Bispecific Antibodies Yield Lower ORR in Extramedullary R/R Multiple Myeloma

"We highly recommend highlighting responses [in patients with extramedullary disease] because they can have a more challenging disease to treat. Combination therapies might hold promise for myeloma with extramedullary disease…but we do need further data from prospective trials to evaluate that," according to Lawrence Liu, MD.

Treatment with bispecific antibodies led to lower overall response rates (ORRs) in patients with extramedullary relapsed/refractory multiple myeloma compared with all patients with relapsed/refractory multiple myeloma, according to findings from a systematic review presented at the 2023 International Myeloma Society Annual Meeting.¹

The combined common effect ORR of all patients included in this analysis who received any bispecific antibody as monotherapy or in a combination regimen was 0.67 (95% CI, 0.64-0.70). The combined random effect ORR of all patients in this population was 0.66 (95% CI, 0.58-0.73).

The 3 bispecific antibodies that are FDA approved for patients with relapsed/refractory multiple myeloma are teclistamab-cqyv (Tecvayli), talquetamab-tgvs (Talvey), and elranatamab-bcmm (Elrexfio). Teclistamab was approved in 2022 for patients who have received at least 4 prior lines of therapy based on findings from the phase 2 MajesTEC-1 trial (NCT04557098), in which the agent elicited an ORR of 61.8% (95% CI, 52.1%-70.9%).² The August 2023 approval of talquetamab for patients who have received 4 or more prior lines of therapy was supported by data from the phase 2 MonumenTAL-1 trial (NCT04634552), in which the agent led to an ORR of 73.6% (95% CI, 63.0%-82.4%).³ Elranatamab was also approved in August 2023 for patients who have received 4 or more prior lines of therapy based on findings from the phase 2 MagnetisMM-3 trial (NCT04649359), in which the agent generated an ORR of 57.7% (95% CI, 47.3%-67.7%).⁴

“Relatively little is known about the responses in relapsed/refractory multiple myeloma with extramedullary disease,” Lawrence Liu, MD, a Hematology/Oncology Fellow at City of Hope Comprehensive Cancer Center in Duarte, California, said in a presentation of the data.¹ “The purpose of this review is to determine the pooled efficacy of bispecific antibody therapy in multiple myeloma with extramedullary disease or high-risk cytogenetic abnormalities.”

The investigators conducted a systematic literature search of the terms (bispecific antibodies) AND (multiple myeloma) using the PubMed, ASH abstract, and ASCO abstract databases to find clinical trials that evaluated bispecific antibodies in multiple myeloma. These searches yielded 83 total results. After removing 19 duplicate records, 10 preclinical studies, 2 studies not related to multiple myeloma, 15 studies that did not include bispecific antibodies, 7 studies that did not report results, 13 studies that did not report ORRs for patients with extramedullary disease or high-risk cytogenetic abnormalities, and 3 systematic reviews, 14 studies were included in this analysis.

The included trials defined high-risk cytogenetic abnormalities as either 17p deletion, translocation 4;14, or translocation 14;16; or International Myeloma Working Group 2016 criteria, which are 17p deletion, translocation 4;14, translocation 14;16, translocation 14;20, nonhyperdiploidity, or 1q gain.

Eleven of the included studies treated a combined total of 787 patients with bispecific antibody monotherapy. Three studies (n = 78) reported ORRs in cohorts of patients with extramedullary disease, and 5 studies (n = 111) reported ORRs in cohorts of patients with high-risk cytogenetic abnormalities. Additionally, 3 studies reported ORRs with combination therapies in a combined total of 176 patients.

Of the cohort of patients included in this study who were treated with bispecific antibody monotherapy, the ORR was 0.59 (95% CI, 0.54-0.65). A linear regression test of funnel plot asymmetry yielded a P value of 0.96, indicating low publication bias for bispecific antibody monotherapy ORR.

When stratified by bispecific antibody, the ORRs were 0.70 with talquetamab, 0.63 with teclistamab, and 0.62 with elranatamab.

The ORR in the entire cohort of patients with extramedullary disease who received bispecific antibody monotherapy was 0.38 (95% CI, 0.28-0.49). Among the studies that reported ORRs in patients with extramedullary disease, talquetamab elicited the highest ORR, of 0.45 (95% CI, 0.17-0.77). Elranatamab and teclistamab elicited respective ORRs of 0.38 (95% CI, 0.23-0.55) and 0.36 (95% CI, 0.19-0.56).

The ORR in the entire cohort of included patients with high-risk cytogenetic abnormalities was 0.63 (95% CI, 0.55-0.72). Among the studies that reported ORRs in patients with high-risk cytogenetic abnormalities, talquetamab elicited the highest ORR, at 0.67 (95% CI, 0.09-0.99). Teclistamab and elranatamab had respective ORRs of 0.61 (95% CI, 0.43-0.76) and 0.55 (95% CI, 0.36-0.73).

The ORR for combination therapy with a bispecific antibody was 0.85 (95% CI, 0.80-0.90). The RedirecTT-1 trial of teclistamab plus talquetamab was the only combination study to report an ORR in patients with extramedullary relapsed/refractory multiple myeloma, which was 0.71 (95% CI, 0.51-0.87).

“We highly recommend highlighting responses [in patients with extramedullary disease] because they can have a more challenging disease to treat. Combination therapies might hold promise for myeloma with extramedullary disease…but we do need further data from prospective trials to evaluate that,” Liu concluded.

Disclosures: Liu reports no financial disclosures.

References

1. Vegivinti CTR, Liu L, Santhi LA, et al. Efficacy of bispecific antibodies in the treatment of relapsed/refractory multiple myeloma with extramedullary disease and high risk cytogenetic abnormalities: a systematic review. Presented at: 2023 International Myeloma Society Annual Meeting; September 27-30, 2023; Athens, Greece. Abstract OA-31.
2. FDA approves teclistimab-cqyv for relapsed or refractory multiple myeloma. News release. FDA. October 25, 2022. Accessed September 28, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-teclistamab-cqyv-relapsed-or-refractory-multiple-myeloma
3. US FDA approves Talvey (talquetamab-tgvs), a first-in-class bispecific therapy for the treatment of patients with heavily pretreated multiple myeloma. News release. Janssen. August 10, 2023. Accessed September 28, 2023. https://www.janssen.com/us-fda-approves-talveytm-talquetamab-tgvs-first-class-bispecific-therapy-treatment-patients-heavily
4. Pfizer’s Elrexfio receives US FDA accelerated approval for relapsed or refractory multiple myeloma. News release. Pfizer. August 14, 2023. Accessed September 28, 2023. https://investors.pfizer.com/Investors/News/news-details/2023/Pfizers-ELREXFIO-Receives-U.S.-FDA-Accelerated-Approval-for-Relapsed-or-Refractory-Multiple-Myeloma/default.aspx