This episode features Dr Shaji K. Kumar reviewing pivotal data on the efficacy, safety, and expanding roles of immunotherapy approaches in multiple myeloma, including bispecific antibodies, CAR T-cell therapies, and novel combination strategies.
In this episode, Shaji K. Kumar, MD, reviews key highlights from ASH 2025 in multiple myeloma (MM), focusing on emerging data for bispecific antibodies and CAR T-cell therapies across earlier and later lines of treatment. The discussion covers the following:
Presenter:
Shaji K. Kumar, MD
Mark and Judy Mullins Professor of Hematological Malignancies
Consultant, Division of Hematology
Professor of Medicine
Research Chair, Division of Hematology
Mayo Clinic
Rochester, Minnesota
Link to full program:
https://bit.ly/4995nFA
Dr. Kumar: Thank you so much. ASH 2025 was an exciting meeting with lots of new data in the field of multiple myeloma. Again, highlighting the remarkable progress that has been made over the past few years, particularly with respect to immunotherapy.
One of the most awaited abstracts was the late-breaking abstract looking at the combination of teclistamab and daratumumab in patients with relapsed/refractory multiple myeloma. As we all know, the BCMA-targeted bispecific antibody teclistamab has been shown to have quite a bit of efficacy in late relapse as a single agent. And this is a bispecific antibody that targets BCMA on the tumor cell and CD3 on the T-cells.
Now, the combination of teclistamab with either monoclonal antibodies or immunomodulated drugs has shown promising activity in the setting of relapsed disease. And this led to the design of this randomized Phase III trial that compared the combination of teclistamab and daratumumab with the standard of care therapy in patients with relapsed myeloma who had one to three prior lines of therapy.
Overall, 587 patients were randomized to getting either teclistamab in combination with daratumumab or a standard of care regimen, either DPD, daratumumab Pom-Dex, or daratumumab bortezomib-Dex. Patients received two step-up doses of teclistamab followed by weekly teclistamab for the first two cycles and then every other week for the next four cycles and then every four weeks after that. The standard of care arms received the usual schedule.
The patient population had a median of two prior lines of therapy in both the arms. More than half of the patients had two or three prior lines of therapy. The patients were well balanced in both the arms. In fact, about a third of the patients in each arm had high-risk cytogenetics, and about 14% of the patients actually had soft tissue plasmacytomas.
[4:19]
Overall, at this point in time, there were 71% of the patients in the Tec-Dara arm were still on steady treatment compared to 28% of the patients in the standard of care arms. The majority of the patients who discontinued therapy did for disease progression primarily in the standard of care arms, which is 58% compared to the 7% in the teclistamab and daratumumab arm.
The primary endpoint for the study was progression-free survival, and the three-year progression-free survival was 83.4% for the Tec-Dara compared to nearly 30% for the DPD or DBD, suggesting significant improvement with a hazard ratio of 0.17.
When you look at the various subgroups, it was clear that all different subgroups, including the patients who had previously been exposed to anti-CD38 monoclonal antibodies, as well as patients over 75 years of age, benefited from the teclistamab and daratumumab. As did the patients with high-risk and standard-risk disease, both groups appearing to achieve similar benefit from the teclistamab plus daratumumab.
[5:32]
Overall, the response rate was 89% with Tec-Dara compared to 75.3% with the standard of care, but importantly, the complete response rate was 82% for Tec-Dara compared to only about 32% for the standard of care arm.
The MRD negativity was significantly higher at 58.4% among the evaluable patients in the Tec‑Dara compared to 17.1% in the standard of care arm. The overall survival also was improved with the Tec-Dara with an 83% overall survival at three years compared to 65%. And again, with respect to the overall survival, just like the progression-free survival, all subgroups of patients appeared to benefit.
The overall safety profile was very consistent with what we have seen with the bispecific antibodies. Cytokine release syndrome was seen in about 60% and neutropenia in about 80% of the patients getting the teclistamab combination. Any infection was seen in the majority of the patients with COVID-19 in nearly half of the patients, and an upper respiratory tract infection in nearly 40% of the patients.
The majority of the infections were seen during the first six months, with a progressive decrease in the proportion of patients getting infections after that. And the use of teclistamab and daratumumab did not seem to affect the overall quality of life.
So this study provides very important data for us in terms of the utility of a bispecific antibody, particularly in combination with an anti-CD38 monoclonal antibody in the earlier lines of therapy. This is in the context of teclistamab only being approved in the late lines currently, and hopefully these results will translate into approval in the earlier lines.
The major drawbacks for this study is the lack of a more effective control arm, like the combination of daratumumab, carfilzomib and dexamethasone, and the inclusion of patients, who have not been exposed to an anti-CD38 monoclonal antibody, which is going to be a smaller proportion of patients in the future, given its use in the upfront setting.
And finally, the high rates of infection, which require very close monitoring of these patients and may make this regimen not very applicable in the community setting.
The ASH meeting also featured the combination of teclistamab and talquetamab in a population that is very difficult to treat, that is the patient population with extramedullary disease. So in a dedicated Phase II trial that included only patients with true EMD, so excluding patients who had extramedullary disease that was in continuity with their bone lesion, the combination of teclistamab and talquetamab was explored. The initial report of this trial was presented at the European Hematology Association meeting a few months ago.
This trial is important because this is one of the very first trials that is specifically dedicated for patients with true extramedullary disease, with responses assessed with dedicated imaging that is done consistently across the study. Overall, 90 patients with true EMD were started on treatment. The patients had a meeting of four prior lines of therapy. Some of these patients had non-secretory or oligosecretory disease, in fact, almost a third of the patients, and the majority of these patients were triple-class refractory, in fact, a third were drug refractory.
With the use of teclistamab and talquetamab, we saw an impressive response rate of 79% and a 12-month durability of response of about 62%. When you look at various imaging studies, we saw that consistently there was a significant decrease in the extramedullary disease in terms of response as measured with PET CT and using the IMWG response criteria as well as the 5-point double scale.
What we saw was that irrespective of the size of the lesion and the location of the lesion, they found high response rates of upwards of 70% in this patient population. The progression-free survival at 12 months with a median of 16.8 months follow-up was about 58%, and the overall survival was 74%, significantly better than what we have seen with any other therapy in this difficult-to-treat patient population.
The safety profile with the combination was quite similar to what we have seen with either teclistamab or talquetamab used alone. The major side effects that we noted were infections, and nearly 80% of the patients had any infection, with almost a third of the patients having an upper respiratory tract infection or pneumonia and almost a fifth of the patients actually having COVID-19. Overall, 11 patients, or 12% of these patients, had died on therapy, the majority related to infections.
Overall, in this first dedicated extramedullary disease myeloma trial, we see an impressive response rate with the Tec plus Tal combination. Clearly, given that this combination is currently included in the NCCN guidelines, we have the ability to use this combination in this patient population. Future studies are exploring this combination as well as trispecific antibodies in patients with extramedullary disease to see if we can make an impact on these patients.
Now, the CAR T-cells, both ide-cel and cilta-cel, are approved for treatment of multiple myeloma. In fact, cilta-cel is approved in patients with one relapse and ide-cel in patients with two relapses.
We have seen some impressive data with cilta-cel, with nearly a third of the patients in the initial CARTITUDE-1 study being free of progression in deep MRD-negative response five years out from the treatment.
Now, in an additional analysis at ASH, the patients with standard-risk disease who are enrolled in the CARTITUDE-1 trial were analyzed. When you look at this patient population with standard-risk cytogenetics, it is clear that the response rates are very high, with nearly 100% of these patients actually responding to the cilta-cel in the CARTITUDE-4 trial. Again, keep in mind the CARTITUDE-4 trial randomized patients with one to three prior lines of therapy to receiving either cilta-cel or a standard of care non-immune therapy regimen.
Among the patients receiving cilta-cel on the CARTITUDE-4 trial with standard-risk cytogenetics, the complete response rate was 90% both in those without a 1q gain or amplification as well as those with a 1q gain or amplification.
When you look at the progression-free survival, the cilta-cel clearly improved the PFS as well as overall survival in the standard-risk patients as well as high-risk patients compared to the standard of care, with the best results seen amongst the standard-risk cytogenetics patients. In fact, the 30-month PFS for those patients with standard-risk multiple myeloma was 80.5%, with an overall survival that was 87.3%. In fact, when you look at the patients with or without the 1q abnormalities, there was a slightly lower PFS in those patients with the 1q abnormalities, though the overall survival was comparable between both these patient populations. When you compare the outcomes with patients in the CARTITUDE-1 study, those patients with standard-risk disease had a 72% PFS at 30 months compared to 60% in the patients with CARTITUDE-1, again suggesting that you can get more durable responses when the cilta-cel was used in the early lines of therapy in the standard-risk patient population.
In summary, the long-term data from the CARTITUDE-4 trial focusing on the standard-risk disease again suggests a significant long-term disease-free interval in patients responding to therapy. In fact, patients who were progression-free at the end of one year of therapy, 93% of those patients remained progression-free at 2.5 years from the start of treatment. Again, indirectly, these data support the earlier use of cilta-cel in patients with relapsed multiple myeloma.
Now, given that the patients who receive the CAR T-cells do relapse eventually, or a significant proportion of those patients eventually relapse, there have been a lot of interest in trying to see how we can expand or extend the remissions that we achieve with CAR T-cells. One of the studies that was presented at ASH explored the use of a limited-duration therapy with cevostamab as a consolidation following a BCMA-targeted CAR T-cell therapy, either ide-cel or cilta-cel. Again, cevostamab is a bispecific antibody that is targeted towards FCRH5, a different antigen on the myeloma cells.
Patients who had received cilta-cel or ide-cel were enrolled on the study and treated for 8 treatments with cevostamab given every 3 weeks. If they were still positive for MRD, they received an additional 8 treatments. Overall, 27 patients were treated on the study. Again, the majority of these patients had advanced disease going into their CAR T-cell therapy. What was found was that the complete response rate went from 63% before the cevostamab to 81% at the end of cevostamab and 93% at one year post-CAR T, suggesting that the added cevostamab led to deepening of response. And most of these patients were free of progression up to 2 years out from the completion of treatment.
Again, this study, while it is small and includes a small number of patients, clearly provides evidence to support additional consolidation therapy, especially in patients who do not get deep responses after their initial CAR T therapy and those patients with high-risk disease who often relapse after their CAR T-cell therapy. Certainly, there were toxicities along the lines of what we have seen with cevostamab. There were some immune side effects that appeared to be more often in the study compared to what we otherwise see.
Knowing that these patients who are on these immune therapies, both the CAR T-cells as well as the bispecific antibodies, the responses are quite heterogeneous. There has been a lot of interest in trying to identify whether the T-cell fitness plays a role in the outcomes in this disease along with the standard outcomes we look at, like minimal residual disease. This is a biomarker analysis from the CAMA-1 trial that looked at the cevostamab in patients with relapsed/refractory disease. The response rates as well as the outcomes when cevostamab was used in combination with pomalidomide. Again, the majority of these patients in the study who achieved CR were able to achieve MRD negativity. The combination induced a deep and durable decline in the soluble BCMA level consistent with other tumor markers.
Interestingly, unlike the BCMA-targeted bispecific antibodies, there was no persistent T-cell depletion. The addition of pomalidomide to the bispecific antibody appeared to decrease the frequency of regulatory T-cells, thus increasing the impact of the bispecific antibody in this patient population.
Overall, many of the studies represent a slice of the large number of interesting studies that were presented at the ASH meeting, again highlights the importance of immune therapies, particularly the T-cell redirection therapies in the setting of multiple myeloma, both early on as well as in the late lines of therapy.