Stunning Advances in Myeloma Presented at ASH Meeting

The 2025 annual meeting of the American Society of Hematology (ASH) in Orlando, Florida, was replete with practice-changing study data, as well as glimpses of the future, as innovative science continues to drive advances in hematology and oncology at an unprecedented speed.

For me, the highlight of the meeting was the late-breaking abstracts session, which featured data from 2 clinical trials that could have a profound impact on outcomes for patients with multiple myeloma. The most immediately transformative of the 2 was the MajesTEC-3 trial (NCT05083169) data, simultaneously published in the New England Journal of Medicine.¹ In the trial, patients who had received 1 to 3 prior lines of therapy and whose myeloma had relapsed were randomly assigned to the control arm of daratumumab (Darzalex)-containing therapy or the investigational arm of daratumumab plus the BCMA-targeting bispecific antibody teclistamab (Tecvayli).

With a median follow-up of nearly 3 years, the progression-free survival (PFS) rates at 36 months were 83% and 30% in the teclistamab-daratumumab and control arms, respectively. The rates of overall survival at the same time point were 83% and 65%, respectively. Fatal infections were more common in the teclistamab-daratumumab group; therefore, physicians prescribing this regimen should be proactive in using intravenous immune globulin and prophylactic antibiotics to mitigate the risk of infections. This regimen is more widely available than chimeric antigen receptor (CAR) T-cell therapy and should, pending regulatory approval and guideline addition, immediately become available to patients. In my opinion, it is hard to overstate the magnitude of clinical benefit this regimen achieved.

Two years ago, findings from the PERSEUS trial (NCT03710603) changed the standard frontline therapy for myeloma by demonstrating improved PFS with the addition of daratumumab to lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone in the initial therapy of multiple myeloma.² At 48 months, the estimated PFS with the novel regimen was 84%; I have heard that statisticians estimate that the median PFS with this regimen may turn out to be about 12 years. Putting together the results of PERSEUS with those of MajesTEC-3, one can imagine that, with modern therapy, myeloma survival curves may approximate those of age-matched controls.

And that is not to mention the incredible results achieved with CAR T-cell therapy.

Yet another triumph of science was presented in the late-breaking abstracts section at ASH. KLN-1010 is an off-the-shelf gene therapy product comprising a lentiviral vector that, after infusion into the patient, transduces circulating T cells to create an anti-BCMA CAR-T cell in vivo, eliminating the need for apheresis or ex vivo cell manufacturing.³ In the inMMyCAR trial (NCT07075185), 4 patients with heavily treated myeloma received the product, and all were found to have no evidence of minimal residual disease just 1 month after infusion. Expansion of the CAR T cells was robust. So far––and this is with short follow-up––toxicities have been manageable.

Of course, this product needs more study to warrant routine use, but the glimpse of the future is stunning. We could certainly use a world in which effective cellular therapies are readily available to all, and this product could represent a major step in that direction.

REFERENCES

1. Costa LJ, Bahlis NJ, Perrot A, et al; MajesTEC-3 Trial Investigators. Teclistamab plus daratumumab in relapsed or refractory multiple myeloma. N Engl J Med. Published online December 9, 2025. doi:10.1056/NEJMoa2514663

2. Sonneveld P, Dimopoulos MA, Boccadoro M, et al. Daratumumab, bortezomib, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2024;390(4):301-313. doi:10.1056/NEJMoa2312054

3. Harrison S, Ho PJ, Lim SL, et al. Minimal residual disease (MRD)-negative outcomes following a novel, in vivo gene therapy generating anti-B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR)-T cells in patients with relapsed and refractory multiple myeloma (RRMM): preliminary results from inMMyCAR, the first-in-human phase 1 study of KLN-1010. Presented at: 67th ASH Annual Meeting and Exposition. December 6-9, 2025. Abstract LBA-1.