Update as of February 2, 2022
Secura Bio has since announced that it has decided to withdraw the accelerated approval of the New Drug Application for Farydak® (panobinostat) for use in combination with bortezomib and dexamethasone for the treatment of patients with multiple myeloma.
Reports from the frontlines of myeloma drug development have been in the news lately. Here is a look at the latest developments:
- Selinexor: It was announced on Friday, March 15, that the U.S. Food and Drug Administration (FDA) will now reach a conclusion about the new drug application for Selinexor by July 6, 2019 rather than by the original date of April 6. This delay is actually good news because following the 8 to 5 vote by the ODAC committee against approval, more time will be available to further review the issue. The FDA will get an early look at the data from the randomized BOSTON trial, in which selinexor is combined with Velcade plus dexamethasone (versus Velcade/dexamethasone alone). Results of both toxicities and early efficacy will be available. There is optimism that this review will tip the balance toward possible FDA approval of selinexor, despite the negative ruling by the ODAC committee.
- Daratumumab subcutaneous: The results of the randomized phase III COLUMBA study were recently released. In this study, daratumumab administered by subcutaneous (under the skin) injection was compared with the standard intravenous infusion administration. The results showed that in the relapsed or refractory setting, the overall response was 41.1 percent for subcutaneous daratumumab versus 37.1 percent for IV infusion daratumumab (meeting criteria for “non-inferiority” [marginally better]) for the subcutaneous administration.
This is obviously very encouraging. In addition, no new safety signals were detected, and the subcutaneous approach appears to have been both convenient—it takes 3-5 minutes to receive a dose--and well-tolerated. Clearly, a submission for regulatory approval is imminent, and can lead to much preferred approach to daratumumab administration.
- Panobinostat (Farydak): Farydak is an HDAC (histone deacetylase) inhibitor already approved by the FDA accelerated approval on February 23, 2015) for use in relapsed or refractory myeloma in combination with Velcade and dexamethasone. Farydak was developed and licensed by Novartis, who has announced that the global rights to the drug have been acquired by Secura Bio, an integrated, commercial-stage biopharmaceutical company. The goal is to enhance availability of Farydak, and, potentially, to develop new dosages and drug combinations.
- Venetoclax: There is not such good news about the new agent venetoclax. On Tuesday, March 19, the FDA announced that they have put a hold on enrollment in myeloma trials, including those using venetoclax combinations. This decision is based on unexpected deaths in the venetoclax/Velcade/dexamethasone treatment arm in the randomized phase III BELLINI trial, in which Velcade/dexamethasone is the control arm or comparator. There were 21 percent deaths (41 out of 194 patients) versus 11.3 percent (11 out of 97 patients) linked primarily to infection. This result is surprising in that earlier venetoclax studies have shown improved treatment benefit without serious added toxicities.
There is broad agreement that venetoclax is an important and helpful agent, especially for patients with the t(11;14) translocation, for whom there is striking single-agent activity. For the combination studies, greater caution will be required related to potential infections, and new guidelines are anticipated. Yet again, this BELLINI trial result emphasizes the need for randomized trials to fully assess both benefits and potential unexpected toxicities. Any off-label use of venetoclax should be accompanied by prophylactic antibiotics to prevent infection. In view of the unexpected increased risk of death in the BELLINI trial, any patient taking venetoclax both within and especially outside of a clinical trial should immediately discuss this new information with his or her doctor.
Notes on the environment
When 2017’s Hurricane Harvey caused severe flooding in Houston, I noted the unfortunate potential for toxic exposure in flooded areas and beyond from known toxic sites. There was a specific risk of benzene exposure, which has been linked to an increased likelihood of myeloma. Today, March 21, 2019, following a chemical fire outside of Houston, authorities issued a “shelter in place” order because of increased levels of benzene and other volatile organic compounds (VOCs). This is a definite concern that should certainly be heeded.
Monsanto weed killer Roundup
On Tuesday, March 19, 2019, a federal jury in San Francisco delivered a unanimous verdict in the U.S. District Court in favor of a man who used Roundup to control weeds and poison oak on his property for 26 years, and who claimed Roundup caused his lymphoma. This follows a prior case of a groundskeeper who ended up being awarded $80 million (reduced on appeal from $289 million). In the current case, there will be a second phase, after which damages will be determined. The correlation between exposure to glyphosate, the active ingredient in Roundup, and cancer has now.
Honey as a biomonitor
In a week that the new “dirty dozen” list of fruits and vegetables likely to be contaminated with pesticides was released, there was an interesting and helpful story about bees and honey. It turns out that if honey is contaminated, it is an important indicator of local chemical pollution. This is on the radar for many groups trying to understand and reverse the dramatic collapse in the numbers of honeybees. An unexpected twist is that cities can be an “urban refuge” for bees, away from the agricultural areas where there is extensive use of chemicals. This is linked to other studies that show that planting flowers does increase pollination. This week in California, there is a wonderful example of the impact of flowers. With all the heavy rains in recent weeks, there has been a dramatic increase in wildflowers in the normally drier and desert regions. This led to literally billions of butterflies emerging and flying north through California. This recovery of nature, despite the chemical onslaughts, was a very bright spot in the day for many Californians.
Dr. Brian G.M. Durie serves as Chairman of the International Myeloma Foundation and serves on its Scientific Advisory Board. Additionally, he is Chairman of the IMF's International Myeloma Working Group, a consortium of nearly 200 myeloma experts from around the world. Dr. Durie also leads the IMF’s Black Swan Research Initiative®.