Teclistamab Shows 100% Response Rate in High-Risk Smoldering Myeloma

Omar Nadeem, MD

Teclistamab-cqyv (Tecvayli), a bispecific antibody, led to significant activity when used as a treatment for patients with high-risk smoldering myeloma (HR-SMM), according to findings from the Immuno-PRISM (PRecision Intervention Smoldering Myeloma) trial (NCT05469893).¹

Among patients with HR-SMM, teclistamab demonstrated an overall response rate (ORR) of 100% among those with minimal residual disease (MRD) negativity. A total of 42% of patients achieved a complete response, 25% achieved a very good partial response, and 33% achieved a partial response.

Teclistamab also had a significantly improved safety profile with no dose-limiting toxicities seen in the safety run-in cohort. Of those treated with teclistamab (n = 12), grade 3 or greater hematologic toxicities observed included neutropenia (n = 4) and thrombocytopenia (n = 1). The grade 3 or greater nonhematologic toxicities included increased alanine aminotransferase in 3 patients and pancreatitis in 1 patient, all of which were resolved.

The multi-arm, randomized, phase 2, platform study of teclistamab vs lenalidomide and dexamethasone for the treatment of HR-SMM is now enrolling into the randomized portion of the trial.

In an interview with Targeted Oncology^TM, Omar Nadeem, MD, physician at Dana-Farber Cancer Institute, discussed the first results from the Immuno-PRISM study.

Microscopic, photorealistic image of myeloma cells - Generated with Adobe Firefly

Targeted Oncology: Could you explain what the Immuno-PRISM trial is evaluating?

Nadeem: This is looking at treatment with bispecific antibodies in high-risk smoldering myeloma. Smoldering myeloma is a disease that has a variable risk of progression to myeloma, and these are the high-risk patients that have a high incidence of developing organ damage for myeloma. We are trying to see, can we bring treatments earlier that we know are effective in patients that have relapsed myeloma?

This is the first trial looking at bispecific antibodies in high-risk smoldering myeloma. It is a randomized trial with the control arm of lenalidomide and dexamethasone. We reported our results of the first 12 patients that have been treated with teclistamab, 6 in a safety run-in cohort, and 6 in the randomized portion of the trial, and we are pleased to report that 100% of those patients responded to therapy. We have an 83% complete response rate in those patients, and notably, a 100% rate of MRD negativity. That is 10-6, so that is the highest level of MRD negativity we have seen with this agent, particularly in this patient population.

What were the methods used in designing this trial?

This is a trial that has a safety run-in of 6 patients, just to show that this bispecific antibody, teclistamab, is safe to give to this group of patients. We completed that, and we did not see any dose-limiting toxicities, and now, it is a randomization of 2:1. They have a 2 out of 3 chance of having teclistamab or 2 years of lenalidomide and dexamethasone, so it is a fixed duration, 2-year study.

Who was included in this trial?

These are [patients with] high-risk smoldering myeloma. We have several criteria that we have established over the years to identify these patients. One model is the 20/20 model. If patients were the high-risk part of that criteria, they were included. But notably, we also included some other known high-risk criteria, including an evolving pattern. So, if they have a rise in their M protein concentration or light chains, those patients clearly have an increase in the disease burden and are at risk of developing myeloma. We included those patients. We also included high-risk patients that have high-risk FISH abnormalities.

What other initial findings from this study can you report on?

There were no safety concerns with the safety run-in, and there were no dose-limiting toxicities in terms of safety. In the teclistamab cohort, we had a cytokine release syndrome rate [CRS] of about 58%, but no patients had grade 3 CRS, and no patients had neurological toxicity, which was reassuring.

Infections are a concern with these agents. We know that from the relapsed/refractory patient population that the risk of grade 3 infections is almost 50%. Thankfully, we only had 2 incidents of grade 3 infections in this trial so far, and 1 was a case of sinusitis and 1 was a case of a salmonella infection. We are giving [intravenous immunoglobulin (IVIG)] to all patients that are on teclistamab in this study, and that is preventing some of the infectious complications we see with teclistamab. Plus, it is an earlier disease state, so you are not having as much immune dysfunction, which I think is helping as well.

In terms of efficacy, we have 100% overall response rate with the 83% complete response rate and 100% MRD negativity rate.

What are the implications of these findings?

This is a proof-of-concept study that, if you give these immunotherapies early, they work even better. That was our hypothesis going into the trial. We are showing that it is safe to do this with the safety profile that we have seen so far, and the activity is greatly enhanced if you give it early. The trial is still ongoing. We are going to be adding more arms of bispecific antibodies to this platform design trial as well, and then longer follow-up is necessary to see how durable these MRD-negative responses are.

What unmet needs still exist in the space?

There is no standard of care yet and there is nothing approved for patients with high-risk smoldering myeloma. That is why these trials are ongoing now, to see what the best approach is, and if we should intervene early in patients and prevent organ damage that occurs in multiple myeloma. If so, what is the exact best approach? Also, what is the best duration of therapy? These are all questions that are going to be answered hopefully in the future.

REFERENCE:

Nadeem O, Magidson S, MidhaS, et al. Immuno-PRISM: A randomized phase II platform study of bispecific antibodies in high-risk smoldering myeloma. Blood. 2023;142(Suppl 1): 206. doi:10.1182/blood-2023-177954