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.

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. &ldquo;So, panobinostat is available; [however] I can tell you that I personally don&rsquo;t use this,&rdquo; 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.

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.

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. &ldquo;Nevertheless, these side effects are manageable,&rdquo; said Huff.

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 &ge;3 prior therapies, based on data from 2 clinical trials.

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 &ldquo;very well tolerated.&rdquo; She did note that infusion-related reactionsmainly with the first infusion&mdash;occur about 40% of the time, including grade 3 reactions in 5% of patients.

Huff added that patients receiving daratumumab, &ldquo;tend to have more upper respiratory tract type of symptoms,&rdquo; 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 &ge;1 prior therapy.

The application to expand daratumumab&rsquo;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 &ge;2 lines of therapy.

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.

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.

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.

Moreau P, Masszi T, Grzasko N, et al; TOURMALINE-MM1 Study Group. Oral ixazomib, lenalidomide, and dexamethasone for multiple myeloma.

2016;374(17):1621-1634. doi: 10.1056/NEJMoa1516282.

Lokhorst HM, Plesner T, Laubach JP, et al. Targeting CD38 with daratumumab monotherapy in multiple myeloma.

2015;373(13):1207-1219. doi: 10.1056/NEJMoa1506348.

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.

Lonial S, Dimopoulos M, Palumbo A, et al; ELOQUENT-2 Investigators. Elotuzumab Therapy for Relapsed or Refractory Multiple Myeloma.

2015;373(7):621-631. doi: 10.1056/NEJMoa1505654.

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Clinical Articles

Beginning with bortezomib (Velcade) in 2004, there have&nbsp;been 10 agents approved over the last 12 years for the&nbsp;treatment of patients with multiple myeloma.

New Myeloma Agents Incorporated into NCCN Guidelines

For individual patients, cancer has been historically rated as one of the mostly costly medical conditions to treat in adults, second only to heart conditions.

In addition to rising treatment costs, analyses indicate that cancer patients are also subject to higher out-of-pocket costs, both during treatment and later as cancer survivors.

Combined with the loss of income due to disease symptoms and debilitating side effects from therapy, cancer patients suffer financial hardships that can severely impact their quality of life and may affect decisions to continue therapy.

As a result, the rising cost of cancer care has been the subject of intense discussion within the oncology community, largely driven by physicians&rsquo; desire to help address and manage the issue of high treatment costs on behalf of their patients. Thus, there is a growing need to assess current therapeutic strategies, based on their overall value, to better inform treatment planning and decisions surrounding cancer care.

Over the last decade, cancer immunotherapies have dramatically changed the therapeutic landscape for cancer patients by providing a clinically beneficial alternative to traditional treatments. Recent FDA approvals have resulted in novel treatment options, and rapidly expanded indications for existing agents, to make immunotherapies accessible to patients across a variety of disease settings, including melanoma, hematologic malignancies, nonsmall cell lung cancer, prostate cancer, kidney cancer, bladder cancer, and head and neck cancer.

With further FDA approvals on the horizon, as well as additional agents and combination therapies in clinical trials, cancer immunotherapies are expected to significantly impact current treatment standards in the coming years. Because these agents enhance or enable the intrinsic ability of the immune system to recognize and eliminate cancer, immunotherapies have been characterized by impressive durable responses, distinct side effects, and response kinetics that are unique compared with traditional cytotoxic and targeted therapies. However, previous reports and value frameworks centered on the value of cancer care have not fully considered the unique aspects of cancer immunotherapeutics, which has led to uncertainty about the real benefit of this therapeutic modality.

The Society for Immunotherapy of Cancer (SITC) was the first to initiate the important dialogue surrounding the value of cancer immunotherapy at the organization&rsquo;s 30th Anniversary Annual Meeting in 2015.

This symposium, organized by Howard Kaufman, MD, FACS, and moderated by Peter Yu, MD, FACP, FASCO, brought together knowledge and insight from diverse perspectives, including academic scientists and physicians, experts in health care coverage and policy, representatives from industry, and patient support representatives. In this symposium, key aspects of the value proposition for cancer immunotherapy were discussed, including the significance of immune-based biomarker development, considerations for the cost of innovation, and both real-world and patient perspectives of value. The symposium concluded with an audience-generated question-and-answer session that paved the way for future discussions surrounding the value proposition for cancer immunotherapy.

Building on the success of the first symposium, a Value of Cancer Immunotherapy Summit will be held, as a part of the SITC 31st Annual Meeting, on November 13, 2016. Developed in collaboration with the American Society of Clinical Oncology (ASCO), the organizers for this program include returning faculty Drs. Kaufman and Yu, as well as Michael Atkins, MD, and Lowell Schnipper, MD, FASCO.

This half-day program will feature presentations by academic physicians, patient advocates, economists, and third-party payers. Highlights will include presentations on perspectives and evaluations of current value models, economic outcomes of cancer therapy, patient-reported outcomes in clinical trials, and patient perspectives on value. In addition to discussing the unique characteristics of immune-based agents and the value proposition for these therapies, the summit is expected to result in a referendum on future directions and priorities to better define the full value of cancer immunotherapy.

By fostering this dialogue between leading experts in the field and key stakeholders within the healthcare system, SITC is uniquely positioned to ensure that cancer immunotherapies are accurately represented within the ongoing discussion surrounding the rising cost of cancer care. In line with the society&rsquo;s vision to make cancer immunotherapy a standard of care and the word &ldquo;cure&rdquo; a reality for cancer patients everywhere, it will be imperative to continue this ongoing discussion to ensure that patients are able to access therapeutic options that will result in high-value care.

Mariotto AB, Yabroff KR, Shao Y, Feuer EJ, Brown ML. Projections of the cost of cancer care in the United States: 2010-2020.

2011;103(2):117-128. doi:10.1093/jnci/djq495.

Soni A. Statistical Brief 470: trends in the five most costly conditions among the U.S. civilian institutionalized population, 2002 and 2012. Agency for Healthcare Research and Quality website.

https://meps.ahrq. gov/data_files/publications/st470/stat470.shtml

. Published April 2015. Accessed Sept 30, 2016.

Guy GP Jr, Ekwueme DU, Yabroff KR, et al. Economic burden of cancer survivorship among adults in the United States.

2013;31(30):3749-3757. doi: 10.1200/JCO.2013.49.1241.

Guy GP Jr, Yabroff KR, Ekwueme DU, et al. Estimating the health and economic burden of cancer among those diagnosed as adolescents and young adults.

2014;33(6):1024-1031. doi: 10.1377/hlthaff.2013.1425.

Guy GP Jr, Yabroff KR, Ekwueme DU, et al. Healthcare expenditure burden among non-elderly cancer survivors, 2008-2012.

2015;49(6[suppl 5]):S489-S497. doi: 10.1016/j.amepre.2015.09.002.

Ekwueme DU, Yabroff KR, Guy GP Jr, et al. Medical costs and productivity losses of cancer survivors--United States, 2008-2011.

U.S. Food and Drug Administration. Hematology/oncology (cancer) approvals & safety notifications. FDA website.

http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm279174.htm

. Updated September 15, 2016. Accessed September 30, 2016.

SITC among first to address value proposition of cancer immunotherapy [press release]. National Harbor, MD: Society for Immunotherapy of Cancer; November 8, 2015.

http://www.sitcancer.org/about-sitc/newsroom/press-releases/sitc-among-first-to-address-value-proposition-of-cancer-immunotherapy

SITC addresses the crucial value of cancer immunotherapy in discussions in a Value of Cancer Immunotherapy Summit.&nbsp;

November 2016 | Targeted Therapies in Oncology

New Myeloma Agents Incorporated into NCCN Guidelines

Beyond Cost: SITC Addresses Critical Issues to Define the Value of Cancer Immunotherapy