Advances in the Treatment of Relapsed/Refractory Myeloma - Episode 1
Ajai Chari, MD: There have been many recent advancements in myeloma, and in the last 15 years, we’ve had 9 drugs approved, including 4 in 2015 alone. These drugs have all resulted in an accumulative increase in overall survival of either double or triple. With regard to the new revised ISS [International Staging System] staging system, we have a group of patients with a median overall survival that has not been reached; that’s tremendous progress in a short amount of time, particularly for a cancer that is not very common.
An important question, regarding the newly approved drugs, is how does this impact community practice physicians who have various choices? It generates tremendous amounts of complexities to the care because, if you have 6 different classes of drugs with multiple drugs within each class, it’s purely a mathematical problem. The number of the combinations are endless. We then have to factor in clinical issues. The other issue that we’re now struggling with, regarding myeloma, is determining the proper sequence with this magnitude of drugs. What should we start with? If you start with A, what comes next? This is probably where community physicians struggle most.
In terms of how community doctors work with academic partners, in our institution we have a philosophy that we’re here to help patients and community doctors. When we get referrals, our job and intent is not necessarily to treat them on-site, and we really try to make the right recommendation for the patient. If it’s something that they get locally, I routinely tell patients that you don’t get extra points for having to drive through traffic to come to New York. Get it from your doctor, and you can come back as needed, perhaps as infrequently as every 3 months. With collaboration we can deal with the academic issues of doing stem-cell transplant, helping guide the initial therapy, and maintenance. Today their care can still be done by community doctors.
We also get patients who self-refer, and they live far away. We then reciprocate by sending the patient to the community doctor to get their care if there’s no clinical trials appropriate to them. It’s a win-win situation for all parties.
One of the key areas of research and confusion is when it is optimal to initiate therapy. Historically, the CRAB symptoms—hypercalcemia, renal insufficiency, anemia, and bone disease—were very straightforward. All community doctors are familiar with this. Then we have this consensus criteria, the so-called SLiM CRAB, which adds the free-light chain ration greater than 100, bone marrow greater than 60%, and multiple focal lesions.
At face value that seems straightforward. Some of the concerns is that these don’t have prospective clinical trial validation for treatment, supporting early treatment instead of watching and waiting. In particular, I personally do not treat free-light chain ration greater than 100 in the absence of other symptoms, because we found that the risk of progression in our patients could be as low as 44%, when we were really looking at it initially for criteria that would predict for progression at 90% in 2 years. More important than these initial baseline characteristics is the kinetics. If somebody is stable, they don’t necessarily need to be treated. That also applies for MRI lesions. If you have more than one MRI lesion, but it’s stable, that’s not concerning. We need to move away from photographs, which are how a patient initially presents, and progress toward video, which shows the evolution of the disease—the so-called evolving model.
When we diagnose a patient with symptomatic myeloma, and we need to do risk stratification, historically people just think about the molecular risk. I would argue that risk is more complicated than that. We have disease burden-related issues, which include the international stage, historic data with Durie-Salmon, and whether there are circulating plasma cells. We have host factors like age, renal function, and comorbidities. Finally, we have the disease itself, which includes the molecular translocation 414, 416, deletion 1p, or amplification of 1q, but also, we have the other features of disease biology like gene expression profiling, doubling time, and LDH [lactate dehydrogenase]. When we integrate these, there’s not a symbol risk stratification. The most practical way to do it in the community would be to revise R-ISS staging, which uses the LDH, FISH [fluorescence in situ hybridization], and ISS stage. When you put those together, you can have low, medium, or high risk, which can lead to a median overall survival as short as 3 to 4 years and as high as not reached for the patients who are low-risk.
Transcript Edited for Clarity