Agents Emerging in Late Relapsed/Refractory Myeloma Space

Sagar Lonial, MD

For patients with multiple myeloma who experience late relapse or are refractory, management of the disease can be challenging; however, a number of new agents are emerging with promising results in this space, explained Sagar Lonial, MD.

At the 23rd Annual International Congress on Hematologic Malignancies: Focus on Leukemias, Lymphomas, and Myeloma^®, Lonial addressed what agents are being investigated now in this space. Early data are showcasing potential with therapies such as targeted agents, antibody-drug conjugates (ADCs), bi-specific T-cell engagers (BiTEs), and chimeric antigen receptor (CAR) T-cell therapies.

“This field is really going to move towards incorporation of more immune-based approaches and really using precision medicine to help define the kinds of patients that might be more sensitive or resistant to certain targeted therapies,” said Lonial.

For example, results of an ongoing phase II study showed that the combination of venetoclax (Venclexta), carfilzomib (Kyprolis), and dexamethasone elicited a 100% objective response rate with a very good partial response or better rate of 86% for patients with multiple myeloma with relapsed/refractory t(11;14) disease.¹

Moreover, the XPO1 (CRM1) inhibitor selinexor has demonstrated intriguing response rates and survival benefit in patients with penta-refractory disease.² However, in February 2019, the FDA’s Oncologic Drugs Advisory Committee (ODAC) voted 8 to 5 against accelerated approval of a new drug application for selinexor in this patient population, citing significant safety concerns that resulted in patient deaths in the phase IIb STORM trial.³ Additionally, STORM was a single-arm combination trial and a prior phase I study had not demonstrated strong monotherapy activity with the agent.

OncLive: What is the current state of multiple myeloma treatment, specifically for patients who are in late relapse?

In an interview with OncLive during the meeting, Lonial, professor and chair, Department of Hematology and Medical Oncology, Emory University School of Medicine, chief medical officer, Winship Cancer Institute of Emory University, discussed some of the emerging agents for the treatment of patients with late relapse in multiple myeloma.Lonial: The management of patients with late relapse or refractory myeloma is very challenging. A group [of researchers] put together a series of almost 150 patients who are basically quad- or penta-refractory in the daratumumab (Darzalex) era and showed that their median expected overall survival is about 11 months. Duration of response to any therapy tends to be very short, so this is a group of patients who clearly represent an unmet medical need.

The use of selinexor or other targets that go after XPO1 is certainly something that looks interesting and exciting, and despite the fact that the FDA's ODAC gave it a negative review, it is clearly an active agent in this subset of patients, and how we combine it is a future question.

What are some of the biggest challenges with this research?

Could you highlight the key points you made during your presentation?

What data have we seen with these agents?

Venetoclax (Venclexta) is another drug that falls into this category. There are very encouraging data with this alone or in combination, suggesting it may be able to overcome drug resistance. Other potential therapies include BCMA-directed CAR T cells, ADCs, or BiTEs. Those do represent a big part of the future of myeloma therapy.One of the biggest difficulties we have is the ability to support these patients because they tend to be very sick when they have reached this stage of myeloma. Cytopenias, anemias, thrombocytopenia, other issues with blood counts, renal function continues to be an issue, and deterioration in performance status overall tends to be a real issue. Getting a patient through their therapy is a big challenge in this situation.We highlighted some of the new drugs and the targets; almost everything that is really necessary to be tried in this space are on clinical trials. There is nothing that’s clearly approved in this situation, so often we discover that how long a patient can live is dependent on their ability to access these potential, life-saving treatments. It is important to have a partner that you work with at an academic center that has these kinds of trials because they’re usually phase I/II studies.When you think about selinexor as a single agent, it’s about 20% to 25%. The median progression-free survival (PFS) is about 2.5 to 3.0 months—somewhere in that ballpark—but there are patients, even who don’t achieve an objective response, who have stabilization that can be quite durable for a period of time. The biggest challenge is adverse events; gastrointestinal toxicity, nausea, vomiting, and weight loss tend to be some of the big ones. There is also a little bit of an issue with thrombocytopenia as well.

Venetoclax is a drug that most folks are fairly comfortable using because they use it in chronic lymphocytic leukemia, lymphoma, and now myeloma. Venetoclax is a pretty well-tolerated drug and alone has a response rate of about 40% in t(11;14)(q13;q32)myeloma. In combination with dexamethasone, that jumps to about 65%, and when you begin to combine it with carfilzomib, bortezomib (Velcade), or even daratumumab, the response rate goes close to near 100%. Those kinds of partners are really important.

With CAR T cells, we are excited about the high overall response rate; almost 80% to 90% of patients with respond to CAR T cells, but getting them onto a trial is often very challenging. There is a little bit of a selection bias there, and how durable those responses are we don’t yet know. In the early-phase setting with bb2121, the remission duration was about 11 months. The larger bb2121 trial has completed enrollment, and we are waiting to see what the PFS looks like in that trial as well.

In terms of GSK2857916, it looks like the median PFS in that trial is somewhere around 8 to 9 months with the updated response rate, making it one of the most active single agents we have in myeloma if this data holds up in a larger trial. There is some ocular toxicity that is associated with using GSK2857916, but it’s certainly an encouraging idea and we are waiting on that phase II trial as well.

Where do you see the field heading in the next decade?

Finally, we saw the BiTE antibodies at the 2018 ASH Annual Meeting. [There was a] very high response rate in a heavily pretreated group of patients. We just need more data to really understand how active that is.This field is going to move towards incorporation of more immune-based approaches and using precision medicine to help define the kinds of patients who might be more sensitive or resistant to certain targeted therapies. With BCL-2, for instance, is there a mutation signature or gene expression signature that could identify sensitivity to venetoclax? The same with MCL1—it is proteasome inhibitor dependence versus resistance. All of those things are going to come as we get more data.

References

1. Costa LJ, Stadtmauer EA, Morgan GJ, et al. Phase 2 study of venetoclax plus carfilzomib and dexamethasone in patients with relapsed/refractory multiple myeloma. J Clin Oncol. 2018; 36 (suppl; abstr 8004).
2. 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-refractory MM. In: Proceedings from the 2018 ASH Annual Meeting; Dec. 1-4, 2018; San Diego, CA. Abstract 598.
3. FDA. Draft Questions for the February 26, 2019 Meeting of the Oncologic Drugs Advisory Committee (ODAC). Accessed February 26, 2019. https://bit.ly/2XnqwpW.

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