Infectious complications of bispecific antibody therapy in patients with multiple myeloma

Sim, Beatrice; Longhitano, Anthony; Er, Jeremy; Harrison, Simon J.; Slavin, Monica; Teh, Benjamin W

doi:10.1038/s41408-023-00808-8

Cited by 27 publications

(10 citation statements)

References 14 publications

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“…BCMA-targeted T-cell-redirecting therapies have been linked to a heightened susceptibility to infectious complications due to their mechanism of action 30 – 33 . Inhibiting BCMA signaling, which is critical for the survival and proliferation of plasma cells, may worsen the pre-existing myeloma-induced immunosupression 31 , 32 , 34 .…”

Section: Discussionmentioning

confidence: 99%

Elranatamab in relapsed or refractory multiple myeloma: phase 2 MagnetisMM-3 trial results

Lesokhin

Tomasson

Arnulf

et al. 2023

Nat Med

193

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Elranatamab is a humanized B-cell maturation antigen (BCMA)-CD3 bispecific antibody. In the ongoing phase 2 MagnetisMM-3 trial, patients with relapsed or refractory multiple myeloma received subcutaneous elranatamab once weekly after two step-up priming doses. After six cycles, persistent responders switched to biweekly dosing. Results from cohort A, which enrolled patients without prior BCMA-directed therapy (n = 123) are reported. The primary endpoint of confirmed objective response rate (ORR) by blinded independent central review was met with an ORR of 61.0% (75/123); 35.0% ≥complete response. Fifty responders switched to biweekly dosing, and 40 (80.0%) improved or maintained their response for ≥6 months. With a median follow-up of 14.7 months, median duration of response, progression-free survival and overall survival (secondary endpoints) have not been reached. Fifteen-month rates were 71.5%, 50.9% and 56.7%, respectively. Common adverse events (any grade; grade 3–4) included infections (69.9%, 39.8%), cytokine release syndrome (57.7%, 0%), anemia (48.8%, 37.4%), and neutropenia (48.8%, 48.8%). With biweekly dosing, grade 3–4 adverse events decreased from 58.6% to 46.6%. Elranatamab induced deep and durable responses with a manageable safety profile. Switching to biweekly dosing may improve long-term safety without compromising efficacy. ClinicalTrials.gov identifier: NCT04649359.

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Section: Discussionmentioning

confidence: 99%

Elranatamab in relapsed or refractory multiple myeloma: phase 2 MagnetisMM-3 trial results

Lesokhin

Tomasson

Arnulf

et al. 2023

Nat Med

193

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“…Infections have been reported with the use of T-cell-redirecting bispecific antibodies; however, infections were reported less frequently in trials of GPRC5D-targeting T-cell-redirecting bispecific antibodies compared with trials of BCMA-and Fc receptor-like protein 5-targeting bispecific antibodies [58][59][60][61], which may be due to the more limited expression profile of GPRC5D in the immune compartment compared with the expression profiles of these other target antigens [20,21,[25][26][27]. Additionally, the lower expression of GPRC5D on normal plasma cells compared with malignant plasma cells may preserve normal plasma cells during treatment [21,59].…”

Section: Bms-986393mentioning

confidence: 99%

GPRC5D as a novel target for the treatment of multiple myeloma: a narrative review

Rodriguez-Otero,

van de Donk,

Pillarisetti

et al. 2024

Blood Cancer J.

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Multiple myeloma is a genetically complex and heterogenous malignancy with a 5-year survival rate of approximately 60%. Despite advances in therapy, patients experience cycles of remission and relapse, with each successive line of therapy associated with poorer outcomes; therefore, therapies with different mechanisms of action against new myeloma antigens are needed. G protein–coupled receptor class C group 5 member D (GPRC5D) has emerged as a novel therapeutic target for the treatment of multiple myeloma. We review the biology and target validation of GPRC5D, and clinical data from early phase trials of GPRC5D-targeting bispecific antibodies, talquetamab and forimtamig, and chimeric antigen receptor T cell (CAR-T) therapies, MCARH109, OriCAR-017, and BMS-986393. In addition to adverse events (AEs) associated with T-cell–redirection therapies irrespective of target, a consistent pattern of dermatologic and oral AEs has been reported across several trials of GPRC5D-targeting bispecific antibodies, as well as rare cerebellar events with CAR-T therapy. Additional studies are needed to understand the underlying mechanisms involved in the development of skin- and oral-related toxicities. We review the strategies that have been used to manage these GPRC5D-related toxicities. Preliminary efficacy data showed overall response rates for GPRC5D-targeting T-cell–redirecting therapies were ≥64%; most responders achieved a very good partial response or better. Pharmacokinetics/pharmacodynamics showed that these therapies led to cytokine release and T-cell activation. In conclusion, results from early phase trials of GPRC5D-targeting T-cell–redirecting agents have shown promising efficacy and manageable safety profiles, including lower infection rates compared with B-cell maturation antigen- and Fc receptor-like protein 5-targeting bispecific antibodies. Further clinical trials, including those investigating GPRC5D-targeting T-cell–redirecting agents in combination with other anti-myeloma therapies and with different treatment modalities, may help to elucidate the future optimal treatment regimen and sequence for patients with multiple myeloma and improve survival outcomes.

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“…The 4 observational studies (141 patients) provided further infection regarding causative pathogen, infection onset, and outcomes ( supplemental Table 4 ). 22 , 23 , 24 , 25 Of the 293 infection events reported in observational studies, 68% were microbiologically-confirmed, including viral (49%), bacterial (45%), and fungal (6%). When reported, gram-negative pathogens were the predominant cause of bacterial infections (64%).…”

Section: Resultsmentioning

confidence: 99%

Infections following bispecific antibodies in myeloma: a systematic review and meta-analysis

Reynolds,

Cliff,

Mohyuddin

et al. 2023

Blood Advances

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Bispecific antibodies, a novel immunotherapy with promising efficacy against multiple myeloma, form immune synapses between T-cell surface marker CD3 and malignant cell markers, including B-cell maturation antigen (BCMA), FcRH5, and G protein–coupled receptor GPRC5D. These bispecific antibodies so effectively deplete plasma cells (and to some extent T-cells) that patients are at increased risk of developing infections. A systematic review and meta-analysis of infections in published studies of patients with myeloma treated with bispecific antibodies was conducted to better characterize the infection risks. A literature search used MEDLINE, EMBASE, and Cochrane to identify relevant studies between inception and February 10, 2023, including major conference presentations. Phase 1b-3 clinical trials and observational studies were included. Sixteen clinical trials comprising 1666 patients were included. Median follow-up was 7.6 months and 38% of the cohort had penta-drug refractory disease. Pooled prevalence of all-grade infections was 56%, whereas the prevalence of grade ≥3 infections was 24%. Patients who were treated with BCMA-targeted bispecifics had significantly higher rates of grade ≥3 infections than non-BCMA bispecifics (25% vs 20%). Similarly, patients treated with bispecifics in combination with other agents had significantly higher rate of all-grade infection than those receiving monotherapy (71% vs 52%). In observational studies (n = 293), excluded from the primary analysis to ensure no overlap with patients in clinical trials, several infections classically associated with T-cell depletion were identified. This systematic review identifies BCMA-targeted bispecifics and bispecific combination therapy as having higher infection risk, requiring vigilant infection screening and prophylaxis strategies.

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Infectious complications of bispecific antibody therapy in patients with multiple myeloma

Abstract: Rhinovirus/enterovirus (n = 8), influenza (n = 1), adenovirus (n = 4), COVID-19 (n = 2). 4 BK virus (n = 1), cytomegalovirus (n = 4), herpes simplex virus 2 (n = 1), Epstein Barr virus (n = 1). 5Mycobacterium avium complex (n = 1). 6 Deaths attributed to preceding infection within 30 days.

Cited by 27 publications

References 14 publications

Elranatamab in relapsed or refractory multiple myeloma: phase 2 MagnetisMM-3 trial results

Elranatamab in relapsed or refractory multiple myeloma: phase 2 MagnetisMM-3 trial results

GPRC5D as a novel target for the treatment of multiple myeloma: a narrative review

Infections following bispecific antibodies in myeloma: a systematic review and meta-analysis

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