Systemic Review and Meta-Analysis of Safety and Efficacy of Bispecific Antibodies Among Older Adults with Multiple Myeloma

Introduction:

T-cell redirecting bispecific antibodies (BsAb) are transforming the care of patients with relapsed/refractory (RR) multiple myeloma (MM). However, despite being a disease of older adults (OA), these patients remain under-represented in pivotal clinical trials and there are limited data to inform the management of this subgroup. To address this knowledge gap, we performed a systematic review and meta-analysis of clinical trials and real-world studies to describe the safety and efficacy of BsAb in OA (age ≥65 years) with RRMM.

Methods:

A comprehensive literature search was conducted across multiple databases, including Medline, Web of Science (WOS), Scopus, CINAHL, Cochrane Library, Open Dissertations, and ProQuest Dissertations for studies involving BsAb in MM independent of target (data cut-off May 14, 2024). Abstracts from major meetings were included. Additionally, Global Index Medicus and Scielo searches were performed to encompass grey literature. Studies were included if one or more primary outcomes measures were reported for OA. The primary outcome measures included overall response rate (ORR), complete response rate (CRR), the incidence of cytokine release syndrome (CRS), immune cell-effector-associated neurotoxicity syndrome (ICANS) and infections (any grade/grade ≥3). Other outcomes assessed included progression-free survival (PFS), non-relapse mortality (NRM) and overall survival (OS). The quality of the included studies was assessed using the methodological index for non-randomized studies (MINORS) scoring system. Subgroup analyses were performed to explore sources of potential heterogeneity and were based on proportion of patients in the study with revised international staging system (R-ISS) stage 3 disease and Eastern Oncology Cooperative Group (ECOG) performance status (PS) ≥2. A proportional meta-analysis was performed when outcomes from ≥2 studies were available. This study was registered with PROSPERO (# CRD42024541711).

Results:

We identified a cohort of 449 patients, of which 48.9% (n=220) were older adults (OA). After identifying 544 records, 116 studies were selected for full-text review, and four studies were included in the meta-analysis (phase 2 clinical trials, n=2; phase 1 clinical trial, n=1; real-world study, n=1). Notably, one study (Dima et al, 2024) used a cut-off of ≥70 years to define older patients but was kept in the analysis. All studies included B-cell maturation agent targetting BsAb. Three out of 4 studies had a MINORS score of ≥15 (indicating high methodological quality) and one study had a MINORS score of 7.

The pooled ORR among OAs was 64% [95% confidence interval (CI), 57%, 70%), which was comparable to the ORR of 63% (95% CI, 56%, 69%) among younger patients. Data on CRR by age group was not reported in any of the included studies. Subgroup analyses revealed no significant heterogeneity in response based on proportion of patients with R-ISS stage 3 disease. Three studies had ≤20% of patients with R-ISS stage 3 disease with a pooled ORR among OA of 62% (95% CI, 55%, 69%) and in one study, 25% of patients had R-ISS stage 3 disease with an estimated ORR of 71% (95% CI, 53%, 85%), p=0.371.

There was no significant heterogeneity in response among studies stratified by proportion of patients with an ECOG PS ≥2. In two studies, <10% of patients had a reported ECOG PS ≥2, with a pooled ORR among OA of 64% (95% CI, 54%, 73%). In one study, >10% of patients had an ECOG PS ≥2 and another study reported patients by ECOG PS ≥1 with >10% of patients in this category. The pooled ORR among OA in these two studies was 64% (95% CI, 55%, 73%) which was comparable to the former subgroup, p=0.973.

Only one study (MagnetisMM-3) reported incidence of toxicities by age group precluding a meta-analysis. The rate of CRS in this study was 57.5% in OA compared to 58.3% in patients <65 years. Similarly, the rate of ICANS was 6.3% versus 2.3% respectively. No patients had grade ≥3 CRS or ICANS. The rate of infections (any grade/grade ≥3) among OA was 72.1%/37.3% which was comparable to patients <65 years (68.8%/46.3%). No studies reported NRM, PFS or OS by age group.

Conclusion:

OA receiving BsAb experience comparable response rates to younger patients. Reporting on toxicities in this age group is very limited but suggests comparable rates of CRS, ICANS and infections. Studies with longer follow up are needed to assess durability of response and risk for NRM in OA.

Dhakal:Sanofi: Research Funding; Carsgen: Research Funding; Genentech: Consultancy, Honoraria; Bristol Myers Squibb: Honoraria, Research Funding; Janssen: Honoraria, Research Funding, Speakers Bureau; Acrellx: Research Funding; C4 therapeutics: Research Funding; Karyopharm: Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; Medical College of Wisconsin: Current Employment. Pasquini:Bristol Myers Squibb: Consultancy, Research Funding; Novartis: Research Funding; Janssen: Research Funding; Kite, a Gilead Company: Honoraria, Research Funding. D'Souza:Prothena: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kedrion: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Caelum: Research Funding; Abbvie: Research Funding; Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Regeneron: Research Funding; Takeda: Research Funding. Mohan:Janssen: Consultancy; Legend biotech: Consultancy; Pfizer: Consultancy; Sanofi: Consultancy, Research Funding, Speakers Bureau; BMS: Consultancy.