite the same limitations. The VAPORHCS tries to
use exclusively for hypercalcemia as well. The data show that when using zoledronic acid compared with pamidronate, you end up with the same outcomes as far as hypercalcemia. The zoledronic acid onset of action is a little faster, around 12 to 24 hours vs 48 to 72 hours with pamidronate, but you can get around that by using calcitonin over a short period; 48 hours is typically the maximum efficacy for calcitonin in treating hypercalcemia. So we use pamidronate in place of that, supplementing with calcitonin.

The result is that at 7 days, pamidronate and zoledronic acid show the same efficacy rates for treating hypercalcemia. But the renal function sometimes prevents us from doing that. Denosumab does become an option for hypercalcemia, but again, I caution against its use for treating hypercalcemia in patients with myeloma due to the risk of advancing the myeloma.

Bone Marrow Transplant

Dr. Ascensão. Do you transplant for 1 or 2 bone marrows? What’s the best maintenance regimen postallograft, and when do you start? Do you use lenalidomide the first month of the transplant or do you wait until day 100?

Dr. Chauncey. From my perspective, hematopoietic stem cell transplantation has never really lost prominence. It is true that the concept of marrow transplantation for MM has been around for more than 20 years for those patients with first best response (Note that I’ll use best response rather than first remission). The concept was developed in an era when we had much less effective therapy, and in comparative trials, progressionfree survival was consistently superior and occasionally, overall survival was better with transplantation. As treatments got better, responses got better, and there were regular questions as to whether we still needed transplantation. But the data show that as responses got better, the progression-free survivals continued to improve, and transplantation still adds something to initial therapy.

Probably the most current data are from the Dana Farber- IFM trial for which Nikhil Munshi, MD, is an investigator. The trial includes induction with lenalidomide/bortezomib/dexamethasone, which is one of the more aggressive induction regimens. When upfront transplant vs delayed transplant are compared, it seems the preliminary data still favor having an upfront transplant after initial induction therapy.

The consensus is that autologous transplantation adds to the better response that we see with better induction therapy. Overall survival has become a less accessible endpoint since the initial trials, and that’s really a consequence of having better salvage therapy, and the confounding effects of subsequent treatments. We have so many options for salvage therapy that it’s now very hard to look at overall survival as an endpoint in trials of initial therapy.

A sometimes contentious question when it comes to payers, and less so in the VA, is how many transplants to do as part of initial therapy? Little Rock and the French did some of the pioneering work on tandem transplants. The BMT CTN 0702–StaMINA trial looks at this directly, and is mature and should be presented soon [Editorial Note: Preliminary results were presented at the American Society of Hematology meeting on December 6, 2016].

The approach at VAPSHCS and most other transplant centers has typically been to harvest a sufficient quantity of peripheral blood stem cells to do 2 transplants. If less than a very good partial response is achieved after the first transplant, then we do a second transplant in tandem fashion.

One exception would be for plasma cell leukemia, which is very aggressive. In that case, we would routinely perform tandem transplantation. We are unlikely to ever have a randomized trial that compares 1 vs 2 transplants in that particular setting.

Another question is whether a second autologous transplantation can be useful in a nontandem fashion, and there is a large amount of retrospective data about its use as salvage treatment. In eras when there were not as many effective therapies, salvage autologous transplant was more attractive. As new therapies came along, its use has somewhat waned, but there’s been renewed interest because dose-intensive melphalan with autologous rescue is relatively safe and not cross-resistant to other therapies. It also offers the option of a drug holiday after the transplant, whereas salvage drug therapy is typically continuous.

There is no universal agreement on nontandem second transplantation, there are no consistent algorithms to say when it is appropriate, but it’s worth discussing with the transplant programs, especially if there is a lot of toxicity with current salvage therapy.

The last question is the role of allogeneic transplantation, and while I’m generally a proponent of allogeneic transplantation for many diseases, in spite of some really significant efforts, the majority of allogeneic data for MM has not been very positive. The large BMT-CTN 0102 trial compared tandem autologous transplant at first response to a single autologous transplantation followed by reduced-intensity autologous transplantation from a matched sibling. This study was limited in part by enrollment bias, but the published results did not favor an allogeneic approach.³ Although there was less relapse in the allogeneic setting, the mortality of allogeneic transplant was not overcome by the decrease in relapse. Neither progression-free or overall survivals at 3 years were better in the allogeneic group.

Despite small studies showing feasibility and promising results, it’s currently very hard to advocate for allogeneic transplantation in MM. There are certainly centers that continue to have their own approach, with some in the U.S. that are pioneering tweaks on allogeneic regimens and graft engineering, but the data are typically small and anecdotal. That doesn’t mean that there won’t ultimately be a better way to do allogeneic transplantation in MM, but rather that we don’t currently know the best way to approach this strategy.

Next Steps in Myeloma Treatment

Dr. Ascensão. There are some people who are now starting to talk about a cure for myeloma. I’m not sure we’re there yet. Certainly, it’s a chronic disease that, if we can take care of the complications and maybe by starting treatment early. I’m not sure Agent Orange-exposed patients do better or worse. That’s something that needs to be researched if we can find a way to compare within this group and within the type of treatment that patients get.

Is it reasonable to start looking for minimal residual disease in cells? Should we shoot for the best response? I think one of the points that Dr. Chauncey made a number of times, and I agree, is that our patient population may not be able to tolerate some of the more aggressive therapies. Perhaps we need to find a slightly different version of this algorithm for VA patients.

Dr. Chauncey. There’s a diverse biology for both veterans and nonveterans alike. There are patients for whom a deeper response will lead to longer remission and better survival, and there are others whose disease will smolder with a lower tumor burden and not progress quickly. A lot of the early gene expression profiling data on this comes from Little Rock. Unfortunately, determination of an individual’s biology is not readily accessible in the clinic, and we are typically unable to clearly define each patient’s inherent disease biology.

Dr. Mehta. We just don’t have the answers as to exactly what to do with the information that we get except watch more closely and treat a little bit earlier. We don’t even know the significance of minimal residue disease and how often to test for it and if it correlates truly with longer-term survival. These are great research questions. We need to accumulate the data and try to analyze it. We need to participate in the big data programs.

Dr. Ascensão. The other thing, of course, is now we have new immunotherapy approaches beyond transplant, which includes some of the checkpoint inhibitors and there’s some exciting data coming out. So I think the future looks good.

We all are committed to treating our patients, our veterans, to the best of our abilities. And I think the VA has done a very good job in allowing us to do this for our patients and allowing us to provide the best treatments available out there.

Click here to read the digital edition.

Early Treatment and Diagnosis

Dr. Ascensão. An area that is becoming very important is identifying and separating smoldering multiple myeloma (SMM) from multiple myeloma (MM) and determining when to start treatment. At the Washington DC VAMC (DCVAMC) we started early on bisphosphonates and thalidomide without much benefit, but perhaps we were treating the wrong disease.

Dr. Mehta. Identifying patients as early as possible is often the best way to start. Treating early disease is easier than treating late disease, and it avoids all the complications. The problem is we don’t want to treat too many people because some of the people with SMM will never develop overt MM and, therefore, may not need treatment. We don’t have benign treatment yet. Whatever treatment we decide to use is going to carry adverse effects and toxicity.

So the trick is identifying those patients with SMM who are likely to progress in a finite period and, therefore, can be helped by treating early to avoid the complications of late diagnosis. We know that early treatment for patients with high-risk SMM helps. In a report from Lancet Oncology, early treatment with lenalidomide and dexamethasone reduces time to progression.¹ There are other reports that treating early reduces time to progression.

So how do we identify those patients who are going to progress? We have a few clues. We know that patients who have a myeloma spike of > 1.5 g/dL are more likely to progress than others…The more discordant the / ratio from 1:1, the higher the risk for progression. And if that ratio is 1:100 or more, that would be a risk factor for progression.

We know from the work of Mayo Clinic researchers that if there are ≥ 60% of plasma cells in the bone marrow then it is a risk factor for progression. And we know from early studies that magnetic resonance imaging (MRI) detection of bone lesions, even long before they become detectable by X-ray, also is a risk factor for rapid development to myeloma.

...Methods such as genotyping, which we do here at the University of Arkansas for Medical Sciences, even in patients with MGUS (monoclonal gammopathy of undetermined significance), can identify high-risk patients, but that is not the standard of care yet. But it may become the standard of care in the days to come.

Another thing to think about for MGUS patients: Are there ways to identify what causes MGUS patients to evolve to SMM and then to overt myeloma, and to develop means of interrupting the progression cascade? There have been clinical trials on treatments (eg, bisphosphonates, thalidomide, aspirin, and cyclooxygenase inhibitors), but we haven’t found any safe, good treatment to prevent progression yet. With better technologies, we may be able to do that.

Dr. Ascensão. At the DCVAMC often we receive consults for a patient who had a little anemia, diabetes, renal disease, and the serum protein electrophoresis reveals a very small peak. How often should you follow patients? Do you do a complete workup the moment you see an MGUS or do you wait until they reach SMM?

Dr. Mehta. I don’t think every patient needs a complete workup. If you have obviously identifiable reasons for the anemia or the renal failure, then it’s less likely to be suspicious for myeloma. But patients with M spikes > 1 g/dL deserve a workup with a bone marrow aspirate and biopsy and at least bone X-rays, although MRIs would be even better.

I would differentiate based on the amount of M protein. Higher M protein patients deserve to have at least a bone marrow aspirate and bone study. Patients
with M protein > 1g/dL deserve to be seen every 3 to 4 months. I see patients with tiny little peaks every 6 months. And then, after 1 or 2 years, I turn over their care to the primary care doctor to follow. If we had research protocols to look at those patients and find the methods for progression, which I had at one point, then of course, we could see them more often and try to unravel the mystery.

Use of Imaging

Dr. Ascensão. That’s pretty close to what we do at DCVAMC. What do you think is the role for a bone survey as opposed to MRIs and positron emission tomography (PET) scans in this setting?

Dr. Mehta. In the real world X-rays are more accessible and much less expensive. So for the patient with very low risk who doesn’t have any complaints and
who has a low M spike, I think a bone survey is adequate. But you need about 30% to 40% bone destruction before you’re going to find anything on the X-ray.
MRIs are much more sensitive, plus they tell you about bone marrow involvement, but that should be reserved for the patient who has symptoms or a high
M protein. At Central Arkansas Veterans Healthcare System we simply can’t get PET scans for myeloma patients. At the myeloma center across the street from us, PET scans are used for routine evaluations.

Dr. Chauncey. I agree with Dr. Mehta. At VA Puget Sound Healthcare System (VAPSHCS) there isn’t a problem getting PET scans, but we probably get far fewer
scans than Arkansas. I still like the skeletal survey because it directs you where to look for potential pathologic fracture. It’s definitely not as sensitive as the dedicated myeloma MRI, but it’s a lot easier to get at VAPSHCS, especially as a screening tool.

Dr. Ascensão. Right, I believe there are some issues about the number of osteolytic lesions that may drive diagnosis.

Dr. Mehta. For patients with high M protein, I always request MRI. But the correlation is poorer in patients who have lower M protein. I try to limit it to the patients who have symptoms or high M protein, but I don’t have any evidence-based data to prove that’s the right way.

Dr. Ascensão. If you were going to start treatment of SMM that you believe is evolving to a more regular myeloma, do you do anything different than you would for any of the patients that you have identified as having active myeloma? Do you have different protocols for those patients as opposed to patients who present de novo with active myeloma?

Dr. Mehta. Those patients should be treated with the same drugs, an IMiD and a steroid. And the question is plus or minus a proteasome inhibitor. Studies have shown that an IMiD with a steroid gets much better results than using observation alone. Whether you would get even better results with the proteasome inhibitor remains to be seen. Maybe we can do that study.

Dr. Chauncey. We strive to identify high-risk SMM patients and treat them accordingly. Alternatively, physicians are pulling the trigger for therapy earlier and earlier and when they come for transplant with a diagnosis of MM, it is critical to review the initial diagnostic information. Most transplant centers have experience with this phenomena and know that they don’t want to transplant a non-high-risk SMM or any MGUS. However, by the time the patient is referred for transplantation, the initial clinical data are sometimes obscured or inaccessible.

Dr. Ascensão. We also look into the bone bearing areas, which allows us to make sure that if the patient has hip problems, we can work on how to approach them, whether we want to radiate those patients to prevent fractures.

Use of Bisphosphonates

Dr. Cosgriff. Myeloma metastasizes to bone, and it is one of the common sites of metastatic disease. It poses some interesting complications, whether it is from hypercalcemia due to metastatic sites, or pain syndromes. Bisphosphonates are indicated for myeloma, and they have been for years. Interestingly, unlike some of the other disease, the use of bisphosphonates induces apoptosis in myeloma. So we have seen some disease control with these agents.

The 2 bisphosphonates that are available for use are pamidronate and zoledronic acid. At the VA Portland Health Care System (VAPORHCS), we have been
using pamidronate exclusively for individuals with myeloma. There was a 2003 paper that evaluated the use of bisphosphonates for skeletal-related events in myeloma and in patients with metastatic breast cancer.2 In the subset analysis of myeloma patients with the bisphosphonates, there was no difference between pamidronate and zoledronic acid.

At the time, zoledronic acid was significantly more expensive than pamidronate, and so VAPORHCS opted to use pamidronate as a cost-saving measure. But there are the other reasons for picking pamidronate: Zoledronic acid has some dose recommendations and guidelines for individuals with renal failure, which is often a significant problem in patients with myeloma as well. To get around dose adjustments that need to be made for zoledronic acid, VAPORHCS switched to pamidronate, which is looser with the recommendations on renal failure.

Earlier use criteria, like the National Comprehensive Cancer Network guidelines, stated that if the renal failure was due to the disease itself and not some other outlying factor, a full 90-mg dose of pamidronate could still be used. That comment has since been removed. We still pay attention to it and reduce pamidronate dosing to 60 mg for patients with renal failure.

The prices for zoledronic acid have dropped significantly since it became a generic. The nice thing about zoledronic acid is that it has a short infusion time of 15 minutes. As chair space becomes a problem—VAPHCS has significant issues with that—zoledronic acid looks more and more attractive. The FDA label states that pamidronate should be infused over 4 hours, but VAPHCS typically has been infusing it for 3 hours.

It should be noted that denosumab (XGEVA), a monoclonal antibody that also is targeted for hypercalcemia, has been specifically excluded for myeloma. It
has no FDA indication for myeloma. It does have an indication for hypercalcemia. Whether or not you can state that the patient with myeloma is hypercalcemic, and that’s the reason you want to use it, it starts crossing into some gray area. The drug is still significantly more expensive and it seems to have similar efficacy rates compared with both pamidronate and zoledronic acid, so VAPHCS limits its use to individuals who would otherwise be contraindicated to zoledronic acid or pamidronate due to renal failure.

Dr. Ascensão. How often do you give it, every month, every 3 months?

Dr. Cosgriff. Currently, VAPORHCS is giving bisphosphonates every month whether in the chemotherapy unit or in the short stay unit. We are starting to reevaluate that. I have heard some emerging data that suggest we can use it once a quarter and get the same results. Those data are still emerging. It would be nice to be able to reduce the infusion frequency. But bisphosphonates adhere to bone and get incorporated into the bone matrix and stay there for an extended period of time, upwards of 6 months to a year, as with zoledronic acid.

Osteonecrosis

Dr. Ascensão. Do you require dental clearance prior to first dose?

Dr. Cosgriff. Bisphosphonates have a warning for 2% incidence of osteonecrosis of the jaw. Risk factors for the development of osteonecrosis of the jaw include poor dentition or major dental work, like extractions and illfitting dentures but not necessarily root canals. Ill-fitting dentures tend to rub on the gums and irritate the bone layer underneath. It’s the irritation of the bone that’s the biggest risk factor for osteonecrosis of the jaw.

We require that patients see the dentist because we’ve had individuals develop osteonecrosis eventhough we thought they had good dentition. If a patient is seeing a dentist outside of the VA system, we ask them to notify their dentist that they’re receiving bisphosphonates. Because of the risk and because we’ve had some individuals with good dentition develop it, VAPORHCS requires all patients, particularly those who are receiving zoledronic acid, to have dental evaluations. Denosumab also has a listed 2% incidence of osteonecrosis of the jaw, so those individuals also need to be evaluated by our dental service.

Dr. Ascensão. The DCVAMC has the same problem. I have a patient that presented primarily with a plasmacytoma, and we tried to get him to see the dentist. The dentist said, ‘You’ve got to get your teeth pulled.’ The patient has tried to see outside dentists and is finding all kinds of excuses because he would like to have implants.

Dr. Cosgriff. Anytime that you somehow damage or irritate that bone, that becomes a risk factor for the development of osteonecrosis. And for those individuals, we delay the bisphosphonate. If they’re having pain syndrome, we try to support them with opiates. We would love to be able to use nonsteroidal anti-inflammatory drugs—they have really good efficacy against bone pain—but renal function and renal failures prevent the use of those in a majority of patients. We start bisphosphonates as soon as dental clears them.

Dr. Mehta. Isn’t there a contraindication for denosumab and some evidence that it may worsen MM outcomes?

Dr. Cosgriff. When the drug first came on the market, it specifically stated in the package insert that it is not to be used in MM (it doesn’t state it specifically anymore). There is a thought that maybe some underlying mechanism exists that might stimulate some of the myeloma problems, which is why I get a little concerned when people say, “Well, I’m using it for hypercalcemia, I’m not using it to treat or to prevent a skeletal-related event in patients with myeloma.” That becomes a gray area and in that type of situation, I would recommend treating the hypercalcemia with a single dose and then switching the
patient to a bisphosphonate.

Dr. Mehta. And of course, bisphosphonates also lower calcium. They can be used to treat hypercalcemia.

Dr. Cosgriff. Yes. Zoledronic acid does have limitations in renal failure, though pamidronate doesn’t have quite the same limitations. The VAPORHCS tries to
use exclusively for hypercalcemia as well. The data show that when using zoledronic acid compared with pamidronate, you end up with the same outcomes as far as hypercalcemia. The zoledronic acid onset of action is a little faster, around 12 to 24 hours vs 48 to 72 hours with pamidronate, but you can get around that by using calcitonin over a short period; 48 hours is typically the maximum efficacy for calcitonin in treating hypercalcemia. So we use pamidronate in place of that, supplementing with calcitonin.

The result is that at 7 days, pamidronate and zoledronic acid show the same efficacy rates for treating hypercalcemia. But the renal function sometimes prevents us from doing that. Denosumab does become an option for hypercalcemia, but again, I caution against its use for treating hypercalcemia in patients with myeloma due to the risk of advancing the myeloma.

Bone Marrow Transplant

Dr. Ascensão. Do you transplant for 1 or 2 bone marrows? What’s the best maintenance regimen postallograft, and when do you start? Do you use lenalidomide the first month of the transplant or do you wait until day 100?

Dr. Chauncey. From my perspective, hematopoietic stem cell transplantation has never really lost prominence. It is true that the concept of marrow transplantation for MM has been around for more than 20 years for those patients with first best response (Note that I’ll use best response rather than first remission). The concept was developed in an era when we had much less effective therapy, and in comparative trials, progressionfree survival was consistently superior and occasionally, overall survival was better with transplantation. As treatments got better, responses got better, and there were regular questions as to whether we still needed transplantation. But the data show that as responses got better, the progression-free survivals continued to improve, and transplantation still adds something to initial therapy.

Probably the most current data are from the Dana Farber- IFM trial for which Nikhil Munshi, MD, is an investigator. The trial includes induction with lenalidomide/bortezomib/dexamethasone, which is one of the more aggressive induction regimens. When upfront transplant vs delayed transplant are compared, it seems the preliminary data still favor having an upfront transplant after initial induction therapy.

The consensus is that autologous transplantation adds to the better response that we see with better induction therapy. Overall survival has become a less accessible endpoint since the initial trials, and that’s really a consequence of having better salvage therapy, and the confounding effects of subsequent treatments. We have so many options for salvage therapy that it’s now very hard to look at overall survival as an endpoint in trials of initial therapy.

A sometimes contentious question when it comes to payers, and less so in the VA, is how many transplants to do as part of initial therapy? Little Rock and the French did some of the pioneering work on tandem transplants. The BMT CTN 0702–StaMINA trial looks at this directly, and is mature and should be presented soon [Editorial Note: Preliminary results were presented at the American Society of Hematology meeting on December 6, 2016].

The approach at VAPSHCS and most other transplant centers has typically been to harvest a sufficient quantity of peripheral blood stem cells to do 2 transplants. If less than a very good partial response is achieved after the first transplant, then we do a second transplant in tandem fashion.

One exception would be for plasma cell leukemia, which is very aggressive. In that case, we would routinely perform tandem transplantation. We are unlikely to ever have a randomized trial that compares 1 vs 2 transplants in that particular setting.

Another question is whether a second autologous transplantation can be useful in a nontandem fashion, and there is a large amount of retrospective data about its use as salvage treatment. In eras when there were not as many effective therapies, salvage autologous transplant was more attractive. As new therapies came along, its use has somewhat waned, but there’s been renewed interest because dose-intensive melphalan with autologous rescue is relatively safe and not cross-resistant to other therapies. It also offers the option of a drug holiday after the transplant, whereas salvage drug therapy is typically continuous.

There is no universal agreement on nontandem second transplantation, there are no consistent algorithms to say when it is appropriate, but it’s worth discussing with the transplant programs, especially if there is a lot of toxicity with current salvage therapy.

The last question is the role of allogeneic transplantation, and while I’m generally a proponent of allogeneic transplantation for many diseases, in spite of some really significant efforts, the majority of allogeneic data for MM has not been very positive. The large BMT-CTN 0102 trial compared tandem autologous transplant at first response to a single autologous transplantation followed by reduced-intensity autologous transplantation from a matched sibling. This study was limited in part by enrollment bias, but the published results did not favor an allogeneic approach.³ Although there was less relapse in the allogeneic setting, the mortality of allogeneic transplant was not overcome by the decrease in relapse. Neither progression-free or overall survivals at 3 years were better in the allogeneic group.

Despite small studies showing feasibility and promising results, it’s currently very hard to advocate for allogeneic transplantation in MM. There are certainly centers that continue to have their own approach, with some in the U.S. that are pioneering tweaks on allogeneic regimens and graft engineering, but the data are typically small and anecdotal. That doesn’t mean that there won’t ultimately be a better way to do allogeneic transplantation in MM, but rather that we don’t currently know the best way to approach this strategy.

Next Steps in Myeloma Treatment

Dr. Ascensão. There are some people who are now starting to talk about a cure for myeloma. I’m not sure we’re there yet. Certainly, it’s a chronic disease that, if we can take care of the complications and maybe by starting treatment early. I’m not sure Agent Orange-exposed patients do better or worse. That’s something that needs to be researched if we can find a way to compare within this group and within the type of treatment that patients get.

Is it reasonable to start looking for minimal residual disease in cells? Should we shoot for the best response? I think one of the points that Dr. Chauncey made a number of times, and I agree, is that our patient population may not be able to tolerate some of the more aggressive therapies. Perhaps we need to find a slightly different version of this algorithm for VA patients.

Dr. Chauncey. There’s a diverse biology for both veterans and nonveterans alike. There are patients for whom a deeper response will lead to longer remission and better survival, and there are others whose disease will smolder with a lower tumor burden and not progress quickly. A lot of the early gene expression profiling data on this comes from Little Rock. Unfortunately, determination of an individual’s biology is not readily accessible in the clinic, and we are typically unable to clearly define each patient’s inherent disease biology.

Dr. Mehta. We just don’t have the answers as to exactly what to do with the information that we get except watch more closely and treat a little bit earlier. We don’t even know the significance of minimal residue disease and how often to test for it and if it correlates truly with longer-term survival. These are great research questions. We need to accumulate the data and try to analyze it. We need to participate in the big data programs.

Dr. Ascensão. The other thing, of course, is now we have new immunotherapy approaches beyond transplant, which includes some of the checkpoint inhibitors and there’s some exciting data coming out. So I think the future looks good.

We all are committed to treating our patients, our veterans, to the best of our abilities. And I think the VA has done a very good job in allowing us to do this for our patients and allowing us to provide the best treatments available out there.

Click here to read the digital edition.

The following is a lightly edited transcript of a portion of a teleconference discussion on treating patients with multiple myeloma in the VHA. The conclusion will be published in the August special issue. For more information and to listen to the conversation, visit FedPrac.com/AVAHOupdates.

Biology of Multiple Myeloma

Dr. Munshi. There are many new advances in understanding of basic molecular and genomic changes in multiple myeloma (MM) that involve signaling pathways that drive MM. We have many drugs that target signaling pathways and the number of newer mutational changes that are identified could have therapeutic as well as prognostic significance.

One of the important findings is the lack of specific myeloma-related mutations. Unlike Waldenström macroglobulinemia, which has about 90% patients with Myd88 mutation, in myeloma we do not see that. The mutation frequency, at the maximum, is in the range of 20% for any one gene, and the 3 to 4 most common genes mutated are KRAS, NRAS, BRAF, and P53.

Importantly, if we look at RAS and RAF combined, they target the MEK pathway. So, almost 45% patients have a mutation affecting the MEK pathway, and potentially we can use drugs in the future to see if MEK inhibitors will provide some benefit. And there are anecdotal reports and 1 medium-sized study that has used either a pure MEK inhibitor or a BRAF inhibitor with responses in MM patients. This is a very exciting new area of development.

The second important biological feature in myeloma is clonal shifts. You see multiple clones even at the time of diagnosis. The clonal complexity increases and different clones shift over time with treatment, various other interventions, and changes in myeloma growth patterns. In the future, we cannot just do genomic or cytogenetic analysis one time and sit on it. Over the course of the disease, we may have to repeat it to see if a new clone has evolved. Low-grade or low-risk disease can become a high-grade disease over time.

What is becoming apparent is that sometimes a clone that has almost disappeared reappears after 3, 4, or 5 years. The patient can become resistant to a drug that he or she previously was responsive to with the emergenceof a resistant clone. Three or 4 years later the old sensitive clone can reappear and again be sensitive to the drug that it was not responsive to. The patient may be able to use the same drug again down the line and/or consider similar pathways for targeting. This is one of the major advances that is happening now and is going to inform how we treat patients and how we evaluate patients.

Dr. Mehta. Dr. Munshi, is this going to become “big data?” Are we going to get a lot of information about the molecular changes and findings in our patients not only over time with the evolution of the disease, but also with treatment with various combinations and single agents? Do you think that we at the VA would be able to contribute to some type of banking of material with reference labs that can help to interpret all of the data that we’re going to be able to generate?

Tissue Banking

Dr. Munshi. I think that’s a very important and interesting question. Some mechanisms should be developed so we could not only bank, but also study these genomic patterns. From the VA point of view, there would be some peculiarities that we should understand. One is the age of the patient population—veterans usually end up being older. Number 2, we know the disease is more common in the African American population, and we need to understand why. Tissue banking may help us compare the genomic differences and similarities to understand who may be predisposed to increased frequency of myeloma.

Finally, we still have to keep Agent Orange in mind. Although it is becoming quite an old exposure, a lot of times myeloma occurs. There is a recent paper in JAMA Oncology that showed that incidence of MGUS [monoclonal gammopathy of undetermined significance] is higher in people who are exposed to Agent Orange. Tissue banking to understand that also would be extremely important, and the banked tissue should be processed to understand what’s happening at the molecular level.

Dr. Ascensão. What’s interesting is that there are some DoD specimens (most of it is serology is my understanding), but we may be able to get other material. Having predisease tissue and watching as the patient develops MGUS, smoldering MM, or MM would allow us to see whether there were already mutational changes in the individual even before Agent Orange exposure or, perhaps, was a result of the exposure.

Dr. Mehta. If we could do that, we could even develop protocols to prevent progression of disease. We could imagine a day when we can see the first event occurring and do something to prevent the progression to MGUS and then to smoldering and overt myeloma. Now, we’re in a particularly good position having a national network to propose this type of national bank.

Dr. Ascensão. We have some advantages as a group with a high prevalence of African American patients, as Dr. Munshi mentioned. And we have the biologic components of pathogenesis with Agent Orange. I think it’s something we can afford. Dr. Roodman, what do people in the field need to know about the biology of myeloma that’s going to help them?

Dr. Roodman. People still don’t understand some of the mechanisms underlying support of myeloma growth by the microenvironment. There are multiple targets that have been examined, and none of them work especially well except for what we already use, proteasome antagonists and immunomodulatory agents. In terms of the biology of myeloma bone disease, healing myeloma bone lesions is still a major issue that needs to be addressed. The question is how to do that. I have a VA grant to look at that question and other groups are actively studying the problem.

How particular myeloma clones become dominant is still a wide-open question. Some researchers are pursuing how the microenvironment selectively allows more aggressive clones to become dominant. Currently, the major research focus is on intrinsic changes in the myeloma cell but the microenvironment may also be contributing to the process.

Relapse

Dr. Ascensão. Years ago, people who relapsed, relapsed with bone disease, which may not be necessarily how people are relapsing these days. We are seeing testicular relapses, hepatic relapses, or pulmonary relapses in individuals who are exposed to some of the new agents. There may be interesting developments in terms of interactions in the hepatocellular microenvironment component and the myeloma cells at that level.

Dr. Roodman. These types of relapses are by myeloma cells that can grow independent of the bone marrow micro-environment and these myeloma cells are behaving more like a lymphoma than a myeloma. Several groups have been studying these types of relapses and are examining the expression of adhesion molecules and loss of expression of adhesion molecules to understand why the myeloma cells aren’t anchored in the marrow. This is just my opinion, but we really need to decide on something that could be done within the VA and ask questions similar to the 2 VA clinical trials Dr. Munshi developed. Those were doable in the VA, and we were able to get support for these trials. I think we have to ask questions that allow us to take advantage of the unique features of the VA patient population.

Dr. Chauncey. I would offer a comment from the clinical perspective. You mentioned that this is an observation with newer therapies, and it’s certainly been an observation in the marrow transplantation setting that the pattern of relapse changes. As treatments become more effective, the pattern of relapse can change. When we first started performing autologous transplantation, the pattern of relapse changed from the chemotherapy used at the time. When we started performing allogeneic transplantation, and to the extent that we use that option, we see a different pattern of relapse with substantially more extramedullary disease. This is really a polyclonal or oligoclonal disease, and as different clones evolve over time, whether it’s immunologically mediated or cytotoxic suppression of the initially dominant clone, you see clonal evolution with a different clinical presentation.

Immune System

Dr. Ascensão. Dr. Munshi, what do you think about the immunologic aspects of the disease in terms of its evolution?

Dr. Munshi. They are both aspects of the impact of myeloma on the immune system as Dr. Chauncey mentioned with progression similar to what Dr. Roodman described in the bone, but with greater impact on immune functions. With both pro- and antifunctions you get more TH17 responses, increased T regulatory cell responses, but also more microenvironmental immune cells change.

The second effect is that the immune cell also affects the myeloma growth. For example, proinflammatory cytokine produce interleukin (IL)6, IL17, IL21, and IL23 that affect myeloma or provide myeloma cell growth and signaling mechanism. Also, the PDC (plasmacytoid dendritic cell) is one of the best bone marrow components that induces and supports myeloma growth. With progression, some of these microenvironmental elements actually play a greater role in having the disease function or progress growth more aggressively than otherwise.

The second important aspect that comes into the picture in the immune and bone marrow microenvironment is the role of selecting the clone. There are literally hundreds of clones in a given patient. Certain clones would be supported preferentially by the immune cells, and in some cases, these aggressive clones become independent and grow without the need of support. That’s when they end up becoming extramedullary disease, which also determines how the myeloma cell is growing with these molecular changes.

Dr. Mehta. Another point of evidence for the immune system dysregulation in allowing growth of myeloma is the impact of some of the new trials. So the KEYSTONE 023 trial, for example, showed that pembrolizumab, the programmed death 1 protein (PD1) inhibitor, helped to prevent progression of disease and actually increased survival. The CAR T [chimeric antigen receptor T-cell] studies, some of which were presented at ASH [American Society of Hematology annual meeting] last December, also are beginning to show promise, almost as well as in chronic lymphocytic leukemia. We could look at the therapeutic response as an indicator of biologic pathogenesis and say, “likely the immune system is a major determinant.”

Standard of Therapy

Dr. Ascensão. The Spanish group published some interesting data on high-risk MGUS and smoldering MM. What do you as investigators and clinicians look at to make a diagnosis of MGUS, and what kind of test would you do in order to separate these different groups? How would you define current standard of therapy, and do you assign specific therapies for specific groups of patients?

Dr. Munshi. The current standard is a 3-drug regimen in the U.S. The most common 3-drug regimen that we all usually use, definitely in younger people, but also in older people with some dose modification, was a proteasome inhibitor and immunomodulator with dexamethasone—commonly lenalidomide, bortezomib, and dexamethasone (RVD). One can use carfilzomib also. Now we are beginning to switch to ixazomib, an oral proteasome inhibitor, and it can become an all-oral regimen that could be very convenient. We will have a VA study utilizing a similar agent to make an all-oral regimen for treatment.

An alternative people use that has a financial difference is to use a proteasome inhibitor with cyclophosphamide and dexamethasone, a VCD-like regimen. The study is going to use ixazomib, cyclophosphamide, and dexamethasone followed by ixazomib maintenance. That’s the usual induction regimen.

The question is do we do this differently whether the patient is high risk or low risk? My personal bias in the answer is, not really. At the beginning, we will present the best treatment for the patient’s health. If they are older patients with a lot of comorbidities, which is more important, we can use weekly bortezomib instead of using the full dose. We can use subcutaneous weekly bortezomib or a similar 3-drug regimen. And so high risk or low risk doesn’t change how we’re doing the beginning.

The place where the risk stratification comes into the picture is if patients get a transplant. We are beginning to do posttransplant consolidation, and that’s where we would add 2 cycles of consolidation. If consolidation is not done, for high-risk patients one may do maintenance with 2 drugs like bortezomib and lenalidomide alone; whereas in a low-risk patient, you could do lenalidomide only and not use bortezomib with it. This is the impact of risk stratification as far as what we do. It comes more at the later time rather than earlier time point.

Dr. Mehta. There are still a lot of unanswered questions. One area where I think the VA is very good at becoming involved, if we choose to do so, would be some of the drug dosings. For example, dexamethasone used to be used in high dose and the ECOG study showed that you can use it in lower dose weekly rather than 4 days on, 4 days off. The Myeloma In VA (MIVA) group led by Dr. Munshi did a study looking at different doses of lenalidomide. There’s still unanswered questions even in this standard of care regimen that we use where we could try to make the regimen more tolerable for patients.

Dr. Roodman. RVd (modified RVD) has been piloted by Dr. Noopur Raje at Mass General, but I don’t think it’s a large study. She uses it in older patients. To follow-up on what you said, which I think is a really great idea, we could look at RVd as well as 2 doses of dexamethasone, or use oral proteasome antagonists instead.

Dr. Mehta. Yes, to reduce the neurotoxicity.

Dr. Roodman. That is correct. But I think the VA is set up to look at those kinds of questions because most of our patients are older.

Dr. Mehta. They have all the comorbidities.

Dr. Chauncey. We have what we think is an optimal regimen for an optimal patient, and then we have what we often see in the clinic. I’m not sure of the quantitative VA demographics, but if you look at the U.S. myeloma population, the median age is 70 years. While a triplet like
RVd or a carfilzomib-based triplet is probably optimal based on depth of response and the theoretical aspect of suppression of all subclones, it’s not really an accessible regimen for many patients that I see in clinic who are not transplant eligible.

For the nontransplant patients and more frail patients, the doublets or the cyclophosphamide/bortezomib/dexamethasone are reasonable options. I know there are proponents saying that everybody should get RVd or dose-attenuated RVd; I don’t think that’s practical for many of the patients that we see in our clinics.

Dr. Mehta. Why is it not practical in most of your patients? Because they have to come once a week to the clinic?

Dr. Chauncey. That’s part of it, but I find that it’s often too intense with excessive toxicity. The patients are older with comorbidities and they have more limited physiologic reserve. Part of it is coming to clinic, and that’s where all oral regimens such as Rd are useful. I don’t know that if you have an older patient and you see a good response that you’re tracking in terms of their Mspike (monoclonal protein) and their CRAB criteria, that everybody requires the aggressive approach of RVd or a similar triplet with a proteasome inhibitor, an IMiD [immunomodulator drug], and a steroid as induction therapy.

This is true even for some of the older patients who come to autologous transplantation. The data we talk about are in a younger group of patients who can tolerate the full dose of those regimens. The all-oral regimens are attractive, but it’s also quite a financial burden, maybe not to an individual patient, but certainly to the whole health care system. I’m not sure if there is a depth or durability of response advantage for the oral proteasome inhibitor over those available as IV or subcutaneous dosing.

Pricing

Dr. Ascensão. It’s interesting you bring that up because at the Washington DC VAMC, ixazomib may be priced similarly to bortezomib.

Dr. Chauncey. Well that would be very good and very interesting. It’s possible the federal pricing would make it a lot more attractive. It’s not the case outside of the VA, but there the cost burden for oral medication is often shifted to the patient.

Dr. Cosgriff. The price of carfilzomib is about $7,000 to $9,000 per month or per cycle. When we priced ixazomib here in Portland, it actually was more expensive than bortezomib, but it was cheaper than carfilzomib.

Dr. Mehta. If we can do a drug company-sponsored study, the ixazomib people would surely be interested in its usefulness as a triplet in VA patients. It also would be good for the VA patient because you don’t have to come once a week and it has much less neurotoxicity compared to the other proteasome inhibitors, which is a big problem.

Dr. Chauncey. That would be a great study to offer the right patient. I see a lot of myeloma patients in clinic that aren’t really eligible for transplantation. Many of those patients do well on doublet therapy, though they will often require dose adjustments, both down and up, as well as tracking disease status.

Dr. Cosgriff. In Portland, we’re using a lenalidomidebased regimen as a first-line therapy. We’re starting to see more and more individuals starting RVD upfront. There are some select individuals who have diabetic neuropathy or something like that, who may go on just
a lenalidomide plus dexamethasone, leaving out the bortezomib because of neuropathy issues.

Our second-line choice at this point in time has been carfilzomib, but with ixazomib being a cheaper option, we may actually consider switching over to that as a second-line choice. When you look at the clinical trials they cite in the product literature, the grade 1 neuropathy is about 18% with ixazomib and 14% with the placebo arm, so it does add some peripheral neuropathy. Maybe not as much as we would think.

While these oral agents and all-oral regimens are nice to have, we still bring in the patients for clinic and for monitoring of white blood count. It doesn’t necessarily decrease the burden of clinic visits. We still have to get lab draws. Yes, the patient is not sitting in a chair waiting for the bortezomib infusion to be mixed by the pharmacy, but we still have considerations for travel and those types of things.

We treat the entire state of Oregon and parts of southwest Washington. Fortunately, we have community-based outpatient clinics (CBOCs) and VAMCs in other areas of the state, and we also utilize places like Walla Walla and Spokane, Washington, where we can draw and check labs remotely, which decreases the travel burden, but it still is a burden to the patient to actually go in for lab tests. We’re not looking at ixazomib as a first line currently.

We’re going to wait for data to be published on ixazomib in the first line. In a couple of presentations, researchers have suggested that if you tease the data, ixazomib may be inferior to bortezomib in the first-line setting. It will be interesting to see what the data say for that as far as a first-line setting choice.

Dr. Chauncey. I second what Dr. Cosgriff said. You can’t just give patients 3 bottles of pills and say, “See you in 3 months.” Here in the Northwest we cover large rural areas, and there are many CBOCs whose labs feed directly into our CPRS (Computerized Patient Record System) so it’s very accessible and easy to follow patients that come in less frequently, but that doesn’t change the need for regular clinical follow-up. The other thing I’d say is the noncomparative data of carfilzomib/lenalidomide/dexamethasone (CRD) is quite compelling in terms of depth and duration of response. We usually don’t want to accept convenience over efficacy. Whether that durability translates long term, we don’t really know, but I think right now, CRD is the best available regimen, again, with the caveat that it’s not really accessible to patients of all ages and performance status.

Dr. Ascensão. At the Washington DC VAMC in our first cycle it is day 1, 4, 8, and 11 with bortezomib, but after that we go pretty much to weekly bortezomib. We also tend to use what I would call lower dose 20 mg dexamethasone in patients over the age of 70 years. And we feel that it is a lot less toxic. We use subcutaneous bortezomib for pretty much everybody else.

Managing Adverse Effects

Dr. Chauncey. I think we’re all using subcutaneous bortezomib at this point. Dexamethasone doesn’t get a lot of independent attention, but there’s no question that, as Dr. Mehta mentioned, the older regimen that we used, the dose-dense dexamethasone of the VAD regimen, was
quite disabling. In addition to obvious hyperglycemia, there were psychiatric problems and, ultimately, profound steroid myopathy that seemed to affect patients in variable fashion. Different patients seem to be more or less susceptible, but after a couple of cycles, it starts to kick in and is progressive.

So we’ve since abandoned those massive doses. But when you look at the ECOG study (E4A03) that really defined the lower dose (40 mg weekly), there’s no question the higher dose was more toxic but also more effective in terms of disease response. While there are many older patients that I would start with a lower dose of dexamethasone, whether it’s with lenalidomide or bortezomib, I keep in mind there can be a steep dose response curve for dexamethasone. If you’re giving 20 mg and you’re not getting the response you need, then you increase the dose. There is definitely a dose response, but the higher doses are just not as well tolerated.

Dr. Cosgriff. I don’t know if other institutions are doing it, but instead of doing 40 mg as a single dose because of patient performance status, providers in Portland will prescribe 20 mg on days 1, 2, 8, 9, 15, and 16. They’ll break up that 40 mg dose and give it that way.

Dr. Chauncey. I don’t know if that strategy is biologically equivalent in terms of antimyeloma activity or less toxic in terms of myopathy. There’s almost always some disease marker to track, so that whether you’re using the serum free-light chain assay or serum protein electrophoresis, you can see if the strategy you’re using is working in real time.

Dr. Cosgriff. I’ve never known whether it’s been shown to be more efficacious or if it’s just a way of getting around some of the adverse effects. However, it does pose some alternate challenges. With higher doses of steroids, you’re looking at 2 days where the patient can become hyperglycemic, if not, a little bit longer.

The other thing with it is that adding on that extra day of dexamethasone can interfere with some other drugs and some other therapies. In individuals who have had a deep vein thrombosis for whatever reason and they’re on warfarin, now we have an agent that really screws up our warfarin monitoring. We would have to consider switching them to another agent.

Thrombosis

Dr. Mehta. It’s also prothrombotic.

Dr. Chauncey. If you actually ask the patient, independent of the hyperglycemia, independent of the myopathy, independent of psychosis, but just quality of life, they’ll typically tell you that the on-and-off of steroids is the worst part of the regimen. It’s often the roller coaster ride of short-term hypomania followed by dysphoria.

Dr. Mehta. And the lack of sleep. They describe it as being out of their skin.

Dr. Chauncey. They are. And as soon as they stop, often there is a depression.

Dr. Mehta. It is very, very difficult. And some actually develop psychosis.

Dr. Ascensão. We all use some form of acyclovir or its derivative for the prevention of shingles in patients exposed to the proteasome inhibitors. We use aspirin, usually low dose (81 mg), for deep vein thrombosis prophylaxis. But is anybody using other anticoagulants or putting everybody prophylactically on proton-pump inhibitors (PPIs) or just seeing how people do first and then adjusting?

Dr. Chauncey. I typically use conventional dose aspirin, and if there’s breakthrough thrombosis, the first response should be that it is not the best regimen for this patient. Sometimes you have to go back to it, and if someone’s an anticoagulation candidate, then full anticoagulation is
needed if that’s the best regimen. Usually if there’s a breakthrough thrombosis, it is a deal breaker, and you’re ready to move on to a nonthrombogenic regimen.

There has been an observation (there is some biological basis to back this up) that if you give bortezomib with an IMiD, the regimen became less thrombogenic than with the IMiD and dexamethasone alone.

Dr. Ascensão. On aspirin, even if they’re on an IMiD plus a proteasome inhibitor, I just don’t know that the data are good enough for us to avoid it at this point in time. And I don’t necessarily put people on a PPI unless they’ve got added gastrointestinal problems and unless they have associated heartburn or dyspepsia symptoms.

Dr. Mehta. I use low-dose aspirin in every patient. And if they breakthrough, they go on full anticoagulation usually with a new oral anticoagulant. I use PPIs only if needed, although most of them do need it, and, of course, bisphosphonates so the bone protective aspect.

Click to read the digital edition.

The following is a lightly edited transcript of a portion of a teleconference discussion on treating patients with multiple myeloma in the VHA. The conclusion will be published in the August special issue. For more information and to listen to the conversation, visit FedPrac.com/AVAHOupdates.

Biology of Multiple Myeloma

Dr. Munshi. There are many new advances in understanding of basic molecular and genomic changes in multiple myeloma (MM) that involve signaling pathways that drive MM. We have many drugs that target signaling pathways and the number of newer mutational changes that are identified could have therapeutic as well as prognostic significance.

One of the important findings is the lack of specific myeloma-related mutations. Unlike Waldenström macroglobulinemia, which has about 90% patients with Myd88 mutation, in myeloma we do not see that. The mutation frequency, at the maximum, is in the range of 20% for any one gene, and the 3 to 4 most common genes mutated are KRAS, NRAS, BRAF, and P53.

Importantly, if we look at RAS and RAF combined, they target the MEK pathway. So, almost 45% patients have a mutation affecting the MEK pathway, and potentially we can use drugs in the future to see if MEK inhibitors will provide some benefit. And there are anecdotal reports and 1 medium-sized study that has used either a pure MEK inhibitor or a BRAF inhibitor with responses in MM patients. This is a very exciting new area of development.

The second important biological feature in myeloma is clonal shifts. You see multiple clones even at the time of diagnosis. The clonal complexity increases and different clones shift over time with treatment, various other interventions, and changes in myeloma growth patterns. In the future, we cannot just do genomic or cytogenetic analysis one time and sit on it. Over the course of the disease, we may have to repeat it to see if a new clone has evolved. Low-grade or low-risk disease can become a high-grade disease over time.

What is becoming apparent is that sometimes a clone that has almost disappeared reappears after 3, 4, or 5 years. The patient can become resistant to a drug that he or she previously was responsive to with the emergenceof a resistant clone. Three or 4 years later the old sensitive clone can reappear and again be sensitive to the drug that it was not responsive to. The patient may be able to use the same drug again down the line and/or consider similar pathways for targeting. This is one of the major advances that is happening now and is going to inform how we treat patients and how we evaluate patients.

Dr. Mehta. Dr. Munshi, is this going to become “big data?” Are we going to get a lot of information about the molecular changes and findings in our patients not only over time with the evolution of the disease, but also with treatment with various combinations and single agents? Do you think that we at the VA would be able to contribute to some type of banking of material with reference labs that can help to interpret all of the data that we’re going to be able to generate?

Tissue Banking

Dr. Munshi. I think that’s a very important and interesting question. Some mechanisms should be developed so we could not only bank, but also study these genomic patterns. From the VA point of view, there would be some peculiarities that we should understand. One is the age of the patient population—veterans usually end up being older. Number 2, we know the disease is more common in the African American population, and we need to understand why. Tissue banking may help us compare the genomic differences and similarities to understand who may be predisposed to increased frequency of myeloma.

Finally, we still have to keep Agent Orange in mind. Although it is becoming quite an old exposure, a lot of times myeloma occurs. There is a recent paper in JAMA Oncology that showed that incidence of MGUS [monoclonal gammopathy of undetermined significance] is higher in people who are exposed to Agent Orange. Tissue banking to understand that also would be extremely important, and the banked tissue should be processed to understand what’s happening at the molecular level.

Dr. Ascensão. What’s interesting is that there are some DoD specimens (most of it is serology is my understanding), but we may be able to get other material. Having predisease tissue and watching as the patient develops MGUS, smoldering MM, or MM would allow us to see whether there were already mutational changes in the individual even before Agent Orange exposure or, perhaps, was a result of the exposure.

Dr. Mehta. If we could do that, we could even develop protocols to prevent progression of disease. We could imagine a day when we can see the first event occurring and do something to prevent the progression to MGUS and then to smoldering and overt myeloma. Now, we’re in a particularly good position having a national network to propose this type of national bank.

Dr. Ascensão. We have some advantages as a group with a high prevalence of African American patients, as Dr. Munshi mentioned. And we have the biologic components of pathogenesis with Agent Orange. I think it’s something we can afford. Dr. Roodman, what do people in the field need to know about the biology of myeloma that’s going to help them?

Dr. Roodman. People still don’t understand some of the mechanisms underlying support of myeloma growth by the microenvironment. There are multiple targets that have been examined, and none of them work especially well except for what we already use, proteasome antagonists and immunomodulatory agents. In terms of the biology of myeloma bone disease, healing myeloma bone lesions is still a major issue that needs to be addressed. The question is how to do that. I have a VA grant to look at that question and other groups are actively studying the problem.

How particular myeloma clones become dominant is still a wide-open question. Some researchers are pursuing how the microenvironment selectively allows more aggressive clones to become dominant. Currently, the major research focus is on intrinsic changes in the myeloma cell but the microenvironment may also be contributing to the process.

Relapse

Dr. Ascensão. Years ago, people who relapsed, relapsed with bone disease, which may not be necessarily how people are relapsing these days. We are seeing testicular relapses, hepatic relapses, or pulmonary relapses in individuals who are exposed to some of the new agents. There may be interesting developments in terms of interactions in the hepatocellular microenvironment component and the myeloma cells at that level.

Dr. Roodman. These types of relapses are by myeloma cells that can grow independent of the bone marrow micro-environment and these myeloma cells are behaving more like a lymphoma than a myeloma. Several groups have been studying these types of relapses and are examining the expression of adhesion molecules and loss of expression of adhesion molecules to understand why the myeloma cells aren’t anchored in the marrow. This is just my opinion, but we really need to decide on something that could be done within the VA and ask questions similar to the 2 VA clinical trials Dr. Munshi developed. Those were doable in the VA, and we were able to get support for these trials. I think we have to ask questions that allow us to take advantage of the unique features of the VA patient population.

Dr. Chauncey. I would offer a comment from the clinical perspective. You mentioned that this is an observation with newer therapies, and it’s certainly been an observation in the marrow transplantation setting that the pattern of relapse changes. As treatments become more effective, the pattern of relapse can change. When we first started performing autologous transplantation, the pattern of relapse changed from the chemotherapy used at the time. When we started performing allogeneic transplantation, and to the extent that we use that option, we see a different pattern of relapse with substantially more extramedullary disease. This is really a polyclonal or oligoclonal disease, and as different clones evolve over time, whether it’s immunologically mediated or cytotoxic suppression of the initially dominant clone, you see clonal evolution with a different clinical presentation.

Immune System

Dr. Ascensão. Dr. Munshi, what do you think about the immunologic aspects of the disease in terms of its evolution?

Dr. Munshi. They are both aspects of the impact of myeloma on the immune system as Dr. Chauncey mentioned with progression similar to what Dr. Roodman described in the bone, but with greater impact on immune functions. With both pro- and antifunctions you get more TH17 responses, increased T regulatory cell responses, but also more microenvironmental immune cells change.

The second effect is that the immune cell also affects the myeloma growth. For example, proinflammatory cytokine produce interleukin (IL)6, IL17, IL21, and IL23 that affect myeloma or provide myeloma cell growth and signaling mechanism. Also, the PDC (plasmacytoid dendritic cell) is one of the best bone marrow components that induces and supports myeloma growth. With progression, some of these microenvironmental elements actually play a greater role in having the disease function or progress growth more aggressively than otherwise.

The second important aspect that comes into the picture in the immune and bone marrow microenvironment is the role of selecting the clone. There are literally hundreds of clones in a given patient. Certain clones would be supported preferentially by the immune cells, and in some cases, these aggressive clones become independent and grow without the need of support. That’s when they end up becoming extramedullary disease, which also determines how the myeloma cell is growing with these molecular changes.

Dr. Mehta. Another point of evidence for the immune system dysregulation in allowing growth of myeloma is the impact of some of the new trials. So the KEYSTONE 023 trial, for example, showed that pembrolizumab, the programmed death 1 protein (PD1) inhibitor, helped to prevent progression of disease and actually increased survival. The CAR T [chimeric antigen receptor T-cell] studies, some of which were presented at ASH [American Society of Hematology annual meeting] last December, also are beginning to show promise, almost as well as in chronic lymphocytic leukemia. We could look at the therapeutic response as an indicator of biologic pathogenesis and say, “likely the immune system is a major determinant.”

Standard of Therapy

Dr. Ascensão. The Spanish group published some interesting data on high-risk MGUS and smoldering MM. What do you as investigators and clinicians look at to make a diagnosis of MGUS, and what kind of test would you do in order to separate these different groups? How would you define current standard of therapy, and do you assign specific therapies for specific groups of patients?

Dr. Munshi. The current standard is a 3-drug regimen in the U.S. The most common 3-drug regimen that we all usually use, definitely in younger people, but also in older people with some dose modification, was a proteasome inhibitor and immunomodulator with dexamethasone—commonly lenalidomide, bortezomib, and dexamethasone (RVD). One can use carfilzomib also. Now we are beginning to switch to ixazomib, an oral proteasome inhibitor, and it can become an all-oral regimen that could be very convenient. We will have a VA study utilizing a similar agent to make an all-oral regimen for treatment.

An alternative people use that has a financial difference is to use a proteasome inhibitor with cyclophosphamide and dexamethasone, a VCD-like regimen. The study is going to use ixazomib, cyclophosphamide, and dexamethasone followed by ixazomib maintenance. That’s the usual induction regimen.

The question is do we do this differently whether the patient is high risk or low risk? My personal bias in the answer is, not really. At the beginning, we will present the best treatment for the patient’s health. If they are older patients with a lot of comorbidities, which is more important, we can use weekly bortezomib instead of using the full dose. We can use subcutaneous weekly bortezomib or a similar 3-drug regimen. And so high risk or low risk doesn’t change how we’re doing the beginning.

The place where the risk stratification comes into the picture is if patients get a transplant. We are beginning to do posttransplant consolidation, and that’s where we would add 2 cycles of consolidation. If consolidation is not done, for high-risk patients one may do maintenance with 2 drugs like bortezomib and lenalidomide alone; whereas in a low-risk patient, you could do lenalidomide only and not use bortezomib with it. This is the impact of risk stratification as far as what we do. It comes more at the later time rather than earlier time point.

Dr. Mehta. There are still a lot of unanswered questions. One area where I think the VA is very good at becoming involved, if we choose to do so, would be some of the drug dosings. For example, dexamethasone used to be used in high dose and the ECOG study showed that you can use it in lower dose weekly rather than 4 days on, 4 days off. The Myeloma In VA (MIVA) group led by Dr. Munshi did a study looking at different doses of lenalidomide. There’s still unanswered questions even in this standard of care regimen that we use where we could try to make the regimen more tolerable for patients.

Dr. Roodman. RVd (modified RVD) has been piloted by Dr. Noopur Raje at Mass General, but I don’t think it’s a large study. She uses it in older patients. To follow-up on what you said, which I think is a really great idea, we could look at RVd as well as 2 doses of dexamethasone, or use oral proteasome antagonists instead.

Dr. Mehta. Yes, to reduce the neurotoxicity.

Dr. Roodman. That is correct. But I think the VA is set up to look at those kinds of questions because most of our patients are older.

Dr. Mehta. They have all the comorbidities.

Dr. Chauncey. We have what we think is an optimal regimen for an optimal patient, and then we have what we often see in the clinic. I’m not sure of the quantitative VA demographics, but if you look at the U.S. myeloma population, the median age is 70 years. While a triplet like
RVd or a carfilzomib-based triplet is probably optimal based on depth of response and the theoretical aspect of suppression of all subclones, it’s not really an accessible regimen for many patients that I see in clinic who are not transplant eligible.

For the nontransplant patients and more frail patients, the doublets or the cyclophosphamide/bortezomib/dexamethasone are reasonable options. I know there are proponents saying that everybody should get RVd or dose-attenuated RVd; I don’t think that’s practical for many of the patients that we see in our clinics.

Dr. Mehta. Why is it not practical in most of your patients? Because they have to come once a week to the clinic?

Dr. Chauncey. That’s part of it, but I find that it’s often too intense with excessive toxicity. The patients are older with comorbidities and they have more limited physiologic reserve. Part of it is coming to clinic, and that’s where all oral regimens such as Rd are useful. I don’t know that if you have an older patient and you see a good response that you’re tracking in terms of their Mspike (monoclonal protein) and their CRAB criteria, that everybody requires the aggressive approach of RVd or a similar triplet with a proteasome inhibitor, an IMiD [immunomodulator drug], and a steroid as induction therapy.

This is true even for some of the older patients who come to autologous transplantation. The data we talk about are in a younger group of patients who can tolerate the full dose of those regimens. The all-oral regimens are attractive, but it’s also quite a financial burden, maybe not to an individual patient, but certainly to the whole health care system. I’m not sure if there is a depth or durability of response advantage for the oral proteasome inhibitor over those available as IV or subcutaneous dosing.

Pricing

Dr. Ascensão. It’s interesting you bring that up because at the Washington DC VAMC, ixazomib may be priced similarly to bortezomib.

Dr. Chauncey. Well that would be very good and very interesting. It’s possible the federal pricing would make it a lot more attractive. It’s not the case outside of the VA, but there the cost burden for oral medication is often shifted to the patient.

Dr. Cosgriff. The price of carfilzomib is about $7,000 to $9,000 per month or per cycle. When we priced ixazomib here in Portland, it actually was more expensive than bortezomib, but it was cheaper than carfilzomib.

Dr. Mehta. If we can do a drug company-sponsored study, the ixazomib people would surely be interested in its usefulness as a triplet in VA patients. It also would be good for the VA patient because you don’t have to come once a week and it has much less neurotoxicity compared to the other proteasome inhibitors, which is a big problem.

Dr. Chauncey. That would be a great study to offer the right patient. I see a lot of myeloma patients in clinic that aren’t really eligible for transplantation. Many of those patients do well on doublet therapy, though they will often require dose adjustments, both down and up, as well as tracking disease status.

Dr. Cosgriff. In Portland, we’re using a lenalidomidebased regimen as a first-line therapy. We’re starting to see more and more individuals starting RVD upfront. There are some select individuals who have diabetic neuropathy or something like that, who may go on just
a lenalidomide plus dexamethasone, leaving out the bortezomib because of neuropathy issues.

Our second-line choice at this point in time has been carfilzomib, but with ixazomib being a cheaper option, we may actually consider switching over to that as a second-line choice. When you look at the clinical trials they cite in the product literature, the grade 1 neuropathy is about 18% with ixazomib and 14% with the placebo arm, so it does add some peripheral neuropathy. Maybe not as much as we would think.

While these oral agents and all-oral regimens are nice to have, we still bring in the patients for clinic and for monitoring of white blood count. It doesn’t necessarily decrease the burden of clinic visits. We still have to get lab draws. Yes, the patient is not sitting in a chair waiting for the bortezomib infusion to be mixed by the pharmacy, but we still have considerations for travel and those types of things.

We treat the entire state of Oregon and parts of southwest Washington. Fortunately, we have community-based outpatient clinics (CBOCs) and VAMCs in other areas of the state, and we also utilize places like Walla Walla and Spokane, Washington, where we can draw and check labs remotely, which decreases the travel burden, but it still is a burden to the patient to actually go in for lab tests. We’re not looking at ixazomib as a first line currently.

We’re going to wait for data to be published on ixazomib in the first line. In a couple of presentations, researchers have suggested that if you tease the data, ixazomib may be inferior to bortezomib in the first-line setting. It will be interesting to see what the data say for that as far as a first-line setting choice.

Dr. Chauncey. I second what Dr. Cosgriff said. You can’t just give patients 3 bottles of pills and say, “See you in 3 months.” Here in the Northwest we cover large rural areas, and there are many CBOCs whose labs feed directly into our CPRS (Computerized Patient Record System) so it’s very accessible and easy to follow patients that come in less frequently, but that doesn’t change the need for regular clinical follow-up. The other thing I’d say is the noncomparative data of carfilzomib/lenalidomide/dexamethasone (CRD) is quite compelling in terms of depth and duration of response. We usually don’t want to accept convenience over efficacy. Whether that durability translates long term, we don’t really know, but I think right now, CRD is the best available regimen, again, with the caveat that it’s not really accessible to patients of all ages and performance status.

Dr. Ascensão. At the Washington DC VAMC in our first cycle it is day 1, 4, 8, and 11 with bortezomib, but after that we go pretty much to weekly bortezomib. We also tend to use what I would call lower dose 20 mg dexamethasone in patients over the age of 70 years. And we feel that it is a lot less toxic. We use subcutaneous bortezomib for pretty much everybody else.

Managing Adverse Effects

Dr. Chauncey. I think we’re all using subcutaneous bortezomib at this point. Dexamethasone doesn’t get a lot of independent attention, but there’s no question that, as Dr. Mehta mentioned, the older regimen that we used, the dose-dense dexamethasone of the VAD regimen, was
quite disabling. In addition to obvious hyperglycemia, there were psychiatric problems and, ultimately, profound steroid myopathy that seemed to affect patients in variable fashion. Different patients seem to be more or less susceptible, but after a couple of cycles, it starts to kick in and is progressive.

So we’ve since abandoned those massive doses. But when you look at the ECOG study (E4A03) that really defined the lower dose (40 mg weekly), there’s no question the higher dose was more toxic but also more effective in terms of disease response. While there are many older patients that I would start with a lower dose of dexamethasone, whether it’s with lenalidomide or bortezomib, I keep in mind there can be a steep dose response curve for dexamethasone. If you’re giving 20 mg and you’re not getting the response you need, then you increase the dose. There is definitely a dose response, but the higher doses are just not as well tolerated.

Dr. Cosgriff. I don’t know if other institutions are doing it, but instead of doing 40 mg as a single dose because of patient performance status, providers in Portland will prescribe 20 mg on days 1, 2, 8, 9, 15, and 16. They’ll break up that 40 mg dose and give it that way.

Dr. Chauncey. I don’t know if that strategy is biologically equivalent in terms of antimyeloma activity or less toxic in terms of myopathy. There’s almost always some disease marker to track, so that whether you’re using the serum free-light chain assay or serum protein electrophoresis, you can see if the strategy you’re using is working in real time.

Dr. Cosgriff. I’ve never known whether it’s been shown to be more efficacious or if it’s just a way of getting around some of the adverse effects. However, it does pose some alternate challenges. With higher doses of steroids, you’re looking at 2 days where the patient can become hyperglycemic, if not, a little bit longer.

The other thing with it is that adding on that extra day of dexamethasone can interfere with some other drugs and some other therapies. In individuals who have had a deep vein thrombosis for whatever reason and they’re on warfarin, now we have an agent that really screws up our warfarin monitoring. We would have to consider switching them to another agent.

Thrombosis

Dr. Mehta. It’s also prothrombotic.

Dr. Chauncey. If you actually ask the patient, independent of the hyperglycemia, independent of the myopathy, independent of psychosis, but just quality of life, they’ll typically tell you that the on-and-off of steroids is the worst part of the regimen. It’s often the roller coaster ride of short-term hypomania followed by dysphoria.

Dr. Mehta. And the lack of sleep. They describe it as being out of their skin.

Dr. Chauncey. They are. And as soon as they stop, often there is a depression.

Dr. Mehta. It is very, very difficult. And some actually develop psychosis.

Dr. Ascensão. We all use some form of acyclovir or its derivative for the prevention of shingles in patients exposed to the proteasome inhibitors. We use aspirin, usually low dose (81 mg), for deep vein thrombosis prophylaxis. But is anybody using other anticoagulants or putting everybody prophylactically on proton-pump inhibitors (PPIs) or just seeing how people do first and then adjusting?

Dr. Chauncey. I typically use conventional dose aspirin, and if there’s breakthrough thrombosis, the first response should be that it is not the best regimen for this patient. Sometimes you have to go back to it, and if someone’s an anticoagulation candidate, then full anticoagulation is
needed if that’s the best regimen. Usually if there’s a breakthrough thrombosis, it is a deal breaker, and you’re ready to move on to a nonthrombogenic regimen.

There has been an observation (there is some biological basis to back this up) that if you give bortezomib with an IMiD, the regimen became less thrombogenic than with the IMiD and dexamethasone alone.

Dr. Ascensão. On aspirin, even if they’re on an IMiD plus a proteasome inhibitor, I just don’t know that the data are good enough for us to avoid it at this point in time. And I don’t necessarily put people on a PPI unless they’ve got added gastrointestinal problems and unless they have associated heartburn or dyspepsia symptoms.

Dr. Mehta. I use low-dose aspirin in every patient. And if they breakthrough, they go on full anticoagulation usually with a new oral anticoagulant. I use PPIs only if needed, although most of them do need it, and, of course, bisphosphonates so the bone protective aspect.

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The following is a lightly edited transcript of a portion of a teleconference discussion on treating patients with multiple myeloma in the VHA. The conclusion will be published in the August special issue. For more information and to listen to the conversation, visit FedPrac.com/AVAHOupdates.

Biology of Multiple Myeloma

Dr. Munshi. There are many new advances in understanding of basic molecular and genomic changes in multiple myeloma (MM) that involve signaling pathways that drive MM. We have many drugs that target signaling pathways and the number of newer mutational changes that are identified could have therapeutic as well as prognostic significance.

One of the important findings is the lack of specific myeloma-related mutations. Unlike Waldenström macroglobulinemia, which has about 90% patients with Myd88 mutation, in myeloma we do not see that. The mutation frequency, at the maximum, is in the range of 20% for any one gene, and the 3 to 4 most common genes mutated are KRAS, NRAS, BRAF, and P53.

Importantly, if we look at RAS and RAF combined, they target the MEK pathway. So, almost 45% patients have a mutation affecting the MEK pathway, and potentially we can use drugs in the future to see if MEK inhibitors will provide some benefit. And there are anecdotal reports and 1 medium-sized study that has used either a pure MEK inhibitor or a BRAF inhibitor with responses in MM patients. This is a very exciting new area of development.

The second important biological feature in myeloma is clonal shifts. You see multiple clones even at the time of diagnosis. The clonal complexity increases and different clones shift over time with treatment, various other interventions, and changes in myeloma growth patterns. In the future, we cannot just do genomic or cytogenetic analysis one time and sit on it. Over the course of the disease, we may have to repeat it to see if a new clone has evolved. Low-grade or low-risk disease can become a high-grade disease over time.

What is becoming apparent is that sometimes a clone that has almost disappeared reappears after 3, 4, or 5 years. The patient can become resistant to a drug that he or she previously was responsive to with the emergenceof a resistant clone. Three or 4 years later the old sensitive clone can reappear and again be sensitive to the drug that it was not responsive to. The patient may be able to use the same drug again down the line and/or consider similar pathways for targeting. This is one of the major advances that is happening now and is going to inform how we treat patients and how we evaluate patients.

Dr. Mehta. Dr. Munshi, is this going to become “big data?” Are we going to get a lot of information about the molecular changes and findings in our patients not only over time with the evolution of the disease, but also with treatment with various combinations and single agents? Do you think that we at the VA would be able to contribute to some type of banking of material with reference labs that can help to interpret all of the data that we’re going to be able to generate?

Tissue Banking

Dr. Munshi. I think that’s a very important and interesting question. Some mechanisms should be developed so we could not only bank, but also study these genomic patterns. From the VA point of view, there would be some peculiarities that we should understand. One is the age of the patient population—veterans usually end up being older. Number 2, we know the disease is more common in the African American population, and we need to understand why. Tissue banking may help us compare the genomic differences and similarities to understand who may be predisposed to increased frequency of myeloma.

Finally, we still have to keep Agent Orange in mind. Although it is becoming quite an old exposure, a lot of times myeloma occurs. There is a recent paper in JAMA Oncology that showed that incidence of MGUS [monoclonal gammopathy of undetermined significance] is higher in people who are exposed to Agent Orange. Tissue banking to understand that also would be extremely important, and the banked tissue should be processed to understand what’s happening at the molecular level.

Dr. Ascensão. What’s interesting is that there are some DoD specimens (most of it is serology is my understanding), but we may be able to get other material. Having predisease tissue and watching as the patient develops MGUS, smoldering MM, or MM would allow us to see whether there were already mutational changes in the individual even before Agent Orange exposure or, perhaps, was a result of the exposure.

Dr. Mehta. If we could do that, we could even develop protocols to prevent progression of disease. We could imagine a day when we can see the first event occurring and do something to prevent the progression to MGUS and then to smoldering and overt myeloma. Now, we’re in a particularly good position having a national network to propose this type of national bank.

Dr. Ascensão. We have some advantages as a group with a high prevalence of African American patients, as Dr. Munshi mentioned. And we have the biologic components of pathogenesis with Agent Orange. I think it’s something we can afford. Dr. Roodman, what do people in the field need to know about the biology of myeloma that’s going to help them?

Dr. Roodman. People still don’t understand some of the mechanisms underlying support of myeloma growth by the microenvironment. There are multiple targets that have been examined, and none of them work especially well except for what we already use, proteasome antagonists and immunomodulatory agents. In terms of the biology of myeloma bone disease, healing myeloma bone lesions is still a major issue that needs to be addressed. The question is how to do that. I have a VA grant to look at that question and other groups are actively studying the problem.

How particular myeloma clones become dominant is still a wide-open question. Some researchers are pursuing how the microenvironment selectively allows more aggressive clones to become dominant. Currently, the major research focus is on intrinsic changes in the myeloma cell but the microenvironment may also be contributing to the process.

Relapse

Dr. Ascensão. Years ago, people who relapsed, relapsed with bone disease, which may not be necessarily how people are relapsing these days. We are seeing testicular relapses, hepatic relapses, or pulmonary relapses in individuals who are exposed to some of the new agents. There may be interesting developments in terms of interactions in the hepatocellular microenvironment component and the myeloma cells at that level.

Dr. Roodman. These types of relapses are by myeloma cells that can grow independent of the bone marrow micro-environment and these myeloma cells are behaving more like a lymphoma than a myeloma. Several groups have been studying these types of relapses and are examining the expression of adhesion molecules and loss of expression of adhesion molecules to understand why the myeloma cells aren’t anchored in the marrow. This is just my opinion, but we really need to decide on something that could be done within the VA and ask questions similar to the 2 VA clinical trials Dr. Munshi developed. Those were doable in the VA, and we were able to get support for these trials. I think we have to ask questions that allow us to take advantage of the unique features of the VA patient population.

Dr. Chauncey. I would offer a comment from the clinical perspective. You mentioned that this is an observation with newer therapies, and it’s certainly been an observation in the marrow transplantation setting that the pattern of relapse changes. As treatments become more effective, the pattern of relapse can change. When we first started performing autologous transplantation, the pattern of relapse changed from the chemotherapy used at the time. When we started performing allogeneic transplantation, and to the extent that we use that option, we see a different pattern of relapse with substantially more extramedullary disease. This is really a polyclonal or oligoclonal disease, and as different clones evolve over time, whether it’s immunologically mediated or cytotoxic suppression of the initially dominant clone, you see clonal evolution with a different clinical presentation.

Immune System

Dr. Ascensão. Dr. Munshi, what do you think about the immunologic aspects of the disease in terms of its evolution?

Dr. Munshi. They are both aspects of the impact of myeloma on the immune system as Dr. Chauncey mentioned with progression similar to what Dr. Roodman described in the bone, but with greater impact on immune functions. With both pro- and antifunctions you get more TH17 responses, increased T regulatory cell responses, but also more microenvironmental immune cells change.

The second effect is that the immune cell also affects the myeloma growth. For example, proinflammatory cytokine produce interleukin (IL)6, IL17, IL21, and IL23 that affect myeloma or provide myeloma cell growth and signaling mechanism. Also, the PDC (plasmacytoid dendritic cell) is one of the best bone marrow components that induces and supports myeloma growth. With progression, some of these microenvironmental elements actually play a greater role in having the disease function or progress growth more aggressively than otherwise.

The second important aspect that comes into the picture in the immune and bone marrow microenvironment is the role of selecting the clone. There are literally hundreds of clones in a given patient. Certain clones would be supported preferentially by the immune cells, and in some cases, these aggressive clones become independent and grow without the need of support. That’s when they end up becoming extramedullary disease, which also determines how the myeloma cell is growing with these molecular changes.

Dr. Mehta. Another point of evidence for the immune system dysregulation in allowing growth of myeloma is the impact of some of the new trials. So the KEYSTONE 023 trial, for example, showed that pembrolizumab, the programmed death 1 protein (PD1) inhibitor, helped to prevent progression of disease and actually increased survival. The CAR T [chimeric antigen receptor T-cell] studies, some of which were presented at ASH [American Society of Hematology annual meeting] last December, also are beginning to show promise, almost as well as in chronic lymphocytic leukemia. We could look at the therapeutic response as an indicator of biologic pathogenesis and say, “likely the immune system is a major determinant.”

Standard of Therapy

Dr. Ascensão. The Spanish group published some interesting data on high-risk MGUS and smoldering MM. What do you as investigators and clinicians look at to make a diagnosis of MGUS, and what kind of test would you do in order to separate these different groups? How would you define current standard of therapy, and do you assign specific therapies for specific groups of patients?

Dr. Munshi. The current standard is a 3-drug regimen in the U.S. The most common 3-drug regimen that we all usually use, definitely in younger people, but also in older people with some dose modification, was a proteasome inhibitor and immunomodulator with dexamethasone—commonly lenalidomide, bortezomib, and dexamethasone (RVD). One can use carfilzomib also. Now we are beginning to switch to ixazomib, an oral proteasome inhibitor, and it can become an all-oral regimen that could be very convenient. We will have a VA study utilizing a similar agent to make an all-oral regimen for treatment.

An alternative people use that has a financial difference is to use a proteasome inhibitor with cyclophosphamide and dexamethasone, a VCD-like regimen. The study is going to use ixazomib, cyclophosphamide, and dexamethasone followed by ixazomib maintenance. That’s the usual induction regimen.

The question is do we do this differently whether the patient is high risk or low risk? My personal bias in the answer is, not really. At the beginning, we will present the best treatment for the patient’s health. If they are older patients with a lot of comorbidities, which is more important, we can use weekly bortezomib instead of using the full dose. We can use subcutaneous weekly bortezomib or a similar 3-drug regimen. And so high risk or low risk doesn’t change how we’re doing the beginning.

The place where the risk stratification comes into the picture is if patients get a transplant. We are beginning to do posttransplant consolidation, and that’s where we would add 2 cycles of consolidation. If consolidation is not done, for high-risk patients one may do maintenance with 2 drugs like bortezomib and lenalidomide alone; whereas in a low-risk patient, you could do lenalidomide only and not use bortezomib with it. This is the impact of risk stratification as far as what we do. It comes more at the later time rather than earlier time point.

Dr. Mehta. There are still a lot of unanswered questions. One area where I think the VA is very good at becoming involved, if we choose to do so, would be some of the drug dosings. For example, dexamethasone used to be used in high dose and the ECOG study showed that you can use it in lower dose weekly rather than 4 days on, 4 days off. The Myeloma In VA (MIVA) group led by Dr. Munshi did a study looking at different doses of lenalidomide. There’s still unanswered questions even in this standard of care regimen that we use where we could try to make the regimen more tolerable for patients.

Dr. Roodman. RVd (modified RVD) has been piloted by Dr. Noopur Raje at Mass General, but I don’t think it’s a large study. She uses it in older patients. To follow-up on what you said, which I think is a really great idea, we could look at RVd as well as 2 doses of dexamethasone, or use oral proteasome antagonists instead.

Dr. Mehta. Yes, to reduce the neurotoxicity.

Dr. Roodman. That is correct. But I think the VA is set up to look at those kinds of questions because most of our patients are older.

Dr. Mehta. They have all the comorbidities.

Dr. Chauncey. We have what we think is an optimal regimen for an optimal patient, and then we have what we often see in the clinic. I’m not sure of the quantitative VA demographics, but if you look at the U.S. myeloma population, the median age is 70 years. While a triplet like
RVd or a carfilzomib-based triplet is probably optimal based on depth of response and the theoretical aspect of suppression of all subclones, it’s not really an accessible regimen for many patients that I see in clinic who are not transplant eligible.

For the nontransplant patients and more frail patients, the doublets or the cyclophosphamide/bortezomib/dexamethasone are reasonable options. I know there are proponents saying that everybody should get RVd or dose-attenuated RVd; I don’t think that’s practical for many of the patients that we see in our clinics.

Dr. Mehta. Why is it not practical in most of your patients? Because they have to come once a week to the clinic?

Dr. Chauncey. That’s part of it, but I find that it’s often too intense with excessive toxicity. The patients are older with comorbidities and they have more limited physiologic reserve. Part of it is coming to clinic, and that’s where all oral regimens such as Rd are useful. I don’t know that if you have an older patient and you see a good response that you’re tracking in terms of their Mspike (monoclonal protein) and their CRAB criteria, that everybody requires the aggressive approach of RVd or a similar triplet with a proteasome inhibitor, an IMiD [immunomodulator drug], and a steroid as induction therapy.

This is true even for some of the older patients who come to autologous transplantation. The data we talk about are in a younger group of patients who can tolerate the full dose of those regimens. The all-oral regimens are attractive, but it’s also quite a financial burden, maybe not to an individual patient, but certainly to the whole health care system. I’m not sure if there is a depth or durability of response advantage for the oral proteasome inhibitor over those available as IV or subcutaneous dosing.

Pricing

Dr. Ascensão. It’s interesting you bring that up because at the Washington DC VAMC, ixazomib may be priced similarly to bortezomib.

Dr. Chauncey. Well that would be very good and very interesting. It’s possible the federal pricing would make it a lot more attractive. It’s not the case outside of the VA, but there the cost burden for oral medication is often shifted to the patient.

Dr. Cosgriff. The price of carfilzomib is about $7,000 to $9,000 per month or per cycle. When we priced ixazomib here in Portland, it actually was more expensive than bortezomib, but it was cheaper than carfilzomib.

Dr. Mehta. If we can do a drug company-sponsored study, the ixazomib people would surely be interested in its usefulness as a triplet in VA patients. It also would be good for the VA patient because you don’t have to come once a week and it has much less neurotoxicity compared to the other proteasome inhibitors, which is a big problem.

Dr. Chauncey. That would be a great study to offer the right patient. I see a lot of myeloma patients in clinic that aren’t really eligible for transplantation. Many of those patients do well on doublet therapy, though they will often require dose adjustments, both down and up, as well as tracking disease status.

Dr. Cosgriff. In Portland, we’re using a lenalidomidebased regimen as a first-line therapy. We’re starting to see more and more individuals starting RVD upfront. There are some select individuals who have diabetic neuropathy or something like that, who may go on just
a lenalidomide plus dexamethasone, leaving out the bortezomib because of neuropathy issues.

Our second-line choice at this point in time has been carfilzomib, but with ixazomib being a cheaper option, we may actually consider switching over to that as a second-line choice. When you look at the clinical trials they cite in the product literature, the grade 1 neuropathy is about 18% with ixazomib and 14% with the placebo arm, so it does add some peripheral neuropathy. Maybe not as much as we would think.

While these oral agents and all-oral regimens are nice to have, we still bring in the patients for clinic and for monitoring of white blood count. It doesn’t necessarily decrease the burden of clinic visits. We still have to get lab draws. Yes, the patient is not sitting in a chair waiting for the bortezomib infusion to be mixed by the pharmacy, but we still have considerations for travel and those types of things.

We treat the entire state of Oregon and parts of southwest Washington. Fortunately, we have community-based outpatient clinics (CBOCs) and VAMCs in other areas of the state, and we also utilize places like Walla Walla and Spokane, Washington, where we can draw and check labs remotely, which decreases the travel burden, but it still is a burden to the patient to actually go in for lab tests. We’re not looking at ixazomib as a first line currently.

We’re going to wait for data to be published on ixazomib in the first line. In a couple of presentations, researchers have suggested that if you tease the data, ixazomib may be inferior to bortezomib in the first-line setting. It will be interesting to see what the data say for that as far as a first-line setting choice.

Dr. Chauncey. I second what Dr. Cosgriff said. You can’t just give patients 3 bottles of pills and say, “See you in 3 months.” Here in the Northwest we cover large rural areas, and there are many CBOCs whose labs feed directly into our CPRS (Computerized Patient Record System) so it’s very accessible and easy to follow patients that come in less frequently, but that doesn’t change the need for regular clinical follow-up. The other thing I’d say is the noncomparative data of carfilzomib/lenalidomide/dexamethasone (CRD) is quite compelling in terms of depth and duration of response. We usually don’t want to accept convenience over efficacy. Whether that durability translates long term, we don’t really know, but I think right now, CRD is the best available regimen, again, with the caveat that it’s not really accessible to patients of all ages and performance status.

Dr. Ascensão. At the Washington DC VAMC in our first cycle it is day 1, 4, 8, and 11 with bortezomib, but after that we go pretty much to weekly bortezomib. We also tend to use what I would call lower dose 20 mg dexamethasone in patients over the age of 70 years. And we feel that it is a lot less toxic. We use subcutaneous bortezomib for pretty much everybody else.

Managing Adverse Effects

Dr. Chauncey. I think we’re all using subcutaneous bortezomib at this point. Dexamethasone doesn’t get a lot of independent attention, but there’s no question that, as Dr. Mehta mentioned, the older regimen that we used, the dose-dense dexamethasone of the VAD regimen, was
quite disabling. In addition to obvious hyperglycemia, there were psychiatric problems and, ultimately, profound steroid myopathy that seemed to affect patients in variable fashion. Different patients seem to be more or less susceptible, but after a couple of cycles, it starts to kick in and is progressive.

So we’ve since abandoned those massive doses. But when you look at the ECOG study (E4A03) that really defined the lower dose (40 mg weekly), there’s no question the higher dose was more toxic but also more effective in terms of disease response. While there are many older patients that I would start with a lower dose of dexamethasone, whether it’s with lenalidomide or bortezomib, I keep in mind there can be a steep dose response curve for dexamethasone. If you’re giving 20 mg and you’re not getting the response you need, then you increase the dose. There is definitely a dose response, but the higher doses are just not as well tolerated.

Dr. Cosgriff. I don’t know if other institutions are doing it, but instead of doing 40 mg as a single dose because of patient performance status, providers in Portland will prescribe 20 mg on days 1, 2, 8, 9, 15, and 16. They’ll break up that 40 mg dose and give it that way.

Dr. Chauncey. I don’t know if that strategy is biologically equivalent in terms of antimyeloma activity or less toxic in terms of myopathy. There’s almost always some disease marker to track, so that whether you’re using the serum free-light chain assay or serum protein electrophoresis, you can see if the strategy you’re using is working in real time.

Dr. Cosgriff. I’ve never known whether it’s been shown to be more efficacious or if it’s just a way of getting around some of the adverse effects. However, it does pose some alternate challenges. With higher doses of steroids, you’re looking at 2 days where the patient can become hyperglycemic, if not, a little bit longer.

The other thing with it is that adding on that extra day of dexamethasone can interfere with some other drugs and some other therapies. In individuals who have had a deep vein thrombosis for whatever reason and they’re on warfarin, now we have an agent that really screws up our warfarin monitoring. We would have to consider switching them to another agent.

Thrombosis

Dr. Mehta. It’s also prothrombotic.

Dr. Chauncey. If you actually ask the patient, independent of the hyperglycemia, independent of the myopathy, independent of psychosis, but just quality of life, they’ll typically tell you that the on-and-off of steroids is the worst part of the regimen. It’s often the roller coaster ride of short-term hypomania followed by dysphoria.

Dr. Mehta. And the lack of sleep. They describe it as being out of their skin.

Dr. Chauncey. They are. And as soon as they stop, often there is a depression.

Dr. Mehta. It is very, very difficult. And some actually develop psychosis.

Dr. Ascensão. We all use some form of acyclovir or its derivative for the prevention of shingles in patients exposed to the proteasome inhibitors. We use aspirin, usually low dose (81 mg), for deep vein thrombosis prophylaxis. But is anybody using other anticoagulants or putting everybody prophylactically on proton-pump inhibitors (PPIs) or just seeing how people do first and then adjusting?

Dr. Chauncey. I typically use conventional dose aspirin, and if there’s breakthrough thrombosis, the first response should be that it is not the best regimen for this patient. Sometimes you have to go back to it, and if someone’s an anticoagulation candidate, then full anticoagulation is
needed if that’s the best regimen. Usually if there’s a breakthrough thrombosis, it is a deal breaker, and you’re ready to move on to a nonthrombogenic regimen.

There has been an observation (there is some biological basis to back this up) that if you give bortezomib with an IMiD, the regimen became less thrombogenic than with the IMiD and dexamethasone alone.

Dr. Ascensão. On aspirin, even if they’re on an IMiD plus a proteasome inhibitor, I just don’t know that the data are good enough for us to avoid it at this point in time. And I don’t necessarily put people on a PPI unless they’ve got added gastrointestinal problems and unless they have associated heartburn or dyspepsia symptoms.

Dr. Mehta. I use low-dose aspirin in every patient. And if they breakthrough, they go on full anticoagulation usually with a new oral anticoagulant. I use PPIs only if needed, although most of them do need it, and, of course, bisphosphonates so the bone protective aspect.

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