New drugs and novel mechanisms of action in multiple myeloma in 2013: a report from the International Myeloma Working Group (IMWG)

Abstract

Treatment in medical oncology is gradually shifting from the use of non-specific chemotherapeutic agents towards an era of novel targeted therapy in which drugs and their combinations target specific aspects of the biology of tumor cells. Multiple myeloma (MM) has become one of the best examples in this regard, reflected in the identification of new pathogenic mechanisms, together with the development of novel drugs that are being explored from the preclinical setting to the early phases of clinical development. We review the biological rationale for the use of the most important new agents for treating MM and summarize their clinical activity in an increasingly busy field. First, we discuss data from already approved and active agents (including second- and third-generation- proteasome inhibitors, immunomodulatory agents (IMIDs) and alkylators). Then we focus on agents with novel mechanisms of action, such as monoclonal antibodies (MoAb), cell cycle specific drugs, deacetylase inhibitors, agents acting on the unfolded protein response, signaling transduction pathway inhibitors, and kinase inhibitors. Among this plethora of new agents or mechanisms some are specially promising: Anti-CD38 MoAb, such as daratumumab, are the first antibodies with clinical activity as single agents in MM. Also the kinesin spindle protein inhibitor Arry-520 is effective in monotherapy as well as in combination with dexamethasone in heavily pretreated patients. Immunotherapy against MM is also being explored, and probably the most attractive example of this approach is the combination of the anti-CS1 MoAb elotuzumab with lenalidomide and dexamethasone, that has produced exciting results in the relapsed/refractory setting.

Antibody-mediated phagocytosis contributes to the anti-tumor activity of the therapeutic antibody daratumumab in lymphoma and multiple myeloma

“…34 For MM patient therapy, the current focus is on combination therapy of mAb with immunomodulatory drugs (IMiDs). 37,38 IMiDs currently used, e.g., lenalidomide and pomalidomide, are described to enhance NK-cell mediated ADCC. 39 Combining DARA with lenalidomide enhanced ADCC-mediated elimination of MM cells.…”

Melphalan and dexamethasone with or without bortezomib in newly diagnosed AL amyloidosis: a matched case–control study on 174 patients

“…9,10 Bortezomib is now a mainstay in the treatment of multiple myeloma. 11 Treatment approaches based on proteasome inhibition are expected to be highly efficacious in AL amyloidosis, because amyloidogenic plasma cells rely on proteasome activity to deal with the proteotoxic stress caused by the misfolded light chain. [12][13][14] Two early series showed promising activity of bortezomib in AL amyloidosis, emphasizing its rapid action.…”

Stem cell transplantation in multiple myeloma and other plasma cell disorders (report from an EBMT preceptorship meeting)

“…[21] Other novel agents have been evaluated in relapsed patients. [22] Combinations including the anti-CS1 elotuzumab and the anti-CD38 daratumumab had the most promising results. These agents have been tested mainly in combination with lenalidomide or bortezomib plus steroids.…”