Luciano J. Costa

Purpose: Outcomes with bispecific T-cell engagers (TCEs) in relapsed/refractory multiple myeloma (RRMM) are heterogeneous. A practical tool to guide prognosis is needed. We developed a model integrating clinical, biological, and treatment-related variables to predict progression-free survival (PFS) in patients receiving B-cell maturation antigen (BCMA)- or G-protein–coupled receptor class 5 member D-directed TCEs. Methods: We evaluated outcomes of 577 BCMA-directed and 366 talquetamab treatments across 15 US Multiple Myeloma Immunotherapy Consortium centers. Variables significantly associated with inferior PFS in a multivariate Cox model were incorporated into a prognostic score and validated in an independent multicenter International Myeloma Foundation cohort. Results: With a median follow-up of 8.4 months, the median PFS was 6.4 months (7.0 months for BCMA TCE; 6.1 months for talquetamab); 92% of patients were triple-class-refractory. Six variables significantly associated with inferior PFS—high-risk cytogenetic abnormalities (HRCAs) [del(17p) or ≥2 HRCAs], hyperferritinemia (≥600 ng/mL), anemia (hemoglobin CHARGE index, stratifying patients into three risk groups. The median PFS was 21.8 months (95% CI, 11.7 to not reached), 7.1 months (95% CI, 6.1 to 10.1), and 1.6 months (95% CI, 1.2 to 2.5) in the low-, intermediate-, and high-risk groups, respectively; hazard ratios (HRs) were 2.0 (95% CI, 1.5 to 2.7) and 4.8 (95% CI, 3.5 to 6.7) for intermediate- and high-risk versus low-risk groups. External validation (n = 173) showed that the median PFS was not reached, 7.0 months, and 3.0 months, with corresponding HRs of 2.9 (95% CI, 1.7 to 4.9) and 4.8 (95% CI, 2.6 to 8.7). Conclusion: The CHARGE index provides a simplified and externally validated framework for predicting treatment outcomes in patients with RRMM receiving TCEs.

Summary: Anti‐cluster of differentiation 38 (Anti‐CD38) monoclonal antibodies such as daratumumab are widely used in multiple myeloma (MM), yet the timing and magnitude of infectious risk remain incompletely defined. We performed an individual patient‐level meta‐analysis of six randomized trials ( N = 2989) comparing daratumumab‐ versus non‐daratumumab–containing regimens in newly diagnosed and relapsed/refractory MM, assessing infectious events over 2 years. Daratumumab‐treated patients had higher rates of any‐grade (79% vs. 61%) and grade ≥3 infections (29% vs. 20%) than controls, with risk peaking in the first 3 months (42% vs. 36%, p = 0.001) before plateauing. After adjustment, daratumumab was independently associated with grade ≥1 (odds ratio [OR] 1.31, 95% confidence interval [CI] 1.10–1.57), respiratory (OR 1.38, 95% CI 1.11–1.71) and grade ≥3 (OR 1.47, 95% CI 1.08–2.00) infection by 3 months. Daratumumab‐treated patients had a higher rate of infection over 2 years (adjusted incidence rate ratio 1.60, 95% CI 1.47–1.73) and more frequently experienced recurrent infections (33% vs. 22% with multiple any‐grade infections; 11% vs. 7% with multiple grade ≥3 infections). Preventive strategies were underused, with <20% of patients with severe respiratory infections receiving immunoglobulin replacement. These findings identify an early window of infectious vulnerability with daratumumab and support temporally targeted prevention and monitoring strategies in contemporary MM care.

Solitary plasmacytomas (SPs) are rare localized tumors of clonal plasma cells, either in the bone (solitary bone plasmacytoma) or in soft tissue/extraosseous (extramedullary) with either no or with minimal bone marrow (BM) infiltration (<10% clonal plasma cells by immunohistochemistry) and no evidence of systemic involvement or myeloma defining events. Approximately 50% of SPs will progress to symptomatic myeloma within 5 years after initial definitive local radiotherapy. Increased availability of improved diagnostic and monitoring tools has increased the sensitivity of detection of additional lesions and marrow involvement and has implications for the follow-up strategy after treatment. Thus, the definitions and requirements for the diagnosis and follow-up of SPs are evolving. The diagnosis of SP requires the careful exclusion of multiple myeloma (MM) that would require systemic therapy, by using all the available methods to detect systemic disease (advanced imaging, sensitive BM assessment methods, blood and urine tests). Local radiotherapy remains the mainstay of therapy, and despite the availability of innovative drugs for MM, the clinical benefit of systemic therapy currently remains poorly defined. The International Myeloma Working Group provides here updated recommendations for the diagnosis, evaluation, treatment, and response assessment of patients with SPs, incorporating recent data and advances in diagnostic tools.

Fc receptor-homolog 5 (FcRH5) is a membrane protein that is ubiquitously expressed on myeloma cells. Cevostamab is a first-in-class, FcRH5×CD3 bispecific antibody. GO39775 is a phase 1 dose-escalation and dose-expansion study evaluating fixed-duration cevostamab in relapsed or refractory multiple myeloma. Cevostamab was initiated with step-up dosing and continued at the target dose (TD) once every 3 weeks for 17 cycles (~12 months) unless disease progression or unacceptable toxicity occurred. Primary objectives were to evaluate safety, including determination of the maximum tolerated dose (MTD), and to identify a recommended phase 2 dose and schedule (RP2D) for cevostamab monotherapy. Secondary objectives included determining the rate of response and the duration of response (DOR). As of 24 February 2025, 324 patients had been enrolled; most were heavily pretreated (median prior lines, 6; triple-class refractory, 89.5% (290/324); prior B-cell maturation antigen (BCMA)-targeted therapy, 47.5% (154/324)). The MTD was not reached. Across all TD levels (0.15–252 mg), grade 3 or 4 adverse events (AEs) and serious AEs occurred in 59.6% (193/324) and 60.2% (195/324), respectively. Grade 5 AEs excluding disease progression occurred in 4.6% (15/324); 0.9% (3/324) were considered treatment related (hemophagocytic lymphohistiocytosis, n = 2; disseminated intravascular coagulation in the context of pseudomonal sepsis, n = 1). Objective response and very good partial response or better rates were 42.1% (136/323) and 25.1% (81/323), respectively. Median DOR was 11.2 months (95% confidence interval, 8.3, 15.6). A total of 167 patients received treatment at the 160 mg TD level (RP2D). Objective response and very good partial response or better rates were 44.3% (74/167) and 25.7% (43/167) in all patients and 60.6% (43/71) and 39.4% (28/71) in the BCMA naive, respectively. Median DOR was 10.4 months in all patients and 19.7 months in the BCMA naive, with durable responses maintained after the completion of treatment. Cytokine release syndrome was grade 1 or 2 in the 0.3/1.2/3.6/160 mg triple step-up cohort (RP2D). Cevostamab had manageable safety and induced durable remissions in late-line relapsed or refractory multiple myeloma. ClinicalTrials.gov registration: NCT03275103.