Encouraging Data Advance Research in Relapsed/Refractory Myeloma

Amrita Krishnan, MD

Therapeutic options for relapsed/refractory multiple myeloma are quickly evolving, following an explosion of data presented over the last several months, explained Amrita Krishnan, MD.

For example, results of the phase III COLUMBA trial found that daratumumab (Darzalex) can be given subcutaneously rather than intravenously without comprising efficacy in patients with relapsed/refractory multiple myeloma.¹ Based on these data, a supplemental biologics license application was submitted to the FDA in July 2019 for the new subcutaneous formulation as a treatment for patients with multiple myeloma.

Data have also read out with another CD38-directed monoclonal antibody. In the ICARIA-MM trial, which looked at isatuximab plus pomalidomide (Pomalyst)/dexamethasone versus pomalidomide/dexamethasone alone, findings showed a greater than 40% reduction in the risk of disease progression or death in the isatuximab arm.² In July 2019, the FDA accepted a biologics license application for isatuximab for the treatment of patients with relapsed/refractory disease.

Moreover, results of the phase II ELOQUENT-3 trial showcased activity with elotuzumab (Empliciti) and pomalidomide/dexamethasone in patients with relapsed/refractory multiple myeloma who previously received treatment with lenalidomide (Revlimid) and a proteasome inhibitor. The median progression-free survival (PFS) with elotuzumab plus pomalidomide and dexamethasone was 10.3 months versus 4.7 months with pomalidomide/dexamethasone alone (HR, 0.54; 95% CI, 0.34-0.86; P = .0078).³ The FDA approved this triplet regimen in November 2018 for patients with relapsed/refractory who progressed on ≥2 prior therapies, including lenalidomide and a proteasome inhibitor.

“The good news is we have multiple new options that continue to evolve. Every month we have something new—a new horizon or exciting new data emerging,” said Krishnan, director of the Judy and Bernard Briskin Center for Multiple Myeloma Research and a professor in the Department of Hematology & Hematopoietic Cell Transplantation at City of Hope.

In an interview during the 2019 OncLive^® State of the Science Summit™ on Hematologic Malignancies, Krishnan highlighted recent research in relapsed/refractory multiple myeloma.

OncLive: Could you discuss the COLUMBA trial and its clinical implications?

Krishnan: This was a phase III randomized trial with more than 500 patients comparing daratumumab as intravenous or subcutaneous therapy; it is a 5-minute injection compared with standard intravenous daratumumab. It showed noninferiority for the subcutaneous formulation in terms of overall response rate (ORR) and very low rates of infusion toxicity. We're all extremely excited about it as a real game-changer, in terms of providing a much easier [method] for patients to receive daratumumab.

What are the next research efforts for daratumumab?

A lot of the research that we're doing is trying to understand why patients are becoming resistant to daratumumab. If you can understand that, it helps you understand what the best [agents] are to partner with daratumumab to overcome that resistance. What will help us understand more is the role of some of these other anti-CD38 agent, such as isatuximab. How are we going to use that? Is it just another CD38-directed antibody, or does it have a role when patients failed daratumumab? There are a lot of questions that are not answered in that space.

What were the data from the ICARIA-MM trial?

That was a trial looking at isatuximab with pomalidomide and dexamethasone, and the control arm was pomalidomide/dexamethasone. The ORR with the isatuximab regimen was 60.4%, so it looks to be very similar to what we saw with the daratumumab/pomalidomide/dexamethasone regimen. It had a relatively low rate of infusion toxicity, and the infusion time is shorter than daratumumab, though many of us have moved to rapid infusion daratumumab—therefore, it's a little more comparable now. If you give daratumumab the traditional way, the isatuximab infusion time is shorter.

Moving onto selinexor (Xpovio), could you share insight on the STORM trial?

The STORM trial comprised advanced refractory patients with a median of 5 prior regimens. They had to be refractory to at least 1 immunomodulatory (IMiD) agent and 1 proteasome inhibitor. Out of 79 patients, 31 of those patients were penta-refractory; therefore, they failed 2 IMiDs, 2 proteasome inhibitors, and 1 monoclonal antibody. They had a response rate of about 21%, which doesn't sound earth-shattering; however, in the context of advanced refractory disease, it was clearly thought to be notable by the FDA and that led to the approval of selinexor.

The reality for most [physicians] is that we're not going to use it as a single agent. The question down the road will be, “What is the best partner for that drug?” There are some phase I [studies] of combinations, including with daratumumab.

Elotuzumab is another agent that has garnered excitement. What is important to note from the ELOQUENT-2 and -3 trials?

ELOQUENT-2 is an older trial that looks at elotuzumab plus lenalidomide/dexamethasone compared with lenalidomide/dexamethasone as a control arm, and results showed a significant PFS advantage for the elotuzumab arm. It is a well-tolerated drug.

In ELOQUENT-3, a randomized phase II study, elotuzumab was combined with pomalidomide/dexamethasone compared with pomalidomide/dexamethasone alone. That showed a PFS of about 10.3 months in the elotuzumab arm versus 4.7 months for the pomalidomide/dexamethasone-alone arm. Many of us were pleasantly surprised at this PFS with elotuzumab, [especially] in a setting of patients who were more heavily pretreated—a median of 3 prior regimens.

There have been some safety concerns with venetoclax (Venclexta). Where does the BCL-2 inhibitor fit into the multiple myeloma paradigm?

Venetoclax is something that we've been using in patients with more advanced refractory disease. It has unique activity in patients with t(11;14); data were presented at the 2018 ASCO Annual Meeting of venetoclax [plus] carfilzomib (Kyprolis) and dexamethasone in the t(11;14) subgroup. These were small groups of patients, but there was a 100% response rate. There have been some single-agent venetoclax data as well. Patients with t(11;14) is the subgroup that seems to have the best response.

The BELLINI trial examined bortezomib (Velcade)/dexamethasone plus venetoclax versus bortezomib/dexamethasone plus placebo, [results of which caused the trial] to be put on hold by the FDA. The study met its primary endpoint, and showed a PFS benefit and higher ORR for the venetoclax arm, but it also was linked with a high death rate—primarily due to infection in that venetoclax group. I don't think anyone could argue that it is an effective drug, especially in patients with t(11;14). The challenges are understanding this toxicity profile; how do we ameliorate that so we can optimize the benefit without that risk?

There is another trial, the CANOVA trial, which had a hold lifted by the FDA for patients with t(11;14). Results showed that the benefits may outweigh the risk, given that we know the response rates are so high in this group.

What research is being done with CAR T-cell therapy?

There are several CAR T constructs. The ones with the longest track record are BCMA CAR T-cell products. The ones that we've seen the most data have similar response rates, about 80% to 90%, which is tremendous given that most of these patients have had a median 5 to 7 prior regimens, depending on the trial. One of the challenges is the durability of these responses. For example, bb2121 was about 11.5 months. To try and understand why patients lose responses, they all have some degree of cytokine release syndrome (CRS). Most of it is grade 1/2, but in patients with more advanced tumor burden, there are higher grades of CRS.

We're still trying to optimize the cell dose. Other trials seem to have found their cell dose in terms of bb2121. We are interested in understanding why people lose their responses to CAR T-cell therapy. Is it persistence of the treatment? Is it loss of target? It's a very exciting space for us. We need to realize BCMA is not the only target out there. City of Hope [researchers] are looking at a CS1-specific CAR T-cell product.

What challenges in relapsed/refractory multiple myeloma would you like to see addressed with future research?

There are so many challenges because, ultimately, we get responses, but durability of these responses is a challenge. Additionally, understanding why patients relapse and the mechanisms of resistance are the big focuses of our scientists at City of Hope. That also holds true in the CAR T-cell and antibody spaces because once we understand that, we'll have better ideas in terms of how to overcome that.

The bad news is: myeloma has not become any less complicated. The good news is: there are so many more treatment options available right now, and I anticipate by next year we're going to have several more as well. We're looking forward to commercial approvals of CAR T-cell therapies [in myeloma]. How to sequence these [treatments] is certainly going to be a challenge for us, as well.

References

1. Mateos MV, Nahi H, Legiec W, et al. Efficacy and safety of the randomized, open-label, non-inferiority, phase 3 study of subcutaneous (SC) versus intravenous (IV) daratumumab (DARA) administration in patients (pts) with relapsed or refractory multiple myeloma (RRMM): COLUMBA. J Clin Oncol. 2019;37(suppl; abstr 8005). doi: 10.1200/JCO.2019.37.15_suppl.8005.
2. Richardson PG, Attal M, Rajkumar SV, et al. A phase III randomized, open label, multicenter study comparing isatuximab, pomalidomide, and low-dose dexamethasone versus pomalidomide and low-dose dexamethasone in patients with relapsed/refractory multiple myeloma (RRMM). J Clin Oncol. 2019;37 (suppl; abstr 8004). doi: 10.1200/JCO.2019.37.15_suppl.8004.
3. Dimopoulos MA, Dytfeld D, Grosicki S, et al. Elotuzumab plus pomalidomide/dexamethasone (EPd) vs Pd for treatment of relapsed/refractory multiple myeloma (RRMM): results from the phase 2, randomized open-label ELOQUENT-3 study. N Engl J Med. 2018;379:1811-1822. doi: 10.1056/NEJMoa1805762.