Expert Highlights Advantage of Triplet Therapies in Relapsed/Refractory Myeloma

Andrew Yee, MD

Triplet regimens continue to elicit durable responses and prolong progression-free survival (PFS) in patients with relapsed/refractory multiple myeloma, explained Andrew Yee, MD, citing readouts of the ICARIA-MM and OPTIMISIMM studies, among others.

In the phase III ICARIA-MM trial, the triplet regimen of isatuximab, pomalidomide (Pomalyst), and dexamethasone was associated with a median PFS of 11.53 months versus 6.47 months for pomalidomide/dexamethasone alone (HR, 0.596; 95% CI, 0.44-0.81; P = .001).¹ The overall response rates (ORRs) were 60.4% and 35.3%, respectively.

Based on these data, the FDA accepted a biologics license application in July 2019 for the triplet combination of isatuximab, pomalidomide, and dexamethasone for use in this patient population.

Similarly, the OPTIMISMM trial examined the regimen of pomalidomide, bortezomib (Velcade), and dexamethasone versus bortezomib/dexamethasone alone. Patients enrolled had received 1 to 3 prior lines of therapy, 1 of which had to contain lenalidomide (Revlimid). The ORRs were 82.2% with the triplet arm versus 50.0% with the doublet arm, and the median PFS was 11.20 months and 7.10 months, respectively (HR, 0.61; 95% CI, 0.49-0.77; P <.0001).²

“With relapsed disease, you want to use your best and most effective therapies, particularly for patients who have more aggressive types of relapses. A theme I want to convey is that we have all of these new emerging combinations, which are more effective and better tolerated,” said Yee. “As we gain more experience [with triplet therapies], there should be an increase in comfort level with using these [therapies] upfront in the management of patients with relapsed disease. This way patients can get the best and deepest possible response as well as maintain an excellent quality of life.”

In an interview during the 2020 OncLive^® State of the Science Summit™ on Multiple Myeloma, Yee, assistant professor of medicine at Harvard Medical School and hematologist/oncologist for the Center for Multiple Myeloma at Massachusetts General Hospital, reflected on recent clinical trials in multiple myeloma that focused on novel multidrug regimens.

OncLive: What challenges are there with treating multiple myeloma?

Yee: One of the challenges with treating multiple myeloma is that there are many potential avenues for treating relapse disease. Many know that the treatment paradigm is shifting for multiple myeloma, in which patients are increasingly treated for continuous therapy and, many times, that includes lenalidomide.

What are some factors that you consider when choosing between the available treatments?

For a patient who has relapsed, we have to tailor an individualized treatment to the type of relapse that they are experiencing. In the majority of patients, they may be having a biochemical relapse that is purely based on the rise of monoclonal protein or free light chain. For patients in whom the relapse is not necessarily a gentle relapse, the treatments are not as intensive.

On the other hand, for patients with a more aggressive relapse—such as bone lesion, a dramatic increase in the monoclonal protein, or high-risk fluorescence in situ hybridization—I try to use a treatment that matches the intensity of the relapse. For those patients, the field is moving towards more intensive cognitions, such as triplet regimens. This is not only because they are more effective, but also because these they demonstrate excellent tolerability.

What trials are evaluating patients who have been previously treated with lenalidomide?

The OPTIMISMM trial randomized patients to receive pomalidomide, bortezomib, and dexamethasone versus bortezomib and dexamethasone. That is one of the first trials to look at patients [who were refractory to lenalidomide]. It was key in demonstrating significant improvements in PFS.

That result illustrates an overall for using pomalidomide in combination with bortezomib and dexamethasone for treating patients with relapsed disease. That trial also sets the stage for looking at other triplet combinations with pomalidomide.

Could you discuss the data from the phase III CANDOR trial?

That trial looked at the combination of daratumumab (Darzalex), carfilzomib (Kyprolis), and dexamethasone versus carfilzomib/dexamethasone alone. One thing to point out is that this trial was for patients with ≤3 prior lines of treatment.

The [3-drug regimen] showed significant an improvement in high-quality responses, as well as a significant improvement in PFS [compared with carfilzomib/dexamethasone]. With all of these treatments [available], we have to tailor them to patients and their preferences.

How could the possible approval of isatuximab change the myeloma landscape?

The more options we have the better for our patients, because multiple myeloma can be a complicated disease with different types of relapses. The ICARIA-MM trial was the first randomized study to demonstrate the value of adding an CD38-directed monoclonal antibody, isatuximab, to pomalidomide/dexamethasone. Certainly, this drug will see use for treating relapse patients.

At this time, we do not know if there is any specific, clinical difference between daratumumab versus isatuximab. Any scenario where you can think of using daratumumab [you could also use] isatuximab.

How is the role of carfilzomib evolving in myeloma? What was its role in the ENDEAVOR trial?

Carfilzomib is an excellent drug. The ENDEAVOR trial set the stage for demonstrating that carfilzomib has superior efficacy in terms of depth of response and PFS compared with bortezomib. Another advantage of carfilzomib is that there is a lower risk of peripheral neuropathy compared with bortezomib.

With these other trials, such as the CANDOR trial, we are seeing more usage with carfilzomib as a triplet-based combination. Another study is the ARROW trial, which looked at [administering] carfilzomib once weekly versus twice weekly. It also sets a platform for 3-drug combinations, but it is important to emphasize that the weekly carfilzomib dosage can be a better partner option when it is used as part of a triplet platform.

Where will future research efforts focus in this area?

We just scratched the surface for relapsed disease, but the field is moving forward. For example, [we are working on] using BCMA as a target. First, we need to have the anti-BCMA therapy approved, but the preliminary data in clinical trials illustrate that this could be a potential game-changer treatment for myeloma care.

Future trials have started to explore the question, "How do we better incorporate targeting BCMA?" Right now, it is looked at for patients who have had multiple relapses of a refractory disease. We are all eager to see how targeting BCMA works in earlier lines of therapy and potentially newly diagnosed patients.

References

1. Richardson PG, Attal M, S. Rajkumar V, 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).&#8239;J Clin Oncol. 2019;37(suppl; abstr 8004). doi: 10.1200/JCO.2019.37.15_suppl.8004
2. Richardson PG, Rocafiguera AO, Beksac M, et al. Pomalidomide, bortezomib, and dexamethasone for patients with relapsed or refractory multiple myeloma previously treated with lenalidomide (OPTIMISMM): a randomised, open-label, phase 3 trial. Lancet Oncol. 2019;20(6):781-794. doi: 10.1016/S1470-2045(19)30152-4