Venetoclax Triplet Shows Promise in Relapsed/Refractory Multiple Myeloma

Luciano Costa, MD, PhD

The combination of venetoclax (Venclexta), carfilzomib (Kyprolis), and dexamethasone may provide a new treatment option for patients with relapsed/refractory multiple myeloma, according to Luciano J. Costa, MD, PhD.

Costa, an associate professor of Medicine in the Blood and Marrow Transplantation and Cell Therapy Program at the University of Alabama at Birmingham School of Medicine, presented results from an ongoing phase II study at the 2018 ASCO Annual Meeting. Data showed a 100% objective response rate (ORR) with a very good partial response (VGPR) or better rate of 86% for patients with multiple myeloma with relapsed/refractory t(11;14) disease.¹

The ORR was 83% for the triplet with a VGPR or better rate of 57% across the full population of evaluable patients treated at various dose levels (n = 30). The ORR was 88% for the combination of venetoclax and carfilzomib/dexamethasone in patients with high-risk cytogenetics (n = 8), with a VGPR or better rate of 63%. In those with standard-risk disease (n = 22), the ORR was 82% and the rate of VGPR or better was 55%.

“If this study proves to be really successful, once all the accrual is done and all the patients are followed for a longer period of time, this could offer an option—particularly for patients refractory to more than 1 line of therapy and those who have been exposed to bortezomib, where you might want to have a second-generation proteasome inhibitor in combination with venetoclax rather than rely on a drug the patient is already resistant to,” Costa said.

“We feel very excited about this combination going forward as an option, particularly for patients previously exposed to other proteasome inhibitors and patients with relapsed/refractory disease,” he added.

OncLive: Can you provide an overview of the phase II triplet study?

In an interview with OncLive^®, Costa discussed the emerging potential of combing venetoclax with carfilzomib and dexamethasone as a treatment for patients with relapsed/refractory multiple myeloma.Costa: We presented phase II results of a combination of venetoclax, carfilzomib, and dexamethasone in patients with relapsed/refractory multiple myeloma. This study was done across multiple institutions in the United States. We accrued 42 patients, and we presented safety data on those 42 patients and efficacy data on a subset of 30 patients who were enrolled 3 or more months prior to the data cutoff.

Our study population was patients with multiple myeloma who had disease progression or who were refractory to their last line of therapy. They had received 1 to 3 prior lines of therapy and had an indication for treatment. Patients initially received this combination on the dose-finding part of the study. We had 4 cohorts with venetoclax being used at 400 mg in the first cohort, and at 800 mg in cohorts 2, 3, and 4.

We explored the combination with different doses and scales of carfilzomib. We explored the label, which is 27 mg/m² twice weekly, and the on-label 56 mg/m² twice-weekly dose. We also explored 70 mg/m² once-weekly, which had been previously presented as a single agent in the CHAMPION-1 study and was presented as the winning arm of the ARROW study, where once-weekly was compared against twice-weekly.

What did you find in terms of efficacy?

The combination was overall well tolerated. The safety profile was very similar to what was seen in prior carfilzomib studies, but also what we are familiar with in clinical practice. We had mostly cytopenias that were asymptomatic. We had a few cardiovascular events, including a low rate of congestive heart failure and some patients developed hypertension. For the most part, the cardiovascular toxicities were reversible once carfilzomib was held. Some of those patients were able to resume carfilzomib at a reduced dose.What we found was very intriguing. We saw a high rate of response. We had an 83% response rate across the subset of patients. Keep in mind, this is a subset of patients with a median of 2 prior lines of therapy, with half of patients being refractory to prior bortezomib and two-thirds were refractory to prior immunomodulatory (IMiDs) agents. The majority of patients on trial were refractory to their last line of therapy.

Interestingly, we saw equally high response rates for patients who were refractory to IMiDs or proteasome inhibitors at greater than 80%. Being refractory to prior agents did not seem to affect the likelihood of responding to the combination.

Venetoclax has been particularly active in prior studies among patients with t(11;14) myeloma. That is a population in which venetoclax has relatively high single-agent activity. In this trial, we saw that among the 7 patients with t(11;14) disease, they all had a response. Six of those 7 patients had VGPR or better.

Among the patients who did not have t(11;14), we also saw a response rate greater than 70%, and half of those patients had VGPR or better. The activity of this combination seems to be very high, even among those who don't have t(11;14).

Where could this approach go next?

Patients with high risk chromosomal abnormalities including 17p deletion, t(4;14), and t(14;16) are often very challenging to manage, particularly in the relapsed setting. We noticed a very high activity rate, again, of greater than 80% for both standard- and high-risk patients.The whole idea of combining proteasome inhibitors with a BCL-2 inhibitor comes from the knowledge that myeloma cells, like most cancer cells, rely greatly on antiapoptotic molecules to survive injury from chemotherapy or other anticancer agents. In multiple myeloma, it seems that MCL-1, which is in the family of BCL-2, is probably more relevant than BCL-2 in the majority of cases.

However, it also happens that proteasome inhibitors, which are nearly ubiquitous in multiple myeloma, inhibit MCL-1 indirectly by preventing degradation of NOXA, which is an MCL-1 binder itself. That makes it more relevant that we inhibit BCL-2, because as the plasma cells develop resistance to proteasome inhibitors, one of the mechanisms is upregulation of BCL-2. Therefore, by combining a BCL-2 inhibitor with a proteasome inhibitor, you have the potential to antagonize, simultaneously, the 2 main molecules that are antiapoptotic in multiple myeloma.

Could a triplet regimen like this be moved into an earlier setting?

This is building on a previous study that combined bortezomib with venetoclax and demonstrated very high rates of response, including among bortezomib-refractory patients. That trial has been followed by a phase III study, in which bortezomib is being compared with bortezomib plus venetoclax. That will hopefully give us a more definitive answer about whether venetoclax adds to a proteasome inhibitor and can at least partially reverse resistance to proteasome inhibition.Absolutely. Since proteasome inhibitors are permeating multiple lines of therapy and are well established in first- and second-line therapy, any approach that enhances the effect of proteasome inhibitors has the potential to move upfront. Venetoclax seems to not add much in terms of toxicity and seems to complement proteasome inhibitors, so I see the potential of moving it upfront. This could potentially happen for all subsets of patients, but also the very unique activity among patients with t(11;14) creates the opportunity to start having real targeted therapies in multiple myeloma—subset-specific approaches in multiple myeloma.

So far, we have done a terrific job of identifying subsets of patients in terms of risk profile, but for the most part we tend to treat patients very similarly. The exquisite activity among t(11;14) creates the opportunity to explore the venetoclax combination very early for those patients.

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).