Quadruplet therapy could be the future in MM


Photo courtesy of NCCN

Attendees at the NCCN 13th hematology congress

New York—Four-drug combinations are holding promise for the treatment of multiple myeloma (MM), although data from additional randomized trials are needed to define their role in clinical practice, according to Natalie S. Callander, MD, of the University of Wisconsin Carbone Cancer Center.

The efficacy of multiple triplet regimens has been well documented, and data are now emerging on the potential of 4-drug combinations.

“Triplet therapy is the standard,” she said during a presentation at the NCCN 13th Annual Congress: Hematologic Malignancies, “and quad therapy may be in the future.”

The study that set the standard for triplets in myeloma, she said, is SWOG 0777, an open label, phase 3 trial that compared bortezomib with lenalidomide and dexamethasone (VRd) to lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma.

Adding bortezomib to lenalidomide and dexamethasone significantly improved both progression-free and overall survival in the 525-patient trial, with a risk-benefit profile that was acceptable. The trial was recently reported in The Lancet.

The median progression free survival (PFS) was 43 months for the triplet, versus 30 months for the two-drug regimen (P=0.0018).

Likewise, median overall survival (OS) was significantly improved, at 75 months versus 64 months for triplet versus doublet therapy (P=0.025).

“Very convincingly, just receiving that short exposure to bortezomib,” she said, “ended up causing a substantial increase of progression-free and overall survival.”

Effective triplet regimens include the combination of carfilzomib, lenalidomide, and dexamethasone (KRd), cyclophosphamide, bortezomib, and dexamethasone (CyBorD), and more recently, ixazomib, lenalidomide, and dexamethasone (IRd).

These regimens have “excellent” response rates and survival data, Dr. Callander noted.

Quadruplet data

The combination of elotuzumab plus VRd produced high response rates that were even higher after transplant, with reasonable toxicity, Dr. Callander said of phase 2 trial data presented at ASCO 2017 (abstract 8002).

Similarly, the combination of daratumumab plus KRd had a 100% rate of partial response or better in phase 2 data also presented at ASCO 2017 (abstract 8000), with rates of very good partial response and complete response that improved with successive cycles of therapy, she said.

Even so, “it remains to be seen whether four drugs will be the new standard,” Dr Callander conjectured.

Four versus three drug strategies are being evaluated in ongoing randomized clinical trials including patients with previously untreated myeloma, she said.

These studies include Cassiopeia (NCT02541383), which is evaluating bortezomib, thalidomide, and dexamethasone with or without daratumumab, and GRIFFIN (NCT02874742), which is looking at VRd with or without daratumumab.

Daratumumab received an additional indication in myeloma, this time as part of a 4-drug regimen, several months ago, Dr. Callander added in a discussion on treatment options for elderly myeloma patients.

The U.S. Food and Drug Administration (FDA) approved the monoclonal antibody in combination with bortezomib, melphalan, and prednisone (VMP) for treatment of newly diagnosed myeloma patients who are transplant ineligible.

That approval was based on results of the multicenter phase 3 ALCYONE (MMY3007) study, published in The New England Journal of Medicine, showing an 18-month PFS of 71.6% for the 4-drug combination versus 50.2% for VMP alone (P<0.001).

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