Novel Agents Move Through Relapsed/Refractory Myeloma Pipeline

Shebli Atrash, MD

With more novel therapies moving through the pipeline, such as selinexor (Xpovio) and belantamab mafodotin, researchers continue to evaluate the patient populations in which these drugs perform best, explained Shebli Atrash, MD.

Another agent, venetoclax (Venclexta), a BCL-2 inhibitor, has also been explored in this setting. In the phase III BELLINI trial, patients with relapsed/refractory myeloma received venetoclax or placebo in combination with bortezomib (Velcade) and dexamethasone. At a median follow-up of 18.7 months, the median progression-free survival (PFS) was 22.4 months for the venetoclax arm versus 11.5 months for the placebo arm (HR, 0.630; P = 0.010).¹

However, at the interim analysis, the venetoclax arm showed an increased risk of death; overall survival, although not reached in either arm, favored the placebo combination (HR, 2.027; 95% CI, 1.042-3.945). An updated analysis showed that patients with t(11;14) or high expression of BCL-2 continued to derive the most benefit from the venetoclax combination.²

“Patients with t(11;14) or BCL-2 high expression is where the drug fits best,” said Atrash. “We saw responses in patients without those 2 signals, but there was an extra toxicity as well. The response was not worth the toxicity.”

Previously, based on the BELLINI data, the FDA placed a partial clinical hold on all studies that were evaluating the BCL-2 inhibitor in patients with multiple myeloma. In July 2019, the agency lifted the partial clinical hold that was placed on the phase III CANOVA (M13-494; NCT03539744) trial, which is examining venetoclax plus pomalidomide (Pomalyst)/dexamethasone in patients with relapsed/refractory multiple myeloma that harbors t(11;14).

Selinexor was evaluated in the phase IIb STORM trial. Here, oral selinexor plus dexamethasone was given twice weekly to patients with multiple myeloma who were refractory to ≥1 proteasome inhibitor, 1 immunomodulatory agent, and daratumumab (Darzalex). A partial response or better was observed in 26% of patients and the median duration of response was 4.4 months.³

In an interview during the 2020 OncLive^® State of the Science Summit^™ on Multiple Myeloma, Atrash, a physician in hematology and medical oncology at Levine Cancer Institute at Atrium Health, discussed some of the latest intriguing research in relapsed/refractory multiple myeloma.

OncLive: How would you define the role of venetoclax in multiple myeloma?

Atrash: Venetoclax is a very exciting drug. It is the first targeted therapy for myeloma. The BELLINI trial showed that venetoclax is effective against patients with myeloma who have t(11;14) and patients who have high BCL-2 expression by polymerase chain reaction. The agent works for patients with multiple myeloma, but we have to use it wisely.

Could you expand on the BELLINI findings?

The BELLINI trial was designed to randomize patients to receive bortezomib/dexamethasone plus venetoclax or placebo. The primary end point for the trial was PFS. The addition of venetoclax was clearly better than placebo and it showed us good results. The trial met its end point with better PFS; however, the trial showed increased mortality in the venetoclax arm. It speaks to the importance of first choosing patients [who are best suited to receive this regimen].

The trial enrolled all patients, regardless of their t(11;14) or BCL-2 status. [The BELLINI trial] also showed the importance of picking an end point for trials. The FDA halted enrollment of the trial. At the 2019 ASH Annual Meeting, we got another update [saying] that the trial continued to show the benefits of venetoclax, especially for patients with t(11;14) or high BCL-2 expression. Going forward, all trials [with venetoclax] should be designed to target this specific population of [patients with] myeloma.

What are some other venetoclax combinations being investigated?

One of the exciting presentations at the 2019 ASH Annual Meeting was by Jonathan L. Kaufman, MD, of Emory University School of Medicine, that looked at combining venetoclax with dexamethasone. Dexamethasone pushes plasma cells to be more dependent on BCL-2 and then venetoclax can inhibit BCL-2. It seems logical from a biological standpoint, and the results of the early-phase trial enrolled a few patients; however, it's showing pretty significant and high overall response rates (ORRs) in the range of 87%.

In [another] early-phase trial of 4 patients with t(11;14) multiple myeloma, [investigators] combined venetoclax with daratumumab and dexamethasone. The trial had another arm where they combined venetoclax, daratumumab, bortezomib, and dexamethasone for patients who had 1 to 3 prior lines of treatment and also were not refractory to any prior proteasome inhibitor. The trial showed great results. The [combination] was very well tolerated, and the ORRs were in the range of 95% in both arms. Those are very promising trials. We should build on those for the future to enroll more patients.

Selinexor is the most recently approved agent in the multiple myeloma space. Could you discuss the STORM data that led to its approval?

The STORM trial looked at combinations of selinexor with different drugs and has about 6 arms. The arm with the combination of pomalidomide, a dose-finding arm, had about 5 patients with an 80% ORR. The trial found that selinexor at a dose of 60 mg combined with pomalidomide at 4 mg is the maximum tolerated dose, in addition to dexamethasone. The arm with carfilzomib and selinexor, also a dose-finding trial, is in an early phase; it seems that selinexor at 80 mg weekly, with carfilzomib at 56 mg/m² on days 1, 8, and 15, is the dose to take to the next level.

Shifting to antibody-drug conjugates, what data have we seen with belantamab mafodotin?

Belantamab mafodotin data were published already for the DREAMM-2 study, which compared 2 belantamab mafodotin doses: 2.5 mg/kg and 3.4 mg/kg. The study enrolled about 100 patients in each arm. Both arms seemed to have an acceptable safety profile, although the 2.5 mg/kg [dose] seemed to be better tolerated. The median PFS was about 3 months for patients with relapsed/refractory multiple myeloma, who are relapsed/refractory to all available treatment options—meaning that these are pretty significant results. The ORRs ranged between 30% to 40% for both doses, so the drug is effective in this arena.

If belantamab mafodotin is approved, how would it impact the myeloma space?

If [belantamab mafodotin] gets approval, it will be approved for relapsed/refractory multiple myeloma—the patients who relapse after all available treatments. Patients must be refractory to immunomodulatory drugs, PIs, and CD38. It's a great option for our patients. We have to watch closely for the adverse events of this drug because it has a specific special safety profile that we need to educate the community about, specifically corneal toxicity. Getting an ophthalmologist on board is important.

We also have to watch for thrombocytopenia, bleeding, and infusion reactions, [but these events] seem to be very well managed. [Belantamab mafodotin] will change the landscape of relapsed/refractory multiple myeloma. I anticipate it will move to earlier lines in combination with other drugs.

References

1. Kumar S, Harrison S, Cavo M, et al. A phase 3 study of venetoclax or placebo in combination with bortezomib and dexamethasone in patients with relapsed/refractory multiple myeloma. Presented at: 2019 European Hematology Association Congress; June 13-16, 2019; Amsterdam, The Netherlands. Abstract LB2601.
2. Moreau P, Harrison S, Cavo M, et al. Updated analysis of BELLINI, a phase 3 study of venetoclax or placebo in combination with bortezomib and dexamethasone in patients with relapsed/refractory multiple myeloma. Blood. 2019;134(suppl_1):1888. doi: 10.1182/blood-2019-126015.
3. Chari A, Vogl DT, Gavriatopoulou M, et al. Oral selinexor—dexamethasone for triple-class refractory multiple myeloma. N Engl J Med. 2019;381(8):727-738. doi: 10.1056/NEJMoa1903455.