Standard Myeloma Therapies Transform to Triplet, Quadruplet Regimens

Caitlin Costello, MD

Doublet therapies are becoming obsolete as triplet regimens emerge as a standard-of-care treatment for patients with multiple myeloma, with quadruplet therapies following close behind, explained Caitlin Costello, MD.

Additionally, novel triplet therapies continue to be evaluated in clinical trials. For example, results of the phase III ICARIA-MM trial showed that isatuximab combined with pomalidomide (Pomalyst) and dexamethasone led to a greater than 40% reduction in the risk of progression or death versus pomalidomide/dexamethasone alone in patients with relapsed/refractory myeloma who received ≥2 prior lines of therapy (HR, 0.596; 95% CI, 0.44-0.81; P = .001).¹ The triplet also showed a trend toward improvement in overall survival (HR, 0.687; 95% CI, 0.461-1.023). In July 2019, the FDA accepted a biologics license application for the triplet in this patient population.

Secondly, the OPTIMISMM trial examined pomalidomide, bortezomib (Velcade), and low-dose dexamethasone versus bortezomib/dexamethasone alone in patients with relapsed/refractory myeloma who had received ≤3 prior lines of therapy, ≥2 of them having contained lenalidomide (Revlimid). Results showed that the triplet significantly improved progression-free survival compared with bortezomib/dexamethasone (HR 0.61; 95% CI, 0.49-0.77; P <.0001).²

In addition to multi-drug combinations, other novel agents are emerging in the space, according to Costello.

“There is so much that's exciting in this space right now. There are different novel combinations of drugs that we've been using now for the last 5 or more years, whether it's daratumumab (Darzalex) or carfilzomib (Kyprolis) in combination with some of our usual suspects. We're just scratching the surface,” said Costello. “[We’re also working on] BCMA targets, whether that's with CAR T-cell therapy, antibody-drug conjugates, or bispecific T-cell engagers.”

In an interview during the 2020 OncLive^® State of the Science Summit^™ on Hematologic Malignancies, Costello, a hematologist/medical oncologist and assistant professor of medicine at University of California, San Diego Health, discussed pivotal research in the relapsed/refractory multiple myeloma setting.

OncLive: How would you define the impact of the ICARIA-MM data?

Costello: The ICARIA-MM data are starting to show us the role of the novel CD38-directed monoclonal antibody isatuximab, which has been in development over the last several years trying to find its role in the landscape of multiple myeloma therapy. This particular study looks at [isatuximab] in combination with pomalidomide and dexamethasone in the relapsed/refractory setting. This study is an opportunity to compare that triplet with pomalidomide/dexamethasone alone.

How is isatuximab different from other agents in this space?

Isatuximab is not dissimilar from daratumumab, the other monoclonal CD38-directed monoclonal antibody that's in the [multiple myeloma] space right now. It targets a slightly different epitope. It's slightly different, but in the grand scheme of things, they are likely pretty similar to one another.

Isatuximab potentially coming to market may offer some competition within the market that could potentially allow for some pricing differences that would benefit our patient population. There's some suggestion that [isatuximab] may have a slightly faster infusion rate and a slightly improved safety profile, in the sense that there may be fewer infusion reactions.

This may be mitigated by the potential upcoming [indication of] daratumumab that would allow the agent to be administered as a subcutaneous formulation. In the meantime, isatuximab is looking like it's going to be another option for a monoclonal antibody. It will be determined if there are other places for it. Isatuximab is also being evaluated in smoldering myeloma and in amyloid light-chain amyloidosis.

Could you discuss the OPTIMISMM trial and the significance of those data?

This is an opportunity to compare a triplet with a doublet regimen. This was presented by Paul G. Richardson, MD, of Dana-Farber Cancer Institute, and it is a combination of pomalidomide, bortezomib, and dexamethasone compared with the control arm of pomalidomide/dexamethasone alone. It was a large phase III study that was performed in over 20 countries at many different centers. It comprised a relapsed/refractory population with many prior lines of therapy; many patients had 3 to 4 prior lines [of therapy].

Not surprisingly, like many of other phase III studies, the triplet was superior in terms of efficacy compared with the doublet. The highlight of that OPTIMISMM study, however, was that patients who were on their subsequent therapy after progressing or relapsing on their first-line of therapy. Those who [received triplet] as their second-line therapy overall had a median PFS of 20 months.

Overall, the triplet therapy did better compared with the doublet, but it looks like the patients who did the best were those who hadn't much prior therapy. Pomalidomide, bortezomib, and dexamethasone potentially offers a nice second-line therapy in relapsed/refractory myeloma.

How has the use of carfilzomib evolved in this landscape?

Carfilzomib is evolving. This is a drug that was originally evaluated with great concerns for tumor lysis, renal failure, and cardiac toxicity. Its initial place in the relapsed/refractory setting is evolving; now, we're talking about using it in the newly diagnosed setting. We're talking about it in high-risk patients and in those with smoldering multiple myeloma. The answer to your question is “We don't quite know yet, but we're evaluating it in all these different places.”

The ARROW study was an opportunity to find a way to administer [carfilzomib] in a way that is much more convenient for patients. [Carfilzomib] is a really good drug that many of us go to for our patients with relapsed/refractory myeloma—sometimes in the upfront setting—but it has a challenging schedule for patients when they have to do receive it twice weekly. As physicians have gotten more comfortable with prescribing it, we have been able to understand the appropriate ways to [administer carfilzomib] to mitigate some of those adverse events (AEs).

At the low dose, [we can administer carfilzomib] around 27 mg/m². We can get to much higher doses by giving it in 30-minute infusions. When we try to understand the right doses, we go to our phase III data, which looked at a variety of different studies comparing carfilzomib/dexamethasone with bortezomib/dexamethasone or looking at carfilzomib/lenalidomide versus lenalidomide/dexamethasone.

The ARROW study was a nice opportunity to look at carfilzomib at various doses. It compared the 27 mg/m² twice-weekly dose to the 70 mg/m² weekly dose. As much as we may have been nervous about [higher doses of carfilzomib], it didn't show some of the AEs or toxicity that we would have potentially wondered about. [The ARROW trial] showed that we can get very high doses with good efficacy, minimal toxicity, and a much more convenient schedule for patients.

What is the role of daratumumab in multiple myeloma?

Daratumumab is the gift that keeps on giving. Every time we look at its role in a combination, it seems like [daratumumab] is providing deepened responses with very little added toxicity. In the newly diagnosed space, in the GRIFFIN trial, we have [daratumumab] in combination with lenalidomide/bortezomib/dexamethasone. We have now seen [daratumumab] in combination with carfilzomib, lenalidomide, and dexamethasone in the MASTER study, which we're all very excited about. [The MASTER trial will help us] understand how we can use minimal residual disease (MRD) as a means [to guide] treatments for some of these patients.

The CASSIOPEIA trial looked at the combination of daratumumab with bortezomib, thalidomide (Thalomid), and dexamethasone for transplant-eligible patients. This was one of the first studies that showed us how deep a response could get and showed a nice prolongation of PFS. The expectation is that this will be extrapolated and further showed in the GRIFFIN study that was done in the United States, with the combination of daratumumab, lenalidomide, bortezomib, and dexamethasone.

What other novel therapies are in the pipeline?

There is so much that's exciting in this space right now; we're just scratching the surface. BCMA targets, whether that's with CAR T-cell therapy, antibody-drug conjugates, or bispecific T-cell engagers, will provide game-changing data for multiple myeloma. The efficacy and safety of it all will be determined soon, but it's all in the works. These are exciting preliminary information. Many of us are very excited for how we can incorporate some of those tools into our arsenal.

How is CAR T-cell therapy being used in multiple myeloma?

Across the board, with CAR T-cell therapy, whether you're targeting it for myeloma or for other hematologic malignancies, is this concern for antigen escape. Is there a way that the lymphomas or myeloma learn how to grow, despite the CAR T-cell targeting? Is the clone itself evolving, where it's learning how to grow despite all of that? There's a BCMA CAR T-cell product that we are very excited to have participated at University of California, San Diego; it is an exciting CAR T-cell therapy that is designed to have some form of a memory phenotype that, when it becomes more quiescent, can reemerge when the growth of the myeloma reemerges again.

This is something that we are excited about. It is to be determined just how long the durability will be with all of these different novel constructs. Perhaps some of the novel constructs are going to require dual epitopes and dual-targeting of CAR T-cell therapies that will help mitigate some of that antigen escape.

With so many combinations available for patients with relapsed/refractory multiple myeloma, is there a sequencing model you adhere to?

No, but it would be so easy if we did. We are evolving in our practices and this will continually change. Broadly, we would like to switch classes, if that's an option; we would like to add new classes that haven't been previously seen.

The OPTIMISMM studies showed us that patients who are refractory to lenalidomide can go on to the next-in-line immunomodulatory drug and can stay within the drug class. My general preference is, if patients are progressing on maintenance lenalidomide, for example, I really like to go to the monoclonal antibodies if they have not previously seen them—and combine them with carfilzomib or pomalidomide. Daratumumab ends up being my second-line therapy for patients who have not previously seen it.

How is MRD being assessed in multiple myeloma?

MRD is important to talk about in multiple myeloma. It's coming, but it's not quite here yet. I can get the data [for a patient’s MRD status], but I don't know what to do with the data quite yet.

Patients are so savvy in this field. They have done their research and they understand that MRD is going to be an important part of the myeloma world now and in the future. While I'm interested in [MRD] for potential prognostic importance, I encourage others to not use it at this point as a means to make treatment decisions. MRD, whether you're using next-generation sequencing, next-generation flow, or whatever modality you're using, has a role. We need a little bit more information from trials, which will finally start to answer some questions about what to do with MRD negativity.

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.