Current and Prospective Therapies Are Improving Outcomes in Relapsed Multiple Myeloma

Thomas G. Martin, MD

During the past decade, there have been dramatic improvements in outcomes for patients with multiple myeloma, with many more achieving an increased depth of response, complete remissions, and longer progression-free survival (PFS) and some even being cured. However, the majority of patients ultimately relapse, which continues to pose a significant challenge.

Treatment Approaches

During a recent OncLive Peer Exchange^®, a panel of experts on multiple myeloma discussed new agents and combinations that are improving the care of patients with relapsed multiple myeloma and reviewed strategies for treating these patients when they develop drug resistance, which is a common problem that often occurs early in the disease course and limits therapeutic options.¹ They also discussed recent data for some investigational treatments generating considerable excitement in the field, including chimeric antigen receptor (CAR) T-cell therapy and novel selective inhibitors.Until recently, the standard treatment for relapsed multiple myeloma has been lenalidomide (Revlimid) plus dexamethasone (Rd) or bortezomib (Velcade) plus dexamethasone (Vd).1 However, many new agents have been recently approved for relapsed disease, including carfilzomib (Kyprolis), ixazomib (Ninlaro), panobinostat (Farydak), elotuzumab (Empliciti), daratumumab (Darzalex), and pomalidomide (Pomalyst).¹ Results from recent randomized studies have shown greater benefit with a triplet regimen that adds 1 of these newer agents to Rd or Vd.^1,2

“In studies that included patients who received 1 to 3 prior lines of therapy, daratumumab/ bortezomib/dexamethasone (DVd), daratumumab/lenal idomide/dexamethasone (DRd), and carfilzomib/lenalidomide/ dexamethasone (KRd) have shown significant advantage,” Thomas G. Martin, MD, said. Martin explained that he uses DVd, DRd, or KRd at first relapse because he tries to be aggressive in his approach, especially when patients are young or can otherwise tolerate it. Currently, DVd, DRd, and KRd are National Comprehensive Cancer Network (NCCN)—preferred regimens with a category 1 recommendation for previously treated multiple myeloma.² On November 6, the FDA added another triplet therapy to the mix. The agency approved elotuzumab for use in combination with pomalidomide and low-dose dexamethasone for the patients with relapsed/refractory multiple myeloma following 2 or more prior therapies, including lenalidomide and a proteasome inhibitor (PI). A significant challenge, however, is that many patients become resistant to lenalidomide and bortezomib early in their disease course because these agents are also used in the frontline.¹

Lenalidomide Resistance

The panelists discussed different strategies for treating patients who develop lenalidomiderefractory disease. A key decision is whether to switch immunomodulatory drugs (IMiDs; ie, replace lenalidomide with pomalidomide) or to switch to a regimen that does not include an immunomodulatory agent (eg, carf ilzomib/dexamethasone [Kd] or DVd).

Martin said he would probably use DVd in these patients but would consider using daratumumab/pomalidomide/ dexamethasone if patients’ complete blood cell counts do not pose a problem, although he prefers saving pomalidomide for subsequent lines.

Ajai Chari, MD, said that while a regimen with a bortezomib backbone could be considered, he, too, prefers a regimen that incorporates daratumumab. He said that he selects the partner drug based on the patient. “I would favor daratumumab with pomalidomide if they have no history of thrombotic events and good blood counts. If they’re t(4;14), maybe [daratumumab] with carfilzomib or with bortezomib,” he said. “Luckily, we have so many combinations to pick from.”

However, Sagar Lonial, MD, FACP, thought that the efficacy of pomalidomide as a partner drug in patients with t(4;14) or 17p deletion is undervalued. “In 17p, it actually looks as good as any other drug that’s out there. So daratumumab/ pomalidomide/dexamethasone for that reason is our go-to in the first salvage. And I’ve been really struck by the t(4;14)s and how well they’ve responded after having short responses to either carfilzomib or bortezomib,” he said.

The panelists proceeded to discuss the phase III OPTIMISMM trial, which lends evidence to support switching IMiDs.³ The trial compared pomalidomide/bortezomib/ dexamethasone (PVd) with Vd in lenalidomide- exposed patients, 70% of whom were lenalidomide refractory. After a median follow-up of 16 months, PVd significantly reduced the risk of progression or death by 39%. Patients in the trial had up to 3 prior treatment lines, with benefit most significant in patients who had received only 1 previous line of therapy. “What’s unique about the study is the movement of pomalidomide to earlier lines of therapy. So if you’re practicing on label, it’s not given in first relapse. Here the first relapse is allowed, which I think shows that if pomalidomide is used earlier, you do see better mileage from the drug,” Chari said.

However, Martin indicated the results should be interpreted with caution and suggested that a nonimmunomodulatory approach might be better. He explained that although PFS was 20 months when PVd was administered at first relapse, it was only 9 months for patients who were lenalidomide refractory. In contrast, he said daratumumab/ carfilzomib/dexamethasone (DKd) showed an even higher PFS of 14.1 months in lenalidomide-refractory patients in the MMY1001 trial, a study in which Chari and Lonial were investigators.⁴

Bortezomib Resistance and Proteasome Inhibitor Selection

Two PIs can be considered for patients who become resistant to bortezomib: ixazomib, which is taken orally, and carfilzomib, which is given intravenously, like bortezomib. “If somebody has an aggressive disease, more than just a biochemical relapse, I would probably use K [carfilzomib] over I [ixazomib]; if it was somebody who had more of a biochemical recurrence and it was a convenience issue, then I would use I,” Chari said. He cautioned, however, that ixazomib data are available only for patients who are bortezomib naïve or have demonstrated bortezomib sensitivity, whereas carfilzomib has shown activity even in bortezomibrefractory patients.

“[Ixazomib] really needs to be [reserved for] patients who are bortezomib sensitive and carfilzomib sensitive. If they’re refractory to any other PI, then ixazomib is probably not the right choice,” Martin added.

A significant challenge with carfilzomib, however, has been its approved dosing schedule, which requires twice-weekly intravenous infusions. However, the panelists discussed findings from the ARROW study, which showed superior results with weekly dosing.⁵ In the study, patients were randomized 1:1 to receive carfilzomib 20/70 mg/ m² once weekly or 20/27 mg/m² twice weekly as part of a Kd regimen. The median PFS was significantly improved with the onceweekly dose (11.2 months vs 7.6 months, respectively), as was the overall response rate (62.9% vs 40.8%, respectively). The once-weekly dose also showed similar tolerability to that of the biweekly dose, with only a slight increase in prevalence of grade ≥3 adverse events (AEs; 67.6% vs 61.7%), treatment-related grade 5 AEs (2.1% vs 0.9%), and grade ≥3 hypertension (5.9% vs 5.5%). Cardiac events were observed less frequently with once-weekly dosing (2.9% vs 4.3% for twice-weekly dosing).

“I think this will be practice changing because it will make us more comfortable to use 70 mg/m² weekly, including in older patients. And frankly, the biggest barrier I think for patients getting carfilzomib has been the dosing schedule,” Amrita Krishnan, MD, FACP, said. Following the Peer Exchange, on October 1, 2018, the FDA approved the once-weekly dosing option of carfilzomib in combination with dexamethasone based on the ARROW data.⁶

Before the ARROW trial, carfilzomib 20/56 mg/m² twice weekly was compared with Vd in the ENDEAVOR trial, which also showed good safety and tolerability and led to FDA approval of this dosing schedule.⁷ “I think it’s clear, both from ENDEAVOR at 56 mg/m² twice a week and ARROW at 70 mg/m² once a week, that you can give these higher doses of carfilzomib with dexamethasone as the partner,” Lonial said.

However, it has been unclear whether such higher doses are possible when carfilzomib is combined with other agents in addition to dexamethasone. “There has been this notion that 70 mg/m² weekly is not going to be the dose you can combine with lenalidomide or cyclophosphamide,” A. Keith Stewart, MB, ChB, who served as moderator for the Peer Exchange program, said.

Table. Response Rates to Selinexor in STORM Trial Part II By Treatment Subgroups

Promising New Treatments

But the panel indicated this notion may be challenged by data from the phase Ib MMY1001 study.4 In this study, patients received DKd with carfilzomib administered at 20/70 mg/m² once weekly. “It showed that it was very safe. Really, we didn’t see a lot of additional toxicities than what you would expect from each drug. The rate of neutropenia was relatively modest. Grade 3/4 was about 20%, so I think that was an interesting safety signal,” Chari said. Nevertheless, Krishnan warned that care must be taken before starting patients on the higher once-weekly dose, to mitigate the risk of AEs. “Before you suddenly jump to 70 mg/m², you really need to make sure all your ducks are in a row, especially in terms of hypertension,” she said. CAR T-Cell Therapy

Immunotherapy has been revolutionizing the treatment of many solid tumors and hematological malignancies, and Stewart suggested it is “the most exciting field in myeloma right now.” He noted that active cellular immunotherapy targeting B-cell maturation antigen (BCMA) is particularly promising.

“There’s no question that the patients who were dying of [multiple myeloma] and who received [cellular immunotherapy] are now doing well long term. So that’s exciting and remarkable. Whether it is the cure for everyone with myeloma is still something that needs to be worked on,” Edward A. Stadtmauer, MD, said. “The way I see it is we have proof of principle. These therapies are definitely working, but now it’s an engineering problem where we have to engineer these cells in a way that will be more broadly applicable and lead to longterm cures for patients,” he added.

The panelists proceeded to discuss a small study evaluating bb2121, a second-generation CAR T-cell therapy that targets BCMA and causes it to redirect T cells to recognize and kill malignant myeloma cells.8 In the study, patients were heavily pretreated, having received a median of 7 lines of therapy. “There was a very rapid response rate of nearly 100%...And the PFS was around 11.8 months. This is an amazing result for such a heavily pretreated population—that the response rate and the PFS are superior to [those of] all other drugs that have typically been tested in this heavily pretreated population,” Chari said.

However, the challenge with bb2121 is that once patients are enrolled in the study assessing this agent, it takes anywhere from 4 to 6 weeks before the manufacturing process is complete and the treatment is administered. Because these patients are at the end stages of their disease and IMiDs and PIs have failed, there are few bridging treatments available, resulting in a fairly high risk that they will succumb to their disease before they can receive treatment. “I think [the study findings have] dramatic implications, especially in these end-line patients, but now we have to move it closer to early relapse, frontline,” Martin said.

Selinexor

Another exciting development the panel discussed is the emerging small molecules. One such agent is selinexor, a first-in-class selective inhibitor of chromosome region maintenance 1 protein (CRM1), which prevents CRM1-mediated nuclear export of cargo proteins, such as tumor suppressor proteins and other growth regulatory proteins. It has been assessed with dexamethasone in patients with penta-refractory multiple myeloma.

The most recent data for this doublet regimen from the STORM II trial show an objective response rate (ORR) of 26.2% and a median overall survival of 8.6 months in patients with penta-refractory disease. Among patients who had received daratumumab-based treatment in their most recent treatment regimen (n = 58), the ORR was 34.5% and the clinical benefit rate was 44.8%. Otherwise, responses rates were similar across subgroups based on prior treatments (Table).⁹

There were some issues with toxicity, particularly grade 3/4 hematological AEs, but the panel emphasized that this likely has a lot to do with how ill these patients are. Many of these patients would have transitioned to hospice care, Chari said.

“I think the expectations need to be commensurate with that setting. And in fact, some of these patients were progressing on DT-PACE, which is guaranteed to give you grade 3/4 [hematologic] toxicity,” he said, referring to the combination regimen of dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, and etoposide.

On October 5, the FDA accepted a new drug application seeking accelerated approval of selinexor and granted priority review to the application, with an assigned action date of April 6, 2019, under the Prescription Drug User Fee Act.¹⁰ The agent has orphan drug and fast track designations from the FDA in the setting of penta-refractory multiple myeloma.

Additional data from the phase IIB STORM study testing selinexor in patients with penta-refractory multiple myeloma (NCT02336815) and updated findings from one of the combination arms of the phase IB/ II STOMP study (NCT02343042) are scheduled to be presented during the 2018 American Society of Hematology (ASH) Annual Meeting, December 1 to 4, in San Diego, California.

In preliminary findings from the STOMP trial reported in an abstract in advance of the 2018 ASH meeting, investigators said that selinexor administered once weekly at 100 mg in combination with daratumumab and dexamethasone resulted in a 74% ORR among 19 patients who had received ≥3 prior lines of therapy not including daratumumab. In 2 participants with daratumumab-refractory multiple myeloma, there was 1 patient with progressive disease and 1 with stable disease.¹¹

Venetoclax

The final promising therapy the panel discussed is venetoclax (Venclexta), a selective inhibitor of BCL-2 protein that is FDA approved for treating patients with chronic lymphocytic leukemia or small lymphocytic lymphoma, with or without 17p deletion, who have received at least 1 prior therapy. Although most myelomas are MCL-1 dependent, “about 15% to 20% of myelomas are BCL-2 dependent,” Lonial said, adding that this subset tends to be enriched among patients with t(11;14). The agent has been assessed alone and in combination with dexamethasone.

“What really struck me is even in pentarefractory patients, venetoclax/dexamethasone does have a response rate somewhere around 65% to 70%, and some of those responses can be quite durable,” he said. He added that he has also seen patients respond who do not have t(11;14) but have B cell—like features.

Conclusions

Lonial’s institution, Winship Cancer Institute in Atlanta, Georgia, is able to conduct sensitivity testing before initiating venetoclax treatment, but not every institution has such resources. Nevertheless, Krishnan said she is willing to try it across the board for penta-refractory patients. “By the time you get to fifth line, I’m willing to try anything. I’ll do venetoclax/carfilzomib/bortezomib, and I’ve been surprised with some of the responses,” she said.In their concluding remarks, the panelists expressed their excitement about where the field is going, especially regarding CAR T-cell therapy and the potential for more personalized treatments. However, until then, Martin advised, clinicians should become familiar with the newer agents, which are already improving outcomes. “Get familiar with daratumumab, pomalidomide, and carfilzomib. Combine 2 of the potent drugs with dexamethasone, and you’ll typically have a good response, and then dose-reduce for toxicities and change drugs if you have toxicities,” he recommended. He anticipates there will be dramatic changes to the treatment landscape in the next 2 to 4 years. “We’re going to go from the Hyundai to the Cadillac, and I think then we’re going to cure patients with myeloma,” he concluded.

References

1. Harousseau JL, Attal M. How I treat first relapse of myeloma. Blood. 2017;130(8):963-973. doi: 10.1182/blood-2017-03-726703.
2. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) Multiple Myeloma. Version 1.2019. National Comprehensive Cancer Network (NCCN) website. nccn.org/professionals/ physician_gls/pdf/myeloma.pdf. Updated July 20, 2018. Accessed October 15, 2018.
3. Richardson PG, Rocafiguera AO, Beksac M, et al. Pomalidomide (POM), bortezomib, and low‐dose dexamethasone (PVd) vs bortezomib and low-dose dexamethasone (Vd) in lenalidomide (LEN)-exposed patients (pts) with relapsed or refractory multiple myeloma (RRMM): phase 3 OPTIMISMM trial. J Clin Oncol. 2018;36(suppl; abstr 8001). meetinglibrary.asco.org/ record/160688/abstract.
4. Chari A, Martinez-Lopez J, Mateos MV, et al. Daratumumab (DARA) in combination with carfilzomib and dexamethasone (D-Kd) in lenalidomide (Len)-refractory patients (Pts) with relapsed multiple myeloma (MM): subgroup analysis of MMY1001. J Clin Oncol. 2018;36(suppl; abstr 8002). meetinglibrary.asco.org/record/160687/abstract.
5. Mateos MV, Moreau P, Berenson JR, et al. Once-weekly vs twice-weekly carfilzomib (K) dosing plus dexamethasone (d) in patients with relapsed and refractory multiple myeloma (RRMM): results of the randomized phase 3 study A.R.R.O.W. J Clin Oncol. 2018;36(suppl 15; abstr 8000). meetinglibrary.asco.org/record/ 160692/abstract.
6. Kyprolis [package insert]. Thousand Oaks, CA: Onyx Pharmaceuticals Inc; 2018. www.accessdata.fda.gov/drugsatfda_docs/ label/2018/202714s021lbl.pdf. Accessed November 4, 2018.
7. Dimopoulos MA, Moreau P, Palumbo A, et al; ENDEAVOR Investigators. Carfilzomib and dexamethasone versus bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma (ENDEAVOR): a randomised, phase 3, open-label, multicentre study. Lancet Oncol. 2016;17(1):27-38. doi: 10.1016/ S1470-2045(15)00464-7.
8. Raje NS, Berdeja JG, Lin Y, et al. bb2121 anti-BCMA CAR T-cell therapy in patients with relapsed/refractory multiple myeloma: updated results from a multicenter phase I study. J Clin Oncol. 2018;36(suppl; abstr 8007). meetinglibrary.asco.org/ record/160693/abstract.
9. Jagannath J, Vogl DT, Dimopoulos MA, et al. Phase 2b results of the STORM study: oral selinexor plus low dose dexamethasone (Sd) in patients with penta-refractory myeloma (penta-MM). Clin Lymphoma Myeloma Leuk. 2018;18(suppl 1; abstr MM- 255):S249-S250. doi: 10.1016/j.clml.2018.07.149.
10. US Food and Drug Administration accepts Karyopharm’s new drug application for selinexor and grants priority review [news release]. Newton, MA: Karyopharm Therapeutics Inc; October 5, 2018. investors.karyopharm.com/news-releases/news-release- details/us-food-and-drug-administration-accepts-karyopharms- new-drug. Accessed October 17, 2018.
11. Gasparetto CJ, Lentzsch S, Schiller, GJ, et al. Deep and durable responses with selinexor, daratumumab, and dexamethasome (SDd) in patients with multiple myeloma (mm) previously exposed to proteasome inhibitors and immunomodulatory drugs: results of phase 1b study of Sdd. Abstract to be presented at: 2018 American Society of Hematology Annual Meeting; December 1-4, 2018; San Diego, CA. Abstract 599. ash.confex.com/ ash/2018/webprogram/Paper117201.html.