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MMRF Data Fuels Greater Understanding of Multiple Myeloma Drug Resistance, Mutational Landscape


NEW YORK – Long-running data-collection studies by the Multiple Myeloma Research Foundation (MMRF) has helped investigators better understand the genetic factors that lead to disease progression and drug resistance.

A study published in Nature Communications this month detailed the latest findings from the MMRF's ongoing longitudinal CoMMpass study, which has collected bone marrow samples from more than 1,100 multiple myeloma patients worldwide. Researchers have identified several genetic mutations associated with resistance to standard-of-care multiple myeloma treatments.

Hearn Cho, a study author and MMRF's chief medical officer, noted that initial treatment for newly diagnosed multiple myeloma usually includes an immunomodulatory agent like Bristol Myers Squibb's Revlimid (lenalidomide), a synthetic glucocorticoid such as dexamethasone or prednisone, and a proteasome inhibitor like Takeda's Velcade (bortezomib). Some patients also receive Janssen's monoclonal antibody Darzalex (daratumumab) in this initial treatment regimen, he said.

Cho and colleagues compared sequencing data from a cohort of 511 patients with relapsed and refractory multiple myeloma against those with newly diagnosed disease to identify any treatment-related resistance mechanisms. They found some patients in the relapsed or refractory cohort acquired mutations in CRBN and CUL4B that may have appeared in response to receiving immunomodulatory agents. Some patients also harbored mutations in NR3C1, which they may have acquired from synthetic glucocorticoid treatments.

"The drugs that are commonly used in the initial therapy of multiple myeloma are highly effective, but patients do become resistant to them," Cho said. "There's a number of different mechanisms, but from a global perspective, pathways that affect cell survival are often culprits in developing resistance to different types of drugs. The evolving hypothesis is that some of these alterations in cell survival pathways, like NFKB or RAS, are contributing to resistance to these different classes of drugs."

The researchers also used the clinical sequencing data from 511 patients to characterize the molecular alterations landscape of relapsed or refractory multiple myeloma. They found that a higher proportion of patients had alterations in the NF-κB and RAS/MAPK pathways than had been previously reported. Nearly half, or 45 percent of patients, harbored alterations in the NF-κB pathway and 65 percent had mutations in RAS/MAPK pathway genes. KRAS was the most frequently mutated RAS/MAPK gene in relapsed or refractory multiple myeloma patients, occurring in 26 percent of the cohort, while NRAS mutations occurred in 25 percent and BRAF in 15 percent.

The high prevalence of RAS pathway mutations opens up the possibility that these patients could benefit from KRAS, BRAF, or MEK inhibitors. The MMRF's ongoing master protocol trial called MyDRUG has been exploring Genentech's MEK inhibitor Cotellic (cobimetinib) plus standard-of-care treatments in multiple myeloma patients with RAF/RAS-mutated tumors. Cotellic is approved in the US for BRAF V600E- or V600K-mutant melanoma.

Early data from the Cotellic arm of the MyDRUG study, presented at the International Myeloma Society annual meeting this week, showed that six of seven evaluable relapsed multiple myeloma patients with RAS/RAF alterations responded to the Cotellic combination.

Showing these drugs' efficacy in the relapsed setting within MyDRUG and identifying the prevalence of these mutations, Cho said, is a step toward making them a frontline therapy option for multiple myeloma. Cho is particularly interested in tailoring upfront therapy to the genomic makeup of every patient's tumor and tailoring upfront treatment for patients who are at high risk of relapse.

But any new precision oncology strategy in the first-line setting will have to best the between 70 percent and 80 percent response rates seen with standard-of-care regimens. "A simple hypothesis might be, if you have a RAS mutation when you're diagnosed with myeloma, should you be getting a MEK inhibitor along with standard of care?" Cho said. "The bar for that kind of clinical trial is higher with the US Food and Drug Administration, so to do a trial for initial therapy you need to be very certain that there's benefit."

Cho estimated that around 20 percent of multiple myeloma patients don't have as deep of a response or long-term benefit from the standard-of-care regimens. Last year, the MMRF published research that characterized the genomic features common among these patients at high risk of relapse based on data from the CoMMpass study. That study found multiple myeloma patients with chromosome 1 gain tended to have higher relapse risk. The MMRF has another master protocol in the works for these high-risk patients to receive targeted therapies along with the standard regimen as their initial therapy.

For this trial, researchers will have to separate patients at high risk from those at average risk of relapse who can receive standard treatments. "For [high-risk] patients who are not going to do well with standard therapy, we want to test the hypothesis that different types of upfront therapy will get better results for those patients," Cho said. "For that, the regulatory bar is a little bit lower, but you still need to have that safety and efficacy data in the relapsed setting to justify moving things forward into the upfront setting."

­­There are two autologous CAR T-cell therapies approved in the US for relapsed multiple myeloma: BMS's Abecma (idecabtagene vicleucel) and Janssen's Carvykti (ciltacabtagene autoleucel). Both companies are exploring the activity of these therapies in the upfront multiple myeloma setting.

The MyDRUG trial is also evaluating other targeted therapies in certain multiple myeloma patients, including BMS's IDH2 inhibitor Idhifa (enasidenib), Eli Lilly's CDK4/6 inhibitor Verzenio (abemaciclib), Janssen's FGFR inhibitor Balversa (erdafitinib), and others.

"We're taking the findings from our laboratory translational research into the clinic with protocols such as MyDRUG," Cho said, adding that researchers then take samples collected within these clinical trials back to the lab for research that improves understanding of resistant mechanisms or identifies new drug targets or combination options. "It's an iterative process, from bench to bedside and back to the bench."