ASH/FDA Joint Symposium on Late-Breaking Drug Approvals: Looking into the Future of Myeloma Treatment

At the 2015 ASH Annual Meeting, the U.S. Food and Drug Administration (FDA) sponsored a session reviewing drugs that received FDA approval in November 2015 – a month that saw an unprecedented three new agents added to the myeloma toolbox: daratumumab, ixazomib, and elotuzumab. The agents’ FDA product-reviewers discussed the safety and efficacy results that led to each drug’s approval, and were joined by clinicians who provided perspective on the use of these products in the real-world setting.

The session was moderated by Albert B. Deisseroth, MD, PhD, from the Division of Hematology Products at the FDA’s Office of Hematology and Oncology Products, who provided an overview of the current myeloma landscape. “We are in the midst of a revolution in cancer therapy in which treatments are targeted to neoplastic cells, thereby reducing damage to the normal tissues of the body,” Dr. Deisseroth said.

“To ensure that promising new products which address an unmet medical need for serious conditions are developed efficiently and approved expeditiously, the FDA has created four expedited programs: accelerated, fast track, breakthrough, and priority approvals,” he explained. Notably, the drugs discussed during this session were all approved via one of these accelerated pathways.


Providing the FDA perspective on daratumumab, a human CD38-directed monoclonal antibody, Barry W. Miller, MSN, CRNP, discussed the drug’s pathway to approval for the treatment of myeloma in patients who had received three or more prior therapies. The approval was based on a multicenter, open-label study evaluating response rates in 106 patients with relapsed/refractory myeloma treated with daratumumab monotherapy. The objective response rate was 29 percent.

“Given the heavily pretreated population, the magnitude of this effect is encouraging,” Dr. Miller said. “Moreover, the responses were durable, with a duration of response of 7.4 months.”

However, he added, “it should be noted that overall response rate and duration of response, the endpoints used for the regulatory decision, were only surrogate endpoints reasonably likely to predict clinical benefit – hence the accelerated rather than regular approval.” As a condition of approval, the superiority of daratumumab’s superiority over standard therapy will have to be confirmed in two ongoing confirmatory trials.


Next, Alexandria Schwarsin, MD, introduced ixazomib, the first oral proteasome inhibitor approved for the treatment of myeloma (in combination with lenalidomide and dexamethasone).

Ixazomib’s approval was based on results from the phase III TOURMALINE-MM1 trial – a randomized, double-blind, placebo-controlled trial of 722 patients with relapsed/refractory myeloma who had received one to three prior therapies. The addition of ixazomib led to longer progression-free survival (PFS) compared with patients taking placebo plus lenalidomide and dexamethasone (20.6 months vs. 14.7 months).

“The majority of adverse actions were gastrointestinal-related,” Dr. Schwarsin said. In terms of hematologic adverse events, grade 3/4 thrombocytopenia was higher in the ixazomib-treated arm, while grade 3/4 neutropenia was comparable between the arms.

Hepatotoxicity was also a concern in patients treated with ixazomib. “For patients with renal impairment, a reduced dose of the ixazomib is recommended,” Dr. Schwarsin added.


Lastly, Nicole J. Gormley, MD, reviewed the approval decision for elotuzumab. The anti-SLAMF7 monoclonal antibody has a similar indication to ixazomib: It is to be combined with lenalidomide and dexamethasone for patients with relapsed/refractory myeloma.

In the pivotal trial leading to the drug’s approval, ELOQUENT-2, median PFS, one of the study’s co-primary endpoint, was 19.4 months when elotuzumab arm was added to lenalidomide and dexamethasone compared with 14.9 months when patients were treated with the two-drug combination. Overall response rate, the other primary endpoint was 78.8 percent in the elotuzumab arm, compared with 65.5 percent in the control arm.

“Respiratory and infectious adverse reactions were common, with patients developing cough, nasal pharyngitis, upper respiratory tract infection, and pneumonia,” Dr. Gormley noted. “Opportunistic infections were also higher in the elotuzumab arm – primarily fungal infections and herpes zoster.” Two patients discontinued treatment due to hepatotoxicity, she added.

The Myeloma Specialist’s Perspective: “Continued Progress and Real Hope”

Focusing on combination therapies and sequencing these newly approved agents, S. Vincent Rajkumar, MD, from the Mayo Clinic in Rochester, Minnesota, and Paul G. Richardson, MD, from the Dana-Farber Cancer Institute in Boston, Massachusetts, then shared their perspectives on integrating daratumumab, ixazomib, and elotuzumab in real-world practice.

To begin, Dr. Rajkumar commented on the advances in the field. “We have witnessed unprecedented progress in the treatment of multiple myeloma, mostly because we now have a plethora of new drugs to support care pathways,” he said. “‘Accelerated,’ ‘fast track,’ ‘breakthrough,’ and ‘priority’ are not just words. We in the United States are fortunate that the FDA can approve these drugs, and more importantly, that they are here to discuss these approvals with us.”

Tracing the evolution of myeloma treatment – from melphalan to lenalidomide plus dexamethasone to bortezomib and to the current crop of approvals – Dr. Rajkumar highlighted the difficulties of choosing among treatments. “There are 22 potential treatment strategies within the National Comprehensive Cancer Network guidelines, which of course adds to the confusion,” he said.

“In myeloma, no matter what choice you make, patients will often have to try the other and the other,” Dr. Rajkumar continued. “It’s only a question of whether you’re making the right call on the sequence – rather than whether you chose the wrong regimen altogether.” Individualizing treatment, including tailoring treatment depending on patient preference, prior side effects, convenience of administration, and patients’ ability to come to the treatment center, is essential.

Both Dr. Rajkumar and Dr. Richardson agreed that treatment choice will often depend on the age and frailty of the patient. Double-drug regimens are preferred in older, frailer patients, while higher-risk and younger patients may derive more benefit from triple-drug regimens. Clinical trials of myeloma therapies also need better endpoints than PFS, such a validated patient-reported outcomes or quality-of-life endpoints that incorporate the patient experience.

“The new drug approvals have made an immense contribution to the armamentarium of drugs available for treatment,” he said, but the question remains, “How do you develop combinatorial treatment strategies for relapsed/refractory patients?”

For this population, immunomodulatory-based triplet therapies hold the most promise, he stated. Ixazomib, for one, is a very well-tolerated oral agent, providing a “strong rationale” for its use in this setting. “Ixazomib offers convenience and high tolerability,” Dr. Richardson noted. “And, in my opinion, daratumumab and elotuzumab are paradigm-changing agents, with a strategy that can be easily added to other drug platforms.”

“We have multiple new agents in the pipeline, and we are fortunate to have third- and fourth-generation novel agents now,” Dr. Richardson concluded. “I would argue that we need all of them, and, therefore, participation in clinical trials is absolutely vital.”

Dr. Rajkumar echoed these sentiments, ending his presentation on a hopeful note: “There are many more myeloma drugs in the pipeline, and most have single-agent activity in the relapsed/refractory state, so the best is yet to come.”