Clinic Conversation of the Week: How to Talk to Patients About the BENEFIT Trial in Multiple Myeloma

This episode is also available as a podcast. Click here to listen!

What Is the BENEFIT Trial?

The BENEFIT trial, which studied isatuximab, lenalidomide, dexamethasone, and bortezomib in transplant-ineligible multiple myeloma, was published earlier this year in Nature Medicine. I’ll be talking about this as if it was one of my patients coming to me with a copy of this paper in their hand that a friend or loved one forwarded to them. What do I tell them?

Here’s What I Would Say…

“So, thank you for asking about this study. I think it’s a very interesting one. The BENEFIT trial was a study of four drugs versus three drugs in patients with newly diagnosed multiple myeloma, who were starting treatment and for whom autologous stem cell transplant or a bone marrow transplant was not planned. For many of our patients in the US who are older, over the age of 70 or 75, our default is possibly to consider transplant, but we don’t really push for it. What do we do for those patients in whom transplant is not planned?

Historically, we’ve been giving patients three drugs—for example, a regimen like Dara-Rd or Isa-Rd. Dara-Rd is daratumumab (Darzalex Faspro^®), R is lenalidomide (Revlimid^®), and dexamethasone or steroids. That works quite well for patients. There was a study of that regimen called the MAIA trial where patients, even without getting a bone marrow transplant, were in remission for five years on average with that regimen. These, again, are patients who are older, a little bit less fit, for whom transplant honestly might have had real harms. A lot of patients are nervous about giving up on transplant. It’s great with Dara-Rd—again, five years of benefit on average. The question is, can we build on that?

So, what the study did was rather elegant. Now, they did not use daratumumab; they used isatuximab (Sarclisa^®), which is now approved in the US for upfront usage. At the time, it wasn’t in the US. It was, to be fair, a French study, not a US study. They gave patients the default. It was a randomized study. Patients were newly diagnosed, not yet started a treatment, and were randomly assigned to get either Isa-Rd or Isa-VRd. Isa-Rd is isatuximab, lenalidomide, and dexamethasone, which is very similar, I would argue, to Dara-Rd—kind of our default. The other half of patients got that, but also got bortezomib (Velcade^®). That’s an injection once a week. In patients who are getting transplant, we routinely use bortezomib for those patients.

What they found was actually that there was a benefit to adding bortezomib in the BENEFIT trial. There was a benefit to adding this once-per-week injection called bortezomib for these patients. It’s a benefit in terms of measurable residual disease (MRD) negativity, which is a long discussion; but long story short, the reason it’s relevant is that MRD is a very sensitive measure, of cells hiding in the bone marrow. Even one in a million cells in the bone marrow, MRD tests can pick out. Being MRD-negative doesn’t equal cure, but it’s certainly a good sign. They found that the group that got once-weekly bortezomib added on did have much higher rates of MRD negativity even within a year of being diagnosed.

We’re going to find out in a couple of years if that corresponds to patients being in remission for longer and feeling better—because the whole point of care for multiple myeloma is to live longer and live better, and ideally to live longer in remission. We don’t know yet, but the nice thing about this is because they looked at that end point of MRD negativity, they’re able to tell pretty quickly that you don’t need to wait four to five years to say that four drugs were better than three drugs. You found out pretty quickly.

This is really a big deal for our field. Again, historically for patients who are going to transplant, we would be giving them four drugs like Dara-VRd or in this case Isa-VRd with the bortezomib. And if we’re not going to transplant, we’d give them three drugs—for example, Dara-Rd, or less commonly, VRD lite, another regimen here. Now they show that even for patients for whom transplant is not planned, four drugs did seem to have a benefit.

Again, if you were to ask, does giving four drugs, if I’m not going to transplant, make me live longer or live better? I don’t know yet. Hopefully it will, because certainly the early science suggests that, based on MRD negativity showing not much disease in the bone marrow, but we’ll find out. I think it’s really changing the field here for patients like yourself. Because if I think that you could get four drugs, I think that you are someone who’s eligible to get four drugs in terms of your side effects. Bortezomib, for example, does have a side effect of neuropathy, of nerve tingling in the fingers or pain in the fingers and toes. If I think that’s a good drug for you, I’m not going to withhold it just because you’re not planning to go to transplant.

I think now, instead of me looking at patients like yourself and deciding everything based whether we are going to do this transplant or not, it’s more deciding if I think you can get four drugs versus three drugs. If I think you can get four drugs with bortezomib, let’s do it and then let’s ask questions later down the line. We can decide about whether to do transplant or not.

So, I think it’s a very big study in the field for patients like you who are coming to me right now or deciding whether to get four drugs versus three. I would say, talk with your doctor about it. In general, I think the study is changing the field so that if you think you could get four drugs and your doctor thinks you could get four drugs, I’d rather start with that and ask questions later. If it works, it works well (transplant or no transplant). If it causes too many side effects, we can always go back down to three. But I think now moving to four drugs as a starting point, a quadruplet, so to speak, is always helpful to think about with patients and discuss it from there.”

About Dr. Banerjee

Rahul Banerjee, MD, FACP, is an Assistant Professor in the Division of Medical Oncology at the University of Washington. He also holds a faculty appointment at the Fred Hutchinson Cancer Center in Seattle, Washington. Dr. Banerjee previously completed his Hematology/Oncology Fellowship and Advanced BMT/CAR-T Fellowship at the University of California, San Francisco. His clinical interests are in multiple myeloma, AL amyloidosis, and CAR-T therapy. His research interests are in toxicity management, digital health, and the patient experience.