Monoclonal Antibodies in the Treatment of Multiple Myeloma with a Focus on Elotuzumab and Daratumumab

Monoclonal antibodies designed against cell surface proteins such as CD20 (rituximab) or HER2 (trastuzumab), cytokines such as VEGF (bevacizumab), and now immune checkpoints such as PD1 (e.g., pembrolizumab) have transformed oncology care and are routinely used across nearly all tumor types. Although treatment options for multiple myeloma (MM) over the last decade have converted the disease into a chronic condition for many patients, it is only now that the potential of monoclonal antibodies in the treatment of MM is being recognized.

Recent publication of important data using two monoclonal antibodies, elotuzomab and daratumomab, in relapsed refractory MM show improving outcomes, and these agents may be paradigm-shifting additions to MM treatment.^1-3  Elotuzumab is a humanized recombinant monoclonal IgG1 antibody targeting signaling lymphocyte activation molecule (SLAMF7), also known as CS1 (CD2-subset-1). SLAMF7 is a cell surface glycoprotein that is highly expressed on both normal and MM plasma cells, and to a lower extent, on lymphocytes such as natural killer (NK) cells; it is absent in other tissues and hematopoietic stem cells.^4,5  Expression of SLAMF7 is nearly universal in MM, irrespective of cytogenetic abnormalities and degree of disease progression. Elotuzumab is proposed to have several modes of action: antibody-dependent cellular cytotoxicity of MM cells involving natural killer NK cells and enhancement of NK cell activity against MM cells by binding to NK cell SLAMF7.⁶ 

As a single agent, elotuzumab does not show significant clinical activity.⁷  However, when it is combined with lenalidomide and dexamethasone, a phase I/II trial in relapsed or refractory MM showed an overall response rate of 84 percent with a median progression-free survival of 29 months.⁸  More recently, a phase III study, ELOQUENT-2, compared the combination of elotuzumab, lenalidomide, and dexamethasone to lenalidomide and dexamethasone in patients with relapsed disease.⁹  Patients with one to three prior lines of therapy were eligible to participate. Of note, the trial limited enrollment of patients with prior lenalidomide treatment to 10 percent, and these patients had to demonstrate at least a partial response to lenalidomide. Elotuzumab 10 mg/kg was given weekly for the first two cycles and then every other week. Lenalidomide and dexamethasone were given according to a conventional 28-day schedule. 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). Adverse effects were similar between both arms, except for infusion reactions with elotuzumab (10% [grade 1-2]). Taken together, ELOQUENT-2 is the first study to show the benefit of adding a monoclonal antibody to conventional treatment in MM.

Daratumumab is a human IgG1κ monoclonal antibody that targets CD38, a transmembrane glycoprotein found at low levels on lymphoid and myeloid cells, and is involved with calcium flux and signal transduction. Conversely, in MM, CD38 is highly expressed,¹⁰  and the idea of targeting CD38 was proposed more than 20 years ago.¹¹  Daratumumab was identified in preclinical studies as having uniquely potent activity against MM through complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity.¹²  Recently it was evaluated in a phase I/II study where it demonstrated striking effectiveness as a single agent in heavily pretreated patients.1 In a cohort of 42 patients receiving 16 mg/kg, 64 percent of patients were refractory to both bortezomib and lenalidomide, 17 percent were refractory to carfilzomib, and 36 percent were refractory to pomalidomide. 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. The most common adverse events were infusion-related reactions (grade 1-2, in 71% of the cohort). These observations were corroborated at the annual meeting of the American Society of Clinical Oncology in 2015 by the SIRIUS study, in a similar refractory MM population.¹³  The SIRIUS study was a phase II trial of daratumumab as a single agent in patients who had three or more prior lines of therapy, including a proteasome inhibitor and an immunomodulatory agent, and it showed an overall response of 29 percent. These findings establish daratumumab as the first monoclonal antibody to have single-agent activity, particularly in a challenging patient population with refractory disease.