Frontline Triplet Therapies in Multiple Myeloma

Keith Stewart, MBChB: Hello, and welcome to this OncLive® Peer Exchange® titled, “Multiple Myeloma, Planning a Continuum of Care in 2020.” I’m Dr Keith Stewart from University Health Network and Princess Margaret Cancer Centre in Toronto, Ontario, Canada. Joining me today in this discussion are my colleagues Dr Natalie Callander from the University of Wisconsin School of Medicine and Public Health in Madison, Wisconsin; Dr Thomas Martin, from the University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center in San Francisco, California; Dr Noopur Raje from Massachusetts General Hospital in Boston, Massachusetts; and Dr Peter Voorhees from Atrium Health in Charlotte, North Carolina.

Today we are discussing the state-of-the-art treatments for patients with newly diagnosed and relapsed/refractory multiple myeloma, including promising agents in the pipeline. We’ll discuss the latest research in the field, including from the ASCO 2020 [American Society of Clinical Oncology Annual Meeting] we just passed and the impact of recent clinical trials on making decisions around treatment selection.

We’re starting with newly diagnosed myeloma. Dr Raje, what are you using for the treatment of your newly diagnosed patients today and have stuck with that regimen if it hasn’t changed recently?

Nooper Raje, MD: We’re doing everything differently now in this COVID-19 [coronavirus disease 2019] era. Hopefully this is all going to work out.

As far as newly diagnosed myeloma, over the last few years now, most of us are using combination. And the jury is out, in fact, and most of us are supporting the use of a triplet combination now. But typically, most of us—or at least I do—tend to use the combination of lenalidomide with bortezomib and dexamethasone, or RVd, in most patients with newly diagnosed myeloma.

Thomas Martin, MD: For most patients, we have started triplet-based regimens. My personal preference is KRd [carfilzomib, lenalidomide, dexamethasone] in patients who are less than age 65 years or have high-risk cytogenetics. For the rest of the patients, RVd [lenalidomide, bortezomib, dexamethasone] is an excellent regimen. For me, it’s both.

Keith Stewart, MBChB: At the ASCO meeting they presented an important randomized controlled trial in the plenary session. Natalie, would you summarize the ENDURANCE clinical trial?

Natalie S. Callander, MD: This was 1 of the largest trials that has ever been conducted. It’s a randomized phase 3 trial, and the purpose was to take patients who are newly diagnosed, did not meet a definition of high-risk, and were willing to postpone transplant or potentially were transplant ineligible.

They did allow patients who had a translocation of 4:14. But usually, the other high-risk features were excluded. Then patients were randomized to receive either 9 cycles of KRd [carfilzomib, lenalidomide, dexamethasone] or 12 cycles of VRd [bortezomib, lenalidomide, dexamethasone], so the dosing would match. The hypothesis was that there would be an improvement in PFS [progression-free survival] in patients receiving KRd [carfilzomib, lenalidomide, dexamethasone].

There’s a second question that hasn’t been reported about length of maintenance with the randomization for 2 years versus indefinite. The results are stratified by an intent to transplant it at progression. Surprisingly, for some people the results showed that in terms of progression-free survival, there was not an advantage for KRd [carfilzomib, lenalidomide, dexamethasone]. If you look at all the groups together, they both actually performed pretty well, around mid-80%.

There were a couple of differences that were striking, in the sense that discontinuation in terms of completion of all planned therapy or all planned cycles of VRd [bortezomib, lenalidomide, dexamethasone] was only about 47%, whereas KRd [carfilzomib, lenalidomide, dexamethasone] had slightly higher at 52%. But at the end of the day, there wasn’t a difference. There was a trend toward improvement in PFS for patients who had stage 3 disease or high-risk cytogenetics, but obviously that’s a very small group. At the end of the day, there really wasn’t any difference at all in PFS. I think the conclusion that a lot of people are drawing from this is that VRd [bortezomib, lenalidomide, dexamethasone] certainly remains the standard in this group of patients. There’s been some talk about this. I’d be very interested to see what the other panelists think about this data.

Keith Stewart, MBChB: Peter, we haven’t heard from you, Dr Voorhees. What do you think of this? How do you interpret it?

Peter Voorhees, MD: This is not overly surprising, from my perspective. There was a similar study in newly diagnosed transplant-ineligible patients that used bortezomib, melphalan, and prednisone vs carfilzomib, melphalan, and prednisone, and it was similarly designed where treatment with the regimen was given for a defined duration of time. In that study, there was also no difference in response rate. There was no difference in progression-free or overall survival. The difference between the ENDEAVOR trial in the relapsed setting and then the carfilzomib versus bortezomib-based regimen in the frontline setting is that with ENDEAVOR, patients were allowed to stay on therapy until disease progression. Because of the lack of neuropathy signal with carfilzomib, patients can stay on it longer, whereas in the frontline setting, if you’re giving it for a defined duration of time, whether you’re using bortezomib or carfilzomib really doesn’t make that much of a difference from an efficacy perspective. The discussion with the patient has to rest largely on the toxicity profiles between the 2 different regimens, whereas with VRd [bortezomib, lenalidomide, dexamethasone], you’re going to see more peripheral neuropathy, which was clearly shown in the ENDURANCE trial. You’re going to see more vascular toxicity as far as renovascular toxicity and cardiovascular and pulmonary toxicity with the carfilzomib-based strategy. I like to use KRd [carfilzomib, lenalidomide, dexamethasone] in higher-risk patients. But I use it in the same manner that it was done in the phase 2 MMRC-061 trial, where the KRd [carfilzomib, lenalidomide, dexamethasone] was really implemented in a very Arkansonian total therapy manner. How you use the triplet matters more than which of the proteasome inhibitors are part of the regimen.

Transcript Edited for Clarity