Expert Insight on Emerging Strategies in Multiple Myeloma
February 19, 2026
Key Points
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Daratumumab is FDA‑approved for high‑risk smoldering multiple myeloma (SMM), with early treatment favored because of a high risk of progression to multiple myeloma (MM).
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The standard of care for patients with newly diagnosed multiple myeloma (NDMM) is daratumumab plus VRd (Velcade [bortezomib], Revlimid [lenalidomide], and dexamethasone).
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In relapsed/refractory multiple myeloma (RRMM), four bispecific antibodies and two chimeric antigen receptor (CAR)‑T cell therapies are approved, and teclistamab-based combinations are seen as promising.
The treatment landscape across the spectrum of plasma cell dyscrasias is rapidly evolving. From risk-based intervention in smoldering myeloma to refined sequencing strategies in newly diagnosed and relapsed disease, a panel discussion led by Rahul Gosain, MD, MBA, of Wilmot Cancer Institute, and Rohit Gosain, MD, of Roswell Park Comprehensive Cancer Center, highlighted how emerging data and novel agents are reshaping MM care.
Held at the 2025 ASH Annual Meeting (ASH 2025), the cohosts of the Oncology Brothers were joined by key opinion leaders, Vincent Rajkumar, MD, of Mayo Clinic, and Robert Orlowski, MD, PhD, of MD Anderson Cancer Center.
Smoldering Multiple Myeloma Intervention
The session began with a contemporary management strategy of high-risk SMM, guided by the AQUILA trial and the FDA approval of daratumumab in November 2025. Dr. Rajkumar defined high-risk SMM using Mayo Clinic’s 20/20/20 risk model by the presence of any two of the following: serum free light chain ratio greater than 20, serum M protein greater than 2 g/dL, or bone marrow clonal plasma cells greater than 20%. He emphasized that high-risk SMM carries a 25% annual risk of progression over the first 2 years, compared with about 10% for low-risk disease, underscoring the importance of early intervention.
Dr. Orlowski favored treating evolving SMM while awaiting results of the ITHACA study, exploring isatuximab plus lenalidomide and dexamethasone (Rd) versus Rd alone. Both agreed that combination-based treatments may offer superior disease control in high-risk SMM through synergistic effects.
Treatment of Newly Diagnosed Multiple Myeloma
In NDMM, the current standard of care is daratumumab plus VRd. The ENDURANCE trial, which compared carfilzomib (K) and bortezomib (V) plus Rd, showed no benefit of carfilzomib over bortezomib. Moreover, Dr. Rajkumar expressed concerns over carfilzomib’s financial toxicity.
The COBRA study, presented at ASH 2025, comparing KRd to VRd, showed superior progression-free survival (PFS) in the KRd arm. However, it was unevenly balanced, with K for 24 cycles and V for only 8.
When comparing isatuximab to daratumumab, Dr. Rajkumar noted that they are clinically similar, except that isatuximab may be more cost-effective for patients weighing less than 60 kg due to weight-based dosing.
Autologous stem cell transplant (ASCT) is not needed upfront in all standard-risk patients, Dr. Orlowski explained. For those achieving complete remission with minimal residual disease (MRD) negativity, a harvest-and-hold strategy to maintenance is reasonable. Patients with NDMM who are high-risk should receive melphalan with ASCT, and the panel favored double maintenance for them, pending results from the SWOG 1803 study. The experts discouraged adding daratumumab in maintenance unless it’s part of the induction regimen or if the patient is MRD-positive post-transplant.
The phase 2 IFM2021-01 study demonstrated that monthly teclistamab dosing in elderly transplant-ineligible patients achieved 100% MRD rates at 6 months in 27 evaluable patients, a result that generated excitement among the panelists.
RRMM: An Individualized Approach
Patients with RRMM have more treatment options than ever before, with the approval of four bispecific antibodies and two CAR T-cell therapies.
However, Dr. Orlowski alluded to the MajesTEC-3 study, which raises concerns for daratumumab-naive patients. Similar overall survival and PFS curves complicate subsequent therapy, including CAR T-cell therapy. Patient-specific variables should be considered when deciding between CAR T-cell therapy, teclistamab/daratumumab, or a clinical trial, he said. To mitigate infection risk with bispecifics, Dr. Orlowski recommended early intravenous immunoglobulin use and checking immunoglobulin G (IgG) subclasses to ensure IgG myeloma is covered.