New Upfront Strategies Emerge for Multiple Myeloma

Keith Stewart, MB ChB

Carfilzomib (Kyprolis)

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.

Daratumumab (Darzalex)

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

On May 8, the FDA approved the VMP regimen for patients with newly diagnosed MM who are ineligible for ASCT, based on findings from the phase III ALCYONE trial. In the study, 706 patients with untreated MM ineligible for transplant were randomly assigned to VMP alone or with daratumumab. “This is a very important study,” Stewart said. The response rate in the daratumumab arm was 90.9% compared with 73.9% in the VMP-only arm (P <.001).3 The daratumumab arm also enjoyed a significantly higher rate of CR or better (42.6% vs 24.4%, respectively; P <.001) and significantly longer progression-free survival (PFS), with a 50% reduction in the risk of progression or death (HR, 0.50; 95% CI, 0.38-0.65; P <.001).³ The VMP triplet was discontinued in both arms after 8 months while patients in the 4-drug arm continued to receive daratumumab every 4 weeks until disease progression, which Gasparetto identified as an important limitation of ALCYONE’s findings.

Raje said while she anticipated the possibility of daratumumab eventually being used in frontline regimens, “it may not necessarily be with the VMP combination.” She mentioned the ongoing GRIFFIN trial (NCT02874742), which is comparing RVD plus daratumumab versus RVd alone; while Hari brought up the phase III MAIA study (NCT02252172), a comparison of dexamethasone plus lenalidomide with or without daratumumab.

Elotuzumab (Empliciti)

Ixazomib (Ninlaro)

The Role of Transplant

Raje said most of the toxicities observed with daratumumab are related to the infusion. “It’s usually just the first 1 or 2 infusions,” she said, adding that the initial infusion time was lenghty. However, routine use of montelukast and other premedications had helped her team decrease infusion-related reactions. “Soon there will be a subcutaneous version that is given over 5 to 10 minutes, and that’s going to change this completely,” Raje predicted.Another novel 4-drug regimen under investigation for newly diagnosed MM combines RVd with elotuzumab, a regimen already approved for relapsed and refractory MM.⁴ Elotuzumab is a monoclonal antibody. Laubach and colleagues presented preliminary findings from a phase IIa study (n = 29) at the 2017 American Society of Clinical Oncology Annual Meeting that showed an overall response rate of 100%, with 71% achieving VGPR or better.4 Orlowski said the rate of infections in the study was concerning. “It’s definitely a regimen that one has to be careful about, and I’m not sure about its role in the upfront setting at this point,” he said. Gasparetto said that for patients who relapse after upfront therapy with daratumumab, she would prefer to retreat with daratumumab.At the 2017 Congress of the European Hematology Association, long-term data were presented from phase I/II clinical trials examining the safety and efficacy of ixazomib (once or twice weekly) plus lenalidomide and dexamethasone for patients with newly diagnosed MM who did not undergo transplant (NCT01383928 and NCT01217957).^5,6 Ixazomib is an oral proteasome inhibitor. Raje said response rates with ixazomib were impressive, with an ORR of 80% in the once-weekly ixazomib trial and 95% in the twice-weekly ixazomib trial.^5,6 Survival outcomes were also impressive in both studies. “I think ixazomib is the perfect drug for the older patient population,” Raje said. Gasparetto said she had also occasionally used ixazomib in older patients, which she noted is generally well tolerated.Orlowski suggested the growing efficacy of induction regimens calls the role of ASCT into question and pointed to results of the Intergroupe Francophone Myelome (IFM)/Dana-Farber study of RVd in patients with newly diagnosed symptomatic MM.⁷ After RVd induction, half the participants were randomly assigned to collection and consolidation therapy with 5 cycles of RVd (n = 350) and half to high-dose melphalan plus ASCT followed by 2 cycles of RVd (n = 350); all patients received 1 year of lenalidomide maintenance therapy.⁷ Orlowski said outcomes were similar in the subgroup of patients who were minimal residual disease (MRD)—negative regardless of whether they underwent transplantation. “If someone’s in the good risk group and gets to MRD negativity, it would be reasonable to give that patient a choice of either harvest and hold or harvest and do the transplant,” he said.

Denosumab (Xgeva)

“I’m going to push back a little here…It’s really important for the audience to understand that everybody [who is transplant-eligible] needs to be collected,” Raje said. “As of right now, the standard of care is still transplant if you’re transplant eligible, based on the data we have,” she explained. The ongoing DETERMINATION trial (NCT01208662) may offer more evidence on the feasibility of delaying transplant.More than 80% of patients with MM have destructive bony lesions. The FDA recently expanded indications for the monoclonal antibody denosumab to include prevention of skeletal-related events (SREs) in patients with MM. Denosumab was already approved for the prevention of SREs in patients with solid tumors. Approval was based on findings from the landmark 482 study (NCT01345019), a head-to-head comparison of denosumab with zoledronic acid in patients with newly diagnosed MM and bone disease.⁸ Raje was a lead investigator for the double-blind, randomized, controlled, phase III trial, which enrolled approximately 1700 patients from 29 countries. “The study was designed to show equivalence in SREs, which we were able to show,” she said.

The median times to first and subsequent SREs were similar between both treatment arms.⁸ “Very interestingly, we found a pretty significant PFS benefit in this patient population—in excess of 10.5 months,” Raje said. The median PFS was 46.1 months in the denosumab arm compared with 35.4 months in the zoledronic acid arm (HR, 0.82; 95% CI, 0.68-0.99; P = .036).⁸ Denosumab was well tolerated with no increase in renal toxicity.

“I loved your study,” Stewart said. He expressed surprise at the 10-month improvement in PFS, which he pointed out was longer than the improvement in PFS observed with carfilzomib, elotuzumab, and ixazomib. Stewart questioned why there was not more excitement about the results within the MM community.

Conclusions

“You worry there is some unknown difference that is bringing it out,” Hari said. “I’m intrigued, but I clearly don’t think I’d change practice just yet,” he concluded. Gasparetto said she struggled to get approval to use denosumab before the FDA approved it for MM but was optimistic that would now change.Promising new regimens and novel agents are emerging that offer the potential for deeper, longer-lasting responses in MM. As more options become available, it becomes increasingly vital to identify biomarkers and other predictors of response that can aid in treatment selection and sequencing. Supportive care remains an important aspect of MM management. The approval of denosumab for patients with bone disease offers a new approach for preventing SREs and delaying progression.

References

1. 1. Zimmerman TM, Griffith KA, Jasielec J, et al. Phase II MMRC trial of extended treatment with carfilzomib (CFZ), lenalidomide (LEN), and dexamethasone (DEX) plus autologous stem cell transplantation (ASCT) in newly diagnosed multiple myeloma (NDMM). J Clin Oncol. 2015;33:(suppl):8510. meetinglibrary.asco.org/record/107982/abstract.
2. Chari A, Usmani SZ, Krishnan A, et al. Daratumumab (DARA) in combination with carfilzomib, lenalidomide, and dexamethasone (KRd) in patients (pts) with newly diagnosed multiple myeloma (MMY1001): updated results from an open-label, phase 1b study. Blood. 2017;130(1 suppl):3110. bloodjournal.org/content/130/Suppl_1/3110.
3. Mateos M-V, Dimopoulos MA, Cavo M, et al. Daratumumab plus bortezomib, melphalan, and prednisone for untreated myeloma. N Engl J Med. 2018;378:518-528. doi: 10.1056/NEJMoa1714678.
4. Laubach J, Nooka AK, Cole C, et al. An open-label, single-arm, phase IIa study of bortezomib, lenalidomide, dexamethasone and elotuzumab in newly diagnosed multiple myeloma. J Clin Oncol. 2017;35(15 suppl):8002. doi: 10.1200/JCO.2017.35.15_suppl.8002.
5. Kumar SJ, et al. Deep and durable responses with weekly ixazomib, lenalidomide and dexamethasone in patients with newly diagnosed multiple myeloma: long-term follow-up of patients who did not undergo SCT. Presented at: 22nd Annual European Hematology Association Congress; June 22-25, 2017; Madrid, Spain. Abstract S408. learningcenter.ehaweb.org/eha/2017/22nd/181695/shaji.k.kumar.deep.and.durable.responses.with.weekly.ixazomib.lenalidomide.and.html.
6. Richardson P, Hofmeister C, Rosenbaum C, et al. Twice-weekly ixazomib plus lenalidomide-dexamethasone in patients with newly diagnosed multiple myeloma: long-term follow-up data for patients who did not undergo stem cell transplantation (SCT). Presented at: 22nd Annual European Hematology Association Congress; June 22-25, 2017; Madrid, Spain. Abstract S780. learningcenter.ehaweb.org/eha/2017/22nd/182067/paul.richardson.twice-weekly.ixazomib.plus.lenalidomide-dexamethasone.in.html.
7. Attal M, Lauwers-Cances V, Hulin C, et al. Lenalidomide, bortezomib, and dexamethasone with transplantation for myeloma. N Engl J Med. 2017;376:1311-1320. doi: 10.1056/NEJMoa1611750.
8. Raje N, Terpos E, Willenbacher W, et al. Denosumab versus zoledronic acid in bone disease treatment of newly diagnosed multiple myeloma: an international, double-blind, double-dummy, randomized, controlled, phase 3 study. Lancet Oncol. 2018;19:370-381. doi: 10.1016/S1470-2045(18)30072-X.