What Are the Most Effective Therapies for Daratumumab-Refractory MM?

A systematic review published in Cancer Medicine identified and compared treatment options for patients with multiple myeloma (MM) whose disease was refractory to daratumumab. Chimeric antigen receptor (CAR) T-cell therapy yielded the best overall survival (OS) and progression-free survival (PFS), with B-cell maturation antigen (BCMA)–directed treatments such as elranatamab and teclistamab showing high rates of response and long-term survival.

The researchers searched the MEDLINE, Cochrane CENTRAL, and EMBASE databases for clinical trials that evaluated response rates and survival outcomes of treatments for daratumumab-refractory MM from November 2015 to October 2023. In total, the researchers compared treatment outcomes from 25 clinical trials across 33 eligible published studies.

Treatment options included CAR T-cell therapy, BCMA-directed antibodies, non–BCMA-directed monoclonal antibodies, cereblon E3 ligase modulators, a peptide-drug conjugate, and other targeted therapies such as selinexor and venetoclax.

CAR T-cell therapy demonstrated the highest overall response rates (ORRs), including ciltacabtagene autoleucel in the CARTITUDE-1 trial with an ORR of 98% and idecabtagene vicleucel (ide-cel) in the KarMMa-3 trial with an ORR of 72%. Monoclonal antibodies such as teclistamab, elranatamab, ABBV-383, and talquetamab also achieved ORRs greater than 50%. Selinexor had an ORR of 67% in the STOMP trial when combined with carfilzomib but showed a ORRs of 26% and 25% as monotherapy in the STORM and MARCH trials, respectively.

CAR T-cell therapy also demonstrated the highest PFS. The median PFS for CART-ddBCMA was not reached at a median follow-up of 12.6 months, and the median PFS for ide-cel was 12.5 months. The median OS was not reached for CART-ddBCMA, and the median OS was 10.1 months for HB10101. With a median follow-up of 14.7 months, the median PFS and OS were not reached for elranatamab in the MagnetisMM-3 trial.

Selinexor combination therapy also showed longer PFS and OS compared with selinexor alone. Selinexor plus carfilzomib had a median OS of 23.7 months and a median PFS of 20.4 months in the STOMP trial. In comparison, selinexor monotherapy had a median OS of 8.6 and 11.9 months and a median PFS of 3.7 and 2.9 months in the STORM and MARCH trials, respectively.

“Based on the results of this systematic review, BCMA-directed therapies such as CAR-T cell therapy and bispecific antibodies demonstrate promising efficacy among patients with anti-CD38 refractory disease,” the researchers concluded. “However, additional evidence from randomized clinical trials is necessary to establish best practice guidelines.”

Reference

Tan CJ, Kacerek D, Kampirapawong N, Godara A, Chaiyakunapruk N. Treatment of multiple myeloma in patients refractory to daratumumab/anti-CD38 monoclonal antibodies: a systematic review. Cancer Med. 2025;14(5):e70585. doi:10.1002/cam4.70585