Bispecific Antibodies Are Associated With Progressive Multifocal Leukoencephalopathy

BACKGROUND AND OBJECTIVES: Bispecific antibodies (BisAbs) have transformed the management of relapsed and refractory multiple myeloma (MM), achieving high response rates in heavily pretreated patients. However, these therapies induce profound immune perturbation, including plasma cell aplasia, hypogammaglobulinemia, and T-cell exhaustion, predisposing patients to serious infections. Progressive multifocal leukoencephalopathy (PML) has rarely been reported in this setting. METHODS: We report on 5 patients with MM who developed PML following BisAbs therapy. Clinical presentation, prior treatments, imaging, CSF studies, pathology, and outcomes were reviewed. In addition, T-cell immunophenotyping and antiviral T-cell responses were evaluated. RESULTS: Five patients (median age 63 years; range 60-77; 3 male) developed PML after treatment with elranatamab (1) or teclistamab (4), with (3) or without (1) talquetamab (1). All patients were under BCMA-directed BisAbs treatment at the time of PML diagnosis. Patients had received a median of 5 prior treatment lines (range 2-7) and 4 had undergone autologous stem cell transplantation. All demonstrated significant immune compromise. Median time from BisAbs initiation to PML diagnosis was 12 months (range 6-24; mean 15.4 months). One patient developed PML after only 2 prior therapies. Three of 5 patients had positive PCR for JC virus (JCV) in the CSF, while the other 2 were positive for JCV on brain biopsy. Clinical manifestations included dysarthria, ataxia, cognitive decline, and focal weakness. Although all patients demonstrated significant immune compromise (lymphopenia and hypogammaglobulinemia), 2 of 4 tested, showed specific anti-JCV/BKV T-cell response. DISCUSSION: PML represents a rare but serious, life-threatening complication of BisAbs therapy in MM. Although most patients were heavily pretreated, occurrence after limited prior therapies and the presence of specific anti-JCV T cells in 2 patients suggests BisAbs-related immune modulation may contribute independently to the risk. Duration of exposure may also be relevant. Given emerging therapeutic options such as immune check point inhibitors and anti-JCV-specific T-cell therapies, early recognition is critical. PML should be considered in patients receiving BisAbs therapy who develop new neurologic symptoms, and prompt evaluation is warranted.