Multiple Myeloma Paradigm Adapts to Novel Therapies Across Disease States

Data from key clinical trials evaluating expanded combination strategies and novel therapies have transformed the treatment paradigms of newly diagnosed, relapsed/refractory, and heavily pretreated multiple myeloma, but it remains important to contextualize the data appropriately without cross-trial comparisons, said Thomas R. Chauncey, MD, PhD, in an interview with OncLive^® during an Institutional Perspectives in Cancer (IPC) webinar on multiple myeloma.

The virtual meeting covered updates in newly diagnosed and relapsed/refractory multiple myeloma management, current therapeutic approaches for patients with smoldering multiple myeloma, and the evolving paradigm of CAR T-cell therapy and other BCMA-directed approaches.

“[Data in multiple myeloma are] not static, it’s an ongoing process. We’re going to learn a lot more during [the 2021] ASH [Annual Meeting and Exposition]. More data will be released because there are a lot of trials [ongoing]. Before we start comparing them, we need to look at the durability and the depth of some of the trials. That doesn’t mean that the data aren’t important, we just need to put it in the appropriate context,” said Chauncey, a physician at the Seattle Cancer Care Alliance, an associate professor in the Department of Medical Oncology at the University of Washington School of Medicine, and an associate member at Fred Hutchinson Cancer Research Center.

During the interview, Chauncey, who chaired the IPC event, highlighted key trials that have changed the management of newly diagnosed and relapsed/refractory multiple myeloma, the danger of comparing across trials, the utility of lenalidomide (Revlimid) for patients with smoldering multiple myeloma, and the potential future of CAR T-cell therapy and other BCMA-directed options in the paradigm.

OncLive^®: Regarding your presentation on newly diagnosed multiple myeloma, how have the data from the phase 2 GRIFFIN trial (NCT02874742) and the phase 3 MAIA (NCT02252172) and CASSIOPEIA (NCT02541383) trials solidified a role for daratumumab (Darzalex) in patients with transplant-eligible and transplant-ineligible multiple myeloma?

Chauncey: When we look at these studies, we see a strong signal that adding daratumumab to existing chemotherapeutic regimens enhances outcomes. We saw this in the phase 3 MAIA trial. In that setting, for non-transplant patients, [that triplet of daratumumab, lenalidomide, and dexamethasone] does improve progression-free survival and overall survival. The big question is [what to do for] most patients in the intent-to-transplant [population]. The phase 2 [GRIFFIN trial data] showed that [adding daratumumab] improves outcomes. CASSIOPEIA was a phase 3 trial, but the comparator arm was not one that we would typically use. We saw improved outcomes in the phase 2 [GRIFFIN trial], but there are a lot of phase 3 trials currently ongoing that we need to see to fully validate the data [from GRIFFIN] with our current standard regimens. The GRIFFIN trial has been expanded into 2 phase 3 trials, both in transplant-eligible and transplant-ineligible [populations].

During the IPC meeting, Nicholas Burwick, MD, of the University of Washington, discussed the current state of treatment for patients with relapsed/refractory multiple myeloma. How have the data from the phase 3 ICARIA-MM (NCT02990338) and IKEMA (NCT03275285) trials with isatuximab-irfc (Sarclisa), as well as the phase 2 DREAMM-2 trial (NCT03525678) with belantamab mafodotin-blmf (Blenrep), changed the treatment of patients with relapsed/refractory disease?

Dr Burwick did an excellent job because, although a lot of trials are ongoing in the up-front setting, the relapsed/refractory setting is a very busy space.

Starting with the ICARIA-MM and IKEMA studies, isatuximab paired with carfilzomib [Kyprolis] or pomalidomide [Pomalyst] showed very good efficacy. Those [combinations] have been incorporated into our standard regimens. They are slightly different in terms of outcomes, but they are also slightly different in terms of who [was enrolled in the trial]. It is also very dangerous to compare across trials, whether that is with phase 2 or 3 trials. We know from eligibility [criteria] that [patient] risk is not the same in both studies. It shouldn’t be surprising that the outcomes are slightly different. However, it does give us options, like what we have with daratumumab beyond the first-line setting if it wasn’t used. I’m not sure what trials are being planned, but there is no reason to believe that other drugs can’t be paired [with isatuximab] as well.

The DREAMM-2 trial with belantamab mafodotin was something completely different. Belantamab mafodotin is an antibody-drug conjugate against BCMA. It is off-the-shelf, so we don’t have to manufacture CAR T cells; belantamab mafodotin can be given to patients with a wide range of performance statuses. It does require coming in once a week and there is a REMS [Risk Evaluation and Mitigation Strategy] program for the ophthalmic exams.

[The drug is] not for everybody. The response rates in DREAMM-2 were not as high as we would like to see, but, on the other hand, the patients were very advanced. When we move [the agent] up [in lines of therapy], we are going to see better responses. The responses are often durable. Despite the toxicities that need to be monitored, many patients can stay on [belantamab mafodotin] for a long time. It’s uncommon for patients to stop [treatment] because of toxicity.

Sarah S. Lee, MD, of the Seattle Cancer Care Alliance, spoke to navigating therapeutic interventions for patients with smoldering multiple myeloma. What lessons have been learned in this disease state?

[Smoldering myeloma] is an interesting area because the National Comprehensive Cancer Network recommends lenalidomide for high-risk disease. I am not sure what the uptake [of lenalidomide] is in practice. [Lenalidomide has] a 2b recommendation, so not too high, but that is what we should be building on.

One lesson for smoldering multiple myeloma is that patients need to be followed extremely closely. The dilemma with smoldering myeloma, even when it is high risk, is that we are committing patients to a treatment that they may not need for some time. That is always the dilemma, which is why these patients need to be followed closely. The higher the risk, the more closely they need to be followed.

Finally, Andrew Cowan, MD, of the Seattle Cancer Care Alliance, talked about the evolving role of CAR T-cell therapy for patients with multiple myeloma. How do you anticipate the field of BCMA-directed therapies evolving in the coming years?

I’m not a CAR T-cell therapy expert, but Dr Cowan did a great job outlining what we know and what we don’t know. Idecabtagene vicleucel [ide-cel; Abecma] is approved and has shown very good responses, some of which are durable. The toxicities are as expected for CAR T-cell therapies. There is a strong dose response, so the higher doses do well although there is often more toxicity.

Ciltacabtagene autoleucel (cilta-cel), as Dr Cowan appropriately emphasized, looks extremely promising, but we don’t have the length of follow-up that we do with ide-cel. Although it looks like the response [rates with cilta-cel] might be superior [to ide-cel] and the toxicity might be lower, the [follow-up] so far on the CARTITUDE study [NCT03548207] has been short. We need to follow these patients for a longer period. Right now, if a patient is going to receive a CAR T-cell therapy, it will be with ide-cel; however, it won’t be that long until cilta-cel is approved. Hopefully, by that time, we will have longer follow-up to have a better sense of the durability [of the agent].

I don’t know if we got into this during the meeting, but there are other ways to target BCMA. Bispecific antibodies can target BCMA and other targets. There can also be other targets for CAR T-cell therapies, so BCMA is not the only game in town. Whether the other targets are as effective or can be used in sequence, we don’t yet know. Bispecific antibodies are a way to engage T cells without CARs. However, they need to be continued and have toxicities.

Right now, all we have seen are early data, but we have seen a very strong signal of activity. I expect the data will hold up with phase 2 trials. We will probably have approval [for bispecific antibodies], so it will be a crowded space in advanced lines of therapy.