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Heterobifunctional proteolysis-targeting chimeric compounds leverage the activity of E3 ligases to induce degradation of target oncoproteins and exhibit potent preclinical antitumor activity. To dissect the mechanisms regulating tumor cell sensitivity to different classes of pharmacological "degraders" of oncoproteins, we performed genome-scale CRISPR-Cas9-based gene editing studies. We observed that myeloma cell resistance to degraders of different targets (BET bromodomain proteins, CDK9) and operating through CRBN (degronimids) or VHL is primarily mediated by prevention of, rather than adaptation to, breakdown of the target oncoprotein; and this involves loss of function of the cognate E3 ligase or interactors/regulators of the respective cullin-RING ligase (CRL) complex. The substantial gene-level differences for resistance mechanisms to CRBN- versus VHL-based degraders explains mechanistically the lack of cross-resistance with sequential administration of these two degrader classes. Development of degraders leveraging more diverse E3 ligases/CRLs may facilitate sequential/alternating versus combined uses of these agents toward potentially delaying or preventing resistance., Competing Interests: Declaration of Interests F.V. receives research funding from Novo Ventures. P.G.R. reports research support from Oncopeptides, Celgene/BMS, and Takeda and is an advisory committee member for Karyopharm, Oncopeptides, Celgene/BMS, Takeda, Janssen, Sanofi, Secura Bio, and GSK. E.S.F. is a founder, science advisory board member, and equity holder in Civetta, Jengu (board member), and Neomorph; an equity holder in C4; and a consultant to Astellas, Novartis, Deerfield, and EcoR1. The Fischer lab receives or has received research funding from Novartis, Astellas, Ajax, and Deerfield. N.P.K. is a consultant to Epiphanes, Inc. W.C.H. is a consultant for Thermo Fisher, Solvasta, MPM Capital, Tyra Biosciences, Jubilant Therapeutics, Frontier Medicines, RAPPTA Therapeutics, and Parexel and is a founder of and advisor to KSQ Therapeutics. L.H.B. receives research funding from AstraZeneca and is a consultant for AstraZeneca and Genentech. B.L.E. has received research funding from Celgene and Deerfield. He has received consulting fees from GRAIL, and he serves on the scientific advisory boards for and holds equity in Skyhawk Therapeutics and Exo Therapeutics. J.E.B. is an author on United States patent applications licensed from the Dana-Farber Cancer Institute to C4 Therapeutics (TPD) and Tensha Therapeutics (now Roche; BRD4 inhibition). He is now an executive of and shareholder in Novartis AG. N.S.G. is a scientific founder, member of the scientific advisory board and equity holder in C4 Therapeutics, Syros Pharmaceuticals, Petra Pharmaceuticals, Ravenna, Inception, Allorion, Jengu, and Soltego (board member) and is the inventor on intellectual property licensed to these entities. R.S., G.M.M., S.G., R.d.M.S., and C.S.M. are authors on a patent application on the use of degraders. C.S.M. also discloses consultant/honoraria from Fate Therapeutics, Ionis Pharmaceuticals and FIMECS; employment of a relative with Takeda; and research funding from Janssen/Johnson & Johnson, TEVA, EMD Serono, Abbvie, Arch Oncology, Karyopharm, Sanofi, and Nurix., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

The field of multiple myeloma therapeutics has been an active one for many years, but perhaps no more so than in the past decade. The introduction of thalidomide, lenalidomide and bortezomib in the treatment of this disease highlights clinical advances made during this period. While these agents were initially utilized in the setting of relapsed and refactory disease, they are now part of the therapeutic armamentarium for transplant-eligible and transplant-ineligible patients with newly diagnosed multiple myeloma. The principles of management applied in the care of newly diagnosed multiple myeloma are reviewed in this article, along with the clinical studies supporting the use of thalidomide, lenalidomide and bortezomib in newly diagnosed multiple myeloma. Management of treatment-related side effects is also discussed, since it constitutes a critical element in the successful management of patients with this disease. Combination regimens utilizing thalidomide, lenalidomide and bortezomib are also highlighted, as these regimens are likely to play an increasingly important role in myeloma therapy in the future.

Peripheral neuropathy (PN) and asthenia (fatigue) occur as both disease- and treatment-related complications in patients with multiple myeloma (MM). Risk factors for treatment-related PN, which has an estimated incidence of 37% to 83% among patients with MM, include therapy duration, dose intensity, cumulative dose, and the presence of preexisting neuropathy. Asthenia is the most common adverse effect of treatment, occurring in approximately 76% to 96% of patients receiving therapy. The severity of PN and asthenia can range from mild to potentially debilitating. These conditions can be dose limiting; they may interfere with optimizing duration of therapy and may also substantially affect patient quality of life. Regular screening and monitoring, combined with patient education and effective management strategies, can reduce the risk of these treatment-related complications, as well as their consequences.

Multiple myeloma (MM) is a clonal B-cell malignancy characterized by aberrant expansion of plasma cells within bone marrow and extramedullary sites. In 2009, 20,580 new cases of MM and 10,580 deaths from the disease occurred in the United States. Treatment traditionally consists of systemic chemotherapy, with adjunctive use of radiation or surgery in selected cases associated with extramedullary disease. The therapeutic landscape in MM has changed markedly in the past decade with the introduction of the novel immunomodulatory agents thalidomide and lenalidomide, and the first-in-class proteasome inhibitor bortezomib. Although MM remains an incurable malignancy, new approaches to therapy incorporating these agents have produced significantly higher response rates and improved intervals of both progression-free and overall survival in the context of randomized, controlled trials. In aggregate, the use of novel therapies in MM has been associated with substantial improvements in patient outcome.

Multiple myeloma (MM) remains incurable with current therapies, and novel biologically based therapies are urgently needed. Thalidomide and its analogues, as well as proteasome inhibitors, are examples of such novel agents that target both the myeloma cell and its microenvironment and can overcome classical drug resistance. In this study we demonstrate that arsenic trioxide (As2O3) mediates anti-MM activity both directly on tumor cells and indirectly by inhibiting production of myeloma growth and survival factors in the bone marrow (BM) microenvironment. Specifically, As2O3 at clinically achievable levels (2-5 microM) induces apoptosis even of drug-resistant MM cell lines and patient cells via caspase-9 activation, enhances the MM cell apoptosis induced by dexamethasone, and can overcome the antiapoptotic effects of interleukin 6. As2O3 also acts in the BM microenvironment to decrease MM cell binding to BM stromal cells, inhibits interleukin 6 and vascular endothelial growth factor secretion induced by MM cell adhesion, and blocks proliferation of MM cells adherent to BM stromal cells. These studies provide the rationale for clinical trials of As2O3, either alone or together with dexamethasone, to overcome classical drug resistance and improve outcome in patients with MM.

Summary: The phase 3 PANORAMA‐1 trial led to regulatory approvals of panobinostat (PAN) in combination with bortezomib (BTZ) and dexamethasone (DEX) for the treatment of multiple myeloma after ≥2 prior regimens, including BTZ and an immunomodulatory drug. Patient‐reported outcomes (PROs) were assessed in PANORAMA‐1, with data available for 73 patients in the PAN + BTZ + DEX arm and 74 patients in the placebo (PBO) + BTZ + DEX arm. Per the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire‐Core 30 (EORTC QLQ‐C30), global health status/quality of life (QoL) scores initially declined with PAN + BTZ + DEX during the first 24 weeks before approaching baseline scores and remaining steady during the next 24 weeks, with no difference between arms at Week 48. The EORTC QLQ‐Myeloma module (EORTC QLQ‐MY20) demonstrated initial improvements and subsequent stabilization of disease symptom scores in both arms and initial worsening and subsequent improvement of side effects of treatment scores, with the initial worsening more pronounced and recovery less pronounced with PAN + BTZ + DEX. Functional Assessment of Cancer Therapy/Gynecologic Oncology Group‐Neurotoxicity scores remained relatively stable and similar between the arms. Overall, these PRO findings support the addition of PAN to the BTZ+DEX regimen as an efficacious treatment option, with limited symptomatology and impact on patients’ QoL. The reported results are based on a descriptive analysis of the data. No formal statistical tests have been performed. [ABSTRACT FROM AUTHOR]