Three-Drug Combo Now Standard in Newly Diagnosed Myeloma

Zosia Chustecka

December 07, 2015

ORLANDO — Many clinicians are already using a three-drug combination for the treatment of multiple myeloma, and there are now enough data to convince even the skeptics about the superiority of a triplet over a doublet, say experts.

Triplet therapy with a proteasome inhibitor and an immunomodulatory drug, together with a steroid, is the new standard of care for newly diagnosed multiple myeloma, declared Sagar Lonial, MD, professor of hematology and medical oncology at the Winship Cancer Institute at Emory University in Atlanta. Speaking here at an education session at the American Society of Hematology 57th Annual Meeting, he said the triplet is a standard that "has come of age."

Dr Lonial highlighted results from the first and so far only randomized trial of a triplet versus a doublet in patients with newly diagnosed multiple myeloma, which shows a survival benefit and the "longest progression-free survival that we have ever seen."

The randomized data in newly diagnosed myeloma patients come from the SWOG S0777 study, reported here by Bruce Durie, MD, from the International Myeloma Foundation and Cedars-Sinai Comprehensive Cancer Center in Los Angeles.

The trial involved 474 patients, who were not intended for stem cell transplant, and the results show the superiority of the triplet combination of bortezomib (Velcade, Millenium/Takeda), lenalidomide (Revlimid, Celgene), and dexamethasone (VRd) when compared with the doublet of lenalidomide plus dexamethasone (Rd). Survival graphs can be seen in the abstract. Median follow-up was 6 years.

Median progression-free survival was 43 months for the VRd triplet versus 31 months for the Rd doublet.

Median overall survival was not reached for the VRd triplet versus 63 months for the Rd doublet. At around 80 months of follow-up, there had been 67 deaths among 242 patients in the triplet VRd group versus 96 deaths in 234 patients in the doublet Rd group. The overall survival was improved for the triplet VRd versus the doublet Rd, with a hazard ratio 0.666 (P = .0114).

"The addition of bortezomib to lenalidomide plus dexamethasone for induction therapy in previously untreated myeloma results in a statistically significant and clinically meaningful improvement in progression-free survival, as well as better overall survival," Dr Durie and colleagues conclude. "VRd had an acceptable safety and tolerability profile, despite increased neurotoxicity, and represents a potential new standard of care," they add.

This trial was highlighted in the Best of ASH lecture at the end of the meeting, and also at another session by Vincent Rajkumar, MD, professor of medicine at the Mayo Clinic in Rochester, Minnesota, who said that the results have already led to changes in treatment guidelines at his institution, where the triplet of bortezomib, lenalidomide, and dexamethasone is now standard of care for newly diagnosed patients, unless they are very frail.

These data from a randomized study in newly diagnosed patients should convince even the skeptics that remain, who are still using only two drugs, Noopur Raje, MD, director of the multiple myeloma program at the Massachusetts General Hospital in Boston, commented to Medscape Medical News.

This study began in 2008 and so it used intravenous bortezomib, which was the formulation available then, but this has since been replaced by a subcutaneous product with a different dosing schedule, which is better tolerated, and in particularly is associated with a lower incidence of peripheral neuropathy. If this new subcutaneous form of bortezomib had been used, the difference would likely have been even more significant, she suggested.

"Absolutely, now a three-drug combination is the standard of care in newly diagnosed patients," Dr Raje commented. There have also been trials showing superiority of three drugs over two in the relapsed/refractory setting, but it may be even more important in the setting of newly diagnosed disease.

"We have now established that three drugs are better than two, with the exception of frail patients," Dr Lonial said. Using a triplet is useful in overcoming resistance and also for clonal suppression, he added. There are about 60 mutations present at the time of diagnosis, and this number increases as the disease progresses, so "the best shot of eliminating or suppressing the disease is at the very beginning," he said.

The SWOG S0777 study was supported by grants from the National Health Institutes, and in part by Millennium (Takeda) for the provision of bortezomib. Dr Durie reports consultancy for Johnson & Johnson, Takeda, Onyx, and Celgene. Several coauthors report consultancy agreements with pharmaceutical companies.

American Society of Hematology (ASH) 57th Annual Meeting: Abstract 25. Presented December 5, 2015.


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