Ryan Haumschild, PharmD, MS, MBA: When we talk about transplant-ineligible patients with multiple myeloma, 1 question that comes up is when a patient achieves an adequate response, do we place them on maintenance therapy? What are some widely used treatments that we use in maintenance therapy?

Omar Nadeem, MD: In terms of response assessment in general in myeloma, we still use traditional methods—serum protein, electro for C, and serum free light chains—and then bone marrow results to identify or describe the response. But as we’re learning more about the disease, and particularly the prognosis, we’re using some tools such as minimal residual disease [MRD] testing on the bone marrow. We’re not using that to make treatment decisions, but it’s prognostic for patients. That information could be valuable.

Then you have to think about the setting in which you’re doing these assessments and whether it’s making a difference in terms of the treatment plan. In transplant-eligible patients in their 50s who are undergoing quadruplet therapy and transplant, and then going on to subsequent therapies, that’s a different population from somebody who’s 75 to 80 years old who has different comorbidities, which is the classic transplant-ineligible population. The goals are a little different. What you’re trying to do in that second population is control the disease and allow the patients to have a good quality of life, hopefully with minimal therapy on board, so they can enjoy a good quality of life for as long as they have. I think of those as different when I’m talking about goals of therapy and response, particularly targeted responses.

In older patients, the goal is to give them a triplet [therapy], get their disease down, and then leave them on some therapy that’s going to keep it away. The word maintenance comes into play in that setting. But maintenance was used post-transplantation. That’s where the term was created and the intent was to maintain the response post-transplant. It gets transposed into the other settings, which is essentially continuous therapy. As we learned, the MAIA study was continuous therapy. There’s no maintenance as part of it, although we think of it that way. Patients go through their first phase and then go on some therapy afterward, depending on which arm it was. Lenalidomide has always been the most common continuous therapy agent. It’s shown the most benefit, particularly post-transplantation. With some of these other trials, we’re learning that you can give a second agent and it’s well tolerated, such as daratumumab given once a month. Patients tolerate it extremely well, and now that it’s subcutaneous, it’s even easier. You can leave patients on daratumumab and lenalidomide in that transplant-ineligible setting for a long time without much day-to-day toxicity.

There are some risks with all these therapies. There’s a risk of infection with the continuous use of CD38 monoclonal antibodies. That comes into play for patients, particularly older patients in the [pandemic] environment of the last few years. Generally speaking, you’re able to keep people on that type of regimen for a long time, particularly in the transplant-ineligible space. In terms of the best maintenance combination, we have several trials that have looked at lenalidomide and a combination of a CD38 and lenalidomide. There are also trials that have looked at a proteasome inhibitor plus lenalidomide maintenance, particularly post-transplant, showing the benefit compared with lenalidomide alone. Which of those is the best and which is ideal for which patient? We don’t know. Some subpopulations benefit from the proteasome inhibitor in particular. We think about high-risk patients, particularly those that may preferentially benefit from continuous proteasome inhibitors, but that piece isn’t clear. We’re moving toward having multiple agents with some patients, at least to start, particularly with high-risk disease. Then we’ll tailor it to the individual patients and hopefully get them on minimal therapy.

Ryan Haumschild, PharmD, MS, MBA: Thank you for talking us through the logic behind it, how you’re keeping some patients on a CD38 in maintenance, and looking at patients who have a succinct pathway. I want to talk about daratumumab. Do we use it in the frontline setting and get a deeper response, or do we save it for later lines of therapy? Dr Lipe, can you talk about this and any studies that analyze outcomes among patients who receive daratumumab in the frontline setting vs the second line?

Brea Lipe, MD: I’m glad I got this question because I hear this a lot from other providers. I like to push back on it because it’s important that patients get our best therapies up front. Part of the reason we know that is because depth of response is prognostic in myeloma across any subgroup you pick: transplant eligible, transplant ineligible, high-risk disease, standard-risk disease. Patients who achieve MRD negativity do better overall than those who don’t. That’s real evidence for why we need to use our best agents up front. Our data have shown that daratumumab is 1 of those drugs. You can look at the MAIA, GRIFFIN, and MASTER studies. All of those studies demonstrate a phenomenal depth of response with the additional daratumumab.

There’s another reason we need to remember that using these drugs up front is important. In the MAIA trial specifically, they looked at PFS2 [progression-free survival 2], which is how we described the time from relapse of the second event. They found that PFS2 is maintained and that overall survival is still improved in patients who got daratumumab up front vs later. When you compare those populations, a trial—a database collection from an electronic health record—analyzed patient treatment paradigms. The [researchers] looked at patients who had gotten daratumumab in the frontline setting with DRd [daratumumab, lenalidomide, dexamethasone], patients who got RVd [lenalidomide, bortezomib, dexamethasone] up front, and patients who got Rd [lenalidomide,dexamethasone] up front. They found about a 2-year overall survival benefit for patients who got the DRd [daratumumab, lenalidomide, dexamethasone]. Depth of response and duration of response are 2 real reasons we want to use our best drugs up front.

The other thing to remember is that the attrition rate for some of our patients, especially our transplant-ineligible patients, is pretty high. Only 43% of patients get second-line therapy after their first relapse in the transplant-ineligible population. Less than half of our patients are getting onto the second line of therapy. If we don’t know that they’re going to have the opportunity, saving an agent for later doesn’t make a whole lot of sense. Maybe this is the optimistic part—some people might think it doesn’t exist, but it does—but new therapies in myeloma are coming. When I look at the pipeline for myeloma and realize how much better our treatments are getting, the fear that I had—what am I going to do when this fails?—is different. I have a whole armamentarium of drugs to give people that can be effective in the relapse setting. Those are some of the reasons that it’s important that we give daratumumab or our best agents up front, whatever you think those are.

Transcript edited for clarity.