The newly approved monoclonal antibody Darzalex, from Janssen. Credit: Janssen Biotech, Inc

A trio of US Food and Drug Administration drug approvals for multiple myeloma, including two immunotherapies, have suddenly broadened oncologists' options for treating this disease. On 16 November, the FDA approved Darzalex (daratumumab), a human IgG1k monoclonal antibody against CD38, discovered by Copenhagen-based Genmab and commercialized by Johnson & Johnson's Janssen Biotech unit in Horsham, Pennsylvania. Four days later, the agency gave the nod to Ninlaro (ixazomib), an oral proteasome inhibitor directed at the subunit beta type-5, from Takeda Pharma in Osaka, Japan. And on November 30, the agency issued a go-ahead to New York-based Bristol-Myers Squibb to market Empliciti (elotuzumab), an immunostimulatory humanized antibody that binds to a cell surface glycoprotein, CS1—also known as signaling and lymphocyte activation molecule F7 (SLAMF7)—that is overexpressed on myeloma cells.

Darzalex and Empliciti are the first monoclonal antibodies approved to treat multiple myeloma, and both are thought to kill the cancer cells by immune-mediated mechanisms. They could achieve blockbuster status, with consensus analyst sales forecasts for each topping $1 billion in 2020, according to EP Vantage.

All of the newly approved drugs drew favorable attention at the American Society of Hematology (ASH) annual meeting held in December. “Every myeloma session was punctuated by appreciation for the three new branded drugs,” analysts at Leerink Research in Boston wrote after the meeting. Data at ASH suggest that Darzalex in particular may significantly improve overall survival over that with current therapies, perhaps owing to its immune-mediated and immunomodulatory mechanisms. Along the same lines, phase 2 data at ASH from Kenilworth, New Jersey-based Merck's checkpoint inhibitor Keytruda (pembrolizumab) suggested a proof of concept that PD-1 (programmed cell death protein 1)-based therapy may provide a clinical benefit in myeloma. “There will now be a headlong rush to explore the activity and utility of the PD-1/PDL-1 medicines in this indication,” the Leerink analysts said.

Oncologist Ken Anderson of Boston's Dana-Farber Cancer Institute said in an interview posted on the Multiple Myeloma Research Foundation (MMRF) website that myeloma research and development is now focused on three types of approaches. One takes aim at the cell's ability to dispose of excess protein, the notion being that if protein degradation is blocked, the myeloma cell fills up with its own waste and commits suicide. Drugs using this approach include proteasome inhibitors, like the newly approved Ninlaro and also the histone deacetylase (HDAC) inhibitor Farydak (panobinostat), which degrades aggregations of misfolded proteins in the cell. A second approach uses immuno-oncology agents such as checkpoint inhibitors and Empliciti, which acts indirectly by activating natural killer cells that in turn stimulate the immune system to attack myeloma cells. A third strategy leverages genomics insights into why myeloma cells with gene damage don't die, to try to drive them toward apoptosis.

To track the molecular changes associated with treatment responses, in 2011, the MMRF launched CoMMpass. The study is designed to profile the genomes of 1,000 newly diagnosed myeloma patients. Interim analyses presented in December at ASH by an MMRF collaborator, the Translational Genomics Research Institute in Phoenix, Arizona, identified 18 tumor-initiating mutations and new subtypes of myeloma associated with distinct molecular events and clinical outcomes.

CoMMpass is also designed to inform the best ways to combine and administer treatments. With the new drug approvals, the multiple myeloma market is becoming increasingly crowded: ten myeloma therapies are now approved in the US. “Questions have been raised at ASH about where new therapies will fit into the treatment algorithm and in what logical ways different combinations of drugs can be applied to maximize clinical benefit,” notes a post-ASH report from Biomedtracker.com.

The space may be crowded, but Darzalex and Empliciti sailed through to approval under an accelerated review based on response rate as a surrogate endpoint. Both received Breakthrough Therapy designation and Priority Review at the FDA. This rapid road to market closely resembled that of Farydak from Basel-based Novartis. Farydak was the first HDAC-oriented cancer drug to prove its mettle outside rare forms of lymphoma. It was approved in multiple myeloma in February 2015 (Nat. Biotechnol. 32, 853, 2014).

The newly approved Empliciti, Ninlaro and Darzalex are all specified for use in patients who have received prior treatment. Only Darzalex may also be used as a monotherapy. However, the future of myeloma treatment will likely involve combinations to further improve patient outcomes, something that Janssen is actively exploring.