Multiagent Regimens Continue to Spearhead Progress in Late Relapsed Myeloma

Peter M. Voorhees, MD

It is already a necessity to incorporate triplet regimens into clinical practice for patients with late relapsed/refractory multiple myeloma, and more intriguing multiagent approaches utilizing proteasome inhibitors, CD38-targeted monoclonal antibodies, immunomodulatory agents, and now XPO1 inhibitors are poised to take this part of the paradigm to the next level, explained Peter Voorhees, MD.

“Combination therapy in a disease that is highly heterogenous is absolutely critical, and there are a large number of available agents for patients with heavily pretreated multiple myeloma, and there are many more on the way,” said Voorhees, a multiple myeloma specialist at Levine Cancer Institute, Atrium Health.

Agents that have already made their way into the multiple myeloma paradigm and continue to be investigated in combination with each other and other novel drugs include daratumumab (Darzalex), isatuximab, elotuzumab (Empliciti), carfilzomib (Kyprolis), bortezomib (Velcade), pomalidomide (Pomalyst), lenalidomide (Revlimid), dexamethasone, and most recently, selinexor (Xpovio).

In an interview with OncLive during the inaugural Charlotte Plasma Disorder Congress, Voorhees discussed the recent data with triplet regimens in late relapsed multiple myeloma and other novel agents shaking up the paradigm.

OncLive: Could you highlight the available treatment options for patients with multiple myeloma who experience late relapse?

Voorhees: We have newly diagnosed patients and [patients who have] early relapse—where we generally think of patients being considered for treatment at first relapse for second-line therapy. My focus was primarily on treatment of third-line patients and beyond, and there are two general concepts that I want to drive home here. Just like in the newly diagnosed setting, it does appear that the combinations that incorporate three different agents are outperforming the doublets, just like in earlier phases of disease.

The other important take-home point is that there is an increasingly larger number of combination regimens available for these patients. While [this disease] appeared to be dire for patients just a few years ago, there are certainly many more opportunities as far as therapeutic options are concerned.

Could you discuss the state of treatment for patients with late relapse?

A lot of progress has been made with pomalidomide-based combinations, so we have several randomized trials that have demonstrated the superiority of pomalidomide-based triplets in patients with late relapsed myeloma. A good example of this is the randomized, phase II study looking at the combo of pomalidomide, dexamethasone and elotuzumab—the SLAMF7 monoclonal antibody—and what that study showed was a higher likelihood of responding to therapy with the three-drug regimen. The depth of response has improved, and that translated into a significant improvement in median progression-free survival (PFS). Even though it was a randomized phase II study, the results were good enough that it led to FDA approval—that is very exciting.

The one caveat with that particular regimen was that there weren’t a lot of patients on that study who didn’t receive daratumumab or other CD38-targeted monoclonal antibodies. The reason that is potentially important is that one of the purported mechanisms of elotuzumab is actually activation of natural killer (NK) cells in addition to antibody-dependent cellular toxicity. The thought is if you deplete NK cells with a CD38-targeted antibody, does that somehow negatively impact the efficacy of an elotuzumab-based regimen subsequently? At this point, we just don’t have those answers, but it’s certainly something we need to tease out further.

The other exciting thing is that there was a recent phase III study of pomalidomide/dexamethasone with or without isatuximab, which is another CD38-targeted monoclonal antibody. These data were presented at the 2019 ASCO Annual Meeting and 2019 EHA Annual Congress. With the three-drug regimen, there was a higher overall response rate (ORR), better depth of response, and that translated into an improvement in PFS.

A smaller phase II study looked at pomalidomide/dexamethasone with or without cyclophosphamide. This is something spearheaded by Moffitt Cancer Center. Although this was a very small phase II study, the ORR was higher and that led to a trend toward median PFS. We have single-arm data with pomalidomide/dexamethasone/daratumumab, with pomalidomide/dexamethasone/carfilzomib, and we will have data from a phase III trial of pomalidomide/dexamethasone/ daratumumab in the not-too-distant future. There is a lot of excitement in the area of pomalidomide-based therapy.

What other agents are having a significant impact on patient outcomes?

We also think about carfilzomib-based therapy in this situation as well. Although I’m thinking about carfilzomib more in early relapse, there have been very interesting data that were recently published looking at the combination of daratumumab, carfilzomib, and dexamethasone. This was [explored] primarily in folks with 1 to 3 prior lines of therapy.

What they showed was a very high ORR and a very impressive median PFS; where I see that particular regimen being used is in second-line therapy. You have a patient who has been through initial induction therapy, with or without autologous stem cell transplant, they then go onto lenalidomide maintenance. Their disease progresses in the face of lenalidomide maintenance, and then you have that combination of daratumumab plus carfilzomib/dexamethasone to go to. That’s a particular regimen that is difficult to get approved by insurance companies in the United States, but I’m happy to report that a phase III study has been conducted, finished enrollment, and we should have a read out from that study in the near future.

More exciting than that is a new class of drug, XPO1 inhibitors, specifically selinexor, which works in a completely different way. There is a membrane channel that’s present on the surface of the nucleus, which basically shuttles tumor suppressor proteins and the glucocorticoid receptor from the nucleus into the cytoplasm.

What selinexor does it actually binds to that membrane pore, and blocks tumor suppressor proteins from exiting the nucleus into the cytoplasm. So, you have nuclear retention of tumor suppressor proteins and you also have retention of the glucocorticoid receptor, which is important as far as efficacy of corticosteroids, such as dexamethasone, in myeloma.

The STORM study was a pivotal, single-arm trial looking at the combination of selinexor and dexamethasone in patients with very refractory, heavily pretreated disease. In this particular trial, the median prior lines of therapy was 5, and patients were very refractory to therapy. If you look at previous exposure to various agents, about 96% of patients were refractory to carfilzomib, pomalidomide, and daratumumab, so these were patients who were really starting to run out of options for therapy.

Impressively, in this group of patients, the ORR was approximately 26% and there were some very good partial responses and complete responses as well. At least with initial developments, the challenge has been toxicity of the agent; there is constitutional toxicity, fatigue, gastrointestinal side effects like nausea, some vomiting, loss of appetite, and sometimes there is weight loss associated with that. There is hematologic toxicity as well. In the STORM study, there was 80 mg of selinexor given twice weekly. As we learn more about the drug, the 100-mg once-weekly dose appears to be better tolerated, both from the nonhematologic toxicity perspective and the hematologic toxicity perspective.

A lot of the combination studies of selinexor moving forward are using this 100-mg weekly dose; there are very nice data combining selinexor with bortezomib/dexamethasone, carfilzomib/dexamethasone, daratumumab/dexamethasone, and pomalidomide/dexamethasone. As we get more familiar with the drug, we know how to dose it better, we know the best schedule, and we know how to manage the side effects better. It’s a completely novel mechanism of action, and it does have a role for the future of myeloma.

What other ongoing studies are of importance for this patient population?

The ones are the selinexor combination studies I just alluded to, particularly the data with selinexor, daratumumab, and dexamethasone, which really look quite promising. I spoke about venetoclax (Venclexta), and I know there has been some controversy that has emerged with [this drug] in myeloma recently. However, I do still think there is a role for its use in patients who have multiple myeloma harboring 11;14 translocation.

In the pivotal study that was spearheaded by Shaji Kumar, MD, of patients with relapsed myeloma with that translocation, the ORR was 40%. We all know now from the phase III BELLINI trial, which looked at bortezomib/dexamethasone with or without venetoclax, that while [it met an improvement in] PFS, there is an increase in deaths in the 3-drug arm. That dataset is being actively scrutinized by regulatory authorities at this point, but I do think the signal of activity is so strong in the 11;14 translocation patients that I do think you’ll see it emerge again. There are ongoing studies on clinical hold right now, but hopefully with further discussions with regulatory authorities those studies will relaunch, at least in the 11;14 translocation patients and we can see what kind of future it has in that group.

How would you describe the biggest challenges in late relapsed myeloma?

Unfortunately, although these developments are exciting, there are still a large number of patients who don’t respond to these novel therapies. Even in those who do, the duration of response is not terribly long lived. We have to give our best shot in frontline therapy and in first relapse as well, but as we develop these new therapies that are active in heavily pretreated patients, we start to bring these up to frontline therapy—where we have the best chance of producing the deepest responses and most durable remissions.