With the addition of DARA, however, substantial levels of lysis were achieved. by the US Food and Drug Administration, DARA shows promise as mono- and combination therapy for the treatment of relapsed/refractory multiple myeloma. strong class=”kwd-title” Keywords: multiple myeloma, relapsed, refractory, monoclonal antibody, daratumumab, CD38 Introduction Multiple myeloma (MM) accounts for approximately 10% of newly diagnosed hematologic malignancies in the US and is characterized by the proliferation of malignant clonal plasma cells that produce a single immunoglobulin isotype, called an M-protein.1 Clonal expansion within bone marrow and tissue leads to bone destruction, hypercalcemia, marrow dysfunction, frequent infections, as well as renal failure.2 Prior to the advent of proteasome inhibitor and immunomodulator-based therapy, when alkylating chemotherapy with corticosteroids was standard of care, survival was for three decades.3 The proteasome inhibitor bortezomib (BORT) and the immunomodulatory drugs thalidomide and lenalidomide induce impressive responses with improvement in overall survival, yet relapse remains inevitable, usually with Mouse monoclonal to Mcherry Tag. mCherry is an engineered derivative of one of a family of proteins originally isolated from Cnidarians,jelly fish,sea anemones and corals). The mCherry protein was derived ruom DsRed,ared fluorescent protein from socalled disc corals of the genus Discosoma. disease refractory to currently available therapies.4 Notably, patients who have disease relapse after treatment with lenalidomide and BORT have a particularly poor prognosis, with median overall survival of nine months.5 In July 2012, carfilzomib became the newest proteasome inhibitor to be US Food and Drug Administration (FDA) approved for relapsed/refractory multiple myeloma (RRMM).6 In February 2013, pomalidomide was approved as the next immunomodulatory drug. The two agents have been shown to be both safe and efficacious in the treatment of heavily pre-treated RRMM, including patients who have relapsed after prior BORT and/or lenalidomide therapy.7C10 Yet, even with encouraging response data and improved progression free survival (PFS), resistance develops rapidly and PFS for patients receiving either of these two agents remains short, in the order of 4C8 months.11,12 Clearly, new effective agents are needed for the management of RRMM galvanizing the search for an immunologic approach similar to the successes seen in B-cell lymphomas. Monoclonal antibodies in multiple myeloma Until recently, monoclonal antibody therapies have not yielded success in the treatment of MM. With the introduction of rituximab, a humanized monoclonal antibody against CD20, as the first FDA-approved monoclonal antibody for lymphoma treatment in 1997, the oncologic community has seen remarkable outcomes spanning several hematologic malignancies. Disappointingly, with regards to MM, two Phase II studies of rituximab have shown overall response rates of only 0%C5%.13,14 The reason for this Sulfo-NHS-SS-Biotin was thought to be due to only a minority of MM clones expressing the target CD20 antigen.15 Nonetheless, it was discovered that even in that minority of specimens that were densely CD20 positive, responses were still poor.16 Two other agents tested for myeloma include elotuzumab (ELO) and milatuzumab.17C20 ELO is a humanized monoclonal IgG1 antibody that targets CS-1, a cell surface glycoprotein with dense expression in malignant plasma cells. Targeting CS-1 has been shown to lead to natural killer (NK)-cell mediated antibody dependent cellular cytotoxicity (ADCC).17,19 Clinical trials Sulfo-NHS-SS-Biotin have combined ELO with lenalidomide (LEN) and dexamethasone (DEX) in patients with relapsed myeloma. The results of these studies have been promising with 90% of patients achieving partial response (PR) and PFS of 2 years.19,20 A Phase III study is ongoing and due to be completed in 2017.20 It is important to note, however, that there have been no clinical trials demonstrating single agent efficacy with ELO and that a Phase I single agent dose escalation study from 2012 demonstrated no objective response.21 Another agent currently under investigation for the treatment of MM (as well as non-Hodgkins lymphoma) is milatuzumab, a selective humanized antibody targeting CD74.18 CD74 is a component of the major histocompat-ibility complex class II complex that is heavily expressed in B-cell neoplasms and found only marginally in normal tissue. CD74 expression has been demonstrated in up to 95% of MM samples.22,23 Preclinical studies have shown that not only can the antibody induce apoptosis when bound to its target, but also that the rapid internalization and recycling of CD74 makes it possible to conjugate chemotherapeutics, radioisotopes and other toxins to the drug to make targeted, efficacious killing a Sulfo-NHS-SS-Biotin possibility.24C30 However, clinical trials using milatuzumab in MM have yet to demonstrate significant activity.31 Daratumumab Daratumumab (DARA) is a Sulfo-NHS-SS-Biotin humanized antibody against CD38, a cell surface glycoprotein.