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Investigators are taking a personalized approach to treating patients with multiple myeloma by introducing novel agents in combination with backbone chemotherapies, based on patients’ individual genetic profiles.
Shaji Kumar, MD
Investigators are taking a personalized approach to treating patients with multiple myeloma (MM) by introducing novel agents in combination with backbone chemotherapies, based on patients’ individual genetic profiles. Extensive genomic studies of patients with MM have led to an understanding that genetic abnormalities may be the drivers for disease in certain patient populations.
The phase I/II platform trial MyDRUG (NCT03732703) is designed to treat patients with drugs targeted to specific genetic mutations. The trial is enrolling patients with MM who have relapsed within 18 months of starting second-line treatment without transplant or within 36 months if transplanted.
Early relapse or poor long-term outcomes can be indicative of underlying biology, said lead investigator Shaji Kumar, MD, in an interview with OncologyLive®. “As we understand more and more about disease heterogeneity, the possibility opens up that we could actually individualize therapy based on the specific underlying abnormality.” Kumar is a professor of medicine at Mayo Clinic in Rochester, Minnesota. MyDRUG is sponsored by the Multiple Myeloma Research Foundation (MMRF).
All patients will undergo comprehensive molecular profiling to evaluate for the presence of informative or actionable mutations, fusions and rearrangements, and amplifications and deletions. The trial will enroll patients with a high mutational load in any of the following genes: CDKN2C, FGFR3, KRAS, NRAS, BRAF V600E, and IDH2. Those with t(11;14) translocation also will be included in 1 of the 6 treatment arms.1
“If they have a particular mutation, they will be treated with the drug that we know from other cancer studies works against the mutation. We will treat the patients with that single targeted drug for a couple of cycles to see if it gets rid of some of the tumor cells,” Kumar said. Patients will receive targeted therapies in advance of or in combination with traditional chemotherapies or other combination therapy for MM.
The trial is expected to enroll 228 patients at 17 sites across the United States beginning in early 2019. Each arm will be made up of 38 patients.In 4 of the arms, patients will be assigned treatment based on specific genetic mutations. A fifth arm will include patients with t(11;14) translocations, who will receive venetoclax (Venclexta). The final arm will consist of patients who do not have an actionable genetic mutation; they will receive daratumumab (Darzalex) in combination with ixazomib (Ninlaro), pomalidomide (Pomalyst), and dexamethasone (Figure).2 “We have identified subgroups of patients [whose biologies] behave differently, and we believe that some of these genetic abnormalities may be the drivers for the disease in some of these cases,” Kumar said.
Patients who identify as having a CDK-activating alteration will receive abemaciclib (Verzenio); those with an IDH2 activating mutation, enasidenib (Idhifa); RAS/RAF mutations, cobimetinib (Cotellic); and an FGFR3 activating mutation, erdafitinib. Patients in each of the arms will receive the novel agents in combination with dexamethasone for 2 cycles, each lasting 28 days. The third and any subsequent cycles will consist of the novel agents in combination with dexamethasone, ixazomib, and pomalidomide.1
Primary endpoints are overall response rate (ORR) with an actionable genetic alteration or ORR with a nonactionable genetic alteration.
Patients who are eligible to participate in the trial must have received at least 1 but no more than 3 prior therapies, have received both a proteasome inhibitor and immunomodulatory drug, have had early relapse after initial treatment, and have a report, at most 120 days old, from their enrollment in the MMRF002 genetic profiling study, also sponsored by the MMRF.“We are looking for proof of principle that using a targeted agent against a mutation can get rid of the cancer cells that carry the mutation,” Kumar said. “But at the same time, we also know that by using [just] 1 drug we are not going to be able to control myeloma in the long run, so what we are hoping to do is to combine the targeted agents with the conventional combinations and that way we can get rid of most of the myeloma cells and get prolonged efficacy.”
Patients who are not being served well by standard-of-care may be able to benefit from early exposure to new agents, he added. “The trial gives us the opportunity to test these new drugs early on compared with other [settings], where it becomes more challenging and we often end up testing these drugs after everything else has failed,” Kumar said.
Should the study results show increased response and durability, Kumar is hopeful they will lead to expansion of the combinations to larger trials and additional settings.