Novel Small Molecule Inhibitors Show Promise in the Treatment of Multiple Myeloma

Los Angeles, California—In a presentation at the 2019 Great Debates and Updates in Hematologic Malignancies meeting, Joseph Mikhael, MD, MEd, FRCPC, Chief Medical Officer, International Myeloma Foundation, Professor, Translational Genomics Research Institute, City of Hope Cancer Center, Phoenix, Arizona, discussed novel small molecule inhibitors in multiple myeloma (MM).

The first agent Dr Mikhael mentioned was selinexor. Selinexor is a first in class, oral selective inhibitor of exportin 1 (XPO1). XPO1 is the major nuclear export protein for tumor suppressor proteins, glucocorticoid receptor, and elF4E-bound oncoprotein mRNA, and is overexpressed in MM. High XPO1 levels enable cancer cells to escape tumor suppressive protein mediated cell cycle arrest and induction of apoptosis. XPO1 levels correlate with poor prognosis and drug resistance.

Preclinical data supports that selinexor reactivates multiple tumor suppressive proteins relevant to MM, inhibits NF-kB signaling, and reduces c-Myc levels. When combined with dexamethasone, it reactivates glucocorticoid receptor signaling.

Dr Mikhael highlighted the pivotal STORM trial, which studied oral selinexor (80 mg) plus dexamethasone (20 mg) in penta-refractory patients with a median of 7 prior treatment regimens. The primary end point of the trial was overall response rate (ORR). Secondary endpoints included duration of response, clinical benefit rate, overall survival (OS), progression-free survival (PFS), and safety.

They concluded that in penta-refractory patients with MM, selinexor plus dexamethasone achieved an ORR of 26.2%, a duration of response of 4.4 months, clinical benefit rate of 39.3%, and a disease control rate of 78.7%. A total of 2 patients achieved sCRs, both of which were MRD negative, and each of the 2 patients with relapse after CAR-T therapy achieved a PR. Median OS among all patients was 8.6 months.

“The challenge with this agent is that it really does require aggressive supportive care,” explained Dr Mikhael.

The most important grade 3 or 4 adverse events are thrombocytopenia (53.7%), anemia (29.3%), fatigue (22.8%), hyponatremia (16.3%), nausea (9.8%), diarrhea (6.5%), anorexia (3.3%), and emesis (3.3%).

“The issue here, of course, is that there were deaths on this study attributable to the drug. One of the great challenges is to distinguish what exactly is by the drug and what is caused by the very sick patient population,” said Dr Mikhael, noting that further data will be necessary before the FDA can make a decision on selinexor for this patient population.

The second agent Dr Mikhael highlighted was venetoclax. Currently, venetoclax is not indicated in MM, but has shown impressive results particularly in patients with t(11;14) and BCL-2 overexpression.

He discussed promising results from a clinical trial of venetoclax monotherapy in relapsed and refractory patients with MM. Among 66 patients on the trial, the ORR was 21%, which jumped to 40% when looking at only those patients with t(11;14).

He highlighted the phase 3 Bellini trial, which randomized patients (2:1) to venetoclax, bortezomib, and dexamethasone (n=194) or bortezomib and dexamethasone (n=97).

Concerning safety signals resulted in a safety warning from the FDA and partial hold on the drug in MM on March 21, 2019. Overall, 40 deaths occurred in the venetoclax arm versus 11 in the bortezomib and dexamethasone alone arm. Of the 40 deaths in the venetoclax arm, 13 were due to infections versus 1 in the bortezomib and dexamethasone alone arm.

However, the trial showed very positive efficacy with venetoclax and met the PFS end point. The ORR was 82% with venetoclax versus 68% with bortezomib and dexamethasone alone (very good partial response or greater 59% vs 36%, respectively). PFS prolonged to 22.4 months with venetoclax compared to 11.5 months with bortezomib and dexamethasone alone (hazard ratio, 0.63).

“Most of us in the myeloma field believe that this [venetoclax] is going to have a role in myeloma. It is just unclear right now if there are precautions that are going to have to be taken or if it is going to be limited to the t(11;14) population or not,” concluded Dr Mikhael.Janelle Bradley

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