Isatuximab Plus Carfilzomib and Dexamethasone for Relapsed MM: Results From the IKEMA Trial
In this interview, Thomas Martin, MD, University of California, San Francisco, discusses results from a study IKEMA trial which explored the addition of isatuximab to carfilzomib and dexamethasone for patients with relapsed multiple myeloma (MM).
The latest update from the IKEMA trial was published in The Lancet (2021;397[10292]:2361-2371. doi: 10.1016/S0140-6736(21)00592-4).
What existing data led you and your coinvestigators to conduct this research?
Isatuximab is an anti-CD38 monoclonal antibody and we've been working with that antibody at UCSF for about 10 years now. Quite a few years ago, we thought a great partner for isatuximab would be carfilzomib for two reasons: (1) carfilzomib is a proteasome inhibitor, which induces apoptosis, and (2) isatuximab has the ability to induce apoptosis without prior crosslinking.
We hypothesized the 2 drugs would work together nicely and did some preclinical work in animal models showing in fact, there was synergistic activity between isatuximab and carfilzomib. We subsequently did a phase 1 study with isatuximab together with carfilzomib at standard dosing of 27 mg/m2 day 1, 2, 8, 9, 15, and 16 in a relapsed/refractory multiple myeloma (MM) population and saw very good activity, even in patients who had prior carfilzomib or were refractory to prior carfilzomib. In fact, in the phase 1 study, we showed an overall response rate in a very heavily protruded population of about 70%.
Building on that, we knew that carfilzomib was approved for use based on the ENDEAVOR study at 56 mg/m2, again, on day 1, 2, 8, 9, 15, and 16 with dexamethasone. This led us to conduct the IKEMA study, which was a phase 3 study assessing the addition of isatuximab to the standard approved dose of carfilzomib and dexamethasone vs just the standard regimen of carfilzomib and dexamethasone in a relapsed or refractory MM population. The aim of the study was to show that the 3-drug combination was better than the 2-drug combination, both in overall response rates, as well as the primary end point of progression free survival (PFS).
Could you briefly describe the study and its primary objectives?
The IKEMA study was a large, randomized, international, multicenter study that enrolled patients with relapsed and refractory myeloma who had received 1 to 3 prior lines of therapy. We actually excluded patients that had prior carfilzomib, but they could have had anti-CD38 antibody. They could not be refractory to prior CD38.
We randomly assigned patients in a 3:2 ratio to the triplet drug regimen of isatuximab carfilzomib and dexamethasone or carfilzomib and dexamethasone. Patients were also stratified by prior lines of therapy (1 prior line vs ≥1 prior line) and by revised ISS stage (ISS stage 1 or 2 vs ISS stage 3). These patients were treated on their particular study arm until disease progression, unacceptable toxicity, or until patients decided to come off therapy.
This was a very large randomized study and included 302 patients. The primary end point was PFS and secondary end points were overall response rate, the number of patients having a deep response and greater than equal to a very good partial response (VGPR). We also looked at minimal residual disease (MRD) negativity, the complete response (CR) rate and overall survival (OS).
Could you discuss the study findings? Were any of the outcomes particularly surprising?
I think it's important to note, in terms of baseline characteristics, that more than half of patients had received 2 to 3 prior lines of therapy. The median was 2 prior lines of therapy and about a third of the patients were refractory to lenalidomide; a quarter of patients had high-risk cytogenetics.
What we found with the overall response is a significantly improved chance of getting a deep response greater than VGPR or better in the 3-drug arm with 72.6% of patients achieving a VGPR vs 56% of patients in the 2-drug arm. That was quite substantial.
We also showed an improvement in PFS, a very significant improvement, where the median PFS in the 2-drug arm was 19 months and was not reached in the 3-drug arm after more than 20 months of follow up. We have further data coming in the next 6 months where we'll have hopefully achieved a median PFS that may be one of the longest seen in a relapsed/refractory MM trial.
In addition, we looked at MRD negativity and in the intention-to-treat population, about 30% of the patients receiving isatuximab, carfilzomib, and dexamethasone achieved MRD negativity while only 13% of the patients in the carfilzomib and dexamethasone arm achieved MRD negativity.
Isatuximab, carfilzomib, and dexamethasone was really a potent combination with higher overall response rates, higher VGPR or better rates and higher MRD negative rates.
What are the real-world applications of these findings?
This is a very potent combination, especially in patients that have 1 to 3 prior lines of therapy. We saw very deep remissions with an MRD negativity rate of about 30% and an improved PFS. The PFS is going to be in the high twenties to early thirties [months] and that’s one of the highest PFS out there.
Isatuximab is currently available by intravenous (IV) infusion and so is carfilzomib. I think this regimen bodes well together as they're both given by IV infusion. I don't think there's any changes or negative effects of having to receive an IV. In terms of the convenience, I think this is a great regimen where the convenience is the same using both drugs.
I also think we're going to have data looking at this combination in patients who have high-risk cytogenetics and specifically in those that have 1q21 gain. I think this is going to be a really potent combination in this subset of patients and I'm really looking forward to seeing what the median PFS is there.
Is there anything else pertaining to your research and findings that you would like to add?
We also did a number of pre-specified subgroup analyses in patients who were older, patients that had advanced stage disease, patients that had renal insufficiency, and patients who had prior stem cell transplant (all high-risk subgroups). In fact, all the patients benefited receiving the 3-drug combination vs the 2-drug combination. This is a regimen that I think can be used broadly in all relapsed patients.
In the United States, where we have a lot of patients receiving lenalidomide, and IMID, as maintenance, I actually like to switch the classes if they're refractory to the IMID. At first relapse or potentially second relapse, if they're refractory to lenalidomide, I think isatuximab, an anit-CD38, plus carfilzomib, a proteasome inhibitor, combined with and dexamethasone really is a nice combination. I have been using it in those patients who are lenalidomide refractory and need salvage therapy because it's a great regimen.
