Novel Triplets, Potent Single Agents Emerge Across Myeloma Spectrum

Yubin Kang, MD

Several triplet and now quadruplet regimens have demonstrated utility in patients with transplant-eligible and -ineligible multiple myeloma, and these advances are being echoed in the relapsed/refractory setting with monotherapies, such as selinexor and venetoclax (Venclexta).

The combination of carfilzomib (Kyprolis), lenalidomide (Revlimid) and dexamethasone (KRd) is one such regimen poised to enter the paradigm after demonstrating superior objective response rates, irrespective of risk status, and attainment of minimal residual disease negativity compared with carfilzomib and cyclophosphamide/dexamethasone in patients with newly diagnosed disease.

In the relapsed/refractory setting, selinexor and venetoclax have shown potent activity in heavily pretreated and high-risk patient populations, respectively. Pending confirmatory data from the phase III BOSTON trial, which is anticipated to read out by July 6, 2019, the FDA will make a decision on approving selinexor.

However, Yubin Kang, MD, a professor of medicine and member of Duke Cancer Institute, explained that despite the activity of these agents, more work will be necessary if myeloma is to be treated curatively rather than chronically.

“Multiple myeloma is the second-most common hematologic malignancy in this country. It accounts for about 32,000 new patients each year,” said Kang. “It’s a very common disease and it is highly treatable. Unfortunately, it is still incurable. We still need to continue to work on developing new drugs and new combinations in the treatment of patients with multiple myeloma.”

In an interview during the 2019 OncLive State of the Science Summit™ on Hematologic Malignancies, Kang discussed how progress made in frontline therapy has impacted the outlook of multiple myeloma and the remaining work that needs to be done across settings.

OncLive^®: Looking back at the 2018 ASH Annual Meeting, what where some of the big data reported in the frontline setting?

Kang: When we talk about upfront treatment, we have to think about a patient who is transplant eligible versus a patient who is transplant ineligible. For the transplant candidate, the most important study looked at KRd with or without transplant versus KRd. The study suggested that KRd is quite effective. I was also very impressed with daratumumab (Darzalex) when it was added to ixazomib (Ninlaro), lenalidomide, and dexamethasone. That regimen is also quite effective; the complete response rate was about 39%. For the transplant-ineligible patients, I was very interested in the MAIA study, which looked at daratumumab, lenalidomide, and dexamethasone.

What is the frontline potential of carfilzomib?

In our institute, we're still using lenalidomide, bortezomib (Velcade), and dexamethasone as upfront therapy (VRd). KRd is also associated with some cardiac toxicity. We need more data, but I'm really excited with KRd in the upfront setting, especially in patients with high-risk cytogenetics.

If KRd gets approved, how will that approval affect the sequencing of therapy?

That's a good question. We have gotten used to [RVd and save KRd for when the patient relapses. Of course, we'll change the sequencing of treatment if KRd is used in the upfront setting. Then, VRd, especially bortezomib, will have less of a role in myeloma in the future.

With many therapies emerging, will transplant still have a role 5 to 10 years from now?

I'm biased because I'm a transplant physician. However, with all of this new treatment, the role of autologous stem cell transplant will need to be evaluated. I still believe high-dose chemotherapy treatment followed by stem cell transplant can induce much deeper responses. I hope it translates into prolonged progression-free survival (PFS) and overall survival (OS).

Are there other notable ongoing trials that you would like to highlight?

I'm interested in the trial with selinexor, which has shown interesting single-agent and combination activity, and trials with venetoclax, which have shown strong activity in patients with translocation (11;14). Unfortunately, there are some data suggesting that venetoclax in combination with proteasome inhibitors increases the mortality and infection rate. However, I don't know what's going to turn out. We need more data to analyze.

Are there other agents that selinexor or venetoclax might have synergy with?

I'm a physician-scientist, so I'm also doing a lot of research. We have been informed that there is a new drug called ABC294640, which is a SK-2 inhibitor. We are conducting the phase I/II trial right now. We just finished the phase I trial and found that this SK-2 inhibitor downregulated M01 and cMET. When combined with venetoclax in animal models, it showed great synergistic effect. I'm hoping SK-2 in combination with venetoclax will be something we can try in the future. [The agent] is related to a sphingolipid; it has the same membrane.

People used to think this lipid only played a structural role, but in the last 10 to 20 years, it has been suggested that the lipid also has secondary messaging in which it also regulated cell signaling. We published the paper in Blood in 2014 showing about 30% of patients with myeloma had upregulation on this gene called SK-2. When we looked at this gene, the myeloma was undergoing apoptosis and dividing. Subsequently, we worked with a biotechnology company. They have a very specific inhibitor called ABC294640. In the preclinical animal model trial, we found it worked pretty well. Therefore, we were able to move that to a phase I/II trial in myeloma. We are hoping it can bind together with venetoclax or some other agent in the future.

Is there anything else that you would like to emphasize?

I wanted to mention bone marrow fibrosis. In the 1970/80s, it had been found in about 10% to 15% of patients with myeloma; that was associated with a high tumor burden. However, the case report was very small. That was before all these novel agents emerged. Recently, we performed a retrospective study at Duke Cancer Institute. We looked at about 400 patients from 2003 to 2015. We extracted the patients without marrow fibrosis. We found that even with these new oral treatments, patients with marrow fibrosis still had poor outcomes. By poor outcomes, I mean that their PFS and OS was much worse than patients without marrow fibrosis. This suggests that we need to find another target in this population.

Gay F, Cerrato C, Petrucci MT, et al. Efficacy of carfilzomib lenalidomide dexamethasone (KRd) with or without transplantation in newly diagnosed myeloma according to risk status: results from the FORTE trial. J Clin Oncol. 2019;37(suppl, abstr 8002). abstracts.asco.org/239/AbstView_239_262867.html.