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Amrita Krishnan, MD, discusses key data may shape the evolving treatment landscape of multiple myeloma from ASCO 2025.
Amrita Krishnan, MD
Following the 2025 ASCO Annual Meeting, Amrita Krishnan, MD, provided perspective on how emerging data from the meeting may shape the evolving treatment landscape of multiple myeloma, including the use of minimal residual disease (MRD)–guided therapy, the role of trispecific antibodies, and the evolving use of bispecific agents in frontline and relapsed/refractory populations.
In an interview with OncLive®, broke down some of the top data from across the multiple myeloma field presented during the meeting and provided perspective on how these findings could help shape the future of myeloma management.
Krishnan is the director of the Judy and Bernard Briskin Center for Multiple Myeloma Research at City of Hope in Duarte, California, where she also serves as a professor in the Department of Hematology & Hematopoietic Cell Transplantation.
Krishnan: The MIDAS study was probably one of the most impactful oral abstracts we heard [at ASCO], and it was [published] in The New England Journal of Medicine. MIDAS had 2 groups, and they were asking several questions.
The question about using MRD to guide clinical decision making has always been [an] important [possibility] to us. Now we have [data from] a randomized trial suggesting that [MRD status] can be impactful. In patients who were MRD negative and were randomly assigned to consolidation or a transplant consolidation, [transplant] did not seem to have any impact in MRD-negative rates prior to maintenance.
Similarly, patients who were MRD positive after induction were randomly assigned to tandem transplant or a single transplant. Again, tandem transplant did not seem to impact MRD rates. In the United States, tandem transplant has not really been widely adopted, so that part of the trial probably was less impactful.
Focusing on the MRD-negative [group], it is certainly notable that transplant did not increase rates of MRD negativity. Having said that, [there are] several points to remember. We didn't have a breakdown [of the population] in terms of high-risk cytogenetics, and I think that's key. Philippe Moreau, MD, [of University Hospital of Nantes in France], made that point as well during the panel discussion. Additionally, this was MRD at one time point, and it may not be sufficient. What we need to see is sustained MRD negativity.
Before we consider abandoning transplant, we need to see a little longer follow-up and more data. [Findings from MIDAS] were informative, but I don't think they should be practice-changing yet.
Trispecific antibodies have the theoretical advantage that if you're dual targeting, you can overcome some degree of clonal heterogeneity. Perhaps you will reduce resistance because you'll have less selective pressure on one antigen. We saw from a prior study using 2 bispecific antibodies together—each with different targets—had a very high response rate in [patients with] extramedullary disease. For all those reasons, the concept of a trispecific antibody that will target 2 antigens, in addition to the T cell, was very attractive.
[In the phase 1 data (NCT05652335) reported at ASCO for JNJ-5322], we saw an overall response rate [ORR] of 100% in the BCMA/GPRC5D-naive cohort [treated at the recommended phase 2 dose of 100 mg once every 4 weeks (n = 27)]. That is certainly higher than what we've seen with any of the single-agent bispecific [antibodies]. This idea that dual targeting can overcome clonal heterogeneity seems to be true. They didn't present data on extramedullary disease because the percentage of patients with extramedullary disease was very low at 8%, so that question remains unanswered.
The follow-up was still relatively short, so we don't really have [data for] progression-free survival [PFS]. Having said that, the results were very compelling in terms of those response rates. If those responses are deep and durable, then this could be practice-changing, including in regard to CAR T-cell therapy.
The safety profile [of JNJ-5322] was also very compelling, and I think that was less due to the targets and more due to schedule. The trispecific was given every 4 weeks, so the incidence of grade 3/4 infections was lower than what we've seen with any of the BCMA-targeted bispecific [antibodies]. It was only 33.3% [at the RP2D]. The GPRC5D-related toxicities, especially in regards to dysgeusia and the subsequent weight loss associated with it, was also much lower.
The safety profile, in a way, was actually superior to what we've seen with bispecific antibodies, which was a pleasant surprise. We shouldn't also overlook the fact that we've become more knowledgeable on how to give bispecific antibodies. Our supportive care measures [have improved], and we're no longer in a pandemic. All of those things play a role.
[This analysis included] a relatively small number of patients. They adjusted the schedule of the bispecific antibody in [cohort G] that was presented. Elranatamab was given every 4 weeks. The good news is that didn't seem to impact ORR. The ORR was very high at [97.3% (95% CI, 85.8%-99.9%); follow-up was relatively short, so we don't know the durability of that response. It was notable for the fact that 24.3% of patients were characterized as frail; it was something of a surprise that they could give this fairly intense regimen to more frail patients.
Also notable was that the incidence of grade 3/4 infections was very similar to what we saw in the phase 3 MAIA trial [NCT02252172] with daratumumab plus lenalidomide and dexamethasone. That’s become a standard of care for older patients with multiple myeloma. [The tolerability could be attributable] to the every-4-week elranatamab dosing and improved supportive care, now that we’re more experienced with bispecific antibodies.
These data showed that you can give a BCMA-directed bispecific antibody in a combination—certainly with daratumumab plus lenalidomide. Is that also part of why you see the higher response rate in addition to better T-cell health? Infection prophylaxis is key, but if infections can be managed—there were 2 deaths [due to infections]—but those patients had preexisting pulmonary infiltrates. Again, patient selection is also key to success with this intense regimen.
With long-term follow-up of the CARTITUDE-1 data, every patient I saw in clinic [one day after ASCO] asked me about them. The most impactful part was really that [the PFS] curve seemed to start to flatten out, and to see a plateau in such heavily pretreated patients really gave a lot of hope to patients. The fact that they didn't see any further emergent neurologic toxicity was also important, and the second malignancy signal did not increase.
Those are also all key, because having a PFS [benefit is important], but toxicity is also not something no one wants to see. The fact that you could see this prolonged PFS, in conjunction with no changes to the safety profile, was key.
As the field continues to advance, what future directions or emerging areas of research are you most interested in observing or contributing to?
I had a conversation with several of my patients after ASCO, because, of course, they were all very interested in [the top dat]a. Certainly, the trispecific [data] were incredibly exciting to us. The use of bispecific antibodies in the newly diagnosed setting certainly is also part of the future. CAR T-cell [therapies are] being studied in the newly diagnosed [setting] and they're approved [for use after] early relapse.
All those [efforts] have become part of our future of myeloma, [and] the biggest thing that we need to focus on is that if we do have such effective therapies, especially in the case of the trispecific antibodies and bispecific antibodies used earlier, is changing our idea of how we have to treat patients continuously. Treating them forever [vs] switching to an idea of fixed-duration therapy is also key. Again, if we say we have such good therapies, they also need to be good in the fact that we can stop them at some point.
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