SAN FRANCISCO – With multiple therapies and refinements in diagnostic and staging criteria, risk stratification, and transplantation, “we have made dramatic improvements in survival” for malignant myeloma, Dr. Damian J. Green told attendees of the NCCN Annual Congress: Hematologic Malignancies. In fact, he said, these advances have propelled the field toward a once unthinkable question: Can myeloma be cured?
Diagnostic criteria
The criteria used to diagnose active myeloma recently changed, noted Dr. Green of the University of Washington, the Multiple Myeloma and Stem Cell Transplant Program at the Seattle Cancer Care Alliance, and the Fred Hutchinson Cancer Research Center, all in Seattle.
Dr. Damian J. Green
Long-used CRAB criteria (calcium elevation, renal failure, anemia, and bone lesions) have been updated to incorporate three additional biomarkers – a bone marrow plasma cell percentage of 60% or greater, a serum free light chain ratio of 100 or greater, and a skeletal MRI or CT showing more than one focal lesion – conferring a very high risk of progression (Lancet Oncol. 2014;15[12]:e538-48).
“Many of us are using these new, independently validated factors, I would say, in select cases, not all the time. But they are now becoming part of the accepted dogma for determining in whom you might initiate therapy,” he said.
This change is likely to affect the epidemiology of smoldering myeloma, he noted. “We are taking the people at highest risk of progression and shifting them now, potentially, into the active group. What that means is whoever remains in the smoldering group, their prognosis is actually going to be better in the future.”
Staging criteria
The criteria used to stage myeloma have also changed, just in the past few months. The International Staging System (ISS) is about 15 years old. “The problem is it predated the era of novel therapy, and it predated our understanding of high-risk cytogenetics. That has been a long-term criticism,” Dr. Green said.
The new revised system, termed R-ISS, incorporates cytogenetics – designating 17p deletion, translocation 4;14, and translocation 14;16 as high-risk cytogenetics – as well as lactate dehydrogenase (J Clin Oncol. 2015;33:2863-9).
“I think there’s going to be uniform acceptance of this change. It’s a big deal in terms of how we manage these folks and in terms of what tests need to be ordered,” he said. “But it’s going to change things because lots of our interpretation of prior data is based on the old [system].”
Primary therapy
Numerous regimens are effective as primary therapy in myeloma, with expert consensus favoring three drugs over two for fit patients. Triple combinations achieve a greater depth of response, and deeper responses – whether assessed with multiparameter high-sensitivity flow cytometry (Blood. 2015;125:1932-5) or deep sequencing (Blood. 2014;123:3073-9) – correlate with better outcomes.
“Now I don’t know if that is just telling us about the basic biology of the disease – you respond better, therefore you have a better outcome – or if three drugs are definitively better than two up front,” Dr. Green said. “But until we know that, I think the consensus from the myeloma community is, three drugs in patients who can tolerate that.”
Forthcoming data to be presented at the ASH meeting will likely shed more light on the comparative efficacy of various primary regimens, he said.
The therapeutic options also are likely to increase soon, as two or three new drugs are likely to be approved for multiple myeloma in the next 6 months, he added.
Risk-adapted management
Another area of rapid change has been therapy that is adapted to a patient’s risk of progression, Dr. Green said. “Because we have all these new agents, that keeps changing. Is it high risk or isn’t it high risk based on cytogenetics? Maybe it was yesterday and it’s not today because some new agent is improving outcomes for a specific subset of patients.”
There is some disagreement on where, exactly, certain cytogenetics fall. But 17p deletion is generally viewed as high risk, and a recent study suggested that the survival benefit of bortezomib (Velcade) induction followed by maintenance after stem cell transplant in newly diagnosed myeloma was especially pronounced among patients with this cytogenetic abnormality (J Clin Oncol. 2012;30:2946-55).
“Although there’s not a randomized trial powered to prove this directly, we are beginning to understand and see that difference clinically. Patients who have 17p disease should see proteasome inhibitor therapy up front and I believe as part of their maintenance, unless they can’t tolerate it or are resistant to it,” Dr. Green recommended.
Stem cell transplant