“Dripping water hollows out stone, not through force but through persistence.” – Ovid
The 2025 American Society of Hematology (ASH) Annual Meeting & Exposition delivered multiple practice-changing datasets surrounding T-cell–redirecting therapies in relapsed or refractory multiple myeloma.
Three abstracts were especially notable: the phase III MajesTEC-3 trial (LBA-6)1, which paired teclistamab-cqyv with daratumumab and reported striking long-term progression-free and overall survival in relapsed or refractory multiple myeloma treated with one to three prior lines of therapy; the phase II RedirecTT-1 study (Abstract 698)2, which tested dual bispecific targeting (GPRC5D and BCMA) in true extramedullary disease; and early results from inMMyCAR (LBA-1)3, which used an intravenously delivered gene therapy (KLN-1010) to generate anti-BCMA chimeric antigen receptor (CAR) T cells in vivo without leukapheresis or lymphodepleting chemotherapy.
For full details of the study abstracts, visit www.hematology.org/meetings/annual-meeting/abstracts.
LBA-6 (MajesTEC-3): Teclistamab Plus Subcutaneous Daratumumab vs Standard Daratumumab Triplets
Background: Daratumumab-based triplets such as daratumumab plus pomalidomide and lenalidomide (DPd) and daratumumab plus bortezomib and lenalidomide (DVd) are commonly used in patients with relapsed or refractory multiple myeloma after one to three prior lines of therapy, but outcomes remain limited, particularly in those previously exposed to proteasome inhibitors and immunomodulatory drugs. Teclistamab, a BCMA × CD3 bispecific antibody, has shown deep and durable responses in later-line disease. In October 2022, teclistamab was granted accelerated approval by the U.S. Food and Drug Administration, based on the results of MajesTEC-1 trial; patients with relapsed or refractory multiple myeloma who received at least three prior lines of therapy and were treated with teclistamab had an overall response rate of 63.0%,4,5 and 46.1% achieved a complete response or better.4 Long-term follow-up from MajesTEC-1 (median follow-up = 30.4 months) showed a median duration of response of 24 months overall, with a 30-month duration of response rate of 60.8% in patients achieving a complete response (median = not reached).4 MajesTEC-3 (ClinicalTrials.gov Identifier: NCT05083169) is a phase III trial evaluating teclistamab plus subcutaneous daratumumab earlier in the disease course.1,6,7
Methods: MajesTEC-3 is an ongoing randomized phase III trial in relapsed or refractory multiple myeloma after one to three prior lines of therapy (including prior lenalidomide and a proteasome inhibitor). Patients with prior BCMA-directed therapy or anti-CD38 antibody refractory disease were excluded. Participants were randomly assigned to receive teclistamab plus subcutaneous daratumumab (n = 291) or investigator’s choice of DPd or DVd (n = 296). Approximately 5% of patients had prior daratumumab exposure, balanced across arms.
Syed A. Abutalib, MD
After step-up dosing, teclistamab was administered at 1.5 mg/kg weekly in the first and second cycles, then 3 mg/kg every 2 weeks in the third through sixth cycles, and every 4 weeks from the seventh cycle and onward. Subcutaneous daratumumab was given weekly in the first and second cycles, every 14 days in the third through sixth cycles, and every 4 weeks from the seventh cycle and onward. The primary endpoint was progression-free survival by independent review; key secondary endpoints included overall survival, overall response rate, complete response rate, measurable residual disease (MRD) negativity, patient-reported outcomes, and safety.
Efficacy Results: With extended follow-up (median = 34.5 months), teclistamab plus daratumumab produced a marked reduction in the risk of disease progression or death (36-month progression-free survival: 83.4% vs 29.7%; hazard ratio [HR] = 0.17, 95% confidence interval [CI] = 0.12–0.23; P < .0001). Of note, 90% of patients who were progression-free at 6 months remained progression-free at 3 years. Overall survival also favored teclistamab plus daratumumab (36-month: 83.3% vs 65.0%; HR = 0.46, 95% CI = 0.32–0.65; P < .0001). Responses were both more frequent and deeper: the overall response rate was 89.0% vs 75.3% in the control group (odds ratio [OR] = 2.65; P < .0001), and the complete response or better rates were 81.8% vs 32.1% (OR = 9.56, 95% CI = 6.46–14.14; P < .0001). Among evaluable patients, MRD-negative complete response at 10–5 sensitivity was 57.6% with teclistamab plus daratumumab vs 17.1% with DPd or DVd (OR = 6.78; P < .0001).
Safety Results: Cytokine release syndrome was reported in 60.1% of patients treated with teclistamab plus daratumumab and was predominantly grade 1 (44.2%) or grade 2 (15.9%); no grade 2 cytokine release syndrome occurred after the first cycle, and discontinuations because of cytokine release syndrome were rare. Immune effector cell–associated neurotoxicity syndrome was uncommon (1.1%).
As expected with BCMA-directed T-cell–engaging therapy, infections and hypogammaglobulinemia were common. Any-grade infections were observed in 96.5% of patients treated with teclistamab plus daratumumab vs 84.1% of those who received the control. Thirteen patients (4.6%) treated with teclistamab plus daratumumab died from infection; of these deaths, 12 occurred within 6 months of treatment, including 3 due to COVID-19, and 9 of the 12 had not received immunoglobulin replacement therapy. After a protocol amendment reinforcing immunoglobulin replacement therapy was made, only one infection-related death occurred. Overall, 87.3% of the patients treated with teclistamab plus daratumumab received at least one dose of intravenous immunoglobulin.
Clinical Implications: MajesTEC-3 is the first phase III randomized study to pair a bispecific regimen with concurrent improvements in progression-free survival, overall survival, response depth, and MRD negativity in relapsed or refractory multiple myeloma treated with one to three prior lines of therapy. The unprecedented efficacy results support teclistamab plus daratumumab as a potential new standard of care for appropriately selected patients with one to three prior lines of therapy who are not refractory to anti-CD38 monoclonal antibodies. Broad adoption will hinge on standardized infection prevention pathways (eg, early intravenous immunoglobulin/immunoglobulin replacement therapy, vaccination strategy, and antimicrobial prophylaxis) and on defining sequencing vs BCMA-directed CAR T-cell therapy.
698 (RedirecTT-1): Talquetamab-tgvs Plus Teclistamab in Relapsed or Refractory Multiple Myeloma With Centrally Confirmed True Extramedullary Disease
Background: True extramedullary disease—defined as bone-independent soft-tissue or organ plasmacytomas—remains among the highest-risk manifestations of myeloma and is associated with heterogeneous antigen expression and immune microenvironment features, as well as inferior response rates and survival compared with patients without true extramedullary disease.8,9 Extramedullary disease lesions can be biologically heterogeneous, including variable expression of BCMA and GPRC5D, raising the possibility that dual antigen targeting could mitigate antigen escape.10,11 RedirecTT-1 (ClinicalTrials.gov Identifier: NCT04586426) tested dual antigen targeting with talquetamab (GPRC5D × CD3) plus teclistamab in this high-risk population.2,12,13
Methods: Eligible patients had triple-class–exposed relapsed or refractory multiple myeloma with centrally confirmed true extramedullary disease (n = 90)—defined as at least one nonirradiated, bone-independent soft-tissue plasmacytoma measuring at least 2 cm in greatest dimension, confirmed by central PET/CT review. Nonsecretory and oligosecretory myeloma were allowed. Prior anti-BCMA CAR T-cell therapy and non-BCMA/non-GPRC5D bispecific therapy were permitted; the median time from CAR T-cell therapy to study treatment was 295 days (range: 98–1,030 days).
Talquetamab and teclistamab were administered subcutaneously on the same day (30 ± 10 minutes apart) with three step-up doses given 2 to 4 days apart, followed by full doses of 0.8 mg/kg of talquetamab every 2 weeks and 3.0 mg/kg of teclistamab every 2 weeks. Patients were permitted to transition to monthly dosing after four cycles if they achieved a very good partial response or better, or after six cycles irrespective of response.
The primary endpoint was overall response rate by an independent review committee per International Myeloma Working Group (IMWG) criteria; extramedullary disease response incorporated centralized PET/CT assessment using the Deauville 5-point scale and IMPeTUs criteria.14,15
Efficacy Results: At a median follow-up of 16.8 months, the overall response rate was 79% (95% CI = 69%–87%), including complete responses or better in 54% of patients. The median time to first response was 2.6 months (range: 1.0–5.8 months), and the median time to best response was 5.1 months (range: 1.0–16.6 months). Responses appeared durable: 62% of patients had an ongoing response at 12 months, and the median duration of response was not reached (95% CI = 11.5 months–not estimable). With extended follow-up, the report cited a median progression-free survival of 15 months; 91% of patients maintained or deepened response in the 6 months following protocol-defined de-escalation to monthly dosing.
Safety Results: Safety was generally consistent with the known profiles of each bispecific. Any-grade and grade 3 or 4 infections occurred in 80% and 33% of the population, respectively; pneumonia and COVID-19 were among the most frequent serious infections. Opportunistic infections were reported in 6.7% (grade 3/4: 3.3%) of patients. Hypogammaglobulinemia was frequent after treatment (71%), and 86% of patients received at least one dose of immunoglobulin replacement therapy. Cytokine release syndrome was observed in 77.8% of patients and was largely low grade. After switching from every-2-week to monthly dosing, new-onset key toxicities were less frequent. Adverse events resulted in death in 10 patients, including 5 infection-related deaths.
Clinical Implications: Dual bispecific targeting of GPRC5D and BCMA produced unusually deep and durable responses in centrally confirmed true extramedullary disease—an outcome that could materially change expectations for this subgroup if replicated. The data also underscore that dose/interval de-escalation is not merely a convenience strategy but may be a critical safety lever to reduce cumulative toxicity while preserving response. In summary, this off-the-shelf bispecific antibody combination regimen offers clinically meaningful efficacy for one of the most challenging-to-treat subgroups of patients with multiple myeloma.
LBA-1 (inMMyCAR): In Vivo Gene Therapy to Generate Anti-BCMA CAR T Cells Without Lymphodepletion
Background: Despite major advances with ex vivo–manufactured BCMA-directed CAR T-cell therapies, delivery remains constrained by leukapheresis, centralized manufacturing, time to infusion, and the need for lymphodepleting chemotherapy—factors that can limit access, increase cost, and add toxicity. The inMMyCAR trial (ClinicalTrials.gov Identifier: NCT07075185) explores an investigational approach to overcome the access and logistical constraints of ex vivo CAR T-cell therapy.3,16 KLN-1010 is an intravenously administered, replication-incompetent lentiviral vector designed to transduce circulating T cells in vivo, generating a fully human anti-BCMA CAR T-cell population without leukapheresis, centralized manufacturing, or lymphodepleting chemotherapy.
Methods: This first-in-human multicenter phase I study uses a 3 + 3 dose-escalation design with primary objectives of safety/tolerability and selection of a recommended phase II dose. Eligibility includes relapsed or refractory multiple myeloma with measurable disease after at least three prior lines of therapy, including prior exposure to a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 monoclonal antibody, with an Eastern Cooperative Oncology Group performance status of 0 to 1 and adequate organ function. The ASH presentation summarized the outcomes of the first four treated patients (three treated at dose level 1 and one treated at dose level −1), with follow-up through at least month 3 in those with the longest observation.
Efficacy Results: KLN-1010 generated measurable CAR T cells in vivo, with peak expansion around day +15. CAR-positive cells comprised a substantial fraction of circulating CD3-positive T cells (at day +15: 22%–72% in dose level 1; 85% in dose level −1). No adverse clinical sequelae were attributed to lymphocytosis during expansion, and dexamethasone promptly resolved lymphocytosis in the patient with the highest level. Circulating CAR T cells were detectable in peripheral blood and bone marrow through month 3 and were predominantly memory phenotype, a feature historically associated with durable remissions after ex vivo CAR T-cell therapy.
All treated patients (n = 4; 100%) achieved early MRD negativity at month 1 by next-generation flow cytometry or next-generation sequencing (10–5–10–6 sensitivity), with sustained MRD negativity through month 2 in the two patients with the longest follow-up.
SafetyResults: Treatment-emergent adverse events clustered around infusion and the period of CAR T-cell expansion. Infusion-related reactions were early and generally self-limited; after an initial reaction, prophylactic tocilizumab was incorporated. Cytokine release syndrome occurred with a median onset of 10 days (range: 10–12 days) and was limited to grade 1 to 2, with no grade 3 or higher events reported. Management included supportive care with tocilizumab and/or dexamethasone when indicated. No immune effector cell–associated neurotoxicity syndrome or delayed neurotoxicity (eg, parkinsonism or cranial nerve palsies) was reported in this early cohort, and cytopenias appeared limited compared with typical ex vivo CAR T-cell experiences.
Clinical Implications: These preliminary first-in-human observations provide proof of concept for an off-the-shelf in vivo CAR T-cell platform, with the potential to shorten time to treatment and reduce the intensity of supportive care required for lymphodepletion-related cytopenias. If durability and safety are confirmed with longer follow-up and across dose levels, in vivo CAR T-cell platforms such as KLN-1010 could significantly advance the field of CAR T-cell therapy. By simplifying logistics, shortening time to treatment, and potentially enabling outpatient delivery, in vivo CAR T-cell products may meaningfully expand access to cellular therapy for appropriate patients with relapsed or refractory multiple myeloma. The study remains ongoing. ν
DISCLOSURE: Dr. Abutalib reported a relationship with AstraZeneca. Dr. Pianko has received research funding and/or consulting fees from AbbVie, AstraZeneca, Bristol Myers Squibb/Celgene, Janssen, Karyopharm, Kite/Gilead, GlaxoSmithKline, Oncopeptides, Pfizer, Regeneron, and Sanofi.
REFERENCES
1. Mateos M-V, Bahlis N, Perrot A, et al: Phase 3 randomized study of teclistamab plus daratumumab versus investigator’s choice of daratumumab and dexamethasone with either pomalidomide or bortezomib in patients with relapsed refractory multiple myeloma: Results of majestec-3. 2025 ASH Annual Meeting & Exposition. Abstract LBA-6. Presented December 8, 2025.
2. Usmani S, Kumar S, Mateos MM, et al: Efficacy and safety of talquetamab + teclistamab in patients with relapsed/refractory multiple myeloma and extramedullary disease: Updated phase 2 results from the redirectt-1 study with extended follow-up. 2025 ASH Annual Meeting & Exposition. Abstract 698. Presented December 2025.
3. Harrison S, Ho PJ, Lim S-L, et al: Minimal residual disease-negative outcomes following a novel, in vivo gene therapy generating anti–B-cell maturation antigen chimeric antigen receptor-T cells in patients with relapsed and refractory multiple myeloma: Preliminary results from inMMyCAR, the first-in-human phase 1 study of KLN-1010. 2025 ASH Annual Meeting & Exposition. Abstract LBA-1. Presented December 2025.
4. Garfall AL, Nooka AK, van de Donk NWCJ, et al: Long-term follow-up from the phase 1/2 MajesTEC-1 trial of teclistamab in patients with relapsed/refractory multiple myeloma. J Clin Oncol 42:7540, 2024.
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12. Kumar S, Mateos M-V, Ye JC, et al: Dual targeting of extramedullary myeloma with talquetamab and teclistamab. N Engl J Med 394:51-61, 2026.
13. Usmani S, Kumar S, Mateos M-V, et al: Efficacy and safety of talquetamab + teclistamab in patients with relapsed/refractory multiple myeloma and extramedullary disease: Updated phase 2 results from the redirectt-1 study with extended follow-up. Blood 146:698, 2025.
14. Nanni C, Zamagni E, Versari A, et al: Image interpretation criteria for FDG PET/CT in multiple myeloma: A new proposal from an Italian expert panel. IMPeTUs (Italian Myeloma criteria for PET USe). Eur J Nucl Med Mol Imaging 43:414-421, 2016.
15. Zamagni E, Nanni C, Dozza L, et al: Standardization of 18F-FDG–PET/CT according to Deauville criteria for metabolic complete response definition in newly diagnosed multiple myeloma. J Clin Oncol 39:116-125, 2021.
16. Harrison S, Ho PJ, Lim S-L, et al: Minimal residual disease-negative outcomes following a novel, in vivo gene therapy generating anti–B-cell maturation antigen chimeric antigen receptor-T cells in patients with relapsed and refractory multiple myeloma: Preliminary results from inMMyCAR, the first-in-human phase 1 study of KLN-1010. Blood 146:LBA-1, 2025.
Dr. Abutalib is Director of the Malignant Hematology and Transplantation & Cellular Therapy Programs at the Advocate/Aurora St. Luke’s Medical Center, Milwaukee, and Associate Professor at Rosalind Franklin University of Medicine and Science, Chicago. Dr. Pianko is Clinical Associate Professor of Internal Medicine at the University of Michigan, Ann Arbor, and a member of the Multiple Myeloma & Amyloidosis Program at the Rogel Cancer Center of the University of Michigan.
