The FDA has approved nearly two dozen monoclonal antibodies (mAbs) that have revolutionized the treatment of a variety of different cancers. Until recently, however, mAbs seemed to have limited capacity to improve survival in multiple myeloma, a common hematologic cancer that remains incurable despite substantial improvements in treatment options.
Now, the prospects for mAbs to change the treatment paradigm for the malignancy have grown considerably brighter as early-phase clinical trial results suggest that emerging agents with novel mechanisms of action are capable of delivering significant efficacy. Two of these agents, elotuzumab and daratumumab, have garnered the FDA’s coveted breakthrough therapy status as part of combination regimens. And, the success of immune checkpoint blockade strategies in other malignances has spurred researchers to consider agents targeting the programmed cell death 1 (PD-1) pathway in multiple myeloma therapy.
Indeed, the field is brimming with discovery efforts (Table)
. Of these novel agents, elotuzumab is the most advanced mAb in terms of clinical development and results from phase III trials are eagerly anticipated.Rationale for Pursuing mAbs
Multiple myeloma, the second most common hematologic malignancy, is characterized by aberrant clonal expansion of malignant plasma cells in the bone marrow. In the past decade, an evolving understanding of the pathophysiology underlying multiple myeloma has fueled successful development of several novel agents, including immunomodulatory drugs (IMiDs) such as lenalidomide (Revlimid) and thalidomide (Thalomid) and the proteasome inhibitors bortezomib (Velcade) and carfilzomib (Kyprolis), which have significantly improved survival.
Despite these advances, multiple myeloma remains mostly incurable; the majority of patients eventually relapse or become refractory to therapy and then face an average survival of less than a year. Researchers, however, believe that multiple myeloma is a fundamentally curable disease, if this therapeutic challenge can be met. This has driven the development of new therapies, including histone deacetylase inhibitors, next-generation proteasome inhibitors, and a number of immunotherapies.
mAbs function as anticancer agents via a number of different mechanisms that are not mutually exclusive. These include:
Boosting antitumor immune response or removing tumor-mediated suppression of the immune system
Targeting cancer cells for destruction by the immune system by engaging immune effector cells via antibody-dependent cellular cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC)
Blocking the activity of proteins that function in the hallmark abilities of cancer cells
Inducing programmed cell death
In 1997, rituximab (Rituxan), which targets the CD20 antigen, became the first mAb to receive regulatory approval for the treatment of B-cell lymphomas but is not specifically indicated for patients with multiple myeloma. Although CD20 is expressed in 15%-20% of multiple myelomas, rituximab has shown limited efficacy in the clinical setting in this malignancy. Similarly, other mAbs spanning a diverse range of targets, including epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), CD40, CD56, and CD74 have not advanced in development despite significant promise in preclinical studies.Novel mAbs Gain Spotlight
The lack of success with mAbs can be attributed, at least in part, to the complex and heterogeneous nature of multiple myeloma. Now, technological advancements and a greater understanding of the disease’s pathophysiology have permitted the identification of target antigens that are more specific and broadly expressed, spawning the development of a number of novel mAbs that are demonstrating clinically meaningful efficacy. The ongoing success of these agents was highlighted in numerous reports at the 2014 American Society of Hematology (ASH) Annual Meeting in San Francisco in December.
Two principal targets for mAb therapy are showing particular promise. CD2 subset 1 (CS1), also known as signaling lymphocytic activation molecule 7 (SLAMF7), and CD38 are both glycoproteins expressed highly and nearly uniformly on the surface of multiple myeloma cells. Importantly, they are also expressed only at low levels on other lymphoid and myeloid cells; CS1 in particular is undetectable on the majority of normal tissues or hematopoietic stem cells, making it an ideal therapeutic target.
Emerging Targets in Multiple Myeloma
This illustration depicts some of the many interactions in the microenvironment that help promote the growth of multiple myeloma cells. Notable targets for anticancer therapy include CS1, IL-6, BAFF, CXCR4, and VEGF.
BAFF indicates B-cell activating factor; BMEC, bone marrow endothelial cell; BMSC, bone marrow stromal cell; CS1, CD2 subset 1; CXC, chemokine receptor; ERK, extracellular signal-regulated kinase; FGF, fibroblast growth factor; HGF, hepatocyte growth factor; IGF, insulin-like growth factor; IDO, indoleamine 2,3-dioxygenase 1; IL-6, interleukin-6; MET, mesenchymal epithelial transition factor; NF-Ä¸B, nuclear factor kappa-light-chain-enhancer of activated B cells; tol-DC, tolerogenic dendritic cell; VEGF, vascular endothelial growth factor.
Adapted from Rutella S, Locatelli F. Targeting multiple-myeloma-induced immune dysfunction to improve immunotherapy outcomes. Clin and Developmental Immunol. 2012; article ID 196063. http://dx.doi.org/10.1155/2012/196063.