Is Molecular Remission the Goal When Treating Myeloma?

Faith Davies, MD

As part of our coverage of the American Society of Hematology (ASH) Annual Meeting & Exposition, being held December 9–12 in Atlanta, we are speaking with Faith Davies, MD, about molecular remission in multiple myeloma. Dr. Davies is a professor of medicine and deputy director of the Myeloma Institute at the University of Arkansas for Medical Sciences in Little Rock. She is giving a talk titled, “Is Molecular Remission the Goal of Multiple Myeloma Therapy?” during an education session at the conference.

Cancer Network: First, Dr. Davies, can you provide a brief overview of the types of therapies that are used to treat multiple myeloma?

Dr. Davies: We actually have an array of therapies and in some ways, multiple myeloma is a hematologic malignancy that has had the most expansion in the number of therapies over the last few years. We have a number of different groups of therapies. There are the immune-modulatory drugs such as lenalidomide, thalidomide, and pomalidomide; and we have the proteasome inhibitors such as bortezomib, carfilzomib, and ixazomib. We still use the traditional chemotherapy drugs such as cyclophosphamide and melphalan, and we now have some antibodies that are also used such as daratumumab and elotuzumab.

Essentially the recent studies have shown that, as a general rule, three drugs tend to be better than two, and ideally we want to pick drugs from those different groups as combinations. It is quite common as an induction therapy to use an immune-modulatory drug with a proteasome inhibitor and a steroid, for example. In the relapse setting it is probably more common to use an antibody such as daratumumab or elotuzumab with either with one of the immunologic drugs or a proteasome inhibitor. This has given us the ability to mix and match drugs and really trying to aim to ensure that we are able to give a patient a drug that is not only effective for them but has a safety profile attached to it.

Cancer Network: What is the role of transplant for patients with multiple myeloma, where does that modality come in during the course of treatment and for which patients?

Dr. Davies: We are still using transplants an awful lot. It is most appropriate for patients who are younger and fitter and have a relatively good performance status. In the majority of the time, the transplant is conditioned with melphalan, and we tend to use an autologous transplant rather than an allogeneic transplant. There was a large study from a French group, which I talked about at last year’s ASH meeting, where patients still seemed to benefit from an autologous transplant in the first treatment course compared to just using some of the newer agents we’ve been talking about.

If patients have a good response to their first transplant, there are also a number of groups that are still using two transplants-so a tandem transplant-and certainly data from European groups suggest that this is effective maybe for patients with high-risk disease. There is also a role for transplantation in the relapse setting if patients had a good initial response to their first transplant. It is definitely another tool that we have in our toolbox.

Cancer Network: Can you define molecular remission, and how does that differ from clinical remission?

Dr. Davies: So one of the interesting things that has happened with this explosion of new therapies is that many patients are now getting very good and very deep remissions. We’ve standardly used the International Myeloma Working Group definitions for remission-a complete remission is defined as having less than 5% of plasma cells in the bone marrow, no evidence of an M protein component, and normalization of the serum free light chain. With many of these new therapies, in combination, we are able to achieve that level of response, but there are lots of new techniques now that are able to look at the depth of response and to be able to measure the amount of myeloma even below that standard complete remission.

The technology that are being used are flow cytometry, which depending on the actual combination of antibodies used in the laboratory can measure 1 myeloma cell in 10,000 or 1 cell in 100,000; then there’s polymerase chain reaction (PCR)-based techniques; and next-generation sequencing–based techniques, which is slightly more sensitive and can measure 1 myeloma cell in 1,000,000 cells. These are some very sensitive techniques that were needed because we were having so many patients who could achieve a complete remission, and we have been able to demonstrate that with these new treatments-and the way we are using them-we are able to get really good, deep, and long-lasting remissions for patients.

Cancer Network: And lastly, what do we currently know about how molecular remission, using these tests you just described, correlate with longer-term treatment outcomes?

Dr. Davies: The important thing is that when we’ve been utilizing these techniques, we’ve been able to demonstrate that patients who have a deeper remission have longer progression-free and overall survival. It seems to be that the deeper remissions-so if you look at it in log values, as you go down the number of log values you get an improvement in that prolonged progression-free survival.

Importantly, it’s not just for the younger, fitter patients who are able to have a transplant as part of their induction treatment, but it also seems to apply for the older less-fit patients who are not having a transplant, and then in the relapse setting as well.

The other area that I think is quite important where this applies is high-risk patients. There is a little bit of controversy about this, but there are a number of studies that are now showing that even if you are high risk, that if you can achieve a minimal residual disease (MRD)-negative remission, then you have a longer progression-free survival than those patients who are high risk and don’t achieve such a deep remission. Other questions being addressed moving forward are, as well as being a prognostic factor, should we be actually using MRD testing as an endpoint for clinical studies or an endpoint for regulatory approval? Or, if our patients are not achieving MRD-negativity, should we be thinking about changing our treatment so that patients can get a deeper remission? Those studies are not quite there yet, but people are beginning to look at that area as the next step for myeloma therapy.

Cancer Network: Thank you so much for joining us today, Dr. Davies, and enjoy the conference!

Dr. Davies: Thank you very much for having me.