IV Immunoglobulin May Cut Infection Risk of Anti-BCMA Agents for Myeloma

Use of intravenous immunoglobulin (IVIg) may substantially reduce the risk for severe infections in multiple myeloma patients treated with an anti-B-cell maturation antigen (BCMA) bispecific antibody, a small retrospective study suggested.

In 26 patients who achieved clinical responses to an anti-BCMA bispecific antibody, all experienced severe hypogammaglobulinemia, but during periods when patients were being treated with IVIg, the rate of grade 3-5 infections was reduced by 90% (incidence rate ratio 0.10, 95% CI 0.01-0.80, P=0.0307), reported researchers led by Guido Lancman, MD, MSc, of the University of Toronto.

These lower “infection rates during periods of immunoglobulin replacement is further evidence of the impact of severely impaired humoral immunity,” the team wrote in Blood Cancer Discovery. “Pending confirmation in other datasets and ideally in randomized prospective studies, these results provide a strong rationale for primary prophylaxis with IVIg or subcutaneous Ig in these patients.”

“To the best of our knowledge,” the authors said, “this is the first study to comprehensively analyze risk factors and mitigation strategies to prevent infections in myeloma patients receiving anti-BCMA bispecific antibodies.”

Results of the study “reinforce the need for vigilance and appropriate counseling of patients about infection risk with these potent immunotherapies,” observed Alfred L. Garfall, MD, and Edward A. Stadtmauer, MD, both of the University of Pennsylvania in Philadelphia, in an accompanying commentary. In particular, they suggested that the results support universal use of immunoglobulin replacement therapy in relapsed/refractory multiple myeloma patients receiving anti-BCMA bispecific antibody therapy.

Such a small study is not usually the basis for clinical practice recommendations, Garfall and Stadtmauer added, but “the results affirm the impressions of clinicians with experience using these agents in clinical trials as reflected in recent consensus statements that recommend universal use of [immunoglobulin replacement therapy] in these patients.”

Bispecific antibodies targeting BCMA have been increasingly used to treat multiple myeloma, with two — elranatamab (Elrexfio) and teclistamab (Tecvayli) — receiving FDA approval in this space.

However, while these therapies have achieved impressive efficacy in patients with heavily pretreated multiple myeloma, and are generally well tolerated, “infection has now emerged as an important toxicity,” Lancman and colleagues observed.

They noted that some previous research suggests that IVIg can be used to successfully reduce infection rates in multiple myeloma patients with hypogammaglobulinemia and non-progressive disease, as well as in multiple myeloma patients receiving the anti-CD38 monoclonal antibody daratumumab (Darzalex).

The retrospective study by Lancman and co-authors included 37 patients with heavily pretreated multiple myeloma who had received an anti-BCMA bispecific antibody. Median age was 66 years and 62% were female. The median time from initial diagnosis to treatment with the bispecific antibody was 7.4 years. Patients had a median of seven prior lines of therapy, about two-thirds had high-risk cytogenetics, 78% were triple-class refractory, and 24% were penta-drug refractory.

The overall response rate to the bispecific antibody was 70%. At a median follow-up time of 18.6 months, the median progression-free survival was 17.0 months and median overall survival was 26.3 months.

Of the 26 patients who responded to anti-BCMA bispecific antibody therapy and developed severe hypogammaglobulinemia (defined as IgG levels below 200 mg/dL), 92% received IVIg at some point during treatment.

There were a total of 118 infections during follow-up. Infections were most frequently reported in the respiratory tract (58%), followed by the urinary tract and skin (15% each). Most of the infections were either viral (46%) or bacterial (43%), with 11% fungal.

Twenty-six of the infections were grade 3-5 (0.7 per patient-year), and occurred in 15 patients. There were two grade 5 infections, which occurred at 15.1 months (COVID-19) and 17.6 months (sepsis).

Infections occurred in the first month in 27% of patients, including 14% with grade 3-5 infections. Six patients (16%) had co-occurrence of infection in the first month and cytokine release syndrome. The estimated median time to first any-grade infection was 3.8 months, and the estimated median time to first grade 3-5 infection was 18.7 months.

Lancman and colleagues acknowledged that the study was limited by its retrospective nature and relatively small size, as well as by the non-random administration of IVIg (delivered at the individual physician’s discretion).

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