Ryan Haumschild, PharmD, MS, MBA: Can you please review the rationale and study design of the 5-year efficacy and safety findings of the MAIA study [NCT02252172]? If you could, maybe we can build upon that a little bit in talking about the subgroup analysis that was evaluated during the response of the patient-reported outcome.

Raymond Thertulien, MD, PhD: Thank you, Ryan. To actually understand the rationale for this study, I’ll give you a historical perspective on the treatment of multiple myeloma. If we go back perhaps 20 or 25 years ago when we were still using dexamethasone as induction treatment and using dexamethasone day 1 to 4, 9 to 12, and 17 to 20, we were also using dexamethasone in the relapse setting because we didn’t have effective agents for multiple myeloma. When lenalidomide was approved in the early 2000s, it was actually compared [with] dexamethasone in the relapse setting in trials MM-009 [NCT00056160] and MM-010 [NCT01712789], and that’s when lenalidomide + dexamethasone was proved to be superior to dexamethasone in the relapse setting. Subsequently, we had this SWOG [Southwest Oncology Group] trial 0232 [NCT00064038], which means that this trial was actually designed in 2002, and the ECOG [Eastern Cooperative Oncology Group] trial E4A03 [NCT00899080]. These 2 trials actually compared lenalidomide + dexamethasone, “little dex” as we call it [dexamethasone weekly at 40 mg], with lenalidomide + “big dex.” And the “big dex” was what I quoted: days 1 to 4, 9 to 12, and 17 to 20. What was found in those trials was that lenalidomide + little dex…was actually superior in overall survival vs big dex because of infections when you expose patients to a lot of dexamethasone. Lenalidomide + little dex, with 40 mg weekly, was adopted as standard, and then there was the first trial––and I remember I was in the ASH [American Society of Hematology] audience for it––where they compared lenalidomide + dexamethasone 40 mg weekly [little dex] as a continuous treatment vs lenalidomide + dexamethasone for 18 months vs MBT [melphalan, prednisone, and thalidomide], which was a regimen that was developed in Europe. Lenalidomide with dexamethasone 40 mg weekly was actually superior to both of these regimens. So in the transplant-ineligible patients, lenalidomide + dexamethasone [40 mg weekly] was established as a standard treatment.

Then daratumumab [Darzalex] was approved in 2015, and at that point, we were all thinking in the field of combining regimens. We were doing doublets until that time, and the opportunity came to actually start triplets, and we felt that we could add daratumumab to any doublets, hence the POLLUX trial [NCT02076009] in the relapse setting. So the POLLUX trial was daratumumab + lenalidomide + dexamethasone vs the standard at the time, which was lenalidomide + dexamethasone. Clearly in the POLLUX trial, we knew that the triplet was very superior to the doublet, and that was in the relapse setting. So it is completely logical to try to bring that regimen in[to] the frontline setting, hence daratumumab + lenalidomide + dexamethasone vs lenalidomide + dexamethasone in the transplant-ineligible patients as first-line treatment. This trial was designed almost the same way as POLLUX except that those patients were patients ages 45 to 90 [with new diagnoses]. We had a whole breadth of patients, and as Dr Nadeem mentioned, myeloma is a disease of older patients, and so those patients were in fact included in that trial, so high-risk cytogenetics were included in that trial at 14%. The trial was a simple design; it’s a triplet, daratumumab + lenalidomide + dexamethasone, vs a doublet, and you randomize the patients 1:1. What I’d like to point out to my colleagues is that this trial was for continuous treatment until progression of disease, and that’s a very important point. It’s 28-day cycles, with lenalidomide day 1 to 21 and dexamethasone weekly. We have daratumumab given weekly for the first 2 cycles for 8 weeks, and then every other week from cycle 3 to cycle 6, and then monthly with lenalidomide + dexamethasone the exact same way as the control again, until progression of disease. It was a very well-designed trial. The only fault that I had with the trial is that they only had 4% Black [patients] in the trial, and we know Black [patients] are affected more than twice as much as White [patients] in terms of multiple myeloma. But it was a very well-designed and well-run trial, and in fact, when you look at the data, daratumumab + lenalidomide + dexamethasone was very well tolerated, and it was superior. The 5-year data that you mentioned were just released recently with progression-free survival of 53% vs 29% for the doublet, and in fact, when the first results were released at 30 months, the data were not yet mature to actually see overall survival. So when the 5-year data [are] released, at that point we start seeing overall survival benefit at 5 years, with 66% overall survival for daratumumab + lenalidomide + dexamethasone vs 53% for lenalidomide + dexamethasone, with the hazard ratio of 0.68. You have a 32% reduction in the risk of death for the triplet vs the doublet. The triplet is very efficacious in that age group in the transplant-ineligible patients.

In terms of safety, we expect more safety signals in the triplet, and in fact, you get infusion reactions that we all see with daratumumab and it wasn’t that different from what we know about the drug. There were 37% infusion reactions, and most of them occur during the first cycle. In fact, during the first week, you get most of the infusion reactions, and in subsequent weeks you get 6%. At 5 years we did not see any new unexpected adverse events besides the infusion reactions. I always tell my colleagues to look at the respiratory systems. There were upper respiratory infections, cough, bronchitis, dyspnea, [and] pneumonia, and all of these say to me that this regimen affects the respiratory system and we need to be aware of it. Then of course we have the GI [gastrointestinal] toxicities, diarrhea, constipation, and nausea, but not a lot of vomiting, and there is some peripheral neuropathy. There are a lot of hematological toxicities––almost 100% of patients did develop some hematological toxicities; 91% developed neutropenia, for example, and there was some lymphopenia, thrombocytopenia, and anemia. We have to look for that, but we are hematologists, so we know how to take care of cytopenias. But it’s a very well-tolerated regimen.

Ryan Haumschild, PharmD, MS, MBA: Excellent. I appreciate your giving us that background on the regimen, because I think it was such an important trial. Like you said, when we’re dealing with plasma cell disorders, we want to treat these patients almost [as though] multiple myeloma were a chronic disease. How do we give them that overall survival and how do we give them that progression-free disease where we can provide longevity of life? I think that’s the ultimate goal, right? We’re working toward…establishing it through shared decision-making with patients.

Transcript edited for clarity.