Frontline Therapy in Multiple Myeloma

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Transcript:

Joseph Mikhael, MD: Hello and welcome everyone. It's a privilege to have you join us today in this educational session entitled, “The Evolving Treatment Landscape in Multiple Myeloma: An Expert Case-Based Discussion.” There is a lot of evolution in the myeloma world right now, and so we're going to talk a little bit about that not only upfront but in relapsed myeloma.

It's my pleasure to serve as our moderator today. My name is Dr Joseph Mikhael, I'm a professor at the Translational Genomics Research Institute in Phoenix, Arizona, and the chief medical officer of the International Myeloma Foundation. I have 3 outstanding faculty and friends who have joined me today, and I will have each of them introduce themselves. We'll start with you, Elisabet.

Elisabet Manasanch, MD: Thank you so much, Joseph, for that great introduction. My name is Dr Elisabet Manasanch, I'm an associate professor at the University of Texas MD Anderson Cancer Center in Houston, Texas where I treat multiple myeloma patients.

Joseph Mikhael, MD: Wonderful. Welcome. It's good to see you. Next, we have not only a friend, but a mentor to me. Keith, could you introduce yourself?

Keith Stewart, MD: Yes. Good morning, everybody. I'm Dr Keith Stewart, I'm a myeloma physician at Ontario Health in Toronto, Ontario, Canada and the director of the Princess Margaret Cancer Centre.

Joseph Mikhael, MD: Wonderful. Thanks so much for joining us, Keith. And last but not least, a former colleague and dear friend, Sikander. Could you introduce yourself?

Sikander Ailawadhi, MD: Thanks. Yes, absolutely. Hello to everybody watching this great program. I'm Dr Sikander Ailawadhi, I'm one of the hematologist oncologists at the Mayo Clinic in Jacksonville, Florida, and my practice is focused mostly on multiple myeloma.

Joseph Mikhael, MD: OK, great. Yeah, we have a bit of a Mayo Clinic theme here, with 3 of us either presently or previously practiced at the Mayo Clinic. And of course, MD Anderson for Dr Elisabet Manasanch. It's so great to have each of you here.

So just a quick review, I know that many of our audience members are familiar with this already, but I do think it's important to highlight this because it's hard to believe now it's been 8 years since we changed the definition of myeloma. We used to say, "Show me the CRAB," meaning, as I always give the analogy to patients, if I'm running towards a cliff, you'd have to wait until someone was falling off the cliff to be diagnosed with myeloma. Hopefully, Sikander, who probably runs faster than I do anyway, would stop me from falling off the cliff, but we used to define myeloma as the presence of that true CRAB criteria: calcium elevation, renal insufficiency, anemia, and bone disease, obviously related to the underlying plasma cell disorder, with a monoclonal protein of greater than 10%. But we've now added 3 more features to that almost as if we drew a line, let's say 50 feet short of the cliff so that we knew when the disease was soon to progress and cause organ damage.

And so, we added those 3 features of 60% plasma cells, light chain ratio over uninvolved of greater than 100. And if there was more than 1 focal lesion on the MRI [magnetic resonance imaging] of the bone marrow, which is typically a homogenous picture, that's indicative of active disease. And so that has now been the new definition of active or symptomatic multiple myeloma, which of course is typically preceded by MGUS, or monoclonal gammopathy of undetermined significance, and perhaps a phase of smoldering myeloma. And still, we are treating the active myeloma, smoldering myeloma ... we're not typically treating, although there are some studies that may indicate that, and it's an area of investigation to determine which fraction of the highest risk patients in smoldering myeloma should be treated.

We’re going to talk a little bit today about patients who are eligible and ineligible for autologous stem cell transplant because indeed, that still seems to be the agreement that we divide patients into that category. And I'm going to ask the experts here for their opinions about how they make that distinction. But if we take for a moment that we are going to plan to have patients going towards an autologous stem cell transplant, we're not going to focus too much on frontline myeloma today, but just as a reminder that the general recommendation is that patients have a 3 drug or now perhaps a 4-drug induction regimen, which typically will include different mechanisms of action from a proteasome inhibitor, an immunomodulatory drug, and a monoclonal antibody, along with dexamethasone, followed by an autologous stem cell transplant, followed then by maintenance therapy, knowing that the goal is a deep response, which generally would translate into a longer duration of response.

Typically speaking, we use lenalidomide as the maintenance therapy, although, and we're going to be talking about the distinction of high-risk patients shortly and I know all 3 of our expert faculty here are experts in defining high risk, but we've come to appreciate that high-risk disease is probably not best served by lenalidomide alone. And so, we're still trying to find what is the best combination for patients. Many will use both a proteasome inhibitor and lenalidomide, and we have evidence for both bortezomib and carfilzomib in that light, and of course, exploring the addition of the CD38 [cluster of differentiation 38] antibody to maintenance therapy. And so the optimal treatment and strategy for a high-risk disease is still unknown, but generally speaking, as I say, we're going to need more than just lenalidomide.

When we now think of patients that are ineligible for an autologous stem cell transplant, the other evolution that we have seen is that we've gone primarily from doublets to triplets and the way in which we administer triplets are feasible in the majority of patients. Fit patients are typically given a triplet combination, the most commonly used combination now would be daratumumab plus lenalidomide and dexamethasone, but we also use versions of VRd [voltage reduction device] or bortezomib, lenalidomide and dexamethasone, sometimes called VRd-lite, if we use lower doses and a less aggressive strategy, but there are maybe particularly frail or unfit patients in whom we may still be using a doublet.

I would suggest that one of the greatest emerging areas in myeloma today is appropriate geriatric assessment. I think we have historically not done this particularly well as hematologists. We pretty much look at the date of birth and suspect that that tells us a probable diagnosis, and what we've come to appreciate is that age alone is not sufficient. And so, I do think it is important as we go forward that we have some kind of validated assessment, of which there are over 10 in myeloma, that can help distinguish as to whether or not they are fit or unfit for transplant, but also what would be the optimal regimen for those patients, which may include dose adjustment for renal insufficiency.

We may take into consideration the risks, if someone has cardiac dysfunction, to use carfilzomib, and that we're careful in using thromboprophylaxis, and that we monitor patients more carefully for potential adverse risks. And furthermore, for the presence already of peripheral neuropathy, let alone the development of it, we've routinely always used bortezomib in a subcutaneous method, and inweekly dosing, there may be some exceptions in that first cycle with very active myeloma, but in general, we're doing that to minimize that risk. And if a patient has pre-existing neuropathy, we may consider not using bortezomib, either to use daratumumab, with lenalidomide and dexamethasone, or perhaps even ixazomib.

So that's frontline therapy in a nutshell, I'm going to pause there for a moment to see if any of our expert faculty, Drs Manasanch, Ailawadhi, and Stuart, have any comments about what we've said before we dive in a little bit more to think about early relapse, which is our focus today. Any thoughts, Sikander?

Sikander Ailawadhi, MD: Yeah, Joe, thanks for setting it up extremely well for the audience. The only thing I wanted to add to that was, I heard you mention transplant eligibility and ineligibility, and while that is still a term used all the time in myeloma and guidelines, etc, personally, I tried to make that assessment with the patient after they have received a couple of cycles of induction therapy, just to see where they lie physiologically, because like you've absolutely rightly said, it is not the chronological age, it's the physiological age that is important.

And the other piece that helps determine that is taking that history about what the patient was doing prior to their myeloma diagnosis. So that gives us a goal where to get them back from a quality-of-life standpoint. I think that's the only other thing that comes to my mind, that maybe we should not label the transplant as eligible or ineligible right off the bat and treat the patient, control the symptoms, and see where they land.

Joseph Mikhael, MD: I totally agree with you. I think that notion is critical, especially in the old days, when we had to make that distinction upfront because we were giving such a different regimen to patients who were transplant-ineligible, that included oral melphalan, that would potentially prevent someone from going to transplant. But I agree with you, now that we're so close, VRd [Velcade, Revlimid, and dexamethasone], DRd [Dara-Rd; daratumumab lenalidomide dexamethasone], [DVRd] [Dara-VRd; lenalidomide, bortezomib, and dexamethasone], and all these combinations are so similar that that it makes a lot of sense and a very good point. I don't know if there are other comments from Keith or Elisabet.

Keith Stewart, MD: Yeah, I think the decision has become much more fluid. I think the high efficiency of Dara-Rd with a long survival outcome has also become more than just age and fitness, it's also become expectations of, if you're doing really well on Dara-Rd or Dara-RVd, is really a transplant all right for a low-risk patient, for example. But I'm sure we'll talk about that during the case.

Joseph Mikhael, MD: I agree with you, Keith, very much. Absolutely, I still transplant, but I have to say, a lot of times I find myself giving permission for patients to not go to transplant because they are doing so well, and they don't necessarily want to go through that process. Elisabet, I know you do both and you do so much with transplant. The University of Texas MD Anderson Cancer Center has been known as one of the biggest transplant centers in the world. What are your thoughts here?

Elisabet Manasanch, MD: Yeah, typically, we have transplanted more than 70% of our patients. And most of the patients that were not transplanted traditionally, it's because the patients chose not to be transplanted with a delayed transplant approach. And this has been the case for the past 10 years. Now, recently, over the last 2 to 3 years, with the addition of daratumumab upfront, I think that has made a big difference in terms of how we reach a very deep response early on in a lot of the patients. So, I think even in these patients they’re transplant-ineligible by choice, or they just don't want to do it. And they're still fit, I think we still use VRd-daratumumab quite a lot with the VRd-lite, so that once we do bortezomib, and if necessary, we reduce the lenalidomide. It's a very well-tolerated regimen as well and we find that at the end of a certain number of cycles, and I think it depends on the patient's physician to ... how many cycles are given initially. But patients do very well, a lot of them are in complete remission, MRD [measurable residual disease] negative, and so I think that that could be also a valid option in some selected patients. But I completely agree with everything that you are saying that this is very fluid and that the treatment of newly diagnosed patients is not as rigid as it used to be with 4 cycles and the transplant. It's a lot more fluid right now, which is good for patients, we have more choices.

Joseph Mikhael, MD: All 3 of you have just summarized that beautifully, absolutely. I think that fluidity is a great word, that flexibility that we have, and I think that's the way the field is moving. And I know that some of you have discussed this in other venues before, that thinking ahead in the future, there may come a day where, frankly, we won't be doing transplants for patients because we have other options. But that's beyond the scope of today, I'm going to refocus us back now. But this is great, thank you for your comments regarding frontline therapy.

Transcript edited for clarity.