Relapsed/Refractory Myeloma Landscape Slated to Expand

Samir Parekh, MD

Selinexor and venetoclax (Venclexta) have each made waves in recent clinical trials of patients with relapsed/refractory multiple myeloma. As novel agents emerging in landscape, they provide potential to improve response rates that are currently lacking with standard treatment options.

"The impact of these drugs has been pretty amazing in the salvage of patients with relapsed and refractory multiple myeloma," said Samir Parekh, MD, in a presentation during the 2018 OncLive^® State of the Science Summit™ on Multiple Myeloma.

Selinexor

At the meeting, Parekh, associate professor of Medicine, Mount Sinai Health System, discussed the excitement of selinexor and venetoclax as possible additions to the myeloma treatment landscape.Selinexor is an oral small molecule inhibitor that blocks the transport of proteins between the nucleus and the cytoplasm, Parekh explained. This agent inhibits XPO1, an overexpression of which promotes tumor suppressor protein dislocation and proto-oncogene translation.

"It blocks a shuttling mechanism, wherein proteins that are usually in the nucleus are shuttled between the cytoplasm and back are blocked from doing so,” explained Parekh. “This redistribution of proteins and messenger RNAs leads to an imbalance in the cell between cell survival signals and cell death signals, causing the cancer cell to die.”

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

Patients enrolled in the STORM trial were heavily pretreated with bortezomib (Velcade), carfilzomib (Kyprolis), lenalidomide (Revlimid), pomalidomide (Pomalyst), daratumumab (Darzalex), an alkylator, and glucocorticoids. The primary endpoint was ORR, with secondary endpoints of duration of response (DoR), clinical benefit rate, overall survival (OS), progression-free survival, and safety. On average, these patients had seen 7 prior lines of treatment.

"This is a notoriously difficult patient population," said Parekh. "But what is interesting to note is that we are seeing responses after [chimeric antigen receptor] T-cell therapy failure with this novel agent. This is a real unmet need that is only bound to increase as time goes by."

Results also showed that the DoR was 4.4 months, with a clinical benefit rate of 39.3% observed, and a disease control rate of 78.7%. Median OS was 8.6 months overall, 15.6 months in patients who achieved a minimal response, and 1.7 months in patients with progressive disease.

The side effects of selinexor are going to be a learning curve as the drug is deployed in the clinic, noted Parekh. There are 3 categories of adverse events (AEs) that have been observed—gastrointestinal, constitutional, and hematologic. Notably, thrombocytopenia was experienced by 67.5% of patients. Other common AEs were leukopenia (29.3%), fatigue (22.8%), hyponatremia (16.3%), nausea (9.8%), diarrhea (6.5%), anorexia (3.3%), and emesis (3.3%). With monitoring, dose modifications, and supportive care, patients can safely complete treatment, said Parekh.

Venetoclax

"What is fascinating about the drug is that it is being tested in a variety of malignancies, and across the different tumors, it has a uniform ORR of about [20%]," said Parekh, adding that a potential biomarker for selinexor response could be E2F1 transcription factor expression.Promising efficacy and acceptable safety have been observed with venetoclax in triplets with agents such as bortezomib and dexamethasone as treatment for patients with relapsed/refractory myeloma. Although this agent is established in chronic lymphocytic leukemia, the BCL-2 inhibitor is considered a new player in the myeloma landscape.

In a phase Ib study of venetoclax plus bortezomib and dexamethasone, an overall response rate of 67% was observed in all patients.² The highest ORRs were observed in the non—bortezomib-refractory population (n = 39, 90%), in patients who had received 1 to 3 prior therapies (n = 37, 89%), and in patients who were BCL-2 high (n = 18, 94%).

"What was interesting was a very clear biomarker signal coming out. Patients who had high levels of BCL-2 were much more prone to respond to the drug," said Parekh. "BCL-2 expression is not easily found, so how can we choose patients at this point for response to this drug?"

Cells that have 11;14 translocation more closely resemble B cells with high levels of BCL-2, explained Parekh. This suggests that 11;14 translocation could be used as a factor to select patients with myeloma for treatment with venetoclax.

Additionally, a next-generation sequencing (NGS) platform has been developed at Mount Sinai Health System to select patients for treatment with venetoclax. Parekh explained that like traditional NGS platforms already in use, this test sequences DNA, but it also sequences RNA using transcriptome sequencing. This is important, Parekh said, because changes that happen in DNA are not necessarily translated to the microRNA or to protein structures. DAPHNI, which stands for Data Associated Patients Healing Infrastructure, is the software that aids in the capture of the exome. Using data from NGS and DAPHNI, clinicians can then find treatment options for difficult-to-treat patients, such as those with relapsed/refractory myeloma.

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-refractory MM. In: Proceedings from the 2018 ASH Annual Meeting; December 1-4, 2018; San Diego, California. Abstract 598.
2. Moreau P, Chanan-Khan A, Roberts AW, et al. Promising efficacy and acceptable safety of venetoclax plus bortezomib and dexamethasone in relapsed/refractory MM. Blood, 2017;130:2392-2400. doi: 10.1182/blood-2017-06-788323.