Using PI-based Combinations in RRMM

Paul G. Richardson, MD: Saad, tell us about your own work with CANDOR, particularly the value of a PI [proteasome inhibitor] combined with a monoclonal antibody. It was pivotal work. Congratulations on the FDA approval very recently. That was terrific, Saad. In that same spirit, I would love for you to comment on IKEMA, recognizing that has also been fascinating and very much validates CANDOR. Finally, if you wouldn’t mind spending time on BOSTON, I think that’s a very important study.

Saad Z. Usmani, MD: I can talk about CANDOR and IKEMA, because in many ways they’re validating the PI/anti-CD38 monoclonal antibody combination regimen efficacy, safety, and tolerability. Even though the clinical trial designs were different, the schedule of giving the anti-CD38 monoclonal antibody is different. Both studies came out positive in favor of the 3-drug combination vs the 2.

CANDOR is a 2-to-1 randomization, whereas the IKEMA study was a 3-to-2 randomization. The number of patients and all those nuances of median follow-up would be a little different. Regarding patient populations, even though they’re a little different, about a third or more of the patients in both studies are lenalidomide refractory, especially as the previous line of treatment. That’s the patient population that’s perhaps more relevant to clinicians in the United States. We’ve talked about continuing maintenance until relapse or progression, and we’ve talked about looking at improving on that lenalidomide maintenance platform. But many of our patients are going to have good exposure to lenalidomide maintenance and then escalated doses of lenalidomide in many cases as well. Overall, that’s where the most value is.

The CANDOR data, after a median follow-up of about 27 months, showed a median PFS [progression-free survival] of about 28.6 months compared with 15.6 months on the Kd [carfilzomib, dexamethasone] arm. In the IKEMA data set, the data are not mature, so the median PFS on the isatuximab–Kd [carfilzomib, dexamethasone] arm has not been reached, but that on the Kd [carfilzomib, dexamethasone] arm has been reached.

One of the striking differences, and the credit goes to the IKEMA investigators, is for the immunofixation-positive patients who are not getting evaluated for MRD [minimal residual disease]. The investigators went back and looked at mass spectrometry to see if it’s the antibody interference, and that may have played a role in not having enough MRD assessments on that study. From the look of it, if you look at the MRD-negativity rates, in CANDOR they’re about 23% compared with 6% or 7% on the control arm. Whereas in the IKEMA trial, they’re about 30% vs about 11% or 12%. Overall, a stark difference between the 3-drug platform vs the 2-drug platform.

For the safety profile, there are higher rates of infection when you combine an anti-CD38 with a PI like carfilzomib, and that’s what was observed in both the studies. Interestingly, there was a lower incidence of grade 2 or higher cardiac events in the daratumumab-containing arm of CANDOR compared with the Kd [carfilzomib, dexamethasone] arm. In the IKEMA study, the grade 3 or higher was similar across the 2 arms. Therefore, no major cardiac signal was observed by addition of an anti-CD38 to carfilzomib. Notably, that was 1 of the main concerns early on with the initial phase 1 study experience.

Turning to the BOSTON trial, I think David has already highlighted how important the exportin 1 inhibitor mechanism [XPO1] of action may be, especially for the high-risk patients. He talked about the TP53 protein enrichment within the nucleus in patients with deletion 17p. The BOSTON trial validated the PI plus XPO1 inhibitor platform in the BOSTON study in early relapse setting. The most impressive part of that study to me was that deletion 17p, as well as translocation 4,14 patients, benefited in terms of PFS to the same degree as the standard-risk patients. The median PFS in those subgroups of patients was like the overall population. That difference was not seen for the translocation 14,16 group, but with the caveat that they were even a smaller number of patients with that. They also commented on the 1q21 amplification patients; the benefit was similar.

Tolerability was certainly better with the once-weekly lower dosing of selinexor at 60 mg. Even though this is not part of the current discussion, I was very impressed with the carfilzomib-selinexor arm of the STUMP trial because the data were better. That’s probably where we will find a lot more use of the selinexor triplet combinations in relapsed/refractory disease.

Nina Shah, MD: I totally agree with that. I think SKd [selinexor, carfilzomib, dexamethasone] is the best selinexor combination. Not to get off topic, but that’s where people might have been exposed to bortezomib before. I want to see SKd [selinexor, carfilzomib, dexamethasone] vs K-POM-d [carfilzomib, pomalidomide, dexamethasone] because it could possibly be useful for our high-risk patients, as Paul was pointing out.

Paul G. Richardson, MD: I agree. The carfilzomib data from Cristina Gasparetto were excellent. In fact, to that end, in the groups in the Alliance [for Clinical Trials in Oncology] and hopefully SWOG and ECOG-ACRIN [Cancer Research Group], they’ll be actually developing ideas looking at selinexor, carfilzomib, pomalidomide, and dexamethasone, to see where we might go with platforms as powerful as that to overcome this particularly dangerous high-risk group. Excellent summary, Saad. Thank you so much.

Transcript edited for clarity.