Treatment of Relapsed and Refractory Multiple Myeloma

PracticeUpdate: At ASH 2021, what studies were discussed on patients with relapsed and refractory multiple myeloma?

Dr. Fonseca: For patients who are experiencing a relapse, the ASH meeting brought us a number of options. But I would say that the most prominent ones remain the use of T-cell engager therapies, by specific antibodies and CAR Ts. We saw series of presentations that were devoted to the CAR T. There was one in particular that was delivered by Dr. Tom Martin from UCSF, that provided an update on the CARTITUDE-1 clinical trial, patients with heavy pre-treatment. Nevertheless, over 97% of them were able to achieve a response with the vast majority of those being a complete response. Of course those results are very promising. But a parallel study, the CARTITUDE-2 study was also presented at ASH. They looked at the same construct, but now in patients who have one to three prior lines of therapy, and again, with the same results. If we continue to see this level of responses, and as we follow patients over time, with special interest in those that are being treated earlier in the course of the disease, we might start seeing more and more durability for the treatment of myeloma in those patients that are experiencing a relapse. This is of interest, of course, for patients who already have received prior therapies, and are looking at what their options might be into the future.

However, it is not far fetched to think that there might be a future where this becomes an integral part, even a frontline therapy. So, we are very excited with that.

PracticeUpdate: What are the other novel strategies being studied for patients with relapsed or refractory multiple myeloma?

Dr. Fonseca: As I mentioned, the other group of drugs or strategies, involve the bispecific antibodies. These bispecific antibodies, not only target BCMA, but they can also target other surface antigens like FcRH5, and GPRC5D, which are quite specific for plasma cells, although they could have expression in other tissues; like GPRC5D appears to have some hair follicle and skin expression, which results in toxicity that has been reported in these clinical trials. The majority of the bispecifics show responses that are somewhere between 50% and 80+%. But it is important to remember, many of these patients are patients who would not have been, in principle, eligible for CAR T-cell clinical trials. So, I would stop short of making comparisons between the bispecifics and the CAR Ts, because at this moment we really cannot do that. We don't have enough information, and we're very excited also with the convenience of bispecifics off the shelf.

Speaking of "off the shelf," my last comment on this particular section is that we do also have the development of allogeneic CAR T cells. That would be universal donor CAR T cells that have been engineered so they can be given to any individual without the need of a cross-match, but still with the features that are so beneficial of CAR T cells with a significant level of response. I can't wait for the next year and see what ASH brings us, but I would anticipate that over the next 18 to 24 months, we will continue to see approvals for these medications or these cell constructs, and that, of course, is going to be great to have for our patients.

PracticeUpdate: What are some drugs that are being evaluated in early-stage trials?

Dr. Fonseca: In addition to the immunotherapy approaches, there were other drugs that were presented at the ASH meeting. I think notable amongst them were venetoclax, which we know works particularly well in that lymphoid variant of multiple myeloma. We predominantly think about it for patients with t(11;14), but there's other patients that may have expression of B-cell markers. There's an important paper by the group from Emory, Dr. Gupta, as well as patients who are more dependent on BCL2 expression. We don't routinely test for this. We don't have clinical assays for this, but the research work suggests, that those groups of patients appear to have an earlier, what I call now a younger, form of multiple myeloma. There was an update of the study of venetoclax in combination with daratumumab, which was recently published in JCO by Dr. Bahlis, with a very, very high level of response. It's going to be only a year or two before we start seeing clinical trials that look at venetoclax in combination with say, daratumumab for the frontline therapy of myeloma that has t(11;14), or one of the other markers. We also saw updates on belantamab mafodotin. There was an important study by Dr. Suzanne Trudel that looked at an alternative schedule once every eight weeks, to try to minimize some of the ocular toxicity. In combination with pomalidomide, they had pretty interesting results.

I think we'll have to see how that plays out. Lastly, there is what's described as an immunocytokine. This is an immune construct that can directly deliver to the myeloma cells, interferon alpha-2B, which historically we've used interferons for the treatment of myeloma, but now it's more specifically delivered into the cells, and showed significant activity. I think amongst the myeloma experts that was also commented about, and we're just hoping to have more tools in our toolkit to continue to fight against this disease.