New Myeloma Agents Incorporated into NCCN Guidelines

At the 2016 NCCN Annual Congress on Hematologic Malignancies, Carol Ann Huff, MD, discussed recent FDA-approved agents incorporated into the NCCN Guidelines for Multiple Myeloma (Version 3.2016): panobinostat (Farydak), ixazomib (Ninlaro), daratumumab (Darzalex), and elotuzumab (Empliciti).

Huff, an associate professor of oncology and medicine at the Johns Hopkins University School of Medicine, discussed the pivotal data for each of these agents that supported their rapid inclusion into NCCN treatment algorithms.

Panobinostat

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In February 2015, the FDA approved the HDAC inhibitor panobinostat in combination with bortezomib (Velcade) and dexamethasone for patients with myeloma who received prior treatment with bortezomib and an immunomodulatory (IMiD) agent, based on a prespecified subgroup analysis from the PANORAMA-1 trial.

The analysis looked specifically at 193 patients from the phase III study who were treated with bortezomib and an IMiD. In this population, the median progression-free survival (PFS) with the panobinostat combination was 10.6 months versus 5.8 months with placebo (HR, 0.52; 95% CI, 0.36-0.76).

Patients in the panobinostat arm had significantly more diarrhea, with all-grade diarrhea of about 70% versus 40% in the control arm. Twenty-five percent of the panobinostat cohort had grade 3/4 diarrhea. “So, panobinostat is available; [however] I can tell you that I personally don’t use this,” said Huff.

She added that research, thus far, exploring panobinostat in combination with other agents, such as carfilzomib (Kyprolis), have shown significantly less toxicity than the PANORAMA-1 data.

Ixazomib

The FDA approved the oral proteasome inhibitor ixazomib in November 2015 for use in combination with lenalidomide (Revlimid) and dexamethasone as a treatment for patients with multiple myeloma who have received at least one prior therapy.

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The approval was based on data from the phase III TOURMALINE- MM1 trial, which showed a median PFS of 20.6 months with ixazomib plus lenalidomide and dexamethasone compared with 14.7 months with lenalidomide and dexamethasone alone.

The benefit with ixazomib was observed in all predefined subgroups, including patients with high-risk cytogenetics and those who had prior exposure to proteasome inhibitors or IMiDs.

Huff noted that in TOURMALINE-MM1, there was a higher incidence of rash, gastrointestinal side effects, and thrombocytopenia among patients who received ixazomib. “Nevertheless, these side effects are manageable,” said Huff.

Daratumumab

In November 2015, daratumumab became the first monoclonal antibody approved for patients with myeloma. The CD38-targeted monoclonal antibody was approved for patients who had received ≥3 prior therapies, based on data from 2 clinical trials.

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In the phase I/II GEN501 study, daratumumab demonstrated an objective response rate of 36%, median PFS was 5.6 months (95% CI, 4.2-8.1), and the 1-year overall survival rate was 77% (95% CI, 58-88).The MMY2002 study showed similar results.

Huff said that the daratumumab regimen is “very well tolerated.” She did note that infusion-related reactions—mainly with the first infusion—occur about 40% of the time, including grade 3 reactions in 5% of patients.

Huff added that patients receiving daratumumab, “tend to have more upper respiratory tract type of symptoms,” such as nasal congestion, throat irritation, cough, and dyspnea.

Janssen and Genmab, the codevelopers of daratumumab, have submitted a supplemental biologics license application (sBLA) to the FDA for the use of daratumumab in combination with lenalidomide/ dexamethasone or bortezomib/dexamethasone for patients with myeloma following ≥1 prior therapy.

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The application to expand daratumumab’s approval was based on 2 phase III trials.The POLLUX trial demonstrated that combining daratumumab with lenalidomide/dexamethasone reduced the risk of disease progression by 63% versus lenalidomide/dexamethasone alone in patients with relapsed/refractory myeloma.

In the phase III CASTOR trial, adding daratumumab to bortezomib/ dexamethasone reduced the risk of progression or death by 61% in patients with recurrent or refractory myeloma. The sBLA also included phase I data for treatment with daratumumab in combination with pomalidomide (Pomalyst) and dexamethasone following ≥2 lines of therapy.

Elotuzumab

The FDA also approved the monoclonal antibody elotuzumab in November 2015 for use in combination with lenalidomide and dexamethasone in patients with multiple myeloma following the failure of one to 3 prior therapies.

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The approval was based on data from the phase III ELOQUENT- 2 trial, in which the median PFS with the 3-drug elotuzumab regimen was 19.4 months (95% CI, 16.6-22.2) versus 14.9 months (95% CI, 12.1-17.2) with lenalidomide and dexamethasone alone (HR, 0.70; 95% CI, 0.57-0.85; P <.001).

Huff said elotuzumab is a &ldquo;very well-tolerated agent.&rdquo; She noted that the rate of infusion-related reactions was only 10% with elotuzumab, with almost all occurring with the first infusion.

Summarizing the current state of myeloma care, Huff said, &ldquo;Survival for patients with multiple myeloma is significantly longer, and, hopefully, we&rsquo;ll continue to improve upon this.

References:

1. San Miguel JF, Hungria VTM, Yoon S-S, et al. Panobinostat plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma who received prior bortezomib and IMiDs: A predefined subgroup analysis of PANORAMA 1. Abstract 8526.J Clin Oncol.2015;33(suppl).
2. Moreau P, Masszi T, Grzasko N, et al; TOURMALINE-MM1 Study Group. Oral ixazomib, lenalidomide, and dexamethasone for multiple myeloma.N Engl J Med.2016;374(17):1621-1634. doi: 10.1056/NEJMoa1516282.
3. Lokhorst HM, Plesner T, Laubach JP, et al. Targeting CD38 with daratumumab monotherapy in multiple myeloma.N Engl J Med.2015;373(13):1207-1219. doi: 10.1056/NEJMoa1506348.
4. Janssen Submits Application to U.S. FDA to Expand Indication for Daratumumab (DARZALEX) [news release]. Raritan, NJ: Janssen Biotech, Inc.; August 17, 2016.http://www.prnewswire.com/ news-releases/janssen-submits-application-to-us-fda-to-expand-indication-for-daratumumab-darzalex- 300315019.html.Accessed October 1, 2016.
5. Lonial S, Dimopoulos M, Palumbo A, et al; ELOQUENT-2 Investigators. Elotuzumab Therapy for Relapsed or Refractory Multiple Myeloma.N Engl J Med.2015;373(7):621-631. doi: 10.1056/NEJMoa1505654.