Trials in Relapsed/Refractory Multiple Myeloma

Thomas Martin, MD: Agreed. Because we have a lot of tools at our disposal, it makes it better for patients. I think early relapse—1 to 3 prior lines of therapy—that’s a scenario where we still want to be aggressive. I will say at ASH (American Society of Hematology), Dr Saad Usmani presented the CANDOR study, which was daratumumab with carfilzomib and dexamethasone (DEX) versus carfilzomib and DEX, and that showed an improvement in progression-free survival (PFS). It was not reached after about 20 months of follow-up in the daratumumab (DARA)/carfilzomib and dexamethasone (Kd) arm versus 16 months in the Kd arm, with a hazard ratio of about 0.63. There were better response rates in the triple versus doublet. Just recently, Dr Philippe Moreau presented the data from the IKEMA study at the European Hematology Association virtual meetings. The IKEMA study was using isatuximab (ISA) again with carfilzomib and DEX, and the carfilzomib was given at 56 mg/m2 twice weekly. It showed an unreached PFS in the triplet arm versus 18 or 19 months in the Kd arm after over 20 months of follow-up. That hazard ratio was 0.53, which was a good hazard ratio. These data are statistically improved, and I like the regimen of ISA/Kd or DARA/Kd in the relapse setting.

They also combined ISA with pomalidomide (POM) in the same 1 to 3 prior lines of therapy; the PFS was 11.5 months versus 6.5 months in the POM/DEX. That’s a good regimen; it’s very well tolerated.

In terms of the CD38 antibodies, where does it fit for you with your therapy now, and what do you think in a year from now? Will it be front-line for everybody, and then you’ll banter between one or the other? What do you think?

Yvonne Efebera, MD: Daratumumab is already in the upfront—DARA/bortezomib, lenalidomide, and dexamethasone (VRd); DARA/lenalidomide and dexamethasone (Rd)—for the transplant-eligible and transplant-ineligible, respectively. I did like the study with the ISA/POM/DEX. In fact, that’s an area isatuximab has been studied in upfront with Kd and even carfilzomib, lenalidomide, and dexamethasone (KRd), the 4-drug study. I think that’s been done in Europe. Given the robust minimal residual disease (MRD) negativity and the dip in the response, with very good partial response (VGPR) or better with CD38, it’s probably going to be a standard in terms of front-line therapy.

What we’re going to be faced with is once you use those as induction and then transplant, or no transplant but induction, and then maintenance, how long do you use CD38 as maintenance in addition to lenalidomide? It’s only 2 years from the study, but we don’t know. From the trials for the non–transplant-eligible, DARA maintenance with lenalidomide (LEN) has been used continuously; I still have like 3 patients on that study with the monthly maintenance and lenalidomide. Even though it’s completed and published, my patients are still on it and getting DARA and lenalidomide monthly.

Does it apply to patients who undergo transplant? Can DARA be given continuously with LEN? The question, once those patients progress—hopefully after median of 7 months or later—is what do you give them when they’ve been exposed to CD38? That’s the challenge: Will a second class of CD38, like isatuximab, be able to overcome the refraction of daratumumab once patients progress? I know there are studies looking at that.

Patients exposed to DARA were excluded in the study that was published with ISA/POM/DEX. I think it was only 1 patient that was exposed. Refraction to daratumumab were excluded, and patients who were exposed to pomalidomide were also excluded in that study. It will be nice to see how DARA fits into the DARA refractory and how ISA fits into the DARA refractory line. I’m sure as time goes, they’re probably going to compete with each other as first-line, in addition to the IMiD (immunomodulatory imide drugs) and proteasome inhibitor. What do you see?

Thomas Martin, MD:They were developed based on different in vitro findings. Isatuximab was able to do apoptosis without cross-linking, and that’s why it was selected. It was the best antibody that could induce apoptosis. I’m excited that it will be combined with carfilzomib because I think there’s synergy between the 2. We know from the ICARIA study that there’s also synergy with pomalidomide, for sure. Daratumumab was selected based on its ability to induce complement-dependent cytotoxicity (CDC). It’s a little different, and it doesn’t do apoptosis without cross-linking.

I do think there is a possibility that you can use 1 for front-line and another in the relapse setting. I do think that using 1 followed by the other within 3 months is probably not going to be successful. If you give a 6-month break and choose a different partner, I think that’s fine to go back to a CD38 antibody-based therapeutic. The nice thing with isatuximab, in terms of giving it, is the infusion-associated reaction rate is about 30% to 50%, and it’s typically grade 1/2. They don’t get a lot of pulmonary symptoms, which is great. We use acetaminophen and intravenous (IV) dexamethasone, either 20 or 40 mg or whatever the regimen calls for, an H1 and H2 blocker, and give that for at least the first 3 or 4 doses. On the package insert for ISA, on the third dose, you can give it over 75 minutes IV, which is actually pretty convenient. At 10 mg/kg, it’s a pretty effective dose. We’re just getting that up and running here at UCSF (University of California San Francisco); although we’ve used a ton of it in the research setting, we’re getting the standard-of-care drug up and going.

Transcript edited for clarity.