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NEW ORLEANS – Everyone aged 40 years and older on the island nation of Iceland is being screened for monoclonal gammopathy of undetermined significance, smoldering myeloma, and full-blown multiple myeloma in an unprecedented project to identify the malignancy’s genetic roots, Joseph Mikhael, MD, said at the annual meeting of the American College of Physicians.
This effort to decode the underlying genetics of multiple myeloma is enormously facilitated by the fact that the DNA sequencing of the entire Icelandic population is already known, and everyone’s blood samples are stored in the national health care system.
The International Myeloma Foundation is funding the Icelandic project, called iStopMM (Iceland Screens Treats or Prevents Multiple Myeloma).
The results of iStopMM could be far reaching, in part because the findings will show whether screening an asymptomatic general population for MGUS – as for example, all American adults – is worthwhile.
In the interim, it’s important for primary care physicians to recognize when it is and isn’t appropriate to order a serum protein electrophoresis (SPE) study, on which the diagnosis of MGUS hinges. It’s also essential to recognize the difference between smoldering and full-blown multiple myeloma, because the distinction has implications for patient monitoring and treatment, added Dr. Mikhael, a hematologist at the City of Hope Cancer Center in Duarte, Calif.
Multiple myeloma accounts for 1% of all cancers and 10% of hematologic malignancies. MGUS is an obligate precursor of multiple myeloma. But MGUS is common, and therein lies a challenge for physicians – as well as a major source of anxiety for many MGUS-positive patients.
In a 12-year-old study, MGUS had a 3% prevalence in the general U.S. population older than age 50 years, and a greater than 5% prevalence after age 70. However, Dr. Mikhael thinks that more refined testing will show the true figure to be close to 10%. Thus, the great majority of patients with MGUS will never develop multiple myeloma.
Pending the potentially practice-changing outcome of iStopMM, Dr. Mikhael said SPE shouldn’t be ordered routinely in an asymptomatic patient, even one with a positive family history for multiple myeloma. The annual cost of monitoring the roughly 540,000 U.S. patients who now carry a diagnosis of MGUS – typically established as an incidental finding by primary care physicians while doing a work-up for another reason – is at least $110 million. And there’s no point in adding to that burden until the benefit of mass screening has been established.
An SPE is appropriate, however, in an older patient with unexplained anemia, known low immunoglobulin levels, unexplained renal insufficiency or neuropathy, or osteopenia or osteoporosis inconsistent with the patient’s age or gender – provided the patient doesn’t have a coexisting plasma cell dyscrasia or B-cell lymphoproliferative disorder, which would throw off the prognostic value of the test results, he continued.
When ordering an SPE to rule in/out MGUS, it’s essential to also order serum free light-chain testing, because it provides key prognostic information.
A landmark study led by investigators at the Mayo Clinic demonstrated that the risk of progression of MGUS to multiple myeloma or a related disorder is independently predicted by three key factors: a high serum M-protein spike of 15 g/L or more on the SPE; the presence of non-IgG MGUS; and an abnormal serum free light-chain ratio of less than 0.26 or more than 1.65. In this study, the 20-year risk of malignant transformation of MGUS ranged from 58% if all three risk factors were present, to just 5% if none were (Blood. 2005 Aug 1;106[3]:812-7).
CRAB vs. SLiM CRAB
Myeloma, smoldering myeloma, and MGUS were redefined a few years ago to reflect differences in prognosis. MGUS still requires the presence of a serum monoclonal protein in a concentration of 3 g/dL or less, less than 10% plasmacytosis in the bone marrow, asymptomatic status, and absence of end-organ damage as traditionally defined in the acronym CRAB (calcium elevation, renal insufficiency, anemia, or bony disease).
If CRAB is present in a patient with at least 10% plasma cells in bone marrow, that is by definition multiple myeloma warranting treatment. Smoldering myeloma requires at least 10% plasmacytosis in bone marrow and absence of the CRAB criteria. However, in a significant change, ultra–high-risk smoldering melanoma, defined by the acronym SLiM CRAB, is now considered active myeloma and should be treated (Lancet Oncol. 2014 Nov;15[12]:e538-48).
“Traditionally, we waited until CRAB [to define myeloma],” Dr. Mikhael explained. “But if you’re running toward a cliff, I don’t have to wait until you’re falling off to know you’re in trouble.”
The SLiM half of SLiM CRAB consists of 60% or more plasmacytosis in bone marrow, light chains in a kappa-to-lambda or lambda-to-kappa ratio of greater than 100, and MRI showing one or more focal lesions. If a patient is SLiM, with or without CRAB, that is now considered active myeloma warranting treatment.
Not all MGUS needs a bone marrow biopsy
A bone marrow biopsy and skeletal survey via whole-body CT or conventional radiographs can be deferred in patients with low-risk MGUS and no bony symptoms. Using the Mayo Clinic risk stratification model, low risk is defined as a serum M protein of 1.5 g/dL or less on SPE, an IgG isotype, and a normal free light-chain ratio.
The lifetime risk of progression in patients with MGUS who meet all three criteria is only about 2%. They can be followed at 6 months with an SPE, free light-chain testing, a CBC, and serum calcium and creatinine, then annually thereafter.
“For those who aren’t in this low-risk category, we actually do need to do a bone marrow test,” according to Dr. Mikhael. “Then, based on that, if they have malignancy, send them to a myeloma geek like me or to another hematologist. And if they don’t have a malignancy, they can be followed at 6 months and then subsequently at least every year.”
Dr. Mikhael has received research grants from AbbVie, Celgene, and Sanofi.
NEW ORLEANS – Everyone aged 40 years and older on the island nation of Iceland is being screened for monoclonal gammopathy of undetermined significance, smoldering myeloma, and full-blown multiple myeloma in an unprecedented project to identify the malignancy’s genetic roots, Joseph Mikhael, MD, said at the annual meeting of the American College of Physicians.
This effort to decode the underlying genetics of multiple myeloma is enormously facilitated by the fact that the DNA sequencing of the entire Icelandic population is already known, and everyone’s blood samples are stored in the national health care system.
The International Myeloma Foundation is funding the Icelandic project, called iStopMM (Iceland Screens Treats or Prevents Multiple Myeloma).
The results of iStopMM could be far reaching, in part because the findings will show whether screening an asymptomatic general population for MGUS – as for example, all American adults – is worthwhile.
In the interim, it’s important for primary care physicians to recognize when it is and isn’t appropriate to order a serum protein electrophoresis (SPE) study, on which the diagnosis of MGUS hinges. It’s also essential to recognize the difference between smoldering and full-blown multiple myeloma, because the distinction has implications for patient monitoring and treatment, added Dr. Mikhael, a hematologist at the City of Hope Cancer Center in Duarte, Calif.
Multiple myeloma accounts for 1% of all cancers and 10% of hematologic malignancies. MGUS is an obligate precursor of multiple myeloma. But MGUS is common, and therein lies a challenge for physicians – as well as a major source of anxiety for many MGUS-positive patients.
In a 12-year-old study, MGUS had a 3% prevalence in the general U.S. population older than age 50 years, and a greater than 5% prevalence after age 70. However, Dr. Mikhael thinks that more refined testing will show the true figure to be close to 10%. Thus, the great majority of patients with MGUS will never develop multiple myeloma.
Pending the potentially practice-changing outcome of iStopMM, Dr. Mikhael said SPE shouldn’t be ordered routinely in an asymptomatic patient, even one with a positive family history for multiple myeloma. The annual cost of monitoring the roughly 540,000 U.S. patients who now carry a diagnosis of MGUS – typically established as an incidental finding by primary care physicians while doing a work-up for another reason – is at least $110 million. And there’s no point in adding to that burden until the benefit of mass screening has been established.
An SPE is appropriate, however, in an older patient with unexplained anemia, known low immunoglobulin levels, unexplained renal insufficiency or neuropathy, or osteopenia or osteoporosis inconsistent with the patient’s age or gender – provided the patient doesn’t have a coexisting plasma cell dyscrasia or B-cell lymphoproliferative disorder, which would throw off the prognostic value of the test results, he continued.
When ordering an SPE to rule in/out MGUS, it’s essential to also order serum free light-chain testing, because it provides key prognostic information.
A landmark study led by investigators at the Mayo Clinic demonstrated that the risk of progression of MGUS to multiple myeloma or a related disorder is independently predicted by three key factors: a high serum M-protein spike of 15 g/L or more on the SPE; the presence of non-IgG MGUS; and an abnormal serum free light-chain ratio of less than 0.26 or more than 1.65. In this study, the 20-year risk of malignant transformation of MGUS ranged from 58% if all three risk factors were present, to just 5% if none were (Blood. 2005 Aug 1;106[3]:812-7).
CRAB vs. SLiM CRAB
Myeloma, smoldering myeloma, and MGUS were redefined a few years ago to reflect differences in prognosis. MGUS still requires the presence of a serum monoclonal protein in a concentration of 3 g/dL or less, less than 10% plasmacytosis in the bone marrow, asymptomatic status, and absence of end-organ damage as traditionally defined in the acronym CRAB (calcium elevation, renal insufficiency, anemia, or bony disease).
If CRAB is present in a patient with at least 10% plasma cells in bone marrow, that is by definition multiple myeloma warranting treatment. Smoldering myeloma requires at least 10% plasmacytosis in bone marrow and absence of the CRAB criteria. However, in a significant change, ultra–high-risk smoldering melanoma, defined by the acronym SLiM CRAB, is now considered active myeloma and should be treated (Lancet Oncol. 2014 Nov;15[12]:e538-48).
“Traditionally, we waited until CRAB [to define myeloma],” Dr. Mikhael explained. “But if you’re running toward a cliff, I don’t have to wait until you’re falling off to know you’re in trouble.”
The SLiM half of SLiM CRAB consists of 60% or more plasmacytosis in bone marrow, light chains in a kappa-to-lambda or lambda-to-kappa ratio of greater than 100, and MRI showing one or more focal lesions. If a patient is SLiM, with or without CRAB, that is now considered active myeloma warranting treatment.
Not all MGUS needs a bone marrow biopsy
A bone marrow biopsy and skeletal survey via whole-body CT or conventional radiographs can be deferred in patients with low-risk MGUS and no bony symptoms. Using the Mayo Clinic risk stratification model, low risk is defined as a serum M protein of 1.5 g/dL or less on SPE, an IgG isotype, and a normal free light-chain ratio.
The lifetime risk of progression in patients with MGUS who meet all three criteria is only about 2%. They can be followed at 6 months with an SPE, free light-chain testing, a CBC, and serum calcium and creatinine, then annually thereafter.
“For those who aren’t in this low-risk category, we actually do need to do a bone marrow test,” according to Dr. Mikhael. “Then, based on that, if they have malignancy, send them to a myeloma geek like me or to another hematologist. And if they don’t have a malignancy, they can be followed at 6 months and then subsequently at least every year.”
Dr. Mikhael has received research grants from AbbVie, Celgene, and Sanofi.
NEW ORLEANS – Everyone aged 40 years and older on the island nation of Iceland is being screened for monoclonal gammopathy of undetermined significance, smoldering myeloma, and full-blown multiple myeloma in an unprecedented project to identify the malignancy’s genetic roots, Joseph Mikhael, MD, said at the annual meeting of the American College of Physicians.
This effort to decode the underlying genetics of multiple myeloma is enormously facilitated by the fact that the DNA sequencing of the entire Icelandic population is already known, and everyone’s blood samples are stored in the national health care system.
The International Myeloma Foundation is funding the Icelandic project, called iStopMM (Iceland Screens Treats or Prevents Multiple Myeloma).
The results of iStopMM could be far reaching, in part because the findings will show whether screening an asymptomatic general population for MGUS – as for example, all American adults – is worthwhile.
In the interim, it’s important for primary care physicians to recognize when it is and isn’t appropriate to order a serum protein electrophoresis (SPE) study, on which the diagnosis of MGUS hinges. It’s also essential to recognize the difference between smoldering and full-blown multiple myeloma, because the distinction has implications for patient monitoring and treatment, added Dr. Mikhael, a hematologist at the City of Hope Cancer Center in Duarte, Calif.
Multiple myeloma accounts for 1% of all cancers and 10% of hematologic malignancies. MGUS is an obligate precursor of multiple myeloma. But MGUS is common, and therein lies a challenge for physicians – as well as a major source of anxiety for many MGUS-positive patients.
In a 12-year-old study, MGUS had a 3% prevalence in the general U.S. population older than age 50 years, and a greater than 5% prevalence after age 70. However, Dr. Mikhael thinks that more refined testing will show the true figure to be close to 10%. Thus, the great majority of patients with MGUS will never develop multiple myeloma.
Pending the potentially practice-changing outcome of iStopMM, Dr. Mikhael said SPE shouldn’t be ordered routinely in an asymptomatic patient, even one with a positive family history for multiple myeloma. The annual cost of monitoring the roughly 540,000 U.S. patients who now carry a diagnosis of MGUS – typically established as an incidental finding by primary care physicians while doing a work-up for another reason – is at least $110 million. And there’s no point in adding to that burden until the benefit of mass screening has been established.
An SPE is appropriate, however, in an older patient with unexplained anemia, known low immunoglobulin levels, unexplained renal insufficiency or neuropathy, or osteopenia or osteoporosis inconsistent with the patient’s age or gender – provided the patient doesn’t have a coexisting plasma cell dyscrasia or B-cell lymphoproliferative disorder, which would throw off the prognostic value of the test results, he continued.
When ordering an SPE to rule in/out MGUS, it’s essential to also order serum free light-chain testing, because it provides key prognostic information.
A landmark study led by investigators at the Mayo Clinic demonstrated that the risk of progression of MGUS to multiple myeloma or a related disorder is independently predicted by three key factors: a high serum M-protein spike of 15 g/L or more on the SPE; the presence of non-IgG MGUS; and an abnormal serum free light-chain ratio of less than 0.26 or more than 1.65. In this study, the 20-year risk of malignant transformation of MGUS ranged from 58% if all three risk factors were present, to just 5% if none were (Blood. 2005 Aug 1;106[3]:812-7).
CRAB vs. SLiM CRAB
Myeloma, smoldering myeloma, and MGUS were redefined a few years ago to reflect differences in prognosis. MGUS still requires the presence of a serum monoclonal protein in a concentration of 3 g/dL or less, less than 10% plasmacytosis in the bone marrow, asymptomatic status, and absence of end-organ damage as traditionally defined in the acronym CRAB (calcium elevation, renal insufficiency, anemia, or bony disease).
If CRAB is present in a patient with at least 10% plasma cells in bone marrow, that is by definition multiple myeloma warranting treatment. Smoldering myeloma requires at least 10% plasmacytosis in bone marrow and absence of the CRAB criteria. However, in a significant change, ultra–high-risk smoldering melanoma, defined by the acronym SLiM CRAB, is now considered active myeloma and should be treated (Lancet Oncol. 2014 Nov;15[12]:e538-48).
“Traditionally, we waited until CRAB [to define myeloma],” Dr. Mikhael explained. “But if you’re running toward a cliff, I don’t have to wait until you’re falling off to know you’re in trouble.”
The SLiM half of SLiM CRAB consists of 60% or more plasmacytosis in bone marrow, light chains in a kappa-to-lambda or lambda-to-kappa ratio of greater than 100, and MRI showing one or more focal lesions. If a patient is SLiM, with or without CRAB, that is now considered active myeloma warranting treatment.
Not all MGUS needs a bone marrow biopsy
A bone marrow biopsy and skeletal survey via whole-body CT or conventional radiographs can be deferred in patients with low-risk MGUS and no bony symptoms. Using the Mayo Clinic risk stratification model, low risk is defined as a serum M protein of 1.5 g/dL or less on SPE, an IgG isotype, and a normal free light-chain ratio.
The lifetime risk of progression in patients with MGUS who meet all three criteria is only about 2%. They can be followed at 6 months with an SPE, free light-chain testing, a CBC, and serum calcium and creatinine, then annually thereafter.
“For those who aren’t in this low-risk category, we actually do need to do a bone marrow test,” according to Dr. Mikhael. “Then, based on that, if they have malignancy, send them to a myeloma geek like me or to another hematologist. And if they don’t have a malignancy, they can be followed at 6 months and then subsequently at least every year.”
Dr. Mikhael has received research grants from AbbVie, Celgene, and Sanofi.
EXPERT ANALYSIS FROM ACP INTERNAL MEDICINE