The Impact of Evolving Treatment Options in Multiple Myeloma, Part 6

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A panel of experts in multiple myeloma review the use of quadruplet therapy in clinical practice and the impact on patients’ depth of response.

Bruce A. Feinberg, DO: Ryan, are any patients receiving any quadruplet therapy outside of the clinical trial at this point?

Ryan Haumschild, PharmD, MS, MBA: Yes, our general approach is working up patients to determine if they’re transplant-eligible or not. If they’re transplant-eligible, we stratify them to the high-risk treatment. If they’re high risk, they may get KRd [carfilzomib, lenalidomide, dexamethasone]. But if they’re low risk, we were doing RVd [lenalidomide, bortezomib, dexamethasone], but now we’re looking at D-RVd [daratumumab plus RVd], putting that CD38 now as part of that standard of care.

I think it’s an internal decision when we’ve looked at some of these outcomes, and based on our research utilizing these agents, and based on some of the GRIFFIN trial, we’ve determined that patients have the best chance using RVd and adding on the CD38 with more of the low risk. I don’t have those data in front of me about how those with high-risk disease perform, but I know that we’ve gotten better, deeper responses using KRd in that patient population.

Joseph Mikhael, MD: Part of the concept there is, you don’t want to undertreat the standard-risk patient, who could have the deepest and most durable remission. This notion that you give high-risk patients more and standard-risk less is maybe not the way we’re thinking about it as much as saying we want to give the best possible treatment to our standard-risk patient. In the higher-risk patient, we may have to make some adjustments. The big adjustment there, as opposed to going from 3 to 4 agents, in the Emory Winship Cancer Institute system, is to go from bortezomib to carfilzomib.

Carfilzomib is a more intense proteasome inhibitor, has a greater activity in high-risk patients, and has proven itself at least in the frontline setting even more. I know when we saw Emory’s decision, we had a bit of the same reaction you did, Bruce, saying, “Wait a minute. Scratching my head. You’re giving quadruplet therapy to the standard and triplet to the high risk? What’s going on here?” But that was part of the rationale, if I’m understanding the Emory system correctly. My gut feeling is that was a step toward thinking when the data are more mature, they may be considering D-KRd [daratumumab plus KRd]. So, the quadruplet with the carfilzomib instead of bortezomib for high-risk patients in the near future, but the data weren’t quite mature yet.

Ryan Haumschild, PharmD, MS, MBA: You summarized it great. That’s exactly the case.

Bruce A. Feinberg, DO: Tom, you listened to these guys, and this is what they do. They eat and breathe and live this. You’re dealing with 200 different cancer types in your practice that you have to also be aware of, and yet you were telling me that there’s already talk in the practice of using quadruplet therapy. Has it actually started to be used?

Thomas Ollis, MS, RPh: I think that we have done a few quadruplet treatments, but we did them out of our academic center. It’s not something that we’re going to do on a local level. I think myeloma is a disease state that is chronic enough that these patients should be managed closer to an academic site rather than just on a local community level.

Bruce A. Feinberg, DO: I don’t know where we are now, but when I discontinued clinical practice at the end of 2010, I was already experiencing 10-year survival rates in my patients with myeloma. I don’t know how far have we extended that.

It makes me think about CLL [chronic lymphocytic leukemia], and I know you’re not a CLL doctor, Joe. But just for purposes of comparison, when you get patients who are 70 years of age, or in their 70s at the time of diagnosis, where their actuarial life expectancy is less than 10 years, we can get more than 10 years with more conventional therapies. We get to that value-based care, and also back to that pathway, and back to this algorithm that when we’re looking at the choice of therapy, it’s not just about the depth of response, but it’s also taking this long-term perspective from that value. I’m curious, am I right in terms of projected survivals getting to more than 10 years, and is the age group the same? How are we starting to introduce those variables into this understanding of where to go?

Joseph Mikhael, MD: I think you’re hitting the key points here because, absolutely, our survival is significantly improving. In fact, right now, I will tell a standard-risk patient that I expect their survival to be over a decade. The challenge is, in the high-risk patient, we’re still probably in that 4- to 5-year range. That’s where, again, we’ve got a dichotomy of diseases within one. However, your point is particularly well taken. Say that I see that patient at the clinic tomorrow, and they’re diagnosed at the age of 74. Ten years puts them beyond their expected survival in this country. And so, one of the things I think that we’re doing to adjust for that is saying, although yes, depth of response matters because depth translates into duration, there are different ways to achieve that depth. And we have to do it with, as I always say, 2 ears, 1 mouth. Listening to our patients more than just speaking to understand what adverse effect profile they have.

What does this mean to my practice? Over the last 5 years, I have to say, and I’m not ageist. When I wrote the ASCO [American Society of Clinical Oncology] guidelines for myeloma, we made sure that we don’t determine transplant eligibility by age alone. But overall, I’m doing fewer transplants in the 65-to-75-year-old range. I know I can do it, but I know that it takes a toll on those patients. Now that we have such amazing outcomes with these novel therapies in these patients, do we have to do it the more aggressive way?

We still want to use multiple combinations, but we want to do it in a way that’s more patient-friendly. There are patients who maybe 5 years ago, I would have said, “Look, you’re 72 years old, I could get you through a transplant. But now I use a triplet combination with daratumumab, lenalidomide, dexamethasone—you’re likelier to get 5 years before your first relapse. And you’re going to get it with relatively gentle therapy.” I think that is the way we’re starting to think, that we don’t have to approach it…. Remember, the average age of diagnosis in this country is still roughly 69, it’s significantly younger in the African-American population, but roughly 69. Many of these patients are in their 70s when they’re diagnosed, and I think we have to be very careful not to have a one-size-fits-all approach.

Transcript Edited for Clarity