Incidence and Severity of Hypogammaglobulinemia, and Profile of Infections in Patients with Relapsed Multiple Myeloma Treated with Belantamab Mafodotin

Introduction: Preferential expression of B cell maturation antigen (BCMA) in malignant plasma cells has been recognized as a therapeutic target in multiple myeloma (MM). Disruption of BCMA signalling, however, interferes with development of humoral immunity and immunotherapeutic agents, particularly bispecific T cell engagers, directed against this target may increase risk of hypogammaglobulinemia (HGG) and severe infection, in the range of 45-68% with grade 3+ infections. The BCMA-targeting antibody-drug conjugate, belantamab mafodotin (belamaf) has demonstrated benefit in heavily pre-treated MM patients and reported positive results in the phase 3 DREAMM-7 and DREAMM-8 trials. Elucidation of the infection profile of belamaf will aid in optimal infection prophylaxis. Methods: All MM patients treated with belamaf, either alone or in combination, at Princess Margaret Cancer Centre from 2015 to 2023 were retrospectively reviewed. We collected data on baseline characteristics, prior treatments, disease response, HGG, infections, and prophylaxis use, such as antimicrobials or intravenous immunoglobulin (IVIg). Time-to-event calculations were done through the Kaplan-Meier method. The exact Poisson method was used to calculate incidence rates ratios (IRR). This study was approved by the Princess Margaret REB/IRB. Results: Of the 62 patients that received belamaf, the median age was 61 (range 41-83), 50% were female, and 24% had high risk cytogenetics. The median time from diagnosis to treatment was 5.5 years, and patients had received a median of 4 prior lines of therapy (range 1-10). A median of 2 infections (range 0-8) were identified in the year prior to belamaf treatment. Patients either received belamaf monotherapy (n=28) or in combination with other anti-MM therapies (n=34). The median duration of belamaf treatment was 4.8 months (range 0.7-56), median number of doses was 4.5 (range 1-37), median PFS was 8.8 months, and median OS was 28.7 months. The median time on this study (first dose to either progression, death, or lost to follow up) was 8.6 months (range 0.7 -85.4). Among the 43 (69%) patients that responded to treatment, at least moderate HGG (IgG < 400 mg/dL) was observed in 74% and 53% were within the severe range (IgG<200mg/dL), censoring for IVIg use if HGG criteria were not met (n=5). Six (10%) patients received IVIg at the start of treatment. For patients with a disease response, IVIg use was documented in 16 (37%) patients and they received IVIG 39% of their time in the study. Among those with infections, 37 patients received antimicrobial prophylaxis, including antiviral (n=35), antibacterial (n=21), and antifungal medications (n=1). Throughout the 950 patient-months of follow-up, 136 total infections were observed (1.7 per patient-year). 30 grade 3-4 infections (0.38 per patient-year) were seen in 31% of patients (n=19) and the median time to first grade 3-4 infection was 4.1 months among this group. No grade 5 infections were observed. 61% of infections were viral, 24% bacterial, 5% fungal, and 10% were of unknown origin. Sites of infection included the upper respiratory tract (55%), lower respiratory tract (13%), skin (10%), urinary tract (5%), gastrointestinal (4%), bloodstream (2%), other (11%). A total of 7 opportunistic infections were observed, including 3 Pneumocystis jiroveci pneumonia (PJP), 1 progressive multifocal leukoencephalopathy, 1 Listeria meningitis, 1 Mycobacterium avium complex infection, and 1 EBV viremia. For patients with data since 2020, 10 (24%) had positive tests for SARS-CoV-2, with 3 severe cases. Among the grade 3-4 infections, none had an absolute neutrophil count (ANC) <0.5 x109/L (21% had ANC <1.0 x109/L) and 32% had an absolute lymphocyte count (ALC) <0.5 x109/L (79% ALC <1.0 x109/L), while 13% had moderate HGG and 25% had severe HGG. Discussion: HGG was common with belamaf, with about half of responders experiencing severe HGG. Infection rates for all infections and for grade 3+ infections appear lower than with BCMA-directed bispecifics and importantly there were no deaths due to infections. IVIg use was relatively low, although its optimal use in this population requires further study. Opportunistic infections did occur, warranting prophylaxis for PJP and vigilance for atypical viral, bacterial, and mycobacterial infections. Overall, belamaf appears to have a favorable infection profile compared to other BCMA-targeting modalities.

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