External Beam Radiation Therapy in Combination With Talquetamab for the Treatment of Multiple Myeloma Patients With Extramedullary Disease

PRIMARY OBJECTIVES: I. To evaluate the safety and tolerability of single-field, palliative, extramedullary disease (EMD)-directed external beam radiotherapy (EMD-EBRT) in combination with talquetamab as assessed by incidence of adverse events (AEs) throughout the trial and unexpected toxicities (UTs) during step-up and cycle 1. (Phase 1b) II. To evaluate the systemic anti-tumor activity/preliminary efficacy of EMD-EBRT in combination with talquetamab as assessed by EMD-modified overall response rate (ORR). (Phase 2) SECONDARY OBJECTIVE: I. To additionally evaluate efficacy through International Myeloma Working Group (IMWG) overall response rate (ORR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS). EXPLORATORY OBJECTIVES: I. To assess the impact of EMD-EBRT combined with talquetamab on peripheral blood immune cell populations. II. To assess the spatial transcriptomic changes in the medullary and extramedullary tumor microenvironment in response to EMD-EBRT combined with talquetamab. OUTLINE: STEP-UP PERIOD: Patients undergo EMD-EBRT once daily (QD) for 5 treatment fractions on weekdays (Monday to Friday), and receive talquetamab subcutaneously (SC) starting after the first fraction of EMD-EBRT and continuing every 2-4 days for up to 3 step-up doses in the absence of unacceptable toxicity. SUBSEQUENT TREATMENT: Starting 2-7 days after step-up dose 3, patients receive talquetamab SC on days 1 and 15 of each cycle. Cycles repeat every 28 days for up to a maximum of 13 total cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo computed tomography (CT) and/or positron emission tomography (PET)/CT and collection of blood samples throughout the trial and undergo image-guided EMD biopsy at screening and on study. Patients undergo bone marrow biopsy/aspiration at screening and optionally at end of treatment. After completion of study treatment, patients are followed up every 28 days for up to 12 months.