Improving Management of Relapsed/Refractory Multiple Myeloma - Episode 3

A Look at the ENDURANCE Trial


Yvonne Efebera, MD: The ENDURANCE trial—KRd [carfilzomib, lenalidomide, dexamethasone] versus VRd [bortezomib, lenalidomide, dexamethasone]—this was a plenary session at ASCO [the American Society of Clinical Oncology annual meeting] today. These were standard-risk patients where they included the translocation 4;14 and excluded the high-risk patient, plasma cell leukemia, the other high-risk translocation 14;20, 14;16, and deletion 17p. They even excluded patients with LDH [lactate dehydrogenase] that was greater than 2 times the upper limit of normal. It was a big study, over 500 patients in each arm. This was a 2-pronged study, first to randomize either to VRd versus KRd and then afterward, randomize each group to LEN [lenalidomide] maintenance for 2 years versus until disease progression or toxicity mandates them to stop maintenance.

This one was just based on the induction regimen. The median PFS [progression-free survival] for VRd was 34.4 months and for KRd it was 34.6 months. There was no difference seen in terms of age, absence or presence of the translocation 4;14 or ISS [International Staging System] stage. The 3-year overall survival was 84% for VRd and 86% for KRd. They did see more cardiac, pulmonary, and renal toxicity with 16.1% in KRd, versus 4.6% in VRd, and there was more neuropathy in the VRd, 53.5% compared with 24.4% in KRd. The majority of that was grade 1 to 2 because treatment was given as subq [subcutaneous].

Based on those data with the cardiac and pulmonary toxicity, I think the conclusion from that trial was that VRd was the first line or mainstay. This wasn’t studied in high risk, so you can make a case with the high-risk patients, using KRd or DARA [daratumumab]/VRd as an induction regimen.

Thomas Martin, MD: I like that study also. I agree, I think the conclusion for me in that is—and this was, as you said, so many patients, more than a thousand patients on the trial—that in the standard-risk patients, because they did exclude all the high risk, VRd and KRd, we’re splitting hairs in terms of how well patients are going to do. What did you think on the toxicity of one versus the other? What was your take-home point on the toxicity?

Yvonne Efebera, MD: The cardiac toxicity was a major concern for the KRd. The dosing was 20 mg/m2 and then 56 mg/m2. Maybe if the dose was a little lower compared to what it was initially approved for, carfilzomib, the 20 and then 27 mg/m2, maybe you would not have seen that much toxicity. That was the deal breaker for me with the cardiac and renal toxicity, 16.1% compared to 4.6% in VRd. Even in the clinic, most of the neuropathy now from bortezomib is grade 1 to 2, and those are manageable, about 45.4% out of the 53% were grade 1 to 2. VRd is my go-to for induction and then adding DARA for the high-risk patients. But I’m still open to using KRd in some cases.

Thomas Martin, MD: I agree, and the neuropathy is probably the biggest thing, right? More patients stop on the VRd arm versus the KRd arm because of neuropathy. The trade-off of toxicities was fairly similar but more people stopped because of neuropathy. At the IMW [International Myeloma Workshop] summit in Boston, there were probably 5 or 7 different abstracts looking at how to give VRd. Do we give it twice weekly, the bortezomib? Do we give it once weekly? At the end of the day, it really doesn’t matter.

Yvonne Efebera, MD: Exactly.

Thomas Martin, MD: I don’t know about you, but we use a 4-week schedule in general, and it’s REV [Revlimid] at the standard dose, 25 mg or adjusted by renal insufficiency, and then we use bortezomib on day 1, 8, and 15. So we do 3 doses of bortezomib per 4-week cycle rather than the twice weekly, 3-week cycle that’s been done in all these trials. There’s less neuropathy and it’s better tolerated.

Yvonne Efebera, MD: Absolutely, yes.

Transcript Edited for Clarity