Since 2001, the achievements of the IMF’s International Myeloma Working Group (IMWG) have made a profound difference in the landscape of myeloma research. Members of the IMWG meet at an annual Summit with a mission to identify, support, and implement the most promising research to prevent onset of active disease, improve treatment, and find a cure for myeloma. A record number of myeloma researchers from around the world assembled for the 5th Annual IMWG Summit, which was held in Milan, Italy, June 9-11, 2014.
The members’ enthusiasm was palpable as they greeted each other, and it fueled lively and sometimes heated debate throughout the Summit. While collaboration is key to the IMWG, the experts often must wrestle with difficult questions as they reach consensus.
The Summit is structured so that the attendees first assess progress and then brainstorm, debate, and determine new areas in which research must be done to push the field forward. Dr. Brian G.M. Durie (IMF Chairman) welcomed the attendees and opened the first session by introducing important presentations of the latest data on advances in flow technology, new diagnostic criteria, and geriatric risk stratification. These are areas of research that the IMWG had previously identified as of the highest priority.
First speaker Dr. Alberto Orfao (University of Salamanca, Salamanca, Spain) presented data on advances in flow technology that makes the test specific for myeloma and highly sensitive. He and his team have tailored this molecular test to aid in a better understanding of the biology of myeloma and why it relapses even in patients who achieve complete responses. The behavior of myeloma has taught us that “complete response” does not mean the same thing in all patients, and that “complete” does not mean that every myeloma cell is gone. Until now, we have not had the tools to detect and characterize what the experts call “minimal residual disease” (MRD), the cells that remain after treatment.
Current flow cytometry techniques vary widely among centers within each country and around the world, and results have been far from uniform. This makes it very difficult to compare clinical trial data. Dr. Orfao’s new multi-parameter 8-color flow test is highly sensitive, is reproducible at any center, and, because results are analyzed using computer software he designed, human subjectivity and potential error are eliminated. This new flow test has clear advantages over the next-generation sequencing (NGS) technique, which may miss myeloma cells in 5-10% of patients tested, and is also more labor-intensive, time-consuming, and expensive than flow cytometry.
Since flow cytometry uses bone marrow samples, it must be accompanied by PET/CT imaging to assess any myeloma activity that may be present outside the marrow (extramedullary). Dr. Orfao and his team are currently working on additional myeloma cell markers, as well as on a technique to analyze blood samples.
The MRD test will make it possible to have a new endpoint to use in clinical trials. Rather than waiting to see which treatment provides the longest remission period or the longest overall survival—a period that could extend for a decade or longer—the new flow test will provide an immediate answer to the question “which drug or regimen led to the lowest rate of MRD in the greatest number of patients”?
Next on the agenda was Dr. Vincent Rajkumar (Mayo Clinic, Rochester, Minnesota), first author of the new IMWG consensus guideline on diagnostic criteria for myeloma. He was charged with the very tricky feat of defining and validating biologic markers that could be used to prevent patients with smoldering multiple myeloma (SMM) from being harmed either by waiting too long for treatment or by being treated too early.
When a project like this is in progress, the entire IMWG contributes data and every member of the IMWG comments on the resulting manuscript. If disagreements arise, there must be compromise and consensus. It can take years to gather the necessary data to support an important paradigm change, and it can take many months thereafter to form a consensus for publication. With Dr. Rajkumar as lead author, this important paper was conceived four years ago and is now in its final form, having been submitted for publication. It sets forth new biomarkers to determine when it is appropriate to begin treating patients who do not have CRAB criteria but who are at 80% or greater risk of progressing to active myeloma with organ damage in the next two years. Such patients are termed “ultra-high-risk,” and they constitute only 10-15% of all patients with SMM.
Dr. Rajkumar noted that the new flow test will be included in the diagnostic criteria for ultra-high-risk SMM when it has been validated. Data on FISH testing and on monoclonal protein level do not support the 80% risk cut-off for immediate treatment, and were therefore not included. The current consensus is that ultra-high-risk SMM should be considered as and treated as MM; high-risk SMM should be treated only in the context of a clinical trial; patients with low-risk SMM should be followed by observation only.
Next week: Part 2 of Highlights from the 2014 IMWG Summit