Key Ideas

Multiple myeloma treatment has shifted meaningfully in the past five years: CAR-T cell therapy is increasingly used earlier for high-risk patients, dual-antigen bispecific combinations are addressing historically difficult extramedullary disease, and a wave of allogeneic, in vivo, and mRNA-based cellular therapy platforms is working to solve the access and manufacturing bottlenecks that have limited who can receive these treatments.

How Myeloma Treatment Has Changed in the Past Two Years

Practice has shifted noticeably over the past year or two. High-risk patients are now more often receiving CAR-T cell therapy in the second line, extramedullary disease is being approached with dual-antigen targeting rather than sequential single-target therapy, and prophylaxis against cytokine release syndrome has made bispecific step-up dosing dramatically safer than it was just a couple of years ago.

CARTITUDE-4 and the Case for CAR-T in High-Risk, Second-Line Myeloma

Data from the CARTITUDE-4 trial showed that ciltacabtagene autoleucel mitigated the otherwise poor prognostic impact of high-risk cytogenetics, with a hazard ratio of 0.38 for progression-free survival in that subgroup. That finding supports providing high-risk patients CAR-T cell therapy in earlier relapse, preferably in second line when effective bridging therapies are still availablePatients with extramedullary disease, who historically have had a particularly poor prognosis, are also increasingly steered toward more aggressive induction and bridging strategies, including talquetamab, with the goal of bringing patients into CAR-T cell therapy with as little residual disease as possible.

RedirecTT-1: Dual-Targeting Bispecific Therapy for Extramedullary Myeloma

The RedirecTT-1 trial combined talquetamab, which targets GPRC5D, with teclistamab, which targets BCMA, in patients with triple-class exposed relapsed or refractory multiple myeloma. In the trial's dedicated cohort of patients with true extramedullary disease, defined by plasmacytomas not contiguous with bone, the overall response rate was around 79 percent, with roughly half of patients achieving a complete response or better, and median progression-free survival exceeding 15 months. That result is genuinely encouraging in a population that has historically had a response rate of approximately 20-25% and progression-free survival measured in just a few months. Cytokine release syndrome with this combination has been consistent with what is seen with each agent individually as monotherapy, meaning the combination has not introduced a new toxicity signal beyond what clinicians already manage with either drug alone.

Ramantamig: A Trispecific Antibody Targeting BCMA, GPRC5D, and CD3

Beyond combining two separate bispecific antibodies, single molecules that engage multiple myeloma antigens at once are now in clinical testing. Ramantamig is a trispecific antibody that binds BCMA, GPRC5D, and CD3 within a single molecule, using a CD3-binding domain engineered for lower affinity to reduce excessive T-cell activation while still recruiting T cells effectively to the tumor. In an early cohort of patients naive to prior BCMA- or GPRC5D-directed T-cell therapy, all cytokine release syndrome events were low grade, and most patients required only a single step-up dose before reaching the recommended subcutaneous dose, given every four weeks. That combination of infrequent, convenient dosing and a favorable early toxicity profile makes ramantamig ideal for outpatient dosing and one of the more promising dual-antigen approaches to watch.

Allogeneic and In Vivo CAR-T Cell Therapy: Solving the Access Problem

Autologous CAR-T cell therapy, built from a patient's own T cells, faces two structural limitations: those T cells have often been heavily exposed to prior chemotherapy and may not function optimally, and manufacturing an individualized product is costly and takes weeks that some patients with aggressive disease do not have. Several platforms are now working to solve one or both of these problems.

CB-011 and ALLO-715: Off-the-Shelf, Donor-Derived CAR-T Options for Myeloma

Allogeneic CAR-T cell therapy uses healthy donor T cells rather than a patient's own, engineered using CRISPR gene editing to reduce the risk of graft-versus-host disease and immune rejection. One such product, CB-011, knocks out the cell surface molecules that would normally trigger T-cell-mediated rejection while inserting an HLA-E fusion protein that blunts natural killer cell-mediated rejection. In an early cohort of BCMA-naive patients treated at the recommended dose, CB-011 produced a 92 percent overall response rate with a 75 percent or better complete response rate. A separate allogeneic BCMA-directed CAR-T product, ALLO-715, has also shown meaningful activity, with an overall response rate in the range of 56 percent and a low rate of graft-versus-host disease in early testing.

In Vivo CAR-T Generation With KLN-1010 and mRNA Platforms

An even more radical departure from conventional manufacturing is generating CAR-T cells directly inside the patient's body, skipping apheresis, ex vivo manufacturing, and lymphodepleting chemotherapy altogether. KLN-1010 is a lentiviral vector engineered to selectively transduce T cells in vivo after a single intravenous infusion; in early testing, patients achieved measurable residual disease negativity within about a month of treatment, without the toxicity or logistical burden of traditional CAR-T manufacturing. A related but distinct approach uses electroporation to introduce anti-BCMA CAR-encoding mRNA directly into a patient's own T cells outside the body, producing a CAR-T product that expresses transiently because the mRNA never enters the cell nucleus, eliminating the risk of insertional mutagenesis; this transient CAR-T approach, exemplified by the agent Descartes-08, is being studied in patients with newly diagnosed myeloma who have residual disease. A third approach delivers lipid nanoparticles carrying mRNA that encodes three separate T-cell engaging antibodies at once, targeting BCMA, FcRH5, and GPRC5D, taken up by liver cells that then produce all three T-cell engagers systemically; this platform is intended to blunt antigen escape by covering multiple targets simultaneously, though unpredictable expression levels remain a challenge to work through.

What's Next: CELMoDs and Personalized MRD Vaccines

Looking ahead, cereblon E3 ligase modulating agents, sometimes called CELMoDs, are being explored as a way to prime T cells before apheresis for CAR-T manufacturing by reducing regulatory T-cell activity and increasing T-cell and natural killer cell cytotoxicity, potentially improving the fitness of the starting material for cellular therapy. Trispecific antibodies are likely to gradually displace single-target bispecific antibodies as the standard T-cell engaging approach, and mRNA- and lentiviral-based platforms may eventually reduce or eliminate the need for lymphodepleting chemotherapy altogether. Further out, personalized vaccines targeting a patient's own measurable residual disease are being explored as a strategy for deeper, more durable remissions.

For Patients

If a myeloma diagnosis includes high-risk features, extramedullary disease, or has relapsed after prior BCMA-directed therapy, it is worth asking the care team about eligibility for newer approaches, including dual-antigen bispecific combinations, trispecific antibodies, or clinical trials of allogeneic or in vivo CAR-T cell therapy. Some of these approaches are designed specifically to address situations, such as limited T-cell fitness after heavy prior treatment or the weeks-long wait for individualized CAR-T manufacturing, that have made it harder for certain patients to access cellular therapy in the past.

Key Takeaways

  • CAR-T cell therapy is increasingly used in earlier relapsebased on CARTITUDE-4 data showing it mitigates their otherwise poor prognosis.

  • The RedirecTT-1 trial combining talquetamab and teclistamab produced meaningful response rates in patients with true extramedullary myeloma, a historically difficult-to-treat population.

  • Ramantamig, a trispecific antibody targeting BCMA, GPRC5D, and CD3, has shown a favorable early safety profile with convenient once-monthly dosing.

  • Allogeneic CAR-T products such as CB-011 and ALLO-715 use donor-derived, gene-edited T cells to offer an off-the-shelf alternative to individualized manufacturing.

  • In vivo CAR-T generation platforms, including lentiviral and mRNA-based approaches, aim to eliminate the wait time, cost, and lymphodepleting chemotherapy associated with conventional CAR-T manufacturing.

  • CELMoD agents may help improve T-cell fitness ahead of cellular therapy manufacturing, and personalized MRD-targeted vaccines are an early-stage area of interest for deepening remissions.

References

  1. San-Miguel J, Dhakal B, Yong K, et al. Cilta-cel or standard care in lenalidomide-refractory multiple myeloma. New England Journal of Medicine. 2023.

  2. Kumar S, Mateos MV, Ye JC, et al. Dual targeting of extramedullary myeloma with talquetamab and teclistamab. New England Journal of Medicine. 2026.

  3. Philippar U, et al. Ramantamig (JNJ-79635322), a novel T-cell-engaging trispecific antibody targeting BCMA, GPRC5D, and CD3, in multiple myeloma models. Blood. 2026.

  4. Caribou Biosciences. CB-011, an allogeneic anti-BCMA CAR-T cell therapy with immune cloaking, for patients with relapsed/refractory multiple myeloma (CaMMouflage phase 1 trial). Presented data, European Hematology Association Annual Meeting. 2026.

  5. Kelonia Therapeutics. KLN-1010, an in vivo-generated anti-BCMA CAR-T therapy, in relapsed/refractory multiple myeloma. Presented data.

  6. Cartesian Therapeutics. Descartes-08, a non-integrating mRNA CAR-T therapy targeting BCMA, in multiple myeloma. Presented data.

  7. ModernaTX. mRNA-2808, a lipid nanoparticle-delivered, multiplexed T-cell engager platform targeting BCMA, FcRH5, and GPRC5D, for multiple myeloma. Presented data, American Society of Hematology Annual Meeting. 2024.