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Heavily Pre-Treated Patients With MM Respond to Cilta-Cel CAR T-Cell Therapy

November 14, 2022

Mid-November 2022

Patients with multiple myeloma (MM) who had received multiple prior therapies, including B-cell maturation antigen (BCMA)–targeting agents, and had progressive disease responded to treatment with ciltacabtagene autoleucel (cilta-cel), resulting in measurable residual disease (MRD) negativity. These results, from cohort C of the phase II CARTITUDE-2 trial, were published in Blood 

Cilta-cel is a chimeric antigen receptor (CAR) T-cell therapy that targets the BCMA antigen. The U.S. Food and Drug Administration (FDA) approved cilta-cel for the treatment of adults with relapsed or refractory (R/R) MM after four or more prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody. The FDA approval was based on the phase Ib/II CARTITUDE-1 clinical trial.  

“Even after patients have progressed on a prior BCMA-targeted therapy, they can still potentially respond to a BCMA-targeted CAR T-cell therapy, demonstrating the feasibility of serial BCMA-targeted therapies,” said first author Adam D. Cohen, MD, of the University of Pennsylvania. “This isn’t totally surprising, since BCMA expression seems to be maintained in the majority of patients progressing on a previous BCMA-targeted therapy.”  

The median age of patients in cohort C was 63 years. Twelve patients were male (60%), 19 were white, and one was Black. Patients had received a median of eight prior lines of therapy. 

Seven patients received a prior BCMA-targeted bispecific antibody, and 13 patients had received a BCMA-targeted antibody-drug conjugate (ADC). One of the patients had received both an ADC and bispecific antibody. Among the patients who had received a prior BCMA-targeted ADC and prior BCMA-targeted bispecific antibody, five and two patients achieved MRD negativity, respectively.  

One of four patients who received an anti-BCMA ADC as their last line of treatment had a clinical response to cilta-cel, compared with seven of nine patients who had at least one other prior line of therapy in between the ADC and CAR T-cell therapy. 

At a follow-up of 11.3 months, 10 patients could be assessed for the primary endpoint of MRD negativity at 10-5. The overall response rate was 60%, and 30% of patients achieved a complete response. Seven patients achieved MRD-negativity. All three patients with high-risk cytogenetics, all of which were a del17p, achieved at least a very good partial response.  

The median duration of response (mDOR) was 11.5 months, and the progression-free survival was 9.1 months. The median time to a first response was 0.95 months.  

“Despite this promising activity, it’s important to note that the response rate and mDOR appear shorter in this study than in CARTITUDE-1, where cilta-cel was given to less-heavily-treated patients who were BCMA treatment-naïve,” Dr. Cohen said. “Thus, the optimal use of cilta-cel, and perhaps other CAR T-cell products, may be earlier in the treatment course of myeloma.” 

The authors observed that, overall, patients who responded to cilta-cel had a shorter median duration of exposure to a previous BCMA-targeted agent (29.5 days, range = 1-277 days) compared to those who did not respond (63.5 days, range = 22-527 days). Most patients who responded to cilta-cel did not respond to a prior BCMA-targeting therapy and had a longer median time between their last anti-BCMA therapy and apheresis compared to non-responders 

“Toxicities were similar to those seen using cilta-cel in other studies,” Dr. Cohen noted. All patients experienced a treatment-related adverse event following cilta-cel therapy. Twelve patients had cytokine release syndrome, all of which were grade 1 or 2.  

The researchers outlined several limitations of the study, including the small sample size, because of which the authors could not evaluate responses for patients who were exposed versus refractory to anti-BCMA therapy before cilta-cel treatment. Another limitation was the heterogeneity of the type, duration, and timing of prior anti-BCMA therapy.  

“This was a small cohort of patients, so definitive conclusions can’t be drawn, [which] highlights the need for larger studies to truly explore the question of optimal sequencing of BCMA-targeted immunotherapies in myeloma,” Dr. Cohen concluded.

Any conflicts of interest declared by the authors can be found in the original article. 

Reference

Cohen AD, Mateos M-V, Cohen YC, et al. Efficacy and safety of cilta-cel in patients with progressive MM after exposure to other BCMA-targeting agents [published online ahead of print, 2022 Sept 12]. Blood. doi: 10.1182/blood.2022015526. 

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