Year in Review: The Rise of Cellular Immunotherapy for Multiple Myeloma

Hamza Hashmi, MD Memorial Sloan Kettering Cancer Center

With the advent of bispecific antibodies and chimeric antigen receptor (CAR) T-cell therapies, cellular therapy has rapidly reshaped the treatment landscape for multiple myeloma. These approaches have not only revolutionized outcomes in relapsed or refractory disease but are now moving earlier in the disease course, including first relapse after frontline therapy. In fact, it continues to challenge the traditional RVD (lenalidomide, bortezomib, dexamethasone) backbone for treatment-naïve newly diagnosed multiple myeloma.

Below are some of the key developments that shaped the multiple myeloma landscape in 2025.

MajesTEC-3 Redefines Early Relapse Therapy

The phase 3 MajesTEC-3 trial, presented at the 2025 ASH Annual Meeting, compared daratumumab plus teclistamab with standard-of-care chemotherapy (DPd, DVd) in early-relapsed multiple myeloma. At 3 years, progression-free survival (PFS) and overall survival (OS) rates were 85%, with minimal residual disease (MRD) negativity achieved in 90% of evaluable patients at a sensitivity of 10^-6. This combination is one of the most effective treatment options for relapsed myeloma to date. However, combination therapy was associated with significant risk of hypogammaglobulinemia and grade 3 infections (33%), supporting early initiation of intravenous immunoglobulin (IVIG), often by second cycle.

In addition, only 5% of patients were previously exposed to daratumumab, and none were daratumumab-refractory, raising questions about the efficacy of this combination in a more contemporary, daratumumab-exposed population. For patients without access to CAR T-cell therapy, a time-limited approach of approximately 12 months, guided by MRD negativity, may help mitigate infection risk, prolonged IVIG dependence, quality-of-life (QoL) impact, and potential resistance to future B-cell maturation antigen (BCMA)-directed therapies.

CAR T-Cell Therapy: Durable Remissions and New Challenges

Long-term follow-up from the CARTITUDE-1 study demonstrated that heavily pretreated, triple-class-refractory patients achieved a median PFS of 3 years and a median OS of 5 years after a single infusion of ciltacabtagene autoleucel (cilta-cel). For a population historically associated with a median OS of less than 9 months, sustained remissions beyond 5 years in nearly one-third of patients were impressive and contributed to cilta-cel being described as a potential curative therapy in The New York Times Magazine.

Although cytokine release syndrome, immune effector cell–associated neurotoxicity syndrome, cytopenias, and infections were common, these toxicities were generally transient and manageable. In contrast, late-onset neurologic toxicities, including Parkinsonism (3%) and enterocolitis, were less frequent but posed significant management challenges and could substantially affect QoL. In earlier-line disease, as demonstrated in CARTITUDE-4, improved efficacy was observed, with PFS rates of 80% at 2.5 years and OS rates exceeding 90%. These benefits highlight the need for careful patient counseling regarding late toxicities when considering cilta-cel at first relapse. Emerging strategies, including more effective bridging therapy and mitigation of rapid postinfusion T-cell expansion, may reduce the risk of delayed neurologic adverse events. Nevertheless, the appeal of a “one-and-done” approach, reduced reliance on IVIG, and preserved options for subsequent BCMA-directed therapies continue to position CAR T-cell therapy as a preferred option in International Myeloma Working Group guidelines.

MRD-Guided Strategies

With the FDA’s approval of MRD negativity as a regulatory endpoint for early efficacy analysis and accelerated drug approval, incorporation of MRD assessment across all clinical trials has accelerated. The MIDAS trial evaluated an MRD-adaptive strategy following 6 cycles of induction chemotherapy, assigning patients to consolidation chemotherapy or autologous stem cell transplant (ASCT) if MRD-negative at 10^-5, or single versus tandem ASCT if MRD-positive.

Although MRD negativity rates were similar between consolidation chemotherapy and ASCT (85% at 10⁻⁵), longer follow-up is needed to assess sustained MRD negativity, ideally confirmed 12 months apart, as well as PFS outcomes, particularly in high-risk subgroups. Importantly, patients with t(11;14), who historically demonstrate lower early MRD negativity rates without compromised PFS or OS, may not be appropriate candidates for treatment escalation with tandem ASCT. These findings highlight the need to interpret MRD results within the context of disease biology. At present, MRD testing remains primarily a research tool, with limited application outside clinical trials, except in select cases where patients with sustained MRD negativity at 10⁻⁶ after prolonged maintenance may cautiously discontinue therapy under close surveillance.

Trispecific Antibodies: The Next Wave

At the 2025 ASCO Annual Meeting, early data on JNJ-5322, a next-generation trispecific antibody targeting BCMA and GPRC5D, were presented in patients with relapsed or refractory multiple myeloma. Despite heavy pretreatment, overall response rates reached 100% in BCMA- and GPRC5D-naïve patients and 55% in those previously exposed to these targets. Responses were rapid, deep, and durable, with a median time to first response of 1.2 months, complete response rates of 70%, and 95% PFS at 12 months.

Notably, the every-4-week dosing schedule after initial step-up dosing was associated with lower rates of skin, nail, taste, and weight-related toxicities compared with the GPRC5D-directed bispecific antibody talquetamab. Given their efficacy and tolerability, trispecific antibodies are likely to be incorporated into clinical trials in both frontline and early-relapse settings.

Controversy in Smoldering Myeloma

The debate surrounding early treatment of smoldering multiple myeloma resurfaced following the FDA approval of daratumumab monotherapy in November 2025. This approval was based on the phase 3 AQUILA trial, which compared 3 years of daratumumab monotherapy with active monitoring. With a median follow-up of nearly 6 years, daratumumab was associated with improved PFS (80% vs 63%) and OS (93% vs 87%), particularly among patients classified as high risk by the Mayo 20/2/20 criteria.

However, most progressions in the observation arm were asymptomatic, with fewer than 10% experiencing clinically morbid events such as anemia or bone disease. In addition, many patients in the control arm did not receive daratumumab at progression, raising questions regarding the observed OS benefit. As risk stratification tools and surveillance strategies continue to improve, treatment of smoldering myeloma remains controversial. Single-agent daratumumab may be considered for select high-risk patients concerned about close follow-up, whereas observation remains appropriate for low- and intermediate-risk disease.

Overall, cellular immunotherapy transformed multiple myeloma care in 2025, with CAR T cells and bispecific antibodies delivering unprecedented response rates and durability, while safety management continues to evolve. As the field moves into 2026, the priority remains delivering the most effective treatment options in a safe, time-limited manner while preserving QoL in patients with multiple myeloma.