Keith Stewart, MB ChB
The approval of new antineoplastic agents over the past 20 years has prolonged the life expectancy of patients with multiple myeloma (MM), but a cure remains elusive. The current standard of care (SoC) for newly diagnosed MM is a regimen of lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone (RVd). However, preliminary findings from ongoing trials of novel therapies may challenge that paradigm, as researchers work to achieve deeper responses in patients with newly diagnosed disease. In an OncLive Peer Exchange®
panel discussion, A. Keith Stewart, MB, ChB, and a group of hematology experts reviewed data concerning emerging frontline strategies for MM that were presented at the 2017 American Society of Hematology (ASH) Annual Meeting. Discussants offered their perspectives on what the findings might mean for their patients and shared their experiences with the evolving approaches.
The SoC for newly diagnosed MM is a regimen of RVd. However, a different combination is showing utility in this space. In 2015, Zimmerman et al presented interim data from the phase II MMRC single-arm trial that showed induction therapy with carfilzomib, lenalidomide, and dexamethasone (KRd) produced deep responses in patients with newly diagnosed MM undergoing autologous stem cell transplant (ASCT).1
Parameswaran Hari MD, MRCP, MS, said he still recommends induction with RVd but now switches patients to a KRd regimen if they do not respond adequately to 3 or 4 cycles of RVd.
Noopur S. Raje, MD, said her approach is similar to Hari’s but that clinical practice may change if results from the ongoing ECOG E1A11 trial (NCT01863550), a head-to-head comparison of RVd versus KRd in newly diagnosed MM, favor KRd. “In the context of a clinical trial, I have used KRd,” she added.
Hari said carfilzomib is “extremely well tolerated, provided you pick the right patient and the right dose.” She cautioned that although treatment- naïve patients tolerate the 36-mg/m2
dose fairly well, tolerability becomes an issue when the dose is increased beyond 56-mg/m2
. “I find a lot of endothelial toxicity, such as hypertension and atrial fibrillation,” she said. Hari recommends starting elderly patients at lower doses and titrating up—but being prepared to reduce the dose if their blood pressure increases. “With the triplet, we see that we have to settle for a lower dose to prevent toxicity. I think the 56-mg/m2
weekly dose is becoming my preference,” Cristina Gasparetto, MD, said.
Raje said one of her main concerns with carfilzomib use was the risk of blood clots, particularly pulmonary embolism. She said the risk was greater in patients with high disease burden.
Several studies presented at the 2017 ASH meeting explored whether more aggressive 4-drug regimens could further improve outcomes for patient with newly diagnosed disease. In the phase Ib open-label MMY1001 study (NCT01998971), the anti-CD38 monoclonal antibody daratumumab was added to KRd and administered to 22 patients with newly diagnosed MM.2
“They had virtually a 100% response rate and very high rate of very good partial response [VGPR] or better,” Robert Z. Orlowski, MD, PhD, said. Reported response rates included 33% VGPR, 43% stringent complete response (CR), 14% CR, and 10% partial response.2
“We typically start [some] high-risk and even standard-risk people on KRd, but if we don’t see a partial response after 1 cycle, we think about adding daratumumab… it’s certainly an active regimen,” Orlowski said. He expressed hope for a randomized trial comparing the 3 regimens: KRd, RVd, and daratumumab plus KRd.
Another study investigated whether adding daratumumab to the triplet of bortezomib, melphalan, and prednisone (VMP) might improve outcomes.3