Key Ideas

CAR-T cell therapy and bispecific antibodies have transformed relapsed multiple myeloma, but sequencing matters. Available data favor CAR-T before bispecific exposure when feasible, since prior bispecific therapy leaves T cells more exhausted and complicates a later CAR-T collection. Both approaches carry meaningful infection risk requiring IVIG support, and dual-antigen strategies are now extending options for high-risk and extramedullary disease.

A Decade That Rewrote the Myeloma Treatment Algorithm

Ten years ago, immunotherapy barely factored into multiple myeloma care. Treatment relied on conventional chemotherapy, high-dose melphalan, and allogeneic stem cell transplant, later joined by immunomodulatory drugs and proteasome inhibitors. Daratumumab's introduction around 2015 marked the first real step into immunotherapy, and since then the field has moved almost entirely in that direction. CAR-T cell products reached the clinic first, followed by bispecific antibodies in 2022. Both classes are now moving into earlier lines of therapy, and clinicians increasingly face a real choice rather than a sequence dictated by availability alone: which T-cell redirecting approach first, and in what order.

CAR-T Cell Therapy: Deep Remissions With Logistical Trade-offs

Idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel) are the two BCMA-directed CAR-T products in routine use. Both were first studied in heavily pretreated patients who had exhausted monoclonal antibodies, immunomodulatory drugs, and proteasome inhibitors, a population with historical overall survival capped around 24 months. Overall response rates in that setting reached roughly 80% with ide-cel and 98% with cilta-cel, and while the two products have not been compared head to head, cilta-cel has generally shown deeper and more durable responses in clinical use. Long-term follow-up of the CARTITUDE-1 trial now extends beyond five years, with roughly half of treated patients still alive and a meaningful share still in ongoing response, an outcome that would have been unthinkable in this population a decade ago.

CARTITUDE-4 later tested cilta-cel against standard combination therapy in patients who had received one to three prior lines and were lenalidomide-refractory. Cilta-cel produced substantially higher response rates and cut the risk of progression or death by roughly 74% compared with standard of care, supporting its approval after first relapse.

The trade-off with CAR-T is logistical. T cells must be collected, manufactured, and infused, a process that takes several weeks, during which some patients progress or become too unwell to proceed. Once infused, however, CAR-T is a single administration, and patients who respond well often get a genuine treatment holiday, something they value highly after years of continuous therapy.

Bispecific Antibodies: Immediate Access, Ongoing Dosing

Bispecific antibodies work differently: rather than manufacturing a patient's own T cells, they redirect existing T cells toward the myeloma cell using an off-the-shelf antibody. Teclistamab and elranatamab target BCMA, the same antigen as most CAR-T products; talquetamab and linvoseltamab (also BCMA-directed) round out the currently available options. Because there is no manufacturing wait, bispecifics can be started immediately, an advantage for patients progressing too quickly to tolerate a CAR-T collection window.

In heavily pretreated patients, response rates with bispecifics generally run 60% to 70%, somewhat below what CAR-T achieves in a comparable population, with progression-free survival and duration of response also numerically shorter. Guidelines have generally favored CAR-T first when both options are on the table, for reasons that go beyond response rate alone.

MajesTEC-3 moved teclistamab (combined with daratumumab) into the first-relapse setting, comparing it against standard combination regimens in patients who had received at least one prior line. The trial showed a dramatic reduction in the risk of progression or death, supporting an expanded role for bispecific combinations earlier in the disease course rather than reserving them for later, more refractory relapses.

The Sequencing Argument: Why Order Changes Outcomes

The biological rationale for favoring CAR-T before bispecific exposure centers on T-cell fitness. Bispecific therapy is given continuously, and that ongoing immune stimulation contributes to T-cell exhaustion over time. Once a patient has been on a bispecific for an extended period, the T cells collected for a subsequent CAR-T product may respond less well, making the CAR-T manufacturing and expansion process less reliable. Sequencing the other direction, CAR-T first followed by a bispecific if needed later, avoids this problem, since the single CAR-T infusion does not chronically stimulate T cells the way ongoing bispecific dosing does.

Practical sequencing principles that follow from this: refer patients for CAR-T evaluation as early as possible in the treatment course, ideally at first relapse or even through a clinical trial; when CAR-T is not feasible due to rapid progression, comorbidities, or access, a bispecific remains a reasonable and effective alternative; and at relapse after one antigen-directed therapy, switching targets (from BCMA to GPRC5D, for example) is generally preferred over reusing the same target, with roughly a three-month gap considered reasonable if switching between two bispecifics of the same class to allow some immune recovery.

Infection Risk Deserves Equal Attention to Efficacy

Both CAR-T and bispecific therapy carry meaningful infection risk, and this deserves as much attention as response rate when counseling patients. BCMA is expressed on healthy plasma cells as well as myeloma cells, so BCMA-directed treatment depletes normal antibody-producing cells along with the tumor. Immunoglobulin G levels can fall below 100 mg/dL, lower than what is typically seen with any other myeloma treatment, leaving patients vulnerable to bacterial and viral infection.

Monthly intravenous immunoglobulin (IVIG) meaningfully reduces the incidence of grade 3 and 4 infections, in some retrospective series by 50% or more, and should be considered standard supportive care for patients on BCMA-targeted treatment, particularly bispecifics given their chronic dosing schedule. This is easy to overlook once a patient transitions back to community follow-up, and the consequences of missing it can be serious.

Extending Reach Into High-Risk and Extramedullary Disease

Patients with aggressive disease features, high-risk cytogenetics, functional high-risk relapse shortly after transplant, extramedullary disease, or plasma cell leukemia continue to do poorly even with modern immunotherapy, with progression-free survival in the range of five to eleven months and overall survival around 24 months in these subgroups. Dual-antigen strategies are one response to this gap. The RedirecTT-1 trial combined teclistamab (BCMA) with talquetamab (GPRC5D) specifically in patients with extramedullary disease and reported response rates near 80%, with roughly half achieving complete remission, a meaningful improvement over historical outcomes in this population.

A related strategy, sometimes called antigen bridging, uses a GPRC5D-directed bispecific for a limited number of doses while a patient awaits BCMA CAR-T manufacturing, with the goal of debulking disease and covering both targets during the vulnerable collection-to-infusion window. Real-world experience with this approach has been encouraging, though it has not yet been tested in a randomized trial.

Where the Field Is Headed

Several developments are likely to reshape this landscape further. CARTITUDE-6 is comparing cilta-cel-based frontline therapy against standard induction and transplant in newly diagnosed, transplant-eligible patients, a trial that could eventually challenge transplant's decades-long position as the default consolidation strategy. Trispecific antibodies capable of engaging two myeloma antigens simultaneously are in early clinical development and may offer another route to durable response without the antigen-escape problem that limits single-target therapies over time. Given how quickly this space has moved over the past several years, the treatment algorithm described here is likely to look different within a relatively short window.

For Patients

Multiple myeloma treatment has changed enormously over the past several years, with therapies that harness the immune system now producing remissions that were not possible a decade ago. Two of the newer options, CAR-T cell therapy and bispecific antibodies, both work by directing the body's own T cells to attack myeloma cells, but they differ in an important way. CAR-T is a one-time treatment made from a patient's own cells, which takes several weeks to prepare but can offer a real break from ongoing treatment afterward. Bispecific antibodies are available immediately and do not require that waiting period, but they are typically given on a continuing schedule.

Emerging evidence suggests that receiving CAR-T therapy before a bispecific antibody, when both are options, may lead to better outcomes with either approach later on. Both treatments raise the risk of infection, so patients on these therapies, especially bispecific antibodies, should ask their care team about immunoglobulin (IVIG) support as a routine part of care. Anyone considering these treatments should discuss timing and sequencing directly with a myeloma specialist, since the right order can meaningfully affect how well future treatment options work.

Key Takeaways

  • CAR-T cell therapy (ide-cel, cilta-cel) and bispecific antibodies (teclistamab, talquetamab, elranatamab, linvoseltamab) have both moved into earlier lines of multiple myeloma treatment, with CARTITUDE-4 and MajesTEC-3 supporting use after first relapse.

  • When both options are feasible, sequencing CAR-T before bispecific therapy is generally preferred, since chronic bispecific dosing contributes to T-cell exhaustion that can compromise a later CAR-T collection.

  • BCMA-directed therapy depletes healthy plasma cells alongside myeloma cells, producing significant hypogammaglobulinemia; monthly IVIG meaningfully reduces grade 3 and 4 infection risk and should be considered routine supportive care.

  • Dual-antigen approaches, including the teclistamab-talquetamab combination studied in RedirecTT-1 and antigen-bridging strategies before CAR-T, are improving outcomes for high-risk and extramedullary disease.

  • Ongoing trials, including CARTITUDE-6 and early trispecific antibody programs, may further reshape where these therapies fit relative to transplant and each other.

References

  1. Jagannath S, Martin TG, Lin Y, et al. Long-term (≥5-year) remission and survival after treatment with ciltacabtagene autoleucel in CARTITUDE-1 patients with relapsed/refractory multiple myeloma. J Clin Oncol. 2025;43(25):2766-2771. doi:10.1200/JCO-25-00760 

  2. Einsele H, et al. Cilta-cel in lenalidomide-refractory multiple myeloma (CARTITUDE-4): updated analysis including overall survival from an open-label, multicentre, randomised, phase 3 trial. Lancet Oncol. 2026. doi:10.1016/S1470-2045(25)00545-5 

  3. Mateos MV, Bahlis NJ, 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 (DPd/DVd) in patients with relapsed/refractory multiple myeloma: results of MajesTEC-3. Presented at: 67th American Society of Hematology Annual Meeting and Exposition; December 6-9, 2025; Orlando, FL. Abstract LBA-6. 

  4. Cohen YC, Magen H, Gatt M, et al. Talquetamab plus teclistamab in relapsed or refractory multiple myeloma. N Engl J Med. 2025;392(2):138-149. doi:10.1056/NEJMoa2415561 

  5. Kumar S, Mateos MV, Ye JC, et al. Dual targeting of extramedullary myeloma with talquetamab and teclistamab. N Engl J Med. 2026;394(1):51-61. doi:10.1056/NEJMoa2514752 

  6. Lawrence L. FDA grants a fourth bispecific antibody, linvoseltamab, accelerated approval for relapsed or refractory multiple myeloma. Cancer. 2025;131(22):e70108. doi:10.1002/cncr.70108 

  7. Firestone R, Lesokhin AM, Usmani SZ. An embarrassment of riches: three FDA-approved bispecific antibodies for relapsed refractory multiple myeloma. Blood Cancer Discov. 2023;4(6):433-436. doi:10.1158/2643-3230.BCD-23-0176