Background: High-risk cytogenetic multiple myeloma (HRMM) confers inferior outcomes despite significant therapeutic advances. Real-world data characterizing contemporary treatment patterns across lines of therapy in this population are limited. Methods: We conducted a multicenter retrospective study of 205 patients with HRMM diagnosed between January 2009 and January 2024. High-risk cytogenetics were defined according to the International Myeloma Working Group (IMWG) and Revised International Staging System (R-ISS) criteria as the presence of del(17p), t(4;14), t(14;16), t(14;20), and/or gain/amplification of 1q21. Treatment regimens were categorized by the number of agents (doublet, triplet, quadruplet), mechanism of action (proteasome inhibitor [PI]-based, immunomodulatory drug [IMiD]-based, and anti-CD38 monoclonal antibody-based), and specific regimen composition. Treatment patterns were analyzed across three treatment eras and stratified by age (<70 vs. ≥70 years). Results: The cohort included 205 patients (median age, 62 years [interquartile range [IQR], 54–68 years]; 78.5% aged <70 years). Double-hit and triple-hit cytogenetics were present in 60.0% and 7.3% of patients, respectively. For first-line induction, triplet therapy predominated (81.0%, n = 166), followed by quadruplet (8.8%, n = 18), doublet (5.9%, n = 12), and multi-agent chemotherapy (2.9%, n = 6). By mechanism of action, PI + IMiD combinations were the most common (63.4%, n = 130), followed by PI-based (19.0%, n = 39), anti-CD38-based (10.2%, n = 21), and IMiD-based (2.9%, n = 6) regimens. Era-stratified analysis revealed a significant increase in quadruplet utilization from 3.2% in Era 1 (2009–2015) to 20.3% in Era 3 (2020–2024), with anti-CD38-containing frontline regimens administered to 26.6% of patients in the contemporary era (p < 0.001). Second-line induction was required in 50 patients (24.4%), with anti-CD38-based triplets comprising the most common approach (30.0%). Autologous stem cell transplantation (ASCT) was performed in 75.1% of patients overall, with significantly higher utilization in those aged <70 years (83.9% vs. 43.2%). Maintenance therapy was administered to 71.7% of patients (n = 147), with IMiD-based regimens predominating (53.1%), followed by PI + IMiD combinations (27.9%) and anti-CD38-containing regimens (10.2%). Despite intensive therapy, 69.4% of patients on maintenance experienced disease relapse, with higher rates observed in younger patients (74.8% vs. 41.7%). Conclusions: In this real-world HRMM cohort, the PI + IMiD triplet regimen remained the predominant induction approach, with a significant shift toward quadruplet and anti-CD38-containing regimens in the contemporary era. However, substantial relapse rates during maintenance underscore the continued unmet need in HRMM and support the early integration of novel therapeutic strategies, including quadruplet induction and BCMA-directed agents, in this population.

Introduction: High-risk multiple myeloma (HRMM) is primarily defined by adverse cytogenetic abnormalities that are associated with inferior outcomes despite contemporary treatment with novel induction agents and autologous stem cell transplantation (ASCT). While the accumulation of high-risk lesions has been proposed to further stratify prognosis, the relative impact of single-hit versus double-hit HRMM on post-transplant outcomes in real-world clinical practice remains incompletely characterized. Methods: We conducted a multicenter retrospective cohort study of transplant-eligible adults with HRMM undergoing upfront ASCT between 2009 and 2024 at three U.S. academic centers. Patients were categorized as single-hit HRMM or double-hit HRMM based on the number of high-risk cytogenetic abnormalities at diagnosis. Response rates, progression-free survival (PFS), and overall survival (OS) were compared between groups using standard statistical methods. Results: A total of 154 patients were included, of whom 63 had SH-HRMM, and 91 had DH-HRMM. Following induction therapy, overall response rates (ORR) were high and comparable between groups. After ASCT, ORR was significantly higher in SH-HRMM compared with DH-HRMM (97% vs. 82%, p = 0.006), although depth of response did not differ significantly. With a median follow-up of 150 months, median OS was 103 months in SH-HRMM and 94 months in DH-HRMM (p = 0.40). Median PFS was 36 months and 31 months, respectively (p = 0.20). Restricted mean survival time analyses similarly demonstrated no significant differences in OS or PFS between groups. Although ORR differed, depth of response and long-term survival did not. Conclusions: In this real-world cohort of transplant-treated HRMM, single-hit disease was associated with a higher likelihood of achieving post-ASCT response; however, no significant differences in long-term survival outcomes were observed between single-hit and double-hit HRMM. These findings suggest that cytogenetic hit burden alone may be insufficient to predict post-transplant survival, highlighting the need for refined risk stratification incorporating additional biological and response-based markers.

B-cell maturation antigen (BCMA)-directed therapies (BDTs) have transformed relapsed/refractory multiple myeloma treatment, but optimal post-failure sequencing remains undefined. We evaluated real-world outcomes from three retrospective, multicenter analyses. Study 1 compared BCMA CAR-T and BCMA T-cell engagers (TCEs) in BDT-exposed patients (n = 95). Study 2 evaluated teclistamab in BDT-exposed versus BDT-naïve patients (n = 164). Study 3 examined talquetamab (GPRC5D-targeting TCE) in heavily pretreated patients (n = 68). CAR-T therapy achieved superior outcomes versus TCE (overall response rate [ORR] 79% vs. 51%, p < 0.001; median overall survival [OS] 30 vs. 12 months, p = 0.008). Teclistamab-treated BDT-exposed patients had lower ORR (53% vs. 68%, p = 0.02) and shorter median progression-free survival (PFS; 2.5 vs. 9.7 months, p = 0.01) compared with BDT-naïve patients. Administration < 6 months post-BDT showed inferior outcomes (hazard ratio [HR] 2.5 for PFS; HR 2.9 for OS). Talquetamab achieved an ORR of 68.3% among BDT-exposed patients, with significantly lower response rates when administered < 6 months post-BDT or when BDT was the immediate preceding treatment (56.8% vs. 84.6% and 48% vs. 80.6%, respectively). Treatment-free intervals of ≥6 months between T-cell-redirecting therapies improved efficacy and survival. Post-BDT sequencing should prioritize CAR-T therapy when feasible, allow >6-month intervals before BDT re-challenge, and utilize non-BCMA targets for early relapse or BDT-refractory disease.

Background: Teclistamab plus daratumumab (Tec-Dara) was approved in March 2026 for relapsed or refractory multiple myeloma, but infections are frequent. We hypothesized that dual BCMA- and CD38-directed immune depletion causes infectious toxicity exceeding that expected from either agent alone. Methods: In the FDA Adverse Event Reporting System (FAERS; Q4 2022–Q4 2025; all combination reports pre-approval), we compared reports listing both agents (n = 353) with teclistamab-only (n = 2774) and daratumumab-only (n = 19,230) reports. Interaction was quantified as Ω = ROR_combination/(ROR_teclistamab × ROR_daratumumab), where ROR is the reporting odds ratio, with sensitivity analyses addressing calendar period, sparse counts, comparator, and confounding. Results: Pneumonia (Ω, 1.50; 95% CI, 1.06–2.12) and influenza (Ω, 2.63; 95% CI, 1.20–5.77) were reported more often than expected. The pneumonia estimate increased against a myeloma-restricted background and after covariate adjustment, but was no longer statistically significant after excluding reports co-listing immunomodulatory drugs or proteasome inhibitors or with a relapsed-disease daratumumab comparator. Cytokine release syndrome, neurotoxicity, and cytopenias were reported less often than expected, a reporting pattern rather than protection. A bone marrow failure signal rested on few reports and is hypothesis-generating only. Conclusions: Consistent with our hypothesis, Tec-Dara was associated with higher-than-expected reporting of respiratory infections, although confounding by treatment population cannot be excluded. Any new respiratory symptom or fever warrants same-day evaluation.

Background: Several B-cell maturation antigen (BCMA)-directed therapy (BDT) modalities have been approved by the US Food and Drug Administration (FDA) for relapsed-refractory multiple myeloma (RRMM). Ideal sequencing of these therapies remains unknown. Methods: We report one of the largest multicenter retrospective patient cohorts in this real-world analysis of patients receiving a BDT in both BDT-naïve and exposed settings at major academic centers. Results: In the BDT-naïve setting, which included 276 patients, 169 (61%) received chimeric antigen receptor T-cell therapy (CAR-T), whereas 107 (39%) received bispecific antibodies (BsAbs). Median progression-free survival (PFS) in the BDT-naïve setting was significantly longer with CAR-T than with BsAbs (16.1 vs. 13.5 months, p = 0.007) with a higher overall response rate (ORR) (87 vs. 68%). Multivariable Cox regression analysis revealed that receiving CAR-T (hazard ratio [HR] = 0.41), cytokine release syndrome (CRS) of any grade (HR = 0.50), achieving a best response of ≥very good partial response (VGPR) (HR = 0.12), and high-risk cytogenetic abnormalities (HRCA) (HR = 2.29) were all significant prognostic indicators of PFS. Similarly, HRCA (HR = 2.32), CRS (HR = 0.36), and a best response of ≥VGPR (HR = 0.16) were all independent prognostic factors of overall survival (OS). Of the 80 patients who received prior BDT, 22 received CAR-T (28%) and 58 (72%) received BsAbs. The median PFS was 6.3 months in the CAR-T group, with 64% ORR, vs. 4.4 months in the BsAb group, with 53% ORR (PFS HR, 0.93). Only the best response, ≥VGPR (HR = 0.20), achieved significance in the multivariable model. Conclusions: CAR-T led to more durable responses in the BDT-naïve setting than BsAbs. Responses to either modality were weaker in the BDT-exposed setting. These results highlight the importance of sequencing BDT in RRMM.