Shifting Treatment Paradigms for Multiple Myeloma

November 2016, Vol 7, No 10

New York, NY—How to integrate the many new drugs recently approved for multiple myeloma into clinical practice was a topic addressed by Carol Ann Huff, MD, Director of the Myeloma Program at the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, at the 2016 National Comprehensive Cancer Network (NCCN) Congress on Hematologic Malignancies.

“From 2004 to the present, 10 agents have been FDA approved for the treatment of multiple myeloma. The new treatment options have more than doubled the survival rates of these patients. We now have to learn how to incorporate these new regimens into the best possible management of patients with multiple myeloma,” said Dr Huff.

The first pan-histone deacetylase inhibitor panobinostat (Farydak) was approved by the FDA in 2015 for the treatment of patients with multiple myeloma. Dr Huff cited the multicenter PANORAMA-1 clinical trial, which randomized 768 patients with relapsed and/or refractory multiple myeloma to panobinostat plus bortezomib (Velcade) and dexamethasone or to placebo plus bortezomib and dexamethasone.

The median progression-free survival (PFS) was 12 months in the panobino­stat group compared with 8.1 months in the placebo group. The proportion of patients with a complete or near-complete response was also significantly higher in the panobinostat group than in the placebo group.

Proteasome Inhibitors

Dr Huff discussed the efficacy of proteasome inhibitors for multiple myeloma. Currently, 3 proteasome inhibitors—bortezomib, carfilzomib (Kyprolis), and ixazomib (Ninlaro)—have been approved for multiple myeloma; 2 new proteasome inhibitors—oprozomib and marizomib—are currently in development and have demonstrated efficacy in clinical trials.

Dr Huff focused on ixazomib, which was the most recent proteasome inhibitor to receive FDA approval (in December 2015). A 2016 phase 3 study by Masszi and colleagues randomized 722 patients with relapsed and/or refractory multiple myeloma to receive ixazomib plus lenalidomide (Revlimid) and dexamethasone or placebo plus lenalidomide and dexamethasone. The median PFS was 20.5 months in the ixazomib group versus 15 months in the placebo group—a significant prolonged PFS with ixazomib. The overall response rates were 78% for the ixazomib arm and 72% for the placebo arms. Furthermore, the complete response rates were 11.7% with ixazomib versus 6.6% with placebo.

Monoclonal Antibodies

The first monoclonal antibodies were approved for multiple myeloma in late 2015—daratumumab (Darzalex), an anti-CD38 monoclonal antibody, and elotuzumab (Empliciti), a monoclonal antibody that targets the signaling lymphocytic activation molecule F7.

In the phase 3 CASTOR clinical trial, 498 patients with relapsed and/or refractory multiple myeloma were randomized to receive daratumumab, bortezomib, and dexamethasone, or bortezomib and dexamethasone alone. The median PFS at 12 months was 60.7% with daratumumab plus bortezomib and dexamethasone versus 26.9% with bortezomib plus dexamethasone alone. The overall response rates were 83% in the daratumumab treatment arm versus 63% in the bortezomib plus dexamethasone treatment arm.

The phase 3 ELOQUENT-2 clinical trial randomized 646 patients with relapsed and/or refractory multiple myeloma to receive elotuzumab, lenalidomide, and dexamethasone, or lenalidomide and dexamethasone. The median PFS was 19.4 months in the elotuzumab arm compared with 14.9 months in the lenalidomide and dexamethasone alone arm. In addition, the overall response rates were 79% and 66%, respectively.

Incorporating Novel Agents into Treatment Guidelines

Dr Huff noted that the 4 therapeutic agents that were approved in 2015 for the treatment of patients with multiple myeloma have been incorporated into the NCCN treatment guidelines. The NCCN lists the following regimens as “preferred” and “category 1” for patients who have received treatment for multiple myeloma:

  • Panobinostat, lenalidomide, and dexamethasone
  • Ixazomib, lenalidomide, and dexamethasone
  • Daratumumab, bortezomib, and dexamethasone
  • Elotuzumab, lenalidomide, and dexamethasone.
“With the FDA approval of pano­binostat, daratumumab, ixazomib, and elotuzumab, the treatment landscape for myeloma has grown significantly. Survival for patients with myeloma is significantly longer, and we have long-term strategies for the management of this disease. Studies looking at these and other treatments as earlier lines of therapy are currently ongoing in hopes of even greater benefits for our patients,” Dr Huff said.

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