FDA Denies Early Access to Selinexor/Dex in Multiple Myeloma

Karyopharm received a vote yesterday denying early approval for the combination of Selinexor/dexamethasone at the FDA briefing meeting to the Oncologic Drugs Advisory Committee (ODAC), or the committee that provides recommendations to the FDA. The FDA typically votes with ODAC recommendations, but a formal vote will be coming on April 8, 2019. 

Karyopharm hoped that the FDA would approve the double combination while it waits for the BOSTON study results to emerge (likely to take an additional two years). The BOSTON study is testing the combination of selinexor with bortezomib and dexamethasone.

There were two key points of pushback from the FDA report on the combination: First, that the side effects of selinexor didn't outweigh the benefits and second, that dex might be providing benefit alone in the combination.

In attendance were many renown myeloma specialists including Dr. Paul Richardson (Dana Farber Cancer Institute), Sundar Jagganath (Mt. Sinai), Ajai Chari, MD (Mt. Sinai), Saad Usmani, MD (UNC) and Philip McCarthy, MD, (Roswell Park Cancer Institute). Additionally, myeloma patients, caregivers and representatives from the Myeloma Crowd, IMF and MMRF were in attendance to share their testimonies. 

Dr. Richardson and Dr. Jagganath described the deep need for patients to have access to this drug combination, stating that once myeloma patients had become penta-refractory (their myeloma was resistant to chemotherapy, proteasome inhibitors, IMiDs, steroids, and daratumumab), they had no other options. Patients in the selinexor/dex study were on average older and had more prior lines of therapy with similar response rate data for drugs that are approved for use today (carfilzomib and pomalidomide).

The FDA noted that many of the patients in the selinexor study had adverse events (side effects) including low platelets, anemia and nausea/vomiting. The myeloma experts reiterated that many myeloma patients who have been on 7 prior lines of therapy already have low platelets and anemia when they begin combinations like these. They mentioned that doctors who treat myeloma are familiar dealing with low platelets and anemia, and that anti-nausea medications can easily be used to mitigate the additional GI side effects. They also noted that the side effects caused by selinexor didn't layer onto existing side effects caused by the other drugs, like neuropathy or cardiac involvement. The myeloma experts pointed out that all patients who had entered this study had already become resistant to dexamethasone, so the response to therapy could not be caused by the dex, but that selinexor was actually enhanced by dexamethasone.  

Fourteen speakers who were patients and caregivers shared their testimonies and reasons why they wanted the combination to be approved. In short, we want it approved because patients who are out of options and are ineligible for clinical trials need access to something other than hospice or death.  

The FDA members stated that without the early approval, the company could provide off-label use for the product. One committee member asked what was involved in doing that. The FDA member noted that a patient or doctor would call the FDA 1-800 number that is open 24x7 and request the drug. Asking patients to do this on their own without the support to the doctors or facilities is unreasonable and unrealistic. Patients don't understand the process and Dr. McCarthy noted that the only centers that would reasonably be able to provide the off-label support would be academic center and not local oncology centers. 

A committee member asked that if the selinexor/dex combo had measurable impact on the disease, and the BOSTON trial was using a completely different combination, exactly what results were we waiting for? The question to wait or not on the other study results seemed irrelevant to the fast track approval.

As a myeloma patient, it was frustrating to watch a committee stop early approval for a drug that showed clinical benefit for patients and that they were unwilling to give the choice to myeloma patients and their doctors to assess the risk/benefit for their individual situation. Even if the drug meant 5-12 months of extra life, that may give a patient the ability to qualify for a CAR T or other clinical trial, or spend time with family. Patients and their doctors should together decide if the side effects are worth the extra life provided. 

The meeting was a reality check to see how far we have come in myeloma and where we are heading. While the progress in myeloma is exciting, it was a stark reminder that the processes we have in place today are not fostering rapid innovation in healthcare or leading us towards faster cures.