Experts Discuss Advanced Therapies in Relapsed/Refractory Multiple Myeloma

Keith Stewart, MB ChB

The advent of new agents and new classes of agents for treating relapsed or refractory multiple myeloma (RRMM), a notably complex disease state, has stimulated efforts to identify the optimal way to sequence or combine these therapies. An OncLive^® Peer Exchange^® panel of hematology experts convened to discuss how to manage RRMM, the role of transplant, and the evidence for immunotherapy.

Relapsed or Refractory Disease After a Lenalidomide-Based Regimen

The panelists expressed enthusiasm for the potential of new combinations and sequences to cure a greater percentage of patients, but also recognized the need to temper that optimism pending better data on how to integrate the various therapeutic approaches. Keith Stewart, MB, ChB, who moderated the discussion, noted that the many options available have made it even more important to tailor treatment to the individual patient, especially in the relapse setting.Several factors must be considered when selecting treatment for RRMM, including timing and aggressiveness of relapse, disease stage at relapse, disease-related comorbidities, eligibility for autologous stem cell transplant (ASCT), prior treatment exposure, and patient age.^1,2 At the time of relapsed or refractory disease, many patients with multiple myeloma (MM) have already received lenalidomide (Revlimid), an immunomodulatory drug (IMiD), as part of a first-line regimen that included dexamethasone or as maintenance therapy after ASCT. For transplant-ineligible patients, one option is to repeat primary therapy with lenalidomide, with a possible dose increase.2 Another option is to switch to a regimen that combines an IMiD with a proteasome inhibitor or a monoclonal antibody.³

Thomas G. Martin III, MD, a member of the National Comprehensive Cancer Network MM guidelines panel, said, “If somebody is relapsing on lenalidomide, I don’t think going up to a higher dose of lenalidomide is going to get you a lot of distance.” He said he typically switches to a carfilzomib (Kyprolis)-based therapy or a combination of pomalidomide (Pomalyst) plus a monoclonal antibody. Carfilzomib is a proteasome inhibitor, whereas pomalidomide is an analog of lenalidomide. Saad Z. Usmani, MD, said he also frequently uses pomalidomide, which he believes patients tolerate slightly better than lenalidomide.

“Until you know whether the kidney function has stabilized, I’m a little hesitant to use [lenalidomide] because chronic myelosuppression is really an issue,” said Sagar Lonial, MD. “If the creatinine level is stable, then I’m comfortable using it at the recommended dose.” Stewart noted that carfilzomib can also affect creatinine levels, so it is important to monitor patients.

“You have to personalize the treatment to what the patient can tolerate,” Ivan M. Borrello, MD, said. Combining carfilzomib or bortezomib (Velcade) with dexamethasone is an option for patients unable to tolerate an IMiD. Bortezomib is an older proteasome inhibitor associated with a high risk of peripheral neuropathy. The phase III ENDEAVOR trial compared bortezomib plus dexamethasone with carfilzomib plus dexamethasone in patients with RRMM (n = 929).⁴ Borrello said outcomes were significantly better in the carfilzomib arm. Median progression-free survival (PFS) observed in ENDEAVOR was almost twice as long in the carfilzomib arm than in the bortezomib arm (18.7 vs 9.4 months, respectively; P <.0001).⁴

For patients who cannot tolerate an IMiD or bortezomib, Lonial recommended combining carfilzomib with panobinostat (Farydak), a histone deacetylase inhibitor. Although panobinostat is sometimes used with bortezomib, Lonial disagrees with that approach. “I don’t think bortezomib is the right partner…there’s just too much overlapping gastrointestinal toxicity,” he said. According to Lonial, trials show that if you administer panobinostat every other week, “you don’t get as much as of the gastrointestinal toxicity that you get with bortezomib, [and] it has pretty reasonable efficacy, as well.”⁵

Triplet and Quadruple Regimens

Usmani said he also uses a doublet of panobinostat and carfilzomib in the third- and fourth-line settings. Martin said he considers ixazomib (Ninlaro) to be a good alternative to bortezomib. “I use it in places where I would use bortezomib, and it’s very convenient to just give once-weekly dosing for 3 out of 4 weeks,” he said. Like bortezomib, ixazomib is a proteasome inhibitor, but it is associated with a much lower rate of peripheral neuropathy.⁶ Borrello said he has not found the 2 drugs to be interchangeable and reserves ixazomib for frail patients or patients with stable disease.According to Gareth Morgan, MD, FRCP, FRCPath, PhD, data suggest a triplet regimen may be more effective than a doublet for RRMM. “You could go for a 3-drug regimen with daratumumab,” Morgan said. A phase III trial (n = 569) observed a significantly higher rate of complete response with the triplet of daratumumab (Darzalex) plus lenalidomide and dexamethasone (RD) versus RD alone (43.1% vs 19.2%, respectively; P <.001).⁷

Another study found adding carfilzomib to RD improved response rates, PFS, and overall survival.2 In light of the success with 3-drug regimens, studies have been looking at 4-drug combinations. Morgan was involved in a trial that compared a quadruplet induction regimen of carfilzomib, cyclophosphamide, and RD with a triplet regimen that combined cyclophosphamide with RD or thalidomide plus dexamethasone.⁸ Participants had newly diagnosed MM and were transplant-eligible. The quadruplet regimen was associated with deeper responses, with 92% of patients achieving a very good partial response or better at 100 days after transplant compared with 77% to 82% of patients in the triplet arms.⁸ “It was well tolerated. There was no cardiotoxicity and everybody was able to go on from that to the transplant,” Morgan said. “I think there is some merit in 4-drug regimens, especially in younger, fitter patients.”

Other quadruplet regimens under investigation in transplant-eligible patients with newly diagnosed MM include RD plus daratumumab and carfilzomib and RD plus bortezomib and veltuzumab, an investigational anti-CD20 monoclonal antibody.^9,10 Preliminary results show deep responses and low rates of high-grade toxicities. The findings support additional investigation into these regimens.

Second Transplants

Although minimal residual disease (MRD) is not an endpoint frequently used in the RRMM setting, Stewart said he sometimes tells patients, “I’m going to aim for MRD-negativity with daratumumab and [carfilzomib].” Morgan said that, with the tools available to clinicians today, he considers targeting MRD negativity a perfectly reasonable approach for RRMM.Second transplants remain an option for patients who did well with their first transplant. “In general, it would be for people who have achieved 5 years [of survival] or more from their first transplant,” Borrello said. Martin said even though clinicians typically collect enough stem cells up front for 2 transplants, database reviews show less than 5% of patients get a second transplant.

Emerging Immunotherapy Approaches

One reason for the low rate of second transplants may be the improvement in pharmacological agents for RRMM. Martin said newer drugs “are less toxic than a second transplant,” which he described as a “last-ditch effort.” He suggested administering a melphalan-based therapy and then using the stored stem cells to improve the patients’ count and make them eligible for clinical trials. Lonial and Usmani agreed, but Morgan said he believes a second transplant at relapse can be very effective, especially for patients who have gone without therapy for an extended amount of time or used nonalkylating agents.Checkpoint Inhibitors

Immunotherapy agents, such as checkpoint inhibitors, have revolutionized treatment for many malignancies—notably melanoma and lung cancer—and are being investigated for MM. “Their history in myeloma has been very interesting because, as single agents, they had absolutely zero activity,” Borrello said. Results were different when a checkpoint inhibitor was combined with an IMiD, however. Data from the KEYNOTE-023 trial at the 2017 ASCO Annual Meeting indicated a 44% overall response rate (ORR) when pembrolizumab, the checkpoint inhibitor, was combined with RD in patients with MM who were refractory to at least 2 prior regimens.¹¹ Martin said the PFS in KEYNOTE-023 was 20 months. In KEYNOTE-183, which evaluated pembrolizumab, pomalidomide, and low-dose dexamethasone in RRMM, Martin said the PFS was 17 months.

Despite such positive preliminary findings, the FDA recently ordered the discontinuation of the pembrolizumab-RD arm in the KEYNOTE-023 trial and placed a clinical hold on KEYNOTE-183 (pembrolizumab plus pomalidomide) and KEYNOTE-185 (pembrolizumab plus RD).^12,13 The FDA concluded there was an increased risk of death and serious adverse events when pembrolizumab was paired with an IMiD and that the risks outweighed the potential benefits for patients with MM.^12,13 The agency disclosed that there were more patient deaths in the pembrolizumab-containing arms of the KEYNOTE-183 and KEYNOTE-185 trials (29 and 19, respectively) than there were in the control arms (21 and 9, respectively).¹³

In September, the FDA placed partial clinical holds on 3 MM trials testing nivolumab (Opdivo) in combination with an IMiD. Existing patients benefiting from the experimental regimens can continue treatment but new patients cannot be enrolled. Bristol-Myers Squibb, which is developing nivolumab, said the clinical holds stemmed from risks identified in the pembrolizumab trials.¹⁴

Similarly, the FDA has placed a full clinical hold on a phase Ib study of a durvalumab (Imfinzi)-based regimen in MM, as well as partial clinical holds on 5 trials studying the PD-L1 inhibitor in combination with IMiDs for MM, chronic lymphocytic leukemia, or diffuse large B-cell lymphoma.¹⁵ Celgene, the manufacturer of durvalumab, also cited the agency’s concerns over the pembrolizumab combinations as the reason for the holds in its trials.

CAR T-Cell Therapy

Also presented at the 2017 ASCO meeting were early data from 2 studies of chimeric antigen receptor (CAR) T-cell therapy in patients with RRMM.^16,17 The CAR T-cell agents target the B-cell maturation antigen (BCMA), a protein expressed by MM cells. “The Chinese abstract, a late-breaking one, reports 14 out of 19 patients [74%] entered a complete remission,” Stewart said.¹⁶ The ORR was 100%.¹⁶ A phase I, US-led, dose-escalation study of bluebird bio’s CAR T-cell therapy, bb2121, also achieved impressive results in 21 heavily pretreated patients. Investigators reported an ORR of 89%, which increased to 100% for patients who had received what was later determined to be an optimal dose.¹⁶

Lonial also questioned whether response rate was the right endpoint for trials of CAR T-cell inhibitors. He pointed out that similarly high response rates were reported in studies of CAR-T cell therapy in patients with acute lymphoblastic leukemia and acute myeloid leukemia but that the cells were not persistent and PFS was “not as long as one would like.” He added that “the data certainly look very impressive, and I think BCMA is…the best target for something like this.”

“The most striking thing [in the bluebird study] was not the response rate; we anticipated that strategy would work. What was more impressive were the low rates of cytokine release syndrome,” Usmani said. Stewart, whose facility is participating in the bluebird study, agreed. “There has not been a lot of toxicity as compared to some other acute leukemia and lymphoma trials. I’m pretty excited about it, actually. It looks really good.”

Conclusion

Borrello predicted that if CAR T-cell data hold up, this therapy might replace transplants one day. “What we need to understand is how to position immunotherapy at the various stages—from induction, transplant, relapse, maintenance, etc— in the context of the plethora of the other drugs that are coming out.” Stewart said the economic burden of the new therapies also will have to be addressed.The panel agreed that the advances in MM therapy were exciting and could lead to dramatic improvement in survival rates. Stewart expressed hope that, in the future, regimens might be active enough so that treatment does not have to be continuous. “That would be the key,” Usmani said. He said that the MM field needs a “phenomenal” regimen that “we can use for a finite amount of time and get patients to very good depths of response…and 5 or 6 years of PFS.”

References

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14. VBristol-Myers Squibb provides an update on three Opdivo-based combination clinical studies in multiple myeloma [news release]. New York, NY: Bristol-Myers Squibb; September 6, 2017. news. bms.com/press-release/corporatefinancial-news/bristol-myerssquibb-provides-update-three-opdivo-based-combin. Accessed September 19, 2017.
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17. Berdeja JG, Lin Y, Raje NS, et al. First-in-human multicenter study of bb2121 anti-BCMA CAR T-cell therapy for relapsed/ refractory multiple myeloma: updated results. J Clin Oncol. 2017;35(suppl; abstr 3010). http://meetinglibrary.asco.org/ record/152481/abstract.