Advances in multiple myeloma: key updates from the ASH 2025 meeting

Abstract

The therapeutic landscape of multiple myeloma (MM) is undergoing rapid transformation with the expansion of immune-based strategies. This editorial summarizes key MM abstracts presented at the American Society of Hematology (ASH) 2025 meeting, highlighting how bispecific antibodies (BsAbs), minimal residual disease (MRD)-adaptive approaches, and next-generation immune platforms are reshaping treatment across all MM disease stages. In newly diagnosed MM (NDMM), minimal residual disease (MRD)-adaptive consolidation with linvoseltamab in IMMUNOPLANT converted persistent MRD positivity to MRD negativity in all evaluable patients, supporting biologically guided treatment intensification. In transplant-ineligible (TIE) NDMM patients, TecLille showed that antibody-only therapy achieved deep responses with manageable infection risks. In early relapsed/refractory MM (RRMM), the pioneering phase III MajesTEC-3 trial demonstrated significant progression-free survival (PFS) and overall survival (OS) benefits with BsAb teclistamab plus daratumumab compared to other standard triplets, with response rates approaching those historically observed with chimeric antigen receptor (CAR) T cell therapy. A novel rational BsAb combination of BsAb elranatamab anda cereblon E3 ligase modulatory drug (CELMoD) iberdomide in MagnetisMM-30 showed promising synergy despite cytopenias and updates to combination BsAb targeting in RedirecTT-1 demonstrated major activity in difficult to treat extramedullary myeloma (EMM). First-in-human inMMyCAR data showcased the forefront of engineered immune strategies, by introducing an in vivo CAR-T product as a proof-of-concept platform, with tremendous potential to streamline the access to therapy. Collectively, these studies signal a shift toward earlier and adaptive immunotherapy in all phases of MM disease, while underscoring the importance of infection mitigation and long-term safety evaluation.

To the editor,

The therapeutic landscape of multiple myeloma (MM) continues to evolve at a fast pace, driven by scientific and engineering advances in immunotherapy. At the American Society of Hematology (ASH) 2025 meeting, multiple presentations generated high enthusiasm, highlighting how bispecific antibodies (BsAbs), minimal residual disease (MRD)-adaptive strategies, and next-generation immune platforms are redefining depth, durability, and sequencing of therapies across all MM stages. Here, we summarize highlights of select few MM abstracts, with relevant properties of therapeutic agents summarized in Table 1 and key results summarized in Table 2.

Table 1.

Key properties of novel immunotherapies and immunomodulator

Agent	Class	Target	Mechanism of Action	Key Features	Ref
Linvoseltamab	BsAb	BCMA × CD3	Binds CD3 on T cells and BCMA on myeloma cells → T-cell activation, cytokine release, myeloma cell lysis	IV administration, quickest time to CRS, lower CRS rate vs. other BsAbs	[1]
Teclistamab	Bispecific Antibody (BsAb)	BCMA × CD3	Redirects T cells to BCMA-expressing myeloma cells, forming immune synapse → T-cell activation → tumor lysis	First BsAb ever approved, SC administration	[2–4]
Elranatamab	BsAb	BCMA × CD3	T-cell redirection to BCMA+ myeloma cells → activation and tumor killing	SC administration, quickest SUD	[5, 6]
Talquetamab	BsAb	GPRC5D × CD3	Redirects T cells to GPRC5D-expressing myeloma cells → T-cell activation → tumor lysis	First and only GPRC5D BsAb; associated with skin/nail/taste changes	[7, 8]
Iberdomide	Cereblon E3 Ligase Modulator	Cereblon	20× higher cereblon affinity than IMiDs → enhanced Ikaros/Aiolos degradation → direct anti-myeloma + immunostimulatory effects; enhances T-cell fitness	Oral, synergy with BsAbs and anti-CD38 antibodies	[5, 11]
KLN-1010	In vivo CAR-T gene therapy	BCMA	IV-administered gene therapy generates anti-BCMA CAR-T cells in vivo	No required apheresis, lymphodepletion or bespoke manufacturing; off-the-shelf	[10]

Table 2.

Key multiple myeloma clinical trial result summary from ASH 2025 meeting

Trial (ASH Abstract no.)	Population	Regimen	Response	MRD	Key Safety**	Clinical Implication
IMMUNOPLANT (248)	NDMM MRD+ post quadruplet therapy (n = 19)	Linvoseltamab	100% MRD +  to MRD- conversion	10⁻⁶: 100%*	Minimal CRS/ICANS	MRD-guided consolidation. Limitation: small sample, durability unknown
TecLille (367)	Elderly TIE NDMM (n = 37)	Tec + Dara	ORR 100%; ≥VGPR 97%	10⁻5and 10⁻⁶: 100%*	G ≥ 3 infection 14%. No G5 AEs	Feasibility of frontline Ab/BsAb in frail populations
MajesTEC-3 (LBA6)	RRMM (1–3 LOT) (n = 587)	Tec + Dara vs. DPd/DVd	ORR 89% ≥CR 82% 36-mo PFS 83.4% vs. 29.7% 36-mo OS 83.3% vs. 65%	10⁻⁵: 58%	G ≥ 3 infections 54%; hypogamma-globulinemia 84.5%	Practice-transforming in early relapse. Limitations: infection risk; CD38-naïve predominance (95%)
MagnetisMM-30 (100)	RRMM (2–4 LOT) (n = 22)	Elra + Iber	ORR 96%; CR ≥ 46%	-	G ≥ 3 neutropenia 73%, G ≥ 3 infection 9.1%	BsAb + CELMoD synergy Limitation: significant neutropenia
RedirecTT-1 (698)	RRMM + EMD (n = 90)	Talq + Tec	ORR 79%; ≥ CR 53% Median DOR NR	-	Infection: 32% G ≥ 3, 12% G5.	Best signal in EMD. Limitation: infection, tolerability
inMMyCAR (LBA1)	RRMM, > 3 LOT (n = 3)	KLN-1010	3/3 MRD negative by NGS or NGF	MRD negative by month 1	CRS ≤G2: 2/3 No ICANS	Cutting-edge, proof-of-concept so far

*MRD negativity in evaluable patients

**Treatment-emergent adverse event according to the Medical Dictionary for Regulatory Activities v28.1 and Common Terminology Criteria for Adverse Events v5 (G= grade)

Bispecific antibodies redefine depth and durability

ASH 2025 marked an inflection point in the field for BsAb–based immunotherapy in newly diagnosed (NDMM) and early relapsed/refractory MM (RRMM). Post-induction MRD-adaptive immunotherapy emerged as a strategy to deepen responses. The phase II IMMUNOPLANT study demonstrated that abbreviated, fixed-duration linvoseltamab consolidation could convert persistent MRD positivity after quadruplet induction into deep MRD-negative remissions with minimal toxicity in all studied patients [1]. While follow-up remains short, an excellent safety profile supports a paradigm in which MRD status informs appropriate therapeutic intensification, facilitating deeper remissions with BsAb without prolonged exposure to other therapies.

Frontline data reinforced the expanding role of BsAbs. In the IFM2021-01 TecLille study, Tec-Dara achieved exceptionally deep responses in elderly, transplant-ineligible patients with NDMM. These results raise the possibility that antibody-only immunotherapy may serve as a powerful alternative to cytotoxic regimens in frail populations. Notably, relatively low (14%) incidence of severe infections was observed with routine immunoglobulin replacement [2], suggesting that SOC infection prevention strategies are effective and integral to the safe delivery of these regimens.

The phase III MajesTEC-3 trial demonstrated significant improvements in both progression-free survival (PFS) and overall survival (OS) with teclistamab (Tec) plus daratumumab (Dara) compared with standard triplet regimens in RRMM. The overall response rate (ORR) in Tec-Dara arm was striking, comparable to CAR-T therapy [3, 4], suggesting that this combination could fundamentally alter our treatment and long-term outcomes expectations. It is important to note that most patients (95%) were anti-CD38 antibody–naïve and infectious complications were common, underscoring the importance of patient selection, and preemptive standard of care (SOC) supportive care.

Next-generation immune strategies-combination, consolidation, and engineering

The phase 1b MagnetisMM-30 trial explored the combination of elranatamab with the iberdomide, cereblon E3 ligase modulator, leveraging immune interplay to enhance T-cell fitness and reduce T-cell exhaustion. Deep responses were observed despite heavily pretreated patients [5, 6], supporting the biological rationale of this approach. Frequent neutropenia and infectious complications have led to further refinement of dosing and scheduling of this powerful combination which will be explored in the part 2 dose optimization effort, in order to prepare this combination for potential broader investigation and adoption.

ASH 2025 also highlighted the combination of immune approaches to address biologically aggressive subsets, including those with extramedullary disease (EMD). Extended follow-up from the RedirecTT-1 study demonstrated that dual BsAb targeting with talquetamab (tal) and tec at flexible dosing schedules produced superior efficacy with manageable safety profiles in RRMM with EMD [7, 8], a high unmet need population historically associated with dismal outcomes [9]. The observed depth of response supports the approach of dual-BsAb engagement which may further mitigate spatial heterogeneity and antigen escape. However, the incidence of infections was common, including infection-related grade 5 events, highlighting the need for continued dose optimization and vigilant supportive care.

Perhaps, the most conceptually provocative data at meeting emerged from the first-in-human inMMyCAR study evaluating in-vivo generation of anti-BCMA CAR T cells. Despite the very small cohort of 3 patients, rapid responses and early MRD negativity at 1 month to this off-the-shelf therapy showed the transformative potential of eliminating delays related to apheresis, bespoke manufacturing, and lymphodepletion [10]. With the limited sample size and short follow-up, long-term biologic uncertainties related to safety and durability remain unknown.

Together, these studies signal a shift in therapeutic MM approach toward earlier, deeper, and more adaptive immune-based approaches, with BsAbs now rivaling cellular therapies in efficacy across all disease stages. As these insights move closer to frontline realities, access to therapy, durability and depth of response will need to be balanced with careful mitigation of infection risks and cumulative immune and pharmacoeconomic toxicity.

Abbreviations

ASH

American Society of Hematology

LOT

Line of therapy

MRD

Minimal residual disease

BCMA

B-cell maturation antigen

GPRC5D

G protein—coupled receptor class C group 5 member D

CD

Cluster of differentiation

CR

Complete response

ORR

Overall response rate

VGPR

Very good partial response

NDMM

Newly diagnosed multiple myelom

TIE

Transplant ineligible

RRMM

Relapsed or refractory multiple myeloma

EMD

Extramedullary disease

g

Grade

AE

Adverse event

PFS

Progression free survival

OS

Overall survival

DOR

Duration of response

NR

Not reached

CAR

Chimeric antigen receptor

G

Grade

CELMoD

Cereblon E3 ligase modulatory drug

IMiD

Immunomodulatory drug

SC

Subcutaneous

IV

Intravenous

SUD

Step up dosing

CRS

Cytokine release syndrome

ICANS

Immune effector cell-associated neurotoxicity syndrome

NGS

Next generation sequencing

NGF

Next generation flow

Author contributions

Both authors were directly involved in writing and revising the manuscript, and production of tables, which were reviewed by all authors.

Funding

This work received no funding.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

The current work was exempted from requiring Ethics approval and consent to participate based on institutional guidelines.

Consent for publication

Not applicable.

Competing interests

MB reports Consultancy: AbbVie, J&J, Sanofi-Genzyme; Advisory Boards: Janssen Biotech, J&J, Sanofi-Genzyme, Pfizer, Prothena, AbbVie, Legend Biotech; Research Grants: Pfizer, J&J; Scientific Advisory Board seat: Xilis Inc.; DSMB: Delta-Fly; IRCs: Parexel International. PTN reports no financial conflict of interest.