Novel Combinations Move Into the Spotlight in Early Relapsed Multiple Myeloma

Shaji K. Kumar, MD

Lenalidomide (Revlimid)-based combinations are not recommended for patients with multiple myeloma experiencing first relapse because the majority are likely refractory to or have had significant exposure to lenalidomide up front, said Shaji K. Kumar, MD, who added that a number of alternative combinations can be considered at the time of progression.

“We have multiple different drugs that can be used to treat patients with multiple myeloma, and various combination [strategies] can be created out of these drugs,” said Kumar. “[It is important] to sequence these combinations appropriately, take into account what drugs patients are refractory to, and [understand] what toxicities patients have been exposed to. That is clearly going to be the way that disease can be kept under control for long periods of time.”

In an interview with OncLive^® during a 2020 Institutional Perspectives in Cancer webinar on multiple myeloma, Kumar, a consultant in the Division of Hematology, Department of Internal Medicine, and a professor of medicine at Mayo Clinic, discussed novel combinations that are being introduced to the relapsed/refractory setting in multiple myeloma.

OncLive^®: Why should lenalidomide-based treatments be avoided at first relapse for patients with multiple myeloma?

Kumar: A lot of new data came out at the 2020 American Society of Hematology [ASH] Annual Meeting and Exposition in terms of [identifying] the appropriate approach to treat early relapses in [patients with] multiple myeloma. As the field has evolved over the past decade with the introduction of novel therapies and combinations, patients who are transplant eligible are typically getting 3-drug combinations and stem cell transplants, followed by lenalidomide maintenance. Patients who are not eligible for autologous stem cell transplant often get continuous therapy, which often contains lenalidomide, until progression.

At the time of first relapse, the majority of patients tend to be refractory to lenalidomide to some degree. That has driven the selection of therapies for patients suffering from first relapse. With subsequent relapses, patients [become] refractory to additional drugs, so treatment selection depends on how they tolerated prior therapies, what [therapies] they have [taken], and what individual drugs or combinations they are refractory to.

What were some of the most compelling data that came out of the 2020 ASH Annual Meeting and Exposition?

In the relapsed setting, we saw follow-up data from several phase 3 trials, as well as data with new therapies. The phase 3 APOLLO trial [NCT03180736] looked at [subcutaneous] daratumumab [Darzalex], pomalidomide [Pomalyst], and dexamethasone vs pomalidomide and dexamethasone and showed that the addition of daratumumab significantly improved progression-free survival [PFS].

Patients in first relapse are mostly refractory to lenalidomide or have been exposed to a significant amount of lenalidomide. The choice at that time is [between] a monoclonal antibody in combination with a newer immunomodulatory drug [IMiD] or a proteasome inhibitor [PI]. There have been 2 phase 3 trials with isatuximab-irfc [Sarclisa] and daratumumab, both of which are targeted toward CD38, showing [that the agents] are quite effective in this setting. Isatuximab and daratumumab, both in combination with carfilzomib [Kyprolis] and dexamethasone, showed superiority compared with carfilzomib and dexamethasone.

Along with the APOLLO trial, [we saw] the results of the ICARIA-MM trial [NCT02990338] that looked at [dexamethasone] in combination with pomalidomide and isatuximab [vs dexamethasone] in combination with pomalidomide. Both [the APOLLO and ICARIA-MM trials] showed that the anti-CD38 agent in combination with pomalidomide improved PFS compared with the doublet [of pomalidomide and dexamethasone]. The results of these trials are comparable, suggesting that the CD38[directed] monoclonal antibodies are quite equal when combined with an IMiD or PI.

Other regimens have been used as well. Data with the combination of carfilzomib and dexamethasone [were presented to] focus more on regimens that do not need an IMiD, given that many of these patients are going to be refractory to lenalidomide at the time of first relapse. The combination of carfilzomib, cyclophosphamide, and dexamethasone also showed improved PFS compared with carfilzomib and dexamethasone, suggesting that [adding an] alkylating agent might be another approach for patients at the time of first relapse.

Although we can’t rely on cross-trial comparisons, we appear to be seeing improved PFS across the board with these regimens. What is the next end point of significance?

For the relapsed setting, PFS has been the end point for many of the registration trials; it is a well-accepted end point in this setting. With longer follow-up, these trials will give us an idea of the overall survival differences, as many of the older phase 3 trials are starting to do now.

Additionally, even in the setting of relapsed disease, it is clear from the [2020 ASH Annual Meeting and Exposition] presentations that minimal residual disease [MRD] negativity has value. MRD is often being considered as a potential surrogate end point, given that these patients are living a long time. Multiple studies in the setting of relapsed multiple myeloma have shown a higher proportion of patients getting to MRD negativity, which translates to a longer PFS. This adds to the wealth of data showing the relationship between depth of response and PFS.

In December 2020, the FDA approved selinexor (Xpovio) in combination with bortezomib (Velcade) and dexamethasone for patients with multiple myeloma after at least 1 prior therapy. Have you started to incorporate that regimen into your clinical practice, or are you going to reserve it for more heavily pretreated patients?

That’s an important question because, unfortunately, patients with multiple myeloma continue to relapse. We have to come up with new therapies for patients when each regimen stops working. We talked about the first relapse, but what about the second-relapse setting? These patients have often already seen monoclonal antibodies and IMiDs, and some may have already seen PIs. It is in that setting where some of these newer drugs that were recently approved have value.

Clearly, selinexor is among these advances. It is an oral drug, and we saw data at the 2020 ASH Meeting and Exposition showing that selinexor can be safely combined with other standard-of-care agents, such as daratumumab or PIs. The phase 3 BOSTON trial [NCT03110562] showed that selinexor added to bortezomib and dexamethasone is better than bortezomib and dexamethasone alone. We have seen data with selinexor and carfilzomib, as well as selinexor and pomalidomide.

Although the selinexor combinations can certainly be considered at the time of first relapse, we have strong data with longer follow-up [showing] durable responses with monoclonal antibodies, PIs, and IMiDs in that setting. Selinexor-based combinations tend to come in 1 or 2 lines later, mostly in patients who have been exposed to monoclonal antibodies, IMiDs, and PIs.

Similarly, belantamab mafodotin[-blmf (Blenrep)] has shown activity and is approved [in relapsed/ refractory multiple myeloma]. We have certainly started incorporating that agent into the clinic as well. There are an increasing amount of early data showing that belantamab mafodotin can be combined with other standard-of-care drugs, including bortezomib and IMiDs. That is something we look forward to.

Without head-to-head comparisons, what factors should be incorporated into clinical trials to help differentiate among available regimens?

Efficacy is one of the most important [parameters], but the toxicity is another [key] aspect, especially when we are combining multiple drugs. It is important to incorporate quality-of-life assessments and more detailed descriptions of [potential] toxicities that patients can have, so that clinicians can get a better sense of what to use.

What is your recommendation with regard to sequencing?

My recommendations would be that we want to start with a triplet [regimen] in the newly diagnosed setting. As more data come in, we may start doing more quadruplets in the newly diagnosed setting. In the second-line setting, the [question is] whether the [next] regimen should be combined with the most effective drugs that the patients have not been exposed to. Then, it’s essentially a question of selecting the subsequent regimens based on what the patients have been exposed to before.