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.