Low-Dose Belantamab Mafodotin/Nirogacestat Demonstrates Encouraging Clinical Activity in R/R Myeloma

Article
Pipeline Report: July 2022

Nirogacestat plus belantamab mafodotin induced promising responses with manageable safety for patients with relapsed/refractory multiple myeloma.

Multiple Myeloma

Multiple Myeloma

Nirogacestat (PF-03084014) plus belantamab mafodotin-blmf (belamaf; Blenrep) induced promising responses with manageable safety for patients with relapsed/refractory multiple myeloma (RRMM), according to findings from the phase 1/2 DREAMM-5 study (NCT04126200) presented at the 2022 ASCO Annual Meeting.1

The phase 1/2 platform study incorporated a master protocol evaluating multiple belamaf-containing combinations to identify effective treatment regimens in specific disease subgroups. These data including findings from a substudy of 10 patients assigned to 0.95 mg/kg of belamaf every 3 weeks plus continuous nirogacestat. Results from a planned interim analysis of this dose escalation cohort led to the opening of a cohort expansion arm with 14 more patients. Another 14 patients were randomly assigned to 2.5 mg/kg belamaf monotherapy every 3 weeks.

The overall response rate (ORR) for the combined dose escalation and cohort expansion cohorts (n = 24) was 38% (95% CI, 18.8%-59.4%) vs 50% (95% CI, 23.0%-77.0%) in the monotherapy arm. However, more patients in the combined cohort had stringent complete response (CR; 4 vs 0) or CR (5 vs 0). The clinical benefit rate was 50% (95% CI, 18.8%-59.4%) in the combined arm vs 57% (95% CI, 28.9%-82.3%) for monotherapy.

Investigators previously evaluated belamaf monotherapy for patients with heavily pretreated RRMM in the DREAMM-2 study (NCT03525678). The ORR was 32% (97.5% CI, 21.7%-43.6%) in 13-month follow-up data.2

Nirogacestat is a gamma secretase inhibitor that prevents the cleavage of several transmembrane proteins, including membrane-bound B-cell maturation antigen (BCMA). This releases the extracellular domain as soluble BCMA into circulation, interfering with and limiting efficacy of BCMA-directed therapies. Preclinical data demonstrated that nirogacestat may increase cell surface levels of BCMA and reduce soluble BCMA levels, which may enhance the activity of the anti-BCMA agent in multiple myeloma.

To determine whether adding nirogacestat to low-dose belamaf produced similar efficacy as single-agent belamaf, investigators recruited adults with RRMM who received at least 3 prior lines of therapy including a proteosome inhibitor, an anti-CD38 monoclonal antibody, and immunomodulatory agent. Other requirements included an ECOG performance score of 0 or 1 and treatment with stem cell transplantation, if feasible. Patients who were administered 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 median age in the combined cohort was 71.3 years (range, 55-86) compared with 65.5 years (range, 56-80) in the monotherapy arm. Fifty percent of patients where women in the combined cohort compared with 64% in the monotherapy arm.

Patients in the combined cohort received a median of 4.25 prior lines of therapy, compared with 4.5 in the monotherapy cohort. In the combined cohort, 6 patients had extramedullary disease compared with 1 in the monotherapy arm.

There were 2 fatal serious adverse effects (AEs) in the dose-expansion cohort: an intracranial hemorrhage and sepsis. In the cohort expansion group, there was 1 fatal case of hematuria and 1 fatal case of COVID-19 infection. There was 1 incident of fatal COVID-19 infection in the monotherapy arm. Investigators determined none of these deaths was related to the study treatment.

All patients in the dose-expansion cohort experienced grade 3 or higher, AEs compared with 86% each in the cohort-expansion and monotherapy cohorts. Of those, 9 (90%) in the dose expansion cohort, 11 (79%) in the cohort expansion group, and 5 (36%) in the monotherapy group were related to treatment with belamaf.

Two (20%) patients in the dose-expansion cohort and 1 (7%) in the cohort-expansion group required permanent discontinuation of study treatment. There were no discontinuations in the monotherapy group.

There were 7 (29.1%) incidents of grade 3 or higher blood and lymphatic AEs in the combination arm, compared with 2 (14%) with monotherapy. Five patients (20.8%) in the combined arm experienced grade 3 or higher thrombocytopenia vs 2 in the monotherapy arm.

Investigators assessed ocular events based on the Common Terminology Criteria for Adverse Events-5 scale and the keratopathy and visual acuity scale. There were 12 any-grade events in the monotherapy arm, compared with 13 in the combination arms. Seven (50%) of those events were grade 3 in the monotherapy arm compared with 3 (12.5%) in the combination arm.

References

  1. Lonial S, Grosicki S, Hus M, et al. Synergistic effects of low-dose belantamab mafodotin in combination with a gamma-secretase inhibitor (nirogacestat) in patients with relapsed/refractory multiple myeloma (RRMM): DREAMM-5 study. J Clin Oncol. 2022;40,(suppl 16; abstr 8019). doi: 10.1200/JCO.2022.40.16_suppl.8019
  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
Related Videos
Hans Lee, MD, associate professor, director, Multiple Myeloma Clinical Research, Department of Lymphoma/Myeloma, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center
Saad Z. Usmani, MD, MBA, FACP, FASCO, chief, Myeloma Service, Memorial Sloan Kettering Cancer Center
Danai Dima, MD
Krina K. Patel, MD, MSc, associate professor, Department of Lymphoma/Myeloma, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center
Ariel Grajales-Cruz, MD, assistant member, Department of Malignant Hematology, Multiple Myeloma Section, Moffitt Cancer Center; assistant professor, University of South Florida
Rachid Baz, MD, section head, Myeloma, Department of Malignant Hematology, Moffitt Cancer Center; co-director, Pentecost Family Myeloma Research Center
Ricardo D. Parrondo, MD, hematologist/oncologist, Mayo Clinic
Joseph Mikhael, MD
Ariel F. Grajales-Cruz, MD, Moffitt Cancer Center
Joshua Richter, MD