Expert reviews myeloma combo treatments

Treatment options for multiple myeloma have proliferated rapidly over recent years, including four new drugs approved in the past year-a welcome “embarrassment of riches” resulting from collaboration between patients, academia, industry and advocacy groups, according to “Multiple Advances in Myeloma” presented December 5 at the 57^th American Society of Hematology (ASH) Annual Meeting in Orlando.

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Dr. Lonial

“With each new drug comes hope for patients,” said Sagar Lonial, MD, Winship Cancer Institute, Emory University, Atlanta. “Now the challenge is how to rationally combine treatments to cure more patients-how to take the pieces and put them together in a coherent fashion.”

Combinations can achieve “better depth and duration of response,” he said. “Combination therapy will be most effective with drugs of different mechanisms of action.”

That’s because they can inhibit more than one facet of cancer cells’ behavior at a time, reducing the number of ways in which cancer cells can develop drug resistance.

A patient’s myeloma is not composed of a single cancer clone, he emphasized. There are multiple, evolving, genetically different clones. Myeloma’s potential for evolving drug resistance increases as its gene mutation burden grows, Lonial noted. “Genomic instability is a hallmark of myeloma, and is worse in high-risk myeloma,” he said.

That is why Lonial and other researchers believe that delivering combination treatments at the same time has more promise than sequential one-agent therapies.

“Combination therapies can be helpful in overcoming drug resistance and in suppressing clonal evolution,” he explained. Progression-free survival among high-risk myeloma patients is prolonged, for example, when they are treated with the three-agent bortezomib-thalidomide-dexamethasone (VTD) regimen as induction therapy, compared to the two-agent thalidomide-dexamethasone (TD) combination, he noted.

Dr. Lonial reasons that combinations of three agents will more beneficial than two-drug combinations. For example, progression-free survival among high-risk myeloma patients is prolonged, for example, when they are treated with the three-agent bortezomib-thalidomide-dexamethasone (VTD) regimen as induction therapy, compared to the two-agent thalidomide-dexamethasone (TD) combination, he noted.

“We await survival data on phase 3 studies in relapse to solidify this three-versus-two argument,” he noted.

The appeal of combination therapies for myeloma is not new, Lonial was quick to point out. In the 1990s, combinations were attempted-all of them based upon alkylating agents and steroids, he noted. But the logic behind those early combination therapies was flawed, he explained: they were not “truly novel combinations.” Their mechanisms of resistance were similar-and worse, their toxicities overlapped, limiting the doses patients could tolerate. Perhaps not surprisingly, then, those early combinations failed to outperform existing therapy.

Not all combinations will be “straight-forward” for all patients, Lonial cautioned. Combinations must be rationally designed, taking advantage of different agents’ complementary biomolecular mechanisms.

Combinations including immunomodulatory drugs (IMiDs) and protease inhibitors (PIs) are a “new standard,” Lonial said. And IMiDs appear to enhance the anti-myeloma effects of the human monoclonal antibody daratumumab, which was recently approved for use in patients whose myeloma has proven resistant to three or more lines of treatment-including an IMiD and a PI. Daratumumab targets CD38, a cell-surface protein that is “highly and ubiquitously expressed on myeloma cells,” he noted. The combination of IMiDs and daratumumab appears to be “synergistic,” Lonial said.

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