Assessing B-Cell Maturation Antigen Directed Therapies in Multiple Myeloma Treatment

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Three posters presented at the 65th American Society of Hematology Annual Meeting and Exposition looked into the efficacy and safety of the therapies.

The prevalence of multiple myeloma—a cancer that forms in plasma cells—has risen 40% in the United States since 1990. The disorder now accounts for roughly 2% of cancer diagnoses and 2% of cancers deaths in the country.1 However, disease survival has increased significantly over the past several decades thanks to new forms of therapy.

Three new studies looked deeper into the treatment landscape of multiple myeloma, examining the efficacy of B-cell maturation antigen (BCMA) directed therapies (BDT). The data were presented at the 65th American Society of Hematology Annual Meeting and Exposition, held December 7 to 10 in San Diego, California.

In the first study, investigators from Memorial Sloan Kettering Cancer Center conducted an observational study comparing infectious complications in patients with relapsed/refractory multiple myeloma (RRMM) who were treated with a commercial or investigational autologous BCMA-targeting chimeric antigen receptor T-cell (CAR-T) therapy versus patients treated with commercial or investigational BCMA-targeting bispecific antibodies (BsAb).2

The study cohort included 147 patients, of which 92 were treated with CAR-T and 55 with BsAb. The date of infusion with CAR-T was between March 22, 2017, and February 27, 2023. The date of treatment for BsAb was between January 21, 2020, and February 7, 2023. The primary study endpoint was incidence of severe infections.

Investigators found that a total of 209 infections were reported during the study period: 115 in CAR-T and 94 in BsAb. Of the 92 patients treated with CAR-T, 24 experienced 1 or more severe infections. In the BsAb cohort, 21 of 55 patients experienced 1 or more severe infections. The incidence of 1 or more severe infections remained high in the BsAb cohort, despite excluding 18 patients with prior CAR-T exposure.

Additionally, the median time from treatment initiation to the first infection of was 2.5 months with CAR-T and 3.4 months with BsAb. There was a significantly higher infection rate after day 100 with BsAb compared to CAR-T.

“Infectious complications were common early after BCMA-targeting BsAb and BCMA CAR-T and declined over time,” the authors concluded. “In this real-world comparison, distinct from their CAR-T counterparts, BsAb recipients appeared to have a more persistent infection risk and higher incidence of severe infections…”

For the second study, a team of investigators conducted a retrospective review to examine the optimal sequencing and outcomes in patients with RRMM who were treated with 2 or more BDTs.3 Data was gathered from a total of 39 patients who were treated at the University of Kansas Medical Center. Responses in the study included overall response rate (ORR), complete response or better (>CR), and very good partial response (VGPR).

Investigators found that patients were treated with a median of 7 prior therapies before they received a second BDT. The median time between relapse after first BDT to initiation of second BDT was 4 months. The most common first BDTs were CAR-T and antibody-drug conjugates (ADC). The most common second BDTs were BsAb and CAR-T. The ORR after first BDT and second BDT was 54%.

Additionally, the estimated median PFS for the first BDT was 5.8 months and 5.2 months for the second BDT. The median OS from exposure to first BDT was 19.5 months.

“This is one of the first reports on outcomes with second BDT in RRMM,” the authors wrote. “Despite a heavily pre-treated patient population, 2 treatment with a BDT resulted in deep and durable responses, similar to treatment with 1 BDT.”

For the third study, investigators from the Icahn School Of Medicine at Mount Sinai conducted a retrospective review to evaluate hematologic recovery in patients treated with CAR-T.4 Data was gathered from 140 patients with multiple myeloma who received a CAR-T product from 2017 through 2022 at the Icahn School Of Medicine at Mount Sinai.

All available lab values of hemoglobin (Hgb), platelet count (Plt) and absolute neutrophil count (ANC) for each patient were recorded and graded according to CTCAE v5.0 criteria. The time to recovery was defined as the number of days from CART infusion until the first day of a 30-day-long period without any grade 3 or 4 values. Patients were also classified according to the CAR-HEMATOTOX scoring system.

Investigators found that the median CAR-HEMATOTOX score was 1, with 45 patients classified as having higher inflammatory marker levels prior to lymphodepletion and 91 as having lower inflammatory marker levels. Median time to recovery from G3/4 anemia was 11.5 days, thrombocytopenia was 10 days, neutropenia was 32 days, and any myeloid cytopenia was 40 days.

Additionally, of 112 patients who remained evaluable, 105 recovered from G3/4 anemia, 94 from G3/4 thrombocytopenia, 99 from G3/4 neutropenia, and 88 from any G3/4 myeloid cytopenia. A high higher inflammatory marker level, older age at CAR-T infusion, 3 or more lines of prior therapy, and being Black was associated with delayed recovery from any G3/4 myeloid cytopenia.

“Our study reinforces the predictive capability of CAR-HEMATOTOX in assessing the risk of delayed hematologic recovery after CAR-T,” the authors concluded. “However, we suggest that this tool could be further refined for MM by factoring in variables such as patient age, race, and number of prior lines of therapy.”

References
1. Padala SA, Barsouk A, Barsouk A, et al. Epidemiology, Staging, and Management of Multiple Myeloma. Med Sci (Basel). 2021;9(1):3. Published 2021 Jan 20. doi:10.3390/medsci9010003
2. Shekarkhand T, Costa BA, Nemirovsky D, et al. A Comparative Analysis of Infectious Complications in Patients with Multiple Myeloma Treated with BCMA-Targeted Bispecific Antibodies and CAR T-Cell Therapy. Presented at: 65th American Society of Hematology Annual Meeting and Exposition; December 9-12, 2023; San Diego, CA. Abstract 1957.
3. Snyder J, Alsaddi Z, Alkharabsheh O, et al. Outcomes of Patients with Relapsed/Refractory Multiple Myeloma Who Received at Least 2 BCMA-Directed Therapies. Presented at: 65th American Society of Hematology Annual Meeting and Exposition; December 9-12, 2023; San Diego, CA. Abstract 1969.
4. Catlett J, Bodnar S, Mia B, et al. Inflammatory Marker Levels, Age, Race and Prior Treatment Burden Independently Predict Delayed Hematologic Recovery after BCMA-Directed CART Therapy in Multiple Myeloma. Presented at: 65th American Society of Hematology Annual Meeting and Exposition; December 9-12, 2023; San Diego, CA. Abstract 2002.
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