ADCs, Triplets, and Transplant Maintain Solid Roles in Multiple Myeloma Therapy

Natalie S. Callander, MD

A number of factors come into play when deciding treatment in the first- and later-line settings for a patient with multiple myeloma, especially when choosing between various combinations, transplant eligibility, and a BCMA-targeted approach, explained Natalie S. Callander, MD.

“There are a couple of issues when you see a newly diagnosed multiple myeloma patient,” Callander said. “We want to pick a regimen that is going to be effective, that's going to produce a deeper response, and something that is going to limit side effects. If that patient is having organ dysfunction related to their myeloma, we want to try to reverse that as quickly as possible.”

In an interview with OncLive® during an Institutional Perspectives in Cancer webinar on multiple myeloma, Callander, a professor of medicine of the Division of Hematology/Oncology at the University of Wisconsin Carbone Cancer Center, discussed the intriguing approaches in both the frontline and relapsed/refractory settings, including trials with antibody-drug conjugates.

OncLive®: Looking up front, how do you currently form a frontline treatment strategy for a patient with myeloma?

Callander: There's a couple of issues when you see a newly diagnosed multiple myeloma patient. We want to pick a regimen that is going to be effective, will produce a deeper response, and will limit side effects. If that patient is having organ dysfunction related to their myeloma, we want to try to reverse that as quickly as possible. Then, we really want to look at that patient in front of us, who may be quite ill, and determine if that's related to the myeloma or preexisting medical conditions that will make them a little bit more difficult to treat, or maybe a little bit frailer.

We certainly separate patients right off the bat into transplant-eligible or noneligible. Although, that distinction can change as patients clinically improve. If we do think they may get a transplant, typically, we want to choose a regimen that will not interfere with stem cell collection. With all of these wonderful choices coming up, we really are looking for something that produces a deep response.

Right now, the controversy is, do you start with 3 drugs? Should you go to 4 drugs? Or, are there still individuals in whom 2 drugs are appropriate?

How do you currently determine whether a patient is fit enough to undergo autologous stem cell transplant?

There are certainly people over the years who have wanted transplants to go away. That's nothing new, and there continues to be data that support the use of transplant.

The FORTE trial looked at 3 different strategies [with transplant]. One was to use carfilzomib with cyclophosphamide and dexamethasone [KCd] for 4 cycles, then transplant, 4 cycles of consolidation, and then a second randomization. Or, there was using carfilzomib, lenalidomide, and dexamethasone [KRd] with 4 induction cycles, transplant, and 4 cycles of consolidation followed by a second randomization, or just using 12 cycles of KRd followed by randomization. The response rates in both KRd arms appeared to be superior to the KCd arm, and the preliminary data looked like the 12 cycles of KRd and the KRd/transplant arms were going to be very equivalent.

What was updated though, is that if you look at KRd transplant versus the 12 cycles of KRd, there was improvement in MRD negativity. We believe that this will probably translate to better control. There is no overall survival [OS] difference in any of the arms at this point, but there was a subgroup analysis looking at KRd/transplant versus the other 2 arms—and looking at different stages of myeloma risk—they all appeared to favor KRd with transplant. That take-home message was that even if you use what we think is one of the best regimens, transplant continues to improve that.

The second update that occurred was in the IFM 2009 study. This is a trial that's been around a long time; it looked at VRd followed by transplant, VRd consolidation, and lenalidomide maintenance for 1 year, versus VRd with lenalidomide maintenance for 1 year. Updated data showed that the initial PFS favored VRd plus transplant, but what they were showing was that in the VRd-only arm, if those patients went back and were salvaged with transplant, they had very equivalent overall survival.

Now, you can look at that and say, “Does that mean that transplants are really important?” Looking at how great the OS was in both arms, knowing that many of those patients in the chemotherapy arm went on to get transplant, we feel that that sustains role for transplant.

What is most exciting about ADCs, such as belantamab mafodotin, in relapsed/refractory myeloma?

I've been fortunate to have experience with belantamabmafodotin [Blenrep], as we have [both] the DREAMM-2 and DREAMM-5 studies open. Belantamab mafodotin is an antibody-drug conjugate that targets BCMA, and it's been a very interesting compound because if you look at the overall response rates as a single agent, they are around 31%. Some of those responses are both very deep and very durable.

At the 2020 ASH Annual Meeting and Exposition, we saw belantamab mafodotin presented in combination with bortezomib [Velcade] and pomalidomide [Pomalyst]. Those combinations look very exciting, and we're going to be seeing more of belantamab mafodotin combined with other agents. There is a trial starting that is will use bortezomib, lenalidomide (Revlimid), and dexamethasone [VRd] with belantamab mafodotin as initial induction. There's a very interesting trial using belantamab mafodotin actually in amyloid light chain (AL) amyloidosis. All of those things are very exciting.

BCMA has proven to be an effective target in myeloma. What else has been learned from this approach?

We have learned that targeting BCMA in a group of patients who have failed lots of other therapies, particularly 3 classes—proteasome inhibitors immunomodulatory agents [IMiDs], and CD38-directed antibodies—that this is actually a very viable strategy. One of the things that we have observed in these patients, is that the possibility [to improve their outcomes] is there. [These patients have] quite advanced myeloma and are symptomatic, [and this approach can] really turn things around. We have had some dramatic, long-lasting responses in patients, so this is another wonderful option for patients to consider. The combinations that are coming up open up a huge number of possibilities for what we're going to be able to do with this, so it's changed things considerably. When you have a patient who has relapsed from all 3 classes of drugs, having something off the shelf to give them immediately is a wonderful option.

What is the rationale to explore the combination of belantamab mafodotin and VRd?

We know from the recent ENDURANCE trial that the ORR with VRd was about 83% in newly diagnosed, transplant-eligible patients. That’s a pretty high bar right off the bat. If you just improve that response rate, the depth of response may improve. It's pretty good with VRd upfront—it is about a 64% very good partial response rate or better—but I think it'll be very exciting to see if we get deeper responses and perhaps in terms of minimal residual disease [MRD] negativity. It's going to take a while to know what the advantages are going to be, because VRD is already a pretty good regimen.

Where will belantamab mafodotin optimally fit into a patient’s sequence of therapies?

Right now it’s the only BCMA-targeted therapy with FDA approval, so a lot of people are turning to that right now. As other BCMA-targeted therapies are introduced, I think we'll find out [how it will be used best]. One of the areas that's of great interest, but is still unknown, is if a patient fails another type of BCMA-targeted therapy, say a bispecific antibody or maybe even a CAR T-cell therapy, can we use belantamab mafodotin to salvage them? Or will there be some sort of refractory time period that one must wait? That is going to be an open question. With DREAMM-9 coming up, is the introduction of early anti-BCMA targeting a good strategy, and is it going to really help improve responses?