Chari Highlights Emerging Options in Heavily Pretreated Myeloma

Ajai Chari, MD

Several treatment options are emerging for patients with heavily pretreated multiple myeloma, explained Ajai Chari, MD.

In November 2018, the FDA granted a priority review designation to a new drug application (NDA) for selinexor for the treatment of patients with penta-refractory multiple myeloma. The NDA was submitted based on positive data from the phase IIb STORM trial, which showed that the combination of selinexor and dexamethasone demonstrated an overall response rate (ORR) of 26.2% and a duration of response of 4.4 months.¹

In the heavily pretreated patients who were refractory to proteasome inhibitors, immunomodulatory agents (IMiDs), at least one alkylating agent, and glucocorticoids, a clinical benefit rate of 39.3% was observed with the combination. Median overall survival was 8.6 months.

Chimeric antigen receptor (CAR) T cells have also shown deep responses, said Chari, who is an associate professor at the Icahn School of Medicine and Mount Sinai Hospital. For example, data presented at the 2018 ASH Annual Meeting, showed that the next-generation CAR T-cell product bb21217 showed an ORR of 83.3%, with a very good partial response or better rate of 75%. The complete remission (CR) or stringent CR rate in those treated with the therapy was 25%, and the minimal residual disease-negativity rate was 100%.² These findings follow the data of a similar CAR T-cell construct, bb2121, that has also demonstrated efficacy in relapsed/refractory disease.

However, physicians should be mindful that this type of therapy has a unique toxicity profile. Of all participants enrolled in the study, 67% developed cytokine release syndrome (CRS), with 1 patient demonstrating a grade 3 event.

Moreover, the anti-BCMA antibody-drug conjugate GSK2857916 has also shown impressive early data in patients with relapsed/refractory myeloma. Results from the phase I DREAMM-1 trial, which were presented at the 2017 ASH Annual Meeting, showed a 60% overall response rate in patients with relapsed/refractory myeloma.³ These data led to its FDA breakthrough therapy designation status in November 2017.

OncLive: What recent advances have been made in the myeloma space?

In an interview with OncLive, Chari discussed novel treatment approaches for patients with heavily pretreated multiple myeloma.Chari: Myeloma is an exciting field because we have a lot of drugs that have been recently approved. About 10 drugs have been approved in the last decade, including 4 in 2015 alone. But when you have 6 different classes of drugs with multiple drugs in each class, it becomes challenging when patients exhaust all of those options. What do you do with these patients, particularly for penta-refractory patients? These are patients who are refractory to the 2 proteasome inhibitors bortezomib (Velcade) and carfilzomib (Kyprolis), the 2 IMiDS pomalidomide (Pomalyst) and lenalidomide (Revlimid), and the CD38 monoclonal antibody daratumumab (Darzalex)? What is the standard of care for these patients?

Could you highlight the data with selinexor?

Three drugs have potential here, one of which recently received a fast track designation from the FDA: selinexor. The other 2, the GSK2857916 compound and bb2121, received breakthrough therapy designations. Those are the most compelling agents that we think have the most promise in this space. Selinexor is an XPO1 inhibitor; this is a protein that pumps proteins from the nucleus into the cytoplasm. By blocking that, we know it can cause cell death. We know this pathway is important because it is upregulated in myeloma when you compare the cancer cells with normal tissue cells. Not only did selinexor have preclinical activity in early data, but in the initial study published in the Journal of Clinical Oncology, we saw response rates of about 20%. These data were presented at the 2018 SOHO Annual Meeting. In this patient population, who had received a median of 7 prior lines of therapy, the PFS was about 3.7 months.

Why are these patients developing resistance to every other therapeutic option?

Will checkpoint inhibitors play a role in combination therapies for these patients?

Those are impressive data because of this patient population; they have exhausted all the other therapies. Of course, there were toxicities that can be broadly divided into hematologic and gastrointestinal. Putting it all together, to have an oral regimen for penta-refractory patients that has single-agent activity, is very encouraging. Unfortunately, we know very little about biomarkers in terms of predicting response and reasons for progression. A lot of work needs to be done in that area. Historically, every drug has only worked for a very short time; that's why we've been doing combination therapy. When we do an initial study, it is not necessarily about how the drug will be used, it's about where it will be combined. We are looking to improve responses and duration of response. When checkpoint inhibitors—specifically PD-1 inhibitors—were combined with IMiDs, it resulted in increased mortality and toxicity. However, this is not something we are seeing with every immunotherapy. The IMiDs have clearly shown benefit in our patients, so we have to be very specific about the drugs we are talking about and in which disease setting.

How have CAR T cells impacted the field?

What are some challenges that still need to be addressed?

Another example is the GSK2857916 compound I mentioned earlier. This is an antibody-drug conjugate that carries a toxin known to cause cell cycle arrest and death; it targets BCMA. We hope that the drug will target the myeloma cells and spare the rest of the body. The use of CAR T-cell therapy in patients with myeloma has been very encouraging. The bb2121 study that was presented at the 2018 ASCO Annual Meeting showed a very impressive 96% response rate and a median PFS of almost 1 year; these patients had 7 or 8 prior lines of therapy. Again, these are encouraging data that we did not expect to see in patients who were as refractory as they were. It is amazing that with a single intervention, we are getting these results, as opposed to other therapies that continue on and on. Of course, we have to be mindful of the toxicities, particularly CRS. There is obviously selection bias in these studies, as well.The other unanswered questions include getting more patients enrolled in these studies, trying to see what happens when you decrease the manufacturing time, expanding it to multiple centers, trying to understand the relapse, and adding more drugs to the regimen.

References

1. Chari A, Vogl DT, Dimopoulos MA, et al. Results of the pivotal STORM study (part 2) in penta—refractory multiple myeloma (MM): deep and durable responses with oral selinexor plus low dose dexamethasone in patients with penta exposed and triple class–refractory MM. In: Proceedings from the 2018 ASH Annual Meeting; December 1-4, 2018; San Diego, CA. Abstract 598.
2. Shah N, Alsina M, Siegel DS, et al. Initial results from a phase 1 clinical study of bb21217, a next—generation anti BCMA CAR T therapy. In: Proceedings from the 2018 ASH Annual Meeting; December 1-4, 2018; San Diego, CA. Abstract 488.
3. Trudel S, MD, Lendvai N, Popat R, et al. Deep and durable responses in patients (Pts) with relapsed/refractory multiple myeloma (MM) treated with monotherapy GSK2857916, an antibody drug conjugate against B-cell maturation antigen (BCMA): preliminary results from part 2 of study BMA117159. In: Proceedings from the 2017 ASH Annual Meeting and Exposition; December 9-12, 2017; Atlanta, GA. Abstract 741.