The 39th David A. Karnofsky Lecture: Bench-to-Bedside Translation of Targeted Therapies in Multiple Myeloma

Abstract

Multiple myeloma (MM) is a remarkable example of rapid bench-to-bedside translation in new drug development. The proteasome inhibitor bortezomib and immunomodulatory drug lenalidomide targeted MM cells in the bone marrow (BM) microenvironment to overcome conventional drug resistance in laboratory and animal models and were rapidly translated into clinical trials demonstrating their efficacy in patients with relapsed and then newly diagnosed MM, with a doubling of the median survival as a direct result. The future is even brighter. First, immune-based therapies are being developed (eg, elotuzumab monoclonal antibody [MoAb]; CD138DM immunotoxin; MM cell–dendritic cell vaccines; CD138, CS-1, and XBP-1 peptide vaccines; anti-17 MoAb; and other treatments to overcome causes of immune dysfunction). Second, promising next-generation agents target the MM cell in its microenvironment (eg, deubiquitinating enzyme inhibitors; chymotryptic [carfilzomib, Onyx 0912, MLN 9708] and broader [NPI-0052] proteasome inhibitors; immunoproteasome inhibitors; and pomalidamide). Moreover, agents targeting bone biology (eg, zoledronic acid, anti–DKK-1 MoAb, anti–B-cell activating factor MoAb and bortezomib, Btk inhibitor) show promise not only in preserving bone integrity but also against MM. Third, rationally based combination therapies, including bortezomib with Akt, mammalian target of rapamycin, or histone deacetylase inhibitors, are active even in bortezomib-refractory MM. Finally, genomics is currently being used in the definition of MM heterogeneity, new target discovery, and development of personalized therapy. Myeloma therefore represents a paradigm for targeting the tumor in its microenvironment, which has already markedly improved patient outcome in MM and has great potential in other hematologic malignancies and solid tumors as well.

European Myeloma Network recommendations on the evaluation and treatment of newly diagnosed patients with multiple myeloma

“…[97][98][99] The majority of MM patients diagnosed today can expect to have disease control over long periods of time, with access to all available therapies. In the attempt to define the best therapeutic strategies, future trials should not only investigate prognostic parameters at diagnosis, but also evaluate disease response within the BM and extramedullary (EM) sites and assess the dynamics of clonal expansion of the disease.…”

The blueberry component pterostilbene has potent anti-myeloma activity in bortezomib-resistant cells

“…It accounts for 1% of all cancers diagnosed and >10% of hematological malignancies (1). Advances in therapeutic strategies have resulted in improvements in the median survival of MM patients over the past decade from 3-4 years to 7-8 years (2). However, MM remains incurable due to its inevitable recurrence and progression, in which drug resistance remains a major problem (3,4).…”

DNA repair of myeloma plasma cells correlates with clinical outcome: the effect of the nonhomologous end-joining inhibitor SCR7

“…3,4 Although advances in the understanding of the biology of the disease have translated into novel therapeutic strategies in the past decade, 5,6 the disease remains incurable because of the development of resistance and relapse in almost all patients. 7,8 Melphalan is a nitrogen mustard clinically used in the treatment of several cancers. 9 This alkylating agent induces N-alkylpurinemonoadducts, with a small fraction of them forming interstrand crosslinks (ICLs).…”