Three New Agents for Multiple Myeloma Expand Armamentarium

Three new multiple myeloma (MM) treatments have recently been approved by the FDA.

Primary clinical reviewers from the FDA who reviewed the applications for the 3 new drugs—Darzalex (daratumumab), Ninlaro (ixazomib), and Empliciti (elotuzumab)—discussed the efficacy and safety issues from the products’ clinical trials and toxicity studies during a joint American Society of Hematology (ASH)/FDA symposium at the 57th ASH Meeting and Exposition. Also, clinician experts offered their perspectives on the use of these drugs in the real-world setting.

Daratumumab

Barry W. Miller, MSN, CRNP, discussed daratumumab, a human CD38-directed monoclonal antibody that received FDA accelerated approval on November 16, 2015. He was the primary clinical reviewer of the application.

Daratumumab is indicated for treatment of MM in patients who have received at least 3 prior lines of therapy, including a proteasome inhibitor (PI) and an immunomodulatory agent, or those who are double refractory to a PI and an immunomodulatory agent.

Miller highlighted findings from the pivotal MMY2002, open-label, 2-part trial submitted for review. The primary endpoint was overall response rate (ORR). Daratumumab, he said, achieved it’s primary endpoint when administered to 106 participants who had received a median of 5 prior therapies. The results showed that 29% of participants experienced a complete or partial reduction in tumor burden; the duration of response was 7.4 months.

Miller noted, “Daratumumab can interfere with the determination of stringent and complete responses,” adding that a few adverse events associated with the drug include infusion reaction (48%), fatigue (39%), and nausea (27%). “To avoid these reactions, patients could be pre-medicated with an antipyretic or a corticosteroid and monitored,” he said. 

Ixazomib

Ixazomib is an oral PI indicated in combination with lenalidomide and dexamethasone (Len/Dex) for the treatment of patients with MM who have received at least 1 prior therapy, according to Alexandria Schwarsin, MD, the primary clinical reviewer for ixazomib. 

The November 20, 2015, approval was based on the efficacy and safety results from a randomized, double-blind, placebo-controlled, multicenter, Phase III study in participants with relapsed and/or refractory MM who had undergone 1 to 3 prior treatment regimens. Participants who were refractory to lenalidomide or PIs were excluded, she said.

A total of 722 participants were randomized 1:1 to ixazomib plus Len/Dex or placebo plus Len/Dex. The primary endpoint was progression-free survival (PFS). The ixazomib arm demonstrated a statistically significant improvement in PFS compared with the placebo arm (20.6 months vs 14.7 months, respectively).

Dr Schwarsin said the most common adverse reactions reported in both groups included diarrhea (more participants in the ixazomib arm had grade 3 diarrhea), constipation, and peripheral neuropathy.  

Elotuzumab

Nicole J. Gormley, MD, was the clinical reviewer for the recently approved elotuzumab, a humanized IgG1 monoclonal antibody that targets the SLAMF7 protein. It is indicated in combination with Len/Dex for the treatment of patients with MM who have received 1 to 3 prior therapies. Elotuzumab was approved on November 30, 2015.

She shared results from the randomized, open-label, pivotal Phase III trial that evaluated elotuzumab in combination with Len/Dex versus Len/Dex alone. A total of 646 participants with relapsed or refractory MM who had received 1 to 3 prior lines of therapy were randomized 1:1 to the elotuzumab arm or the Len/Dex arm. Prior lenalidomide treatment was allowed. The coprimary endpoints were PFS and ORR.

The median PFS was 19.4 months in the elotuzumab arm versus 14.9 months in the Len/Dex arm. Further, ORR was 78.5% in the elotuzumab arm compared with 65.5% for Len/Dex. The most common adverse reactions that increased with addition of elotuzumab included fatigue (61.6%), diarrhea (46.9%), pyrexia (37.4%), and constipation (35.5%). “Opportunistic infections were reported in 22% of patients in the elotuzumab arm and 13% of patients in the Len/Dex arm with opportunistic infections being comprised of fungal infections and cases of herpes zoster,” she said.

Clinical Perspective

Two clinician experts discussed the potential role these newly approved agents may play in the treatment of MM. “We have witnessed an unprecedented change in multiple myeloma,” said S. Vincent Rajkumar, MD, professor of medicine, Mayo Clinic, noting that decades ago alkylating agents and steroids where the only options to treat the disease.

He said that bortezomib Len/Dex triplet therapy is the routinely preferred frontline therapy, even in nontransplant patients; however, this treatment may be harsh for the frail and elderly population. Thus, Len/Dex doublet therapy should be continued in this patient population. He suggested that ixazomib could be combined with the doublet in the remaining patient population with standard risk. For high-risk patients, more progress is needed, said Dr Rajkumar, who recommends adding carfilzomib to the doublet therapy or either daratumumab or elotuzumab. 

Paul G. Richardson, MD, Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, spoke on new directions in treating relapsed and refractory MM. He outlined factors affecting treatment decisions in advanced MM: 

• Response to prior therapy, tolerability of prior therapy

• Patient-related factors such as age, peripheral neuropathy, and renal impairment

• Aggressiveness of disease and prognostic features of individual patient

• Number of relapses and refractory disease

In clinical trials, 3 drug platforms in relapsed disease have been shown to be better than 2 drug platforms. 

For example, Dr Richardson said that ixazomib is a very well-tolerated agent and provides a strong rationale for use in triplet therapy, particularly in older patients and patients with high-risk disease. Additionally, there may be rationale in combining ixazomib with penobinostat in relapsed refractory MM patients.—Eileen Koutnik-Fotopoulos