Key Studies Shaping Hematology, Community Oncology at ASH 2025
January 11, 2026
The 2025 ASH Annual Meeting (ASH 2025) delivered transformative data in multiple myeloma (MM). Below are four pivotal studies presented at the conference that may help redefine treatment paradigms across the disease continuum.
COBRA: KRd Challenges VRd as Frontline in Newly Diagnosed MM
The phase 3 COBRA trial (NCT03729804) directly compared carfilzomib, lenalidomide, and dexamethasone (KRd) with the longstanding standard of care, bortezomib, lenalidomide, and dexamethasone (VRd), in patients with newly diagnosed multiple myeloma (NDMM). Patients with NDMM were randomized 1:1 to receive either KRd or VRd, regardless of transplant eligibility or cytogenetic risk status. Following induction, both arms received lenalidomide maintenance at 15 mg until disease progression or treatment intolerance. The coprimary end points of the study were minimal residual disease (MRD)-negative complete response at 12 months and progression-free survival (PFS).
A total of 250 patients were randomized. Baseline characteristics were well balanced between the KRd and VRd arms, including median age (66 vs 67 years), International Staging System stage (26% vs 22%), ECOG performance status of 1 or 2 (75% vs 75%), and the presence of high-risk cytogenetic abnormalities (defined as presence of del(17p), t(4;14), or t(14;16) [23% vs 23%]). After a median follow-up of 35 months, PFS was significantly longer with KRd compared with VRd (HR, 0.57). A higher percentage of patients achieved a complete response (CR) in the KRd arm compared with the VRd arm (71% vs 53%), along with higher overall response rates (ORR), 2.11, at the time of data cutoff.
However, an important consideration is that treatment duration differed between arms. Patients in the VRd arm received eight 21-day cycles followed by 18 cycles of lenalidomide and dexamethasone on a 28-day schedule, whereas patients in the KRd arm received 24 cycles on a 28-day schedule. In contrast, the ENDURANCE study, presented at the 2025 ASCO Annual Meeting, compared KRd versus VRd with similar treatment durations and showed comparable PFS and overall survival (OS) between the regimen.s
MajesTEC-3: Teclistamab + Daratumumab Redefines Early Relapse Treatment
In the phase 3 MajesTEC-3 trial (NCT05083169), investigators evaluated teclistamab, a BCMAxCD3 bispecific antibody, in combination with subcutaneous daratumumab versus the investigator’s choice of daratumumab-based triplets (daratumumab-pomalidomide-dexamethasone or daratumumab-bortezomib-dexamethasone) in relapsed/refractory MM (RRMM) and 1 to 3 prior lines of therapy.
Patients (n=587) were randomized 1:1, with PFS as the primary end point. With nearly 3 years of follow-up, the combination delivered significant improvements in PFS compared with control (83.4% vs 29.7%, respectively). OS also significantly improved with the combination therapy (HR, 0.46), along with high rates of MRD negativity. Rates of grade 3 or 4 treatment-emergent adverse events (95.1% vs 96.6%) and grade 5 events (7.8% vs 6.2%) were comparable between arms. Infections were manageable with established antimicrobial and immunoglobulin prophylaxis protocols.
This all-antibody regimen outperformed standard care, marking a potential new benchmark for second-line therapy. Importantly, patients eceiving teclistamab plus daratumumab require close monitoring, routine monthly intravenous immunoglobulin administration, and comprehensive infection prevention measures as outlined in the trial protocol.
AQUILA: Daratumumab Monotherapy in High-Risk Smoldering MM
The phase 3 AQUILA trial (NCT03301220) randomized patients with high-risk smoldering multiple myeloma (SMM) to receive subcutaneous daratumumab (n=194) as monotherapy for up to 39 cycles or to active monitoring (n=196). With a median follow-up of 65.2 months, daratumumab significantly reduced the risk of progression to active MM or death by 51% (HR 0.49). PFS at 5 years was 63.1% in the daratumumab group and 40.8% in the active monitoring group. OS also favored daratumumab, and the safety profile was favorable, with no new signals beyond known risks. The study results led to the FDA and EMA approval of daratumumab for high-risk SMM. In community practice, these data support a risk-adapted approach to early intervention, with ongoing studies evaluating the best management strategies for this patient population.
RedirecTT-1: Dual Bispecific Targeting in Heavily Pretreated MM
In the phase 2 RedirecTT-1 (NCT04586426) trial, talquetamab (anti-GPRC5DxCD3) plus teclistamab was assessed in heavily pretreated RRMM, with a dedicated cohort for extramedullary disease (EMD).
The combination achieved an ORR rate of about 79%, with CR or better observed in roughly 53% of patients. Responses were durable, including in patients with EMD, a subgroup historically associated with poor outcomes. Among individuals with a response, 64% maintained a response for at least 12 months. Grade 3 or 4 adverse events—most common hematologic—occurred in 76% of patients, with high-grade infection occurring in 31%.
This dual-targeting, chemotherapy-free approach offers a salvage option for triple-class–exposed patients, including those with EMD. However, the safety profile demands careful consideration, and the data support the need for vigilant supportive care.
Looking Ahead: Multiple Myeloma
ASH 2025 highlighted rapid progress in MM, from frontline optimization and early intervention to immunotherapy combinations. These advances help provide better access, tolerability, and survival for patients. For community oncologists, these data introduce exciting new tools to extend survival and improve quality of life, while emphasizing the importance of careful patient selection, toxicity management, and supportive care. As these regimens move into practice, they signal another step forward in building a brighter future for patients living with MM.