Novel Drugs Push the Envelope in Multiple Myeloma

The year 2015 has been truly remarkable for the treatment of multiple myeloma (MM). The first oral proteasome inhibitor, ixazomib, is now approved for the treatment of MM. Data from the Tourmaline-MM1 study presented at the 57th ASH Annual Meeting demonstrated the benefit of ixazomib when combined with lenalidomide and dexamethasone in relapsed and/or refractory MM, with improvement in progression-free survival (20.6 months vs. 14.7 months for patients receiving lenalidomide and dexamethasone) and without significant toxicity.¹ 

While there have been continued advances in novel drugs for MM, this has easily been the year where immuno-oncology and monoclonal antibodies (MoABs) have stolen the spotlight. A few days prior to and after ixazomib approval, two new MoABs were approved by the U.S. Food and Drug Administration (FDA): daratumumab and elotuzumab. Daratumumab, a MoAB directed against CD38, was approved for the treatment of MM patients who have received at least three prior lines of therapy including a proteasome inhibitor and an immunomodulatory agent, or those who are refractory to both these classes of drugs (i.e., double-refractory). In a pivotal phase I/II study, daratumumab demonstrated striking effectiveness as a single agent in heavily pretreated patients including double-refractory patients.²  The overall response rate in this group was 36 percent, including two patients who had a complete response and two patients with a very good partial response. Furthermore, responses were durable, and 65 percent of patients who had a response were free of progression at one year. These observations were corroborated by the Sirius study, in a similar refractory MM population.³  At the 2015 ASH Annual Meeting, we heard about early-stage trials combining daratumumab with lenalidomide⁴  or pomalidomide,⁵  with encouraging data demonstrating deeper responses. These studies will inform use of daratumumab as a partnering agent in the evolving MM treatment landscape.

Elotuzumab is a humanized recombinant IgG1 MoAB that targets signaling lymphocyte activation molecule (SLAMF7), also known as CS1 (CD2-subset-1). In a phase III study, ELOQUENT-2, the combination of elotuzumab, lenalidomide, and dexamethasone was compared with lenalidomide and dexamethasone in patients with relapsed disease.⁶  Patients with one to three prior lines of therapy were eligible to participate. This trial enrolled 646 patients with a median of two prior lines of therapy. A significant proportion had high-risk cytogenetics (32% with del[17p] and 9% with t[4;14]). The elotuzumab-containing arm had superior progression-free survival (19.4 months vs. 14.9 months in the control group; p<0.001), and the overall response rate was also higher (79% vs. 66%; p<0.001). Based on these findings, elotuzumab was approved in combination with lenalidomide and dexamethasone in patients with one to three prior lines of treatment. These studies with elotuzumab and daratumumab are among the first to show promising activity for MoAB therapy in MM, and they will be practice-changing additions to our arsenal against MM.

Cellular therapies such as chimeric antigen receptor-T (CAR-T) cell therapy are now being actively studied in MM. Although still in the early days of development, the promising data presented this year with the use of CD19-directed CAR-T cells in a heavily pretreated MM patient with nine prior lines of therapy provide proof of concept for the promise of this strategy.⁷  During the Late-Breaking Abstracts session at the 2015 ASH Annual Meeting, early data on a series of MM patients undergoing CAR-T cell therapy directed against a different target, B-cell maturation antigen, may translate into the use of personalized cellular therapy with the potential for long-term disease control.⁸ 

Continuing the theme of immuno-oncology, data from solid tumors highlight the successful paradigm of using checkpoint inhibitors to target inhibitory mechanisms of the immune system. Nivolumab and pembrolizumab, MoABs targeting the programmed death 1 checkpoint, have shown activity in melanoma and lung cancer and were recently approved by the FDA. In relapsed MM, trials studying the use of immune checkpoint blockade with MoABs such as pembrolizumab are showing promise when the drug is combined with lenalidomide⁹  or pomalidomide.¹⁰  Exploring the full potential of MoABs in the treatment of myeloma is an area of great interest for 2016.