Belantamab Mafodotin/Pembrolizumab Combo Elicits Favorable ORR in Heavily Pretreated Multiple Myeloma

Attaya Suvannasankha, MD

The addition of pembrolizumab (Keytruda) to belantamab mafodotin (Blenrep) resulted in a higher overall response rate (ORR) in patients with relapsed/refractory multiple myeloma than what has been observed with the antibody-drug conjugate (ADC) alone, according to results from the phase 1/2 DREAMM-4 trial (NCT03848845).¹

At a median follow-up of 14.7 months, the combination elicited an ORR of 47% (95% CI, 29.8%-64.9%) among 34 patients who were enrolled to parts 1 and 2 of the trial. Of those who responded to treatment, 12% had a complete response, 18% had a partial response, and 18% had a very good partial response (VGPR). Twenty-nine percent (95% CI, 15.1%-47.5%) of patients had a VGPR or better.

When belantamab mafodotin was evaluated as a monotherapy in patients with heavily pretreated relapsed/refractory multiple myeloma, as a part of the DREAMM-2 study (NCT03525678), the ORR achieved with the ADC was 32% (97.5% CI, 21.7%-43.6%).²

Additional data from DREAMM-4 showed that the median time to response with the combination in parts 1 and 2 was 0.7 months (95% CI, 0.7-1.4), and the median duration of response (DOR) was 8.0 months (95% CI, 2.1–not reached [NR]). Investigators noted that the upper 95% confidence interval for DOR was NR in either part of the trial. Moreover, the median progression-free survival (PFS) with the doublet was 3.4 months (95% CI, 1.4-5.6).

“The result of this study helped reinforce the body of research supporting belantamab mafodotin use in patients with myeloma,” Attaya Suvannasankha, MD, lead study author, associate professor of clinical medicine at Indiana University School of Medicine, and a staff physician at Richard L. Roudebush VA Medical Center, said in a poster presentation of the data during the 2022 ASCO Annual Meeting. “Future studies will pursue other combination therapy options to enhance the efficacy and safety profile [of the ADC].”

In August 2020, the FDA granted an accelerated approval to belantamab mafodotin, the BCMA-targeted ADC, for use in adult patients with relapsed or refractory multiple myeloma who have received 4 previous therapies, including an immunomodulatory drug (IMiD), a proteasome inhibitor (PI), and an anti-CD38 antibody.³ The agent has a multimodal mechanism that eliminates myeloma cells via direct cytotoxicity and a systemic antitumor immune response, that investigators hypothesized could be augmented by an immune checkpoint inhibitor.

In DREAMM-4, eligible patients had received at least 3 prior lines of therapy including an anti-CD38 monoclonal antibody, a PI, and an IMiD. Patients were also required to have an ECOG performance status of 0 or 1 and have undergone stem cell transplantation, if eligible. Patients who received a monoclonal antibody within 30 days of enrollment; received prior therapy with an agent targeting PD-1, PD-L1, or PD-L2; or received treatment with a coinhibitory T-cell receptor–directed agent were excluded.

The primary end point for part 1 of the trial was number of patients with dose-limiting toxicities and percentage of those with adverse effects (AEs), and the primary end point of part 2 was investigator-assessed ORR. Secondary end points in part 1 included ORR and pharmacokinetics (PK); in part 2, secondary end points included clinical benefit rate, DOR, time to response, time to best response, PFS, time to progression, overall survival, AEs, and PK

Study participants received belantamab mafodotin at 2.5 mg/kg in combination with pembrolizumab at 200 mg.

The median patient age in parts 1 and 2 of the trial was 61.0 years (range, 40-81). Forty-four percent of patients were female and 82% were White. Twenty-nine percent of patients had high-risk cytogenetic abnormalities, 26% had extramedullary disease, and 41% were triple-class refractory. The median number of prior therapies received was 5 (range, 3-13).

The data cutoff for the primary analysis of all treated patients was October 17, 2021. Of the 24 patients included in the analysis, 6 were from part 1 and 28 were from part 2 of the research.

Ninety-seven percent of patients in both parts of the trial experienced any-grade AEs, and the rate of grade 3 or higher AEs was 74%. Similarly, 97% of patients experienced any-grade treatment-related AEs; 65% of these cases were grade 3 or higher in severity. The most common toxicities reported with the regimen were keratopathy (76%), blurred vision (38%), and thrombocytopenia (35%).

Nine patients experienced serious AEs; 4 patients had at least 1 serious AE related to study treatment. The most common serious AEs included pneumonia (15%), infusion-related reaction (9%), infection (6%), and urinary tract infection (6%). Infusion-related reactions and pneumonia were determined to be related to treatment, as well as 1 case of serious platelet count decrease.

Notably, no deaths that occurred on the study were attributed to AEs.

Thirty-two percent of patients experienced AEs that required dose reductions, and 65% required dose interruptions. The most common toxicities that resulted in dose interruptions were keratopathy (44%) and thrombocytopenia (12%).

References

1. Suvannasankha A, Bahlis NJ, Trudel S, et al. Safety and clinical activity of belantamab mafodotin with pembrolizumab in patients with relapsed/refractory multiple myeloma (RRMM): DREAMM-4 study. J Clin Oncol. 2022;40,(suppl 16):8018. doi:10.1200/JCO.2022.40.16_suppl.8018
2. Lonial S, Lee HC, Badros A, et al. Longer term outcomes with single-agent belantamab mafodotin in patients with relapsed or refractory multiple myeloma: 13-month follow-up from the pivotal DREAMM-2 study. Cancer. 2021;127(22):4198-4212. doi:10.1002/cncr.33809
3. FDA granted accelerated approval to belantamab mafodotin-blmf for multiple myeloma. News release. FDA. August 5, 2020. Accessed July 14, 2022. https://bit.ly/3PiFE26