Isa-EloPD Shows Promise in Multiple Myeloma Management

Binod Dhakal, MD, MS

The combination of 2 different monoclonal antibodies with dual targeting of CD38 and SLAMF7 led to promising safety and efficacy data when used for the treatment of patients with relapsed/refractory multiple myeloma, according to findings from the phase 2 IMPEDE trial (NCT04835129).

Response evaluation showed there to be an 80% overall response rate (ORR), with 6 patients achieving a very good partial response or better. The progression-free survival (PFS) rate at 12 months was 67% (95% CI, 45%-99%). Five patients discontinued, mainly due to disease progression, and while lymphocyte analysis indicated changes, natural killer (NK) cell activity remained stable throughout the study.

In the study, 15 patients with relapsed/refractory multiple myeloma were enrolled and treated with isatuximab (Sarclisa), pomalidomide (Pomalyst), elotuzumab (Empliciti), and dexamethasone (Isa-EloPD). The median age of patients included was 68 years (range, 54-79), 3 were African American, all patients had disease that was refractory to lenalidomide (Revlimid), and 3 patients had disease that was refractory to both bortezomib (Velcade) and lenalidomide. Further, 6 patients were previously exposed to anti-CD38 monoclonal antibodies, and 11 (73%) patients had presence of high-risk cytogenetics.

Investigators evaluated the primary end point of ORR and secondary end points of safety, duration of response, PFS, and overall survival.

All 6 patients in the safety lead-in cohort completed at least 2 cycles of treatment, while the rest completed at least 1. The median follow-up was 8.5 months (range, 1-16.6), and none of the patients experienced any dose-limiting toxicities during this phase. Grade 3 to 4 adverse events occurred in all patients, with lymphopenia and neutropenia being most common (93% each). Only 1 patient had a grade 3 to 4 infection, no grade 5 events occurred, and infusion reactions were rare, only occurring in 1 patient.

In an interview with Targeted Oncology^TM, Binod Dhakal, MD, MS, assistant professor of medicine in the Division of Hematology and Oncology at the Medical College of Wisconsin, discussed the phase 2 IMPEDE trial, focusing on the treatment regimen Isa-EloPD for patients with relapsed/refractory multiple myeloma.

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Targeted Oncology: Please explain the rationale behind the IMPEDE study.

Dhakal: This is a phase 2 study combining elotuzumab and isatuximab to the backbone of pomalidomide and dexamethasone in patients with relapsed and refractory multiple myeloma. This study also has a safety lead-in phase because this combination has not been tested before, so [we] want to look at the safety of the combination as well. The primary objective of the study, it being phase 2, is to look at the efficacy of the combination, so the overall response rate is the primary end point. The secondary objectives included the safety profile of the combination of the isotope isatuximab with elotuzumab, pomalidomide, dexamethasone, and the number of other secondary objectives included very good partial response rates and better [minimal residual disease (MRD)] negativity rates at 10-5 by next-generation sequencing, duration of response, progression-free survival, and overall survival.

We also looked at a correlative objective. NK cells are needed for the acuity of the electrodes, but the NK cells have CD38-expressing in them and can be depleted by CD38-blocking antibodies like daratumumab [Darzalex]. We wanted to look at the change in the lymphocytes population, looking at different lymphocytes, including NK cells. During the treatment with this combination, we also looked at the NK cell function, not only the number, especially in the first 2 cycles. This is mainly focused on patients for the safety lead-in.

How was the study designed? What criteria were used to select patients eligible for enrollment?

The inclusion criteria included patients with the 2 prior therapies that [were] exposed to proteasome inhibitors and lenalidomide. The 2 prior therapies would include patients even with a single agent or in combination and those who have been exposed to a proteasome inhibitor and lenalidomide. For example, the typical patients who had induction, transplant, and were refractory to maintenance, especially if they have been exposed to [a proteasome inhibitor] and lenalidomide, they could be eligible. We also allowed the prior anti-CD30 antibody exposure as long as the patients were not refractory to the antibody.

For the exclusion criteria, we did not allow the prior use of anti-SLAMF7 antibody. Right now, we have only 1. Also, we did not allow the prior [exposure] to pomalidomide. These are the key exclusion criteria. Besides that, the rest of the standard exclusion criteria applies to this as well as compared with the other products on the trials.

How does the dual targeting of SLAMF7 and CD38 contribute to the potential efficacy of treatment?

CD38 is expressed in the majority of the myeloma cells, and SLAMF7 is also expressed in the myeloma cells. Studies previously have shown that simultaneous expression of CD38 and SLAMF7 is present in almost about 97% of primary multiple myeloma cells, suggesting that targeting both these antigens at the same time could provide a synergistic approach. We do not know whether this approach is going to be efficacious or more effective than compared with single antigen targeting of what we have [and] what is approved by the FDA. We hope that the combination with the backbone of pomalidomide, dexamethasone is going to be more effective than binding it as a single agent.

When [we] look at that, we also want to make sure that it is a safe combination. We do not want to have additional toxicities by combining this, we want to look at both efficacy and safety at the same time. We hope that this combination is going to be much more effective than just binding 1 antigen. We have studies ongoing and what we have seen in the first group of patients that we imported the data [from], we think that we are going to serve the 2 goals of more effective and a safe combination with this approach.

How was success measured in terms of patient outcomes and treatment efficacy?

The primary end point is overall response rate. The overall response rate is measured based on International Myeloma Working Group criteria. After the patient finished at least 1 cycle of treatment, we look at the response and in addition to that, we look at a number of secondary end points. The safety events will be measured based on the adverse events and we compiled that. Then for the first 6 patients, which comprise the safety lead-in, we have to define dose-limiting criteria and dose-limiting toxicities. These patients have been enrolled in a fashion that they have to meet certain safety criteria based on dose-limiting toxicities, and then they can go onto the expansion phase. That is how we met the safety. While the patients are in the expansion phase, there is, as based on the [dose-limiting toxicities], a protocol or the stopping rules based on the number of safety events that happened in a certain number of patients. Then we go from there.

In terms of other end points like duration of response, progression-free survival, overall survival, we use the standard criteria to measure that for the correlative end points. It is pretty simple; it is correlative, so it must have things done in the lab. We look at the population, the specific descriptive analyzes, using the number of lymphocytes, and the change in the lymphocytes over time.

In your opinion, what were the most exciting findings from this study?

As of the data cut off of 15 patients, and that includes 6 patients in the safety lead-in, if you look at the overall patient population, the median age was 68 years, which is pretty standard for [a patient with] myeloma, ranging from 54 to 79. All patients [were] lenalidomide-refractory and had prior use of an anti-CD38, that was mainly daratumumab used in 6 patients. About 73% of patients had evidence of high-risk cytogenetics. All 6 patients completed the safety lead-in phase. That is where we were able to expand some phase that means that they must complete at least 2 cycles of the treatment. In those 6 patients who completed at least 2 cycles, we did not observe any dose-limiting toxicities, which is pretty good.

In terms of overall patient population the grade 3/4 treatment-emergent adverse events we saw in all patients were mainly hematological adverse events, lymphopenia [in] 90% neutropenia in 90%, which are pretty manageable with either a dose reduction or a dose delay or with the growth factor support. Grade 3/4 infection was seen in 1 patient. That was mainly complicated by RSV infection, so it is difficult to say whether it is related to the combination. The infusion-related reaction, because there was 1 of concern with a combination of 2 different molecule antibodies, we were only able to see it in 1 patient, and that was a maximum of grade 2. So safety-wise, what we saw was pretty promising.

In terms of efficacy, it is pretty early, but all patients are at least on 1 cycle so they all are evaluable for response, and the response was about 80%. That means at least 80% of patients had partial responses or better in the International Myeloma Working Group criteria. In terms of depth of response, 40% of the patients had a very good partial response rate or better. None of the patients had a complete response. That partly could be from the use of 2 antibodies. The 12-month PFS was 67% at the last follow-up, and out of 15 patients, 5 discontinued the study treatment. Disease progressed in 1. I think this is the safety and efficacy data that we have and when we looked at them, those correlative studies were done in 6 patients in the safety lead-in phase. We saw that there is a decrease in lymphocyte subpopulations, specifically NK cells populations, in the first 2 cycles, but after the third cycle, we can start seeing the increasing numbers. For unknown reasons, we also saw that while the other lymphocytes and NK cells were decreasing, the monocytes were increasing in the first 2 cycles. We do not know why that happened, but when we specifically look at the NK cell cytotoxicity by melanocyte devices, that more or less remained unaffected.

One of the concerns of the depletion of the NK cells and potentially impacting the NK cell function, at least even though there was a decrease in the NK cell number, we did not see the decline in the function, which is pretty good. In the first ever combination of these 2 monoclonal antibodies with the dual targeting of CD38 and SLAMF7, we found that the combination was safe with no dose-limiting toxicities. The combination also resulted in no impact on the NK cell function, despite the decline in the NK cell number. The most common adverse events were cytopenias, but there is no significant increase or higher grades of infections, or the inflammatory reaction.

In terms of efficacy, it is pretty preliminary, but 80% response rate in this patient population with a 12-month progression-free survival [rate of] 67%. It compares favorably with other agents. Looking at this when compared with the single agent targeting of either CD38 or SLAMF7, I think this compares favorably, at least at this point of time. The study is ongoing. Total accrual is about 53 patients. I think we are going to get more information about this combination once we accrue all the patients. One thing I also want to point out is that the patients who are CD38-naive had a 100% response rate.

If successful, how might these findings influence future treatment strategies for relapsed/refractory multiple myeloma?

It is a phase 2 study, but this will form the basis of either the phase 3, depending on the activity, or going forward for the development of newer compounds, newer agents that could potentially target these 2 entities at the same time, like in the form of bispecific antibodies or trispecific antibodies. I think this forms a kind of basis of using this to target at the same time in myeloma. I think that is what I think I could say at this time, but more information and the implications will all depend on how the study sews once we complete all the on the patient enrollment.

Are there any potential applications for dual targeting and other hematologic malignancies or cancer types?

In myeloma, this 1 target has not been enough, at least not being a curative. People still relapse, despite that 1 part of it being effective. There is a lot of interest in targeting the 2 antigens at the same time. There is a trial in lymphoma and that could apply to other cancers, like solid tumors as well. But in myeloma, this is based on what we have seen with the single-agent activity. It is highly effective, but at the same time, [it is] not able to maintain that activity for a long time and people [are still] relapsing. I think there is a lot of interest in combining those [with an] early preclinical presentation that was done at [the American Society of Medical Oncology Annual Meeting]. That study was presented before. It combined CD19 and BCMA in myeloma as well as CD19, BCMA-CD38. Going forward, all these combinations [may] be seen. The question is whether combining these at the same time would be beneficial vs just using a single agent at 1 time, and then perhaps, sequencing with the other 1 after that. That question needs to be investigated as well.

REFERENCE:

Dhakal B, Mohan M, Narra R, et al. Dual targeting of slamf-7 and CD38 in multiple myeloma (MM): A phase II study of isatuximab, elotuzumab, pomalidomide and dexamethasone (Isa-EloPD) in relapsed and/or refractory MM (RRMM). Presented at the 2023 American Society of Hematology (ASH) Annual Meeting and Exposition; December 9-12; San Diego, CA; 3379.