Lenalidomide, bortezomib, and dexamethasone (RVd) followed by autologous stem cell transplantation (ASCT) is standard frontline therapy for transplant-eligible patients with newly diagnosed multiple myeloma (NDMM). The addition of daratumumab (D) to RVd (D-RVd) in transplant-eligible NDMM patients was evaluated. Patients (N = 207) were randomized 1:1 to D-RVd or RVd induction (4 cycles), ASCT, D-RVd or RVd consolidation (2 cycles), and lenalidomide or lenalidomide plus D maintenance (26 cycles). The primary end point, stringent complete response (sCR) rate by the end of post-ASCT consolidation, favored D-RVd vs RVd (42.4% vs 32.0%; odds ratio, 1.57; 95% confidence interval, 0.87-2.82; 1-sided P = .068) and met the prespecified 1-sided α of 0.10. With longer follow-up (median, 22.1 months), responses deepened; sCR rates improved for D-RVd vs RVd (62.6% vs 45.4%; P = .0177), as did minimal residual disease (MRD) negativity (10−5 threshold) rates in the intent-to-treat population (51.0% vs 20.4%; P < .0001). Four patients (3.8%) in the D-RVd group and 7 patients (6.8%) in the RVd group progressed; respective 24-month progression-free survival rates were 95.8% and 89.8%. Grade 3/4 hematologic adverse events were more common with D-RVd. More infections occurred with D-RVd, but grade 3/4 infection rates were similar. Median CD34+ cell yield was 8.2 × 106/kg for D-RVd and 9.4 × 106/kg for RVd, although plerixafor use was more common with D-RVd. Median times to neutrophil and platelet engraftment were comparable. Daratumumab with RVd induction and consolidation improved depth of response in patients with transplant-eligible NDMM, with no new safety concerns. This trial was registered at www.clinicaltrials.gov as #NCT02874742.

Great hope for the future: CAR T-cell and bispecific antibody therapies in multiple myeloma.

For eligible patients with newly diagnosed multiple myeloma (NDMM), standard of care includes induction therapy followed by autologous stem cell transplantation (ASCT). Daratumumab as monotherapy and in combination treatment is approved across multiple lines of therapy for multiple myeloma (MM), and lenalidomide is an effective and commonly used agent for induction and maintenance therapy in MM. However, there is concern that lenalidomide and daratumumab given as induction therapy might impair mobilization of stem cells for ASCT. Therefore, we assessed stem cell mobilization in patients following frontline induction therapy in the MASTER and GRIFFIN phase 2 clinical studies by examining stem cell mobilization yields, apheresis attempts, and engraftment outcomes for patients from each study. Adult transplantation-eligible patients with NDMM received induction therapy consisting of daratumumab plus carfilzomib/lenalidomide/dexamethasone (D-KRd) for four 28-day cycles in the single-arm MASTER trial or lenalidomide/bortezomib/dexamethasone (RVd) with or without daratumumab (D) for four 21-day cycles in the randomized GRIFFIN trial, followed by stem cell mobilization and ASCT in both studies. Institutional practice differed regarding plerixafor use for stem cell mobilization; the strategies were upfront (ie, planned plerixafor use) or rescue (ie, plerixafor use only after mobilization parameters indicated failure with granulocyte colony-stimulating factor [G-CSF] alone). Descriptive analyses were used to summarize patient characteristics, stem cell mobilization yields, and engraftment outcomes. In MASTER, 116 D-KRd recipients underwent stem cell mobilization and collection at a median of 24 days after completing induction therapy. In GRIFFIN, 175 patients (D-RVd, n = 95; RVd, n = 80) underwent mobilization at a median of 27 days after completing D-RVd induction therapy and 24 days after completing RVd induction therapy. Among those who underwent mobilization and collection, 7% (8 of 116) of D-KRd recipients, 2% (2 of 95) of D-RVd recipients, and 6% (5 of 80) of RVd recipients did not meet the center-specific minimally required CD34⁺ cell yield in the first mobilization attempt; however, nearly all collected sufficient stem cells for ASCT on remobilization. Among patients who underwent mobilization, plerixafor use, either upfront or as a rescue strategy, was higher in patients receiving D-KRd (97%; 112 of 116) and D-RVd (72%; 68 of 95) compared with those receiving RVd (55%; 44 of 80). The median total CD34⁺ cell collection was 6.0 × 10⁶/kg (range, 2.2 to 13.9 × 10⁶/kg) after D-KRd induction, 8.3 × 10⁶/kg (range, 2.6 to 33.0 × 10⁶/kg) after D-RVd induction, and 9.4 × 10⁶/kg (range, 4.1 to 28.7 × 10⁶/kg) after RVd induction; the median days for collection were 2, 2, and 1, respectively. Among patients who underwent mobilization, 98% (114 of 116) of D-KRd patients, 99% (94 of 95) of D-RVd patients, and 98% (78 of 80) of RVd patients underwent ASCT using median CD34⁺ cell doses of 3.2 × 10⁶/kg, 4.2 × 10⁶/kg, and 4.8 × 10⁶/kg, respectively. The median time to neutrophil recovery was 12 days in all 3 treatment groups across the 2 trials. Because both trials used different criteria to define platelet recovery, data on platelet engraftment using the same criteria are not available. Four cycles of daratumumab- and lenalidomide-based quadruplet induction therapy had a minimal impact on stem cell mobilization and allowed predictable stem cell harvesting and engraftment in all patients who underwent ASCT. Upfront plerixafor strategy may be considered, but many patients were successfully collected with the use of G-CSF alone or rescue plerixafor.

Chimeric antigen receptor T (CAR T) cell therapies have emerged as a valuable treatment modality for patients with plasma cell disorders. As the population of patients receiving CAR T therapies grows, identification and management of associated rare toxicities have become increasingly crucial. To identify safety signals associated with commercial anti-B-cell maturation antigen (BCMA) CAR T therapies using the Food and Drug Administration Adverse Event Reporting System (FAERS). This is a cross-sectional analysis of the adverse events (AE) reports associated with ciltacabtagene autoleucel (cilta-cel) and idecabtagene vicleucel (ide-cel), submitted to FAERS between January 2021 and December 2023. AE frequencies were summarized using descriptive statistics, and safety signals were explored by measuring the reporting odds ratio (ROR) compared to control groups. Among 4,472,782 unique FAERS reports, 1,496 involved BCMA-directed CAR-T therapies. AEs reported more frequently included immune associated conditions and neurological disorders. Neurotoxicity associated with cilta-cel predominantly manifested as cranial nerve palsies, parkinsonism, acute and chronic polyneuropathies, while ide-cel neurotoxicity presented as confusion, disorientation, seizures, balance disturbances, and tremors. In cilta-cel reports, other safety signals included Guillain-Barre syndrome (ROR: 17.1, 95% CI 6.1 -47.5), intracranial hemorrhage and cerebrovascular accidents (ROR: 2.9, 95% CI 1.8 -4.8), haemophilus infections (ROR: 34.2, 95% CI 11.8-98.9) and cytomegalovirus infections (ROR: 3.9, 95% CI 1.6 -9.5). For ide-cel, new signals included parkinsonism (ROR: 13.7, 95% CI 5.5-34.5), acute and chronic sarcoidosis (ROR: 197.1, 95% CI 32.9 -1180.1), ventricular arrhythmias, and cardiac arrest (ROR: 3.9, 95% CI 2.1-7.3). This data provides a comprehensive insight into the safety profiles of the commercial BCMA-directed CAR T therapies, underscoring the importance of vigilant post-marketing surveillance to mitigate potential risks.