Thomas Martin, MD, Clinical Professor of Medicine in the Adult Leukemia and Bone Marrow Transplantation Program and Associate Director of the Myeloma Program at the University of California San Francisco Helen Diller Family Comprehensive Cancer Center, presented data on chimeric antigen receptor (CAR) T-cell therapy, bispecific antibodies, and antibody-drug conjugates for multiple myeloma (MM) at the Fourth Annual National General Medical Oncology Summit February 28 to March 2, 2025.
CAR-T
First, Dr. Martin discussed idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel) for patients with heavily pretreated MM.
Among the 248 patients enrolled in the CARTITUDE-1 trial, the overall response rate (ORR) was 95%, the CR rate was 76%, and the measurable residual disease (MRD) negativity rate was 95% for those who achieved a CR. The 1-year progression-free survival (PFS) was 73%.
“This is very encouraging that in the real world, we’re seeing very good responses,” Dr. Martin said in his presentation. “There are still Achilles’ heels for us in terms of patients who don’t have the durable responses even with CAR T-cell therapy, like those with high-risk, those with EMD [extramedullary multiple myeloma], and those who have had prior BCMA [B-cell maturation antigen] therapies.”
He explained that patients who received a prior BCMA had a lower PFS than those without exposure to BCMA. Specifically, those who received a prior BCMA within 6 months of cilta-cel had a PFS of less than three months. “That speaks a lot to sequencing these therapeutics,” he added.
In a comparison study between ide-cel and cilta-cel in the relapsed or refractory setting, cilta-cel shows a higher PFS but also higher toxicities. This includes more severe cytokine release syndrome, more delayed neurotoxicity, and more infection. According to Dr. Martin, some clinicians may opt for ide-cel for an older, more frail patient population and cilta-cel for a younger patient population.
Natalie Callander, MD, of the University of Wisconsin Carbone Cancer Center, further spoke on neurotoxicity associated with cilta-cel. “It tends to be delayed, it tends to be showing up maybe 2-3 months post-CAR-T,” she said during the meeting. “The worrisome thing is that it doesn’t respond very well to typical Parkinson’s-like treatment.” While Dr. Callander noted that neurotoxicity is rare, ‘debulking’ patients before CAR-T seems to be associated with less neurotoxicity.
Next, Dr. Martin covered optimal sequencing therapy in MM. “When we see in the late-line setting something that has a really good response, the general paradigm in myeloma is to try to bring it up earlier,” he said during the presentation.
The phase 3 KarMMa-3 and CARTITUDE-4 trials evaluated ide-cel and cilta-cel, respectively, in earlier lines of treatment. In both trials, the CAR-T therapy shows higher overall response rates and higher CR rates (39% for ide-cel and over 70% for cilta-cel). In KarMMa-3, the PFS rate was 13 months for ide-cel versus 3 months for standard-of-care. In CARTITUDE-4, the PFS for cilta-cel was not reached and under 1 year for standard-of-care. As for safety, neurotoxicity is still seen in earlier lines of therapy 3 weeks to 3 months after CAR-T.
“These data point to the fact that we can start using CAR-T in earlier lines of therapy,” Dr. Martin said during the meeting. “CAR-T is now going to be all over the map for treating patients with MM. We’re looking forward to seeing frontline therapy in the KarMMa-4, CARTITUDE-5, and CARTITUDE-6 studies.”
Bispecifics
Next, Dr. Martin discussed the two approved bispecific antibodies for the treatment of MM: teclistamab and elranatamab. Other bispecifics like linvoseltamab (REGN5458), ABBV-383, alnuctamab (BMS-93269), and HPN217 are in development.
In the MajesTEC-1 trial, teclistamab achieved an ORR of 63% (including a CR or better rate of 46.1%), a median duration of response of 24 months, and a PFS of 11 months. The most important toxicities, Dr. Martin noted, are cytopenias, neutropenia, and infection.
In MagnetisMM-3, elranatamab achieved a PFS of about 17 months and a median overall survival of 25 months in the relapsed or refractory setting. The most common treatment-emergent adverse events included hematologic toxicities and infections, which were mitigated by spreading the dose from weekly to every 4 weeks.
Dr. Martin also presented emerging data on bispecifics as dual-targeted agents. In the tRIMM-2 trial of talquetamab plus daratumumab and pomalidomide, patients who were pomalidomide naïve achieved an ORR of 84.3%. The RedirecTT-1 trial also found high ORR rates when combining talquetamab with teclistamab, especially in patients with EMD.
“This is the best data that we have for EMD,” Dr. Martin said during the presentation. “This is something that we’re going to investigate further, and we’ll see if it might be the treatment of choice.”
Finally, Dr. Martin discussed the efficacy of belantamab combined with other agents in phase 3 trials. In DREAMM-7 (belantamab, bortezomib, and dexamethasone versus daratumumab, bortezomib, and dexamethasone), the belantamab combination achieved an ORR of 83% and a CR rate of 35%. In DREAMM-8 (belantamab, pomalidomide, and dexamethasone vs bortezomib, pomalidomide, and dexamethasone), the belantamab combination achieved an ORR of 77% and a CR rate of 40%.
According to Dr. Martin, Belantamab also led to “impressive” PFS data. In DREAMM-7, the PFS was 37 months in the belantamab combination arm and 13 months in the daratumumab, bortezomib, and dexamethasone arm. While belantamab is associated with “significant” ocular toxicity in 20% of patients, Dr. Martin noted, mitigation strategies consist of dose holds and reductions.
Reference
Martin, T. Module 12: CAR T-cell therapy, bispecific antibodies and antibody-drug conjugates. Presented at: Fourth Annual National General Medical Oncology Summit; February 28-March 2, 2025; Miami, FL.
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