Study Tests Targeted Drugs for Multiple Myeloma

Multiple myeloma treatment may soon move into the realm of personalized medicine thanks to a trial recently launched by the Multiple Myeloma Research Foundation (MMRF): Myeloma—Developing Regimens Using Genomics, or MyDRUG, one of the only large-scale trials run by a charitable organization in the United States, aims to match patients with high-risk relapsed/refractory multiple myeloma with targeted therapies based on their tumor mutations.

The idea of tailoring treatments to patients based on genomics is not new, says Shaji Kumar, MD, of the Mayo Clinic in Rochester, MN, the leader of MyDRUG. However, no trials of tailored therapies have been done in multiple myeloma, a relatively rare, highly heterogenous cancer. “A lot of the difference [in patient outcomes] seems to be driven by presence of specific genetic abnormalities,” Kumar explains. “We would like some proof of principle that targeted agents are actually able to get rid of those myeloma cells that carry that abnormality.”

Previously, the MMRF launched the CoMMpass study, in which researchers performed genomic sequencing on tumors from 1,150 patients newly diagnosed with multiple myeloma to establish the range and frequency of mutations. The study also tracked how patients responded to therapies. Researchers used this information to design MyDRUG.

In the trial, patients with relapsed/refractory multiple myeloma will be assigned to a targeted therapy based on their genomic alteration: Along with standard dexamethasone, those with a mutation in RAF/RAS would receive cobimetinib (Cotellic; Genentech); IDH2, enasidenib (Idhifa; Celgene/Agios); CDK, abemaciclib (Verzenio; Eli Lilly); and FGFR3, erdafitinib (Janssen). After two treatment cycles, standard ixazomib (Ninlaro; Takeda) and pomalidomide (Pomalyst; Celgene) would be added to the regimen. Patients with a t(11;14) translocation would receive venetoclax (Venclexta; AbbVie/Genentech) plus ixazomib, pomalidomide, and dexamethasone (IPD). Lastly, patients with no detectable or actionable mutations would receive daratumumab (Darzalex; Janssen) plus IPD.

Researchers will assess patient responses to the targeted drugs alone and to the targeted drugs plus IPD. The trial is designed to continue indefinitely, with no limit on the number of patients enrolled; new arms will be added as additional agents are deemed suitable for testing.

“Myeloma is not just one cancer, and we need to move to a paradigm where we treat different people differently based on these specific abnormalities,” Kumar says. “We are hoping that [MyDRUG] will set the stage for transitioning from a one-size-fits-all to a more personalized therapy.”

“Overall, I think it's an important step in trying to identify novel therapies for patients with high-risk disease,” who tend to have poor outcomes with standard treatments, says Jason Valent, MD, of the Cleveland Clinic in Ohio, who is not involved in MyDRUG. Valent is particularly interested in whether targeting single mutations will destroy myeloma cells, or whether the cells contain additional mutations that are driving growth.

Noopur Raje, MD, of Massachusetts General Hospital in Boston, which is one of the institutions involved in MyDRUG, is enthusiastic about the trial's umbrella design because it brings together multiple pharmaceutical companies and experimental multiple myeloma therapies. Moreover, she says that the trial's large size makes it better suited to studying rarer mutations, such as FGFR and IDH2, for which it can be difficult to accrue enough patients in a traditional trial.

“If we can see that this works here, this would be the paradigm of how we do clinical trials in the future,” she says. –Catherine Caruso

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