Treating Multiple Myeloma With Earlier CAR T-Cell Therapy

Chimeric antigen receptor (CAR) T-cell therapy continues to move into earlier lines of treatment for patients with relapsed/refractory multiple myeloma. Adriana Rossi, MD, assistant professor of medicine and director of CAR T and the Stem Cell Transplant Clinical Service at the Center of Excellence for Multiple Myeloma at Mount Sinai, discussed recent advancements at a live event in White Plains, New York. Rossi detailed the change in post-infusion monitoring requirements, and reviewed data from the CARTITUDE-4 trial [NCT04181827] of ciltacabtagene autoleucel (cilta-cel).

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CASE SUMMARY

• A 60-year-old man who was diagnosed 2 years ago with IgG-kappa multiple myeloma presented to his oncologist at first relapse.
• Medical history: hypertension controlled with lisinopril
• He received previous treatments with:
  • D-VRd (daratumumab [Darzalex], bortezomib [Velcade], lenalidomide [Revlimid], dexamethasone) followed by autologous stem cell transplant (ASCT) with lenalidomide maintenance
  • Achieved very good partial response (VGPR) post-ASCT
• Seventeen-months following ASCT, the patient is now progressing and complains of excessive fatigue and low back pain exacerbated by movement.
  • ECOG performance status: 0
  • Weighed 170 lbs (down 15 lbs in last 4 months)
• The patient was started on DKd (daratumumab, carfilzomib [Kyprolis], and dexamethasone) and referred to CAR T-cell center.
• Completed 2 cycles with PR, then held for 2 weeks prior to leukapheresis (T cell collection)
• Resumed DKd for 1 cycle as bridging during manufacturing, with VGPR
• Ultimately proceeded to cilta-cel CAR T-cell infusion
• Achieved stringent complete response at day 30

Targeted Oncology: What have been some roadblocks when referring patients for CAR T-cell therapy?

Adriana Rossi, MD: Part of the big hassle was these Risk Evaluation and Mitigation Strategies [REMS] limitations, because we didn't know what to expect, and we'd rather err on the side of caution. The original REMS had a requirement for patients to spend 4 weeks near the hospital, and now that's been cut back to 2. They weren't allowed to drive for 8 weeks, which in New York, no problem, nobody drives. But anywhere else, how do you even get to your appointments? It makes the requirement of the caregiver that much more. It's now 2 weeks as the minimum requirement. It doesn't mean that at 2 weeks, everybody gets to drive, but at least we can start that conversation. The post-infusion monitoring went from 10 days to 7 days. I think if the patient is actively having cytokine release syndrome [CRS], we're not going to send them out [just because we can].¹

This speaks to the fact that as we're learning these things are becoming more predictable, they're more manageable, and they're probably on their way to being managed as outpatient [treatment] at our academic centers. It demystifies and hopefully shares that it's not because I said so, there is consensus that these things are not as scary as they were, because it's the unknown that's scary. Now we know what we're up against.

Can you discuss data behind treating this patient with cilta-cel after 2 prior lines of therapy?

CARTITUDE-4 is a phase 3 trial. If you look at the patient population under study, [patients needed to have] 1 to 3 prior lines, including a proteasome inhibitor [PI] and immunomodulatory drug, and be refractory to lenalidomide. That's where the indication comes from. Most of these patients had not had anti-CD38 antibody, so I think important to note that randomization was 1:1, the control arm only had 2 triplets available, and the bridging therapy was mandated, but could only be 1 of those 2 triplets. Not every patient who was randomly assigned to cilta-cel made it to cilta-cel because the control arm was not the most robust.²

There was a smattering of patients refractory to 1 or both PIs and any anti-CD38 antibody. Triple-class and penta-drug refractory starts to get to small numbers, but these were patients who had most of the drugs [available]. About half of patients were exposed to daratumumab.

What was the efficacy seen with cilta-cel in this relapsed/refractory myeloma population?

There was a median follow-up of approximately 3 years, and the 30-month progression-free survival [PFS] rate was 59.4% [with cilta-cel] vs 25.7% on the control arm [HR, 0.29; 95% CI, 0.22-0.39; P < .0001].³ The control arm wasn't great, but these are probably the drugs we're using if you had D-VRd and a transplant, daratumumab/pomalidomide [Pomalyst]/dexamethasone or pomalidomide/bortezomib/dexamethasone seem reasonable. Who knows how long it will be for median PFS, but we are definitely exceeding expectations.

Similarly, when we look at all of the prespecified subgroup analyses, there is a benefit for cilta-cel over standard of care for all of the categories. The subgroups with the bigger confidence intervals are just the ones with smaller numbers. So potentially the International Staging System stage 3 confidence interval was bigger, but it's because it's underrepresented.

The median overall survival [OS] for this is going to be way beyond its utility, but already, within 30 months, we're seeing an OS separation of the Kaplan-Meier curves in favor of cilta-cel [30-month OS rate, 76.4% vs 63.8%; HR, 0.55]. For all of the prespecified group OS, it's too soon to tell for most of the data points, but they are all favoring cilta-cel.

How did the PFS in this trial compare with previous studies of cilta-cel?

If you compare CARTITUDE-1 [NCT03548207], the heavily pre-exposed patients, the 30-month PFS rate hit at 54.2% and for CARTITUDE-4, with 1 to 3 prior lines, the 30-month PFS rate was up to 68.4%. That's not surprising. Every drug that we have, if we use it in an earlier line, we get more for our efforts, but maybe even more so with CAR T because we're depending on these T cells that are now not as beat up over years and years.

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_{DISCLOSURES: Rossi previously reported consulting for Adaptive, Bristol Myers Squibb, Janssen, Karyopharm, Johnson & Johnson, and Sanofi.}

_References:

_{1. FDA eliminates Risk Evaluation and Mitigation Strategies (REMS) for autologous chimeric antigen receptor CAR T cell immunotherapies. FDA. June 27, 2025. Accessed September 23, 2025. https://tinyurl.com/bp5pxxks}

_{2. San-Miguel J, Dhakal B, Yong K, et al. Cilta-cel or standard care in lenalidomide-refractory multiple myeloma. N Engl J Med. 2023;389(4):335-347. doi:10.1056/NEJMoa2303379}

_{3. Mateos M-V, San-Miguel J, Dhakal, et al. Overall survival (OS) with ciltacabtagene autoleucel (cilta-cel) versus standard of care (SoC) in lenalidomide (len)-refractory multiple myeloma (MM): phase 3 CARTITUDE-4 study update. Presented at: 2024 International Myeloma Society Annual Meeting; September 25-28, 2024; Rio de Janeiro, Brazil. Abstract OA – 65.}