CD38-Directed Regimens Lead the Pack in Relapsed/Refractory Myeloma Treatment

Combinations featuring the monoclonal antibodies daratumumab (Darzalex) or isatuximab-irfc (Sarclisa) have made notable differences in outcomes for patients with relapsed/refractory multiple myeloma, but it will be imperative to see how the 2 agents compare with longer follow-up, according to Rebecca Silbermann, MD, MMS.

“In the laboratory, it appears that isatuximab does have a different mechanism of action than daratumumab in how the cells actually die,” Silbermann explained. “We don't know yet whether that's going to translate into a difference in larger clinical studies when you compare the efficacy of 1 monoclonal antibody to the other. The other piece that we don't have good information on yet is whether you could use isatuximab for a patient who no longer responds to daratumumab or vice versa. Hopefully, we'll be learning about that in the future.”

While daratumumab has various indications for use as a single agent and in combination for patients with newly diagnosed and relapsed/refractory disease, isatuximab is approved for use in combination with pomalidomide (Pomalyst) and dexamethasone as a treatment for patients who have received at least 2 prior therapies, including lenalidomide (Revlimid) and a proteasome inhibitor.

Daratumumab has also been found to have a benefit in patients who have high-risk features. For example, in the phase 3 CASTOR trial randomized patients with high-risk multiple myeloma to either daratumumabplus bortezomib (Velcade) and dexamethasone or bortezomib/dexamethasone alone. At a median follow-up of 40.0 months, updated results showed that the triplet regimen significantly improved median progression-free survival (PFS) in patients with standard-risk disease compared with the doublet at 16.6 months and 6.6 months, respectively (HR, 0.26; 95% CI, 0.19-0.37; P <.0001). In those with high-risk disease, the PFS rates were 12.6 months and 6.2 months, respectively (HR, 0.41; 95% CI, 0.21-0.83; P = .0106).

In an interview with OncLive® during the 2020 Institutional Perspectives in Cancer webinar on Leukemia/Lymphoma, Silbermann, an assistant professor of medicine in the Division of Hematology/Medical Oncology, School of Medicine at Oregon Health & Science University, discussed trials of interest involving CD38-directed monoclonal antibodies in relapsed/refractory multiple myeloma and the next steps with this class of agents.

OncLive®: In the early relapse setting, what are some therapeutic regimens that you would consider for a healthy, fit patient?

Silbermann: For patients who we think still have sensitivity to immunomodulatory drugs, you can consider using lenalidomide again. We would prefer that you consider using a triplet rather than a doublet. There are data with daratumumab in combination with lenalidomide and, certainly, that combination is extremely effective for patients. Similarly, for patients who are not likely to be responsive to lenalidomide anymore, we can do similar combinations of therapy with proteasome inhibitors.

There is also updated, long-term follow-up of the CASTOR trial. Also, [from the ENDEAVOR trial, we learned that], we also can use carfilzomib (Kyprolis) [instead of bortezomib in some regimens].

What did the updated findings of the CASTOR trial show?

The CASTOR study was a large study of almost 500 patients. Data were initially presented at the end of 2015 and were published in 2016. It showed us that the combination of daratumumab, bortezomib, and dexamethasone was very good for patients who had received at least 1 prior line of therapy and achieved at least a partial response to that treatment. Patients who were refractory to proteasome inhibitors were excluded from that study.

[The initial analysis had] a median follow-up of 7.5 months or so. The more recent data provided 40 months of median follow-up, and also included a subgroup analysis on standard-risk versus high-risk patients and how those patients did with the regimen. What we saw was that patients even with high-risk disease did well, and they had a significant improvement in PFS for the daratumumab combination [arm]. The [median PFS in] standard-risk patients was about 16.6 months as compared with 6.6 months for the doublet combination.

What did the results of the ENDEAVOR trial reveal?

The ENDEAVOR trial comprised the combination of carfilzomib/dexamethasone versus bortezomib/dexamethasone. That [study] demonstrated an improvement in PFS in the carfilzomib arm as compared with the bortezomib arm with an overall response rate of 77% in patients who received carfilzomib. [There was] a hazard ratio of 0.79 for overall survival, which was certainly very impressive to see.

Could isatuximab become the preferred monoclonal antibody in the relapsed/refractory setting?

We don't know the answer to [that question]. Certainly, we have become very comfortable using daratumumab as an intravenous (IV) therapy. We are gaining confidence in using the newer formulation of daratumumab which is the subcutaneous injection [Faspro] . It's going to be very interesting to see how isatuximab is positioned.

In your opinion, which studies with monoclonal antibodies have had the biggest impact on clinical practice?

Well, even though we don't know enough yet about how to use isatuximab as opposed to daratumumab, the 2 isatuximab studies are actually both very exciting because they show that we do have another option to consider in addition to daratumumab. The IKEMA study [looked at] carfilzomib and dexamethasone with or without isatuximab, and the ICARIA-MM study [utilized] isatuximab plus pomalidomide and dexamethasone. We can't make perfect comparisons between the 2 monoclonal antibodies by [comparing across studies] but it's very exciting to see that the target of CD38 remains very good in separate, relapsed/refractory populations.

What exactly is the role of carfilzomib in relapsed/refractory myeloma?

In appropriately selected patients, carfilzomib can be extremely effective. The lower risk of peripheral neuropathy as compared with bortezomib is certainly very enticing. We need to be careful of the cardiac risks associated with carfilzomib and watch closely to make sure a patient's blood pressure is reasonably controlled when we are just starting out on a carfilzomib-containing regimen. However, it certainly provides a great option for patients.

When would you think about introducing CAR T-cell therapy, antibody-drug conjugates, and/or bispecific T-cell engagers?

It’s important to consider them, even at the time of relatively early relapse. We don't know yet what [agent] is going to be the “winner” in these trials as they continue to evolve. The clinical trial availability for these agents is sometimes a little bit of a challenge and you have to have the patient lined up with when there's a place available for them on an appropriate trial. We tend to think that a patient is likely to have a good chance with a BCMA-targeting therapy. Therefore, you want to be thoughtful about which therapy is going to be offered to which patient, in terms of their potential risks and tolerability differences.

A lot of the therapies in myeloma are of IV formulations. Has the coronavirus 2019 pandemic affected your treatment plans at all?

It's very geographically dependent. We have been really lucky in Portland, [Oregon] where our numbers have been relatively low compared with other areas of the country. We have done a lot of work to try to minimize the amount of time that a patient needs to be physically present in the infusion center and be [in close proximity with] other people. We have not had to change a lot of our treatment practices for patients who do need IV therapy. If they need it, we figure out a way to get it for them. We try to do that in a way where the patient feels comfortable with their potential risks of exposure. There are some individuals who are certainly more worried about it than others. If that's the case, we try to meet them in the middle and find a way that we can make things tolerable.

What else is meaningful to note regarding management of patients with relapsed disease?

It's really important that patients have a sense of whether their doctors think that their relapse is an emergency or not. If they have the benefit of a little bit of time, it's important that they try to look around and [determine if they should get a second opinion]. We have a lot of tools that we can use in myeloma right now.

We're still learning a lot about this disease. We will find out that it's more than just a few different types of myeloma that are out there. There is a lot of variation.

Someone with high-risk disease and was very symptomatic should be considered differently from somebody with standard-risk disease and [whose disease] was relatively easy to control. That being said, if someone had standard-risk disease and it was very difficult to get them into their first response with initial therapy, they should also be looked at very carefully at relapse because there's probably something that we don't fully understand about their disease biology.

The patient's individual disease biology at the time of diagnosis really does play a large role in how we should be thinking about a patient's disease at the time of relapse. We're not yet to the point where we can have a single algorithm that follows every type of patient with myeloma effectively. We need to think it through, in a systematic way, for each patient we encounter.

Reference

Weisel K, Spencer A, Lentzsch S, et al. Daratumumab, bortezomib, and dexamethasone in relapsed or refractory multiple myeloma: subgroup analysis of CASTOR based on cytogenetic risk. J Hem & Onc. 2020;13(115). doi:10.1186/s13045-020-00948-5