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

2012 ◽  
Vol 30 (4) ◽  
pp. 445-452 ◽  
Author(s):  
Kenneth C. Anderson
Keyword(s):  
Multiple Myeloma ◽  
Histone Deacetylase Inhibitors ◽  
Enzyme Inhibitors ◽  
Mammalian Target Of Rapamycin ◽  
Proteasome Inhibitors ◽  
Hematologic Malignancies ◽  
Direct Result ◽  
Bone Biology ◽  
Dendritic Cell Vaccines ◽  
Definition Of

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.

scholarly journals Evolution of Therapy for Relapsed/Refractory Multiple Myeloma

2019 ◽  
Vol 17 (11.5) ◽  
pp. 1433-1436 ◽  
Author(s):  
Jorge J. Castillo
Keyword(s):  
Multiple Myeloma ◽  
Nuclear Export ◽  
Histone Deacetylase Inhibitors ◽  
Proteasome Inhibitors ◽  
Hematologic Malignancies ◽  
Current Treatment ◽  
Related Factors ◽  
Refractory Multiple Myeloma ◽  
Annual Congress ◽  
Individual Disease

With so many recent advances in relapsed/refractory multiple myeloma, keeping abreast with current treatment recommendations can be challenging. Novel immunomodulators, proteasome inhibitors, monoclonal antibodies, histone deacetylase inhibitors, and nuclear export inhibitors have all been added to the armamentarium, and the choice of which of these drugs or drug combinations to use depends on individual disease-related and patient-related factors, previous therapies, and treatment toxicities. At the NCCN 2019 Annual Congress: Hematologic Malignancies, Dr. Jorge J. Castillo provided an overview of the myriad treatments available for patients with relapsed/refractory multiple myeloma, as well as therapies on the horizon.

Discovery and Characterization of Macrocyclic Thiopeptide Proteasome Inhibitors for Hematologic Malignancies

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3669-3669
Author(s):  
Sridevi Ponduru ◽  
Raymond Moellering ◽  
Edward Greenberg ◽  
John Paul Ying-Ching Shen ◽  
Benjamin Z Stanton ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Protein Degradation ◽  
High Throughput ◽  
Active Sites ◽  
Proteasome Inhibitors ◽  
Hematologic Malignancies ◽  
Bone Marrow Stroma ◽  
Shh Signaling ◽  
Marrow Stroma

Abstract The ubiquitin proteasome pathway comprises a coordinated, dynamic cellular system critical to cellular metabolism, signaling and proliferation. The expanding clinical utility of the peptide boronate, bortezomib, in the treatment of patients with multiple myeloma and other hematologic malignancies has established the human 26S proteasome as a validated target in cancer. Still, only one FDA-approved proteasome inhibitor presently exists. Restricted activity against one enzymatic function of the proteasome and dose-limiting toxicities associated with bortezomib warrant further discovery efforts aimed at the identification of structurally and functionally distinct protein degradation inhibitors (PDIs). Here, we report a novel family of natural product proteasome inhibitors discovered by high-throughput, high-content screening at the National Cancer Institute Initiative for Chemical Genetics. A primary screen of 14,000 small molecules was performed in 384-well plate format using a cell line stably transfected with a destabilized fluorescent protein chimera. Assay positives were retested in the primary screen in dose-response format. Thiostrepton was selected for further characterization due to its unique macrocyclic chemical structure, the recent publication of its total synthesis, reports of anticancer properties and the lack of prior annotation as a PDI. First, thiostrepton was linked to previously characterized molecules acting on the protein degradation pathways by transcriptional small molecule connectivity mapping (CMAP). Subsequent cell-state analyses confirmed strong induction of functional and annotated gene sets associated with misfolded protein stress and proteasome inhibition. Mechanism of action was confirmed by biochemical profiling of human 20S proteasome active site inhibition and specificity using homogeneous assays and selective substrates for each of three catalytic active sites. Importantly, inhibitory activity of thiostrepton differs from bortezomib by blocking both the chymotryptic-like and PGPH active sites with sub-micromolar potencies. Dose-dependent inhibition of multiple myeloma cell growth was observed, with a concomitant increase in polyubiquitinated protein stress and induction of apoptosis. Inhibition of conferred proliferation by bone marrow stroma was confirmed using a novel miniaturized high-content assay modeling the bone marrow stroma-multiple myeloma microenvironment. Structurally related compounds to thiostrepton, nosiheptide and siomycin, were confirmed also as proteasome inhibitors as above. Our discovery of this class of natural products as proteasome inhibitors and a recent report of siomycin inhibition of Sonic Hedgehog (Shh) signaling begged the question whether established proteasome inhibitors would inhibit Shh signaling in human cancer. This hypothesis was confirmed in a set of reporter-gene assays. In sum, these studies identify thiopeptide macrocycles as a class of naturally-occurring proteasome inhibitors poised for clinical development in hematologic malignancies, establish novel high-throughput assays for modeling MM-stroma microenvironment interactions and pave the way for the development of proteasome inhibitors in disease states where Shh signaling is central to pathogenesis.

scholarly journals Multiple myeloma: a model for scientific and clinical progress

Hematology ◽  
2014 ◽  
Vol 2014 (1) ◽  
pp. 1-7 ◽  
Author(s):  
Jesus San Miguel
Keyword(s):  
Multiple Myeloma ◽  
Histone Deacetylase Inhibitors ◽  
Plasma Cells ◽  
Residual Disease ◽  
Critical Role ◽  
Proteasome Inhibitors ◽  
New Drugs ◽  
High Dose ◽  
New Treatment ◽  
Almost All

Abstract Multiple myeloma (MM) is a unique cancer paradigm for investigating the mechanisms involved in the transition from a premalignant condition (monoclonal gammopathy of undetermined significance) into a malignant disease (MM). In the pathogenesis of myeloma, the dialogue between plasma cells and their microenvironment is as important as the genotypic characteristics of the tumor clone. MM is genetically highly complex, with almost all patients displaying cytogenetic abnormalities and frequent intraclonal heterogeneity that play a critical role in the outcome of the disease. In fact, it is likely that myeloma will soon no longer be considered as a single entity. This, along with the availability of an unexpected number of new treatment possibilities, has reinforced the need for better tools for prognosis and for monitoring treatment efficacy through minimal residual disease techniques. The outcome of MM patients has significantly improved in the last 2 decades, first through the introduction of high-dose therapy followed by autologous stem cell transplantation and, more recently, due to the use of proteasome inhibitors (bortezomib and carfilzomib) and immunomodulatory agents (thalidomide, lenalidomide, and pomalidomide). Moreover, the need to reexamine the diagnostic criteria of early MM and the possibility of early intervention opens up new therapeutic avenues. New drugs are also emerging, including second- and third-generation proteasome inhibitors and immunomodulators, monoclonal antibodies, histone deacetylase inhibitors, and kinesin spindle protein inhibitors, among others. Our goal is to find a balance among efficacy, toxicity, and cost, with the ultimate aim of achieving a cure for this disease.

scholarly journals Modulating proteasome inhibitor tolerance in multiple myeloma: an alternative strategy to reverse inevitable resistance

2020 ◽  
Author(s):  
Maolin Ge ◽  
Zhi Qiao ◽  
Yan Kong ◽  
Hongyu Liang ◽  
Yan Sun ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Histone Deacetylase Inhibitors ◽  
Resistance Mechanism ◽  
Proteasome Inhibitors ◽  
Intermittent Therapy ◽  
Bioinformatics Analyses ◽  
Inhibitor Tolerance ◽  
Epigenetic Regulators

Abstract Background Resistance to proteasome inhibitors (PIs) is a major obstacle to the successful treatment of multiple myeloma (MM). Many mechanisms have been proposed for PI resistance; however, our mechanistic understanding of how PI resistance is inevitably acquired and reversed remains incomplete. Methods MM patients after bortezomib relapse, MM cell lines and mouse models were used to generate matched resistant and reversed cells. RNA sequencing and bioinformatics analyses were employed to assess dysregulated epigenetic regulators. In vitro and in vivo procedures were used to characterise PI-tolerant cells and therapeutic efficacy. Results Upon PI treatment, MM cells enter a slow-cycling and reversible drug-tolerant state. This reversible phenotype is associated with epigenetic plasticity, which involves tolerance rather than persistence in patients with relapsed MM. Combination treatment with histone deacetylase inhibitors and high-dosage intermittent therapy, as opposed to sustained PI monotherapy, can be more effective in treating MM by preventing the emergence of PI-tolerant cells. The therapeutic basis is the reversal of dysregulated epigenetic regulators in MM patients. Conclusions We propose an alternative non-mutational PI resistance mechanism that explains why PI relapse is inevitable and why patients regain sensitivity after a ‘drug holiday’. Our study also suggests strategies for epigenetic elimination of drug-tolerant cells.

scholarly journals How I treat myeloma with new agents

Blood ◽  
2017 ◽  
Vol 130 (13) ◽  
pp. 1507-1513 ◽  
Author(s):  
Philippe Moreau
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Histone Deacetylase Inhibitors ◽  
Treatment Options ◽  
Proteasome Inhibitors ◽  
Mechanisms Of Action ◽  
Third Generation ◽  
New Agents ◽  
Immunomodulatory Agents ◽  
The Third

Abstract At present, multiple classes of agents with distinct mechanisms of action are available for the treatment of patients with multiple myeloma (MM), including alkylators, steroids, immunomodulatory agents (IMiDs), proteasome inhibitors (PIs), histone deacetylase inhibitors (DACIs), and monoclonal antibodies (mAbs). Over the last 5 years, several new agents, such as the third-generation IMiD pomalidomide, the second-generation PIs carfilzomib and ixazomib, the DACI panobinostat, and 2 mAbs, elotuzumab and daratumumab, have been approved, incorporated into clinical guidelines, and have transformed our approach to the treatment of patients. These agents may be part of doublet or triplet combinations, or incorporated into intensive strategies with autologous stem cell transplantation. In this review, I discuss the different treatment options available today for the treatment of MM in frontline and relapse settings.

scholarly journals Multiple Myeloma: Available Therapies and Causes of Drug Resistance

Cancers ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 407 ◽  
Author(s):  
Vanessa Pinto ◽  
Rui Bergantim ◽  
Hugo R. Caires ◽  
Hugo Seca ◽  
José E. Guimarães ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Drug Resistance ◽  
Intracellular Signaling ◽  
Drug Transport ◽  
Histone Deacetylase Inhibitors ◽  
Alkylating Agents ◽  
Proteasome Inhibitors ◽  
Epigenetic Alterations ◽  
Cancer Treatments ◽  
Treatment Regimens

Multiple myeloma (MM) is the second most common blood cancer. Treatments for MM include corticosteroids, alkylating agents, anthracyclines, proteasome inhibitors, immunomodulatory drugs, histone deacetylase inhibitors and monoclonal antibodies. Survival outcomes have improved substantially due to the introduction of many of these drugs allied with their rational use. Nonetheless, MM patients successively relapse after one or more treatment regimens or become refractory, mostly due to drug resistance. This review focuses on the main drugs used in MM treatment and on causes of drug resistance, including cytogenetic, genetic and epigenetic alterations, abnormal drug transport and metabolism, dysregulation of apoptosis, autophagy activation and other intracellular signaling pathways, the presence of cancer stem cells, and the tumor microenvironment. Furthermore, we highlight the areas that need to be further clarified in an attempt to identify novel therapeutic targets to counteract drug resistance in MM patients.

scholarly journals How I treat relapsed and/or refractory multiple myeloma

2020 ◽  
Vol 12 (s1) ◽  
Author(s):  
Hans C. Lee ◽  
Claudio Cerchione
Keyword(s):  
Multiple Myeloma ◽  
Nuclear Export ◽  
Histone Deacetylase Inhibitors ◽  
Alkylating Agents ◽  
Treatment Options ◽  
Unmet Need ◽  
Proteasome Inhibitors ◽  
Antibody Drug Conjugate ◽  
Refractory Multiple Myeloma ◽  
Therapeutic Landscape

The expanding therapeutic landscape of relapsed and/or refractory multiple myeloma (RRMM) has contributed to significant improvements in patient outcomes. These have included combinations of proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), monoclonal antibodies (mAbs), histone deacetylase inhibitors, and/or alkylating agents. More recently, the approval of the first-in-class nuclear export inhibitor selinexor and the first-in-class B-cell maturation antigen (BCMA) antibody-drug conjugate (ADC) belantamab mafodotin has helped address the current unmet need in patients refractory to PI, IMiD, and anti-CD38 mAb directed therapy, otherwise known as triple class refractory myeloma. With the growing number of treatment options in the RRMM therapeutic landscape, the choice and sequencing of drugs and combinations has become increasingly complex. In this review we discuss our approach and considerations in the treatment of both early and late RRRM based on best available data and our clinical experience.

Carfilzomib-induced tumor lysis syndrome in relapsed multiple myeloma: a report of two cases

2018 ◽  
Vol 105 (6) ◽  
pp. NP24-NP27
Author(s):  
Esra Terzi Demirsoy ◽  
Elif Birtas Atesoglu ◽  
Necmi Eren ◽  
Ayfer Gedük ◽  
Ozgur Mehtap ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Case Report ◽  
Proteasome Inhibitor ◽  
Tumor Lysis Syndrome ◽  
Proteasome Inhibitors ◽  
Hematologic Malignancies ◽  
Metabolic Abnormalities ◽  
Fatal Complication ◽  
Tumor Lysis ◽  
Proven Efficacy

Background: Tumor lysis syndrome (TLS) is a potentially fatal complication of cancer therapy characterized by severe electrolyte and metabolic abnormalities such as hyperphosphatemia, hyperkalemia, and hypocalcaemia. TLS usually occurs in aggressive hematologic malignancies such as Burkitt lymphoma and acute leukemia. TLS has rarely been observed in multiple myeloma (MM). Case report: We present 2 patients with relapsed MM who developed TLS after the first cycle of carfilzomib treatment. Conclusion: Carfilzomib is a next-generation proteasome inhibitor with proven efficacy in relapsed/refractory MM. Recently, increasing frequency of TLS has been reported in MM, especially after treatment with proteasome inhibitors. The potential complications of TLS should be considered especially during the first cycle of carfilzomib treatment.

scholarly journals CD38 antibodies in multiple myeloma: back to the future

Blood ◽  
2018 ◽  
Vol 131 (1) ◽  
pp. 13-29 ◽  
Author(s):  
Niels W. C. J. van de Donk ◽  
Paul G. Richardson ◽  
Fabio Malavasi
Keyword(s):  
Multiple Myeloma ◽  
Blood Compatibility ◽  
Lymphoblastic Leukemia ◽  
Single Agent ◽  
Proteasome Inhibitors ◽  
Suppressor Cells ◽  
Progression Free Survival ◽  
Hematologic Malignancies ◽  
Mechanisms Of Action ◽  
Immune Effector

CD38 is highly and uniformly expressed on multiple myeloma (MM) cells, and at relatively low levels on normal lymphoid and myeloid cells, and in some tissues of nonhematopoietic origin. CD38 is a transmembrane glycoprotein with ectoenzymatic activity, and also functions as a receptor and adhesion molecule. Altogether, this has triggered the development of several CD38 antibodies including daratumumab (fully human), isatuximab (chimeric), and MOR202 (fully human). CD38 antibodies have pleiotropic mechanisms of action including Fc-dependent immune-effector mechanisms, direct apoptotic activity, and immunomodulatory effects by the elimination of CD38+ immune-suppressor cells. CD38-targeting antibodies are generally well tolerated and induce partial response or better in ∼30% of heavily pretreated MM patients as monotherapy. Based on their distinct mechanisms of action, favorable toxicity profile, and single-agent activity, CD38 antibodies are attractive partners in combination regimens. Indeed, deep responses and prolonged progression-free survival can be achieved in relapsed/refractory MM patients when CD38 antibodies are combined with immunomodulatory agents or proteasome inhibitors. Infusion-related reactions, which typically occur during the first infusion, are the most frequent adverse events. Attention should also be paid to the interference of CD38 antibodies with certain laboratory assays, which may complicate response evaluation and blood compatibility testing. Several studies are currently examining the role of CD38-based therapies in newly diagnosed and high-risk smoldering MM. Furthermore, CD38 antibodies are currently also under investigation in other hematologic malignancies, including acute lymphoblastic leukemia, natural killer/T-cell lymphoma, and acute myeloid leukemia, as well as in solid tumors.

Identification of Novel Inhibitors That Specifically Target the Immunoproteasome, and Selectively Induce Apoptosis in Multiple Myeloma and Other Immunoproteasome-Expressing Model Systems.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 248-248 ◽  
Author(s):  
Robert Z. Orlowski ◽  
Deborah J. Kuhn ◽  
George W. Small ◽  
Charlene Michaud ◽  
Marian Orlowski
Keyword(s):  
Multiple Myeloma ◽  
Cell Lines ◽  
Proteasome Inhibitors ◽  
Therapeutic Index ◽  
Hematologic Malignancies ◽  
The Body ◽  
Model Systems ◽  
Chymotryptic Activity ◽  
Specific Inhibitors

Abstract Inhibition of the proteasome, a multi-catalytic proteinase complex responsible for regulated intracellular proteolysis, with bortezomib (VELCADE®) is a rational strategy against relapsed/refractory multiple myeloma, and studies are ongoing to further define the efficacy of this agent in other settings. However, bortezomib is associated with several toxicities, such as peripheral neuropathy, which can limit the ability of patients to receive maximal doses, possibly compromising anti-tumor efficacy. Novel proteasome inhibitors with an improved toxicity profile and improved anti-tumor activity are therefore needed. Most cells contain the constitutive version of the proteasome with three catalytic subunits, designated X, Y, and Z. Exposure of these cells to cytokines, such as γ-interferon, causes replacement of these subunits with three others, referred to as low molecular weight proteins (LMP)−2, −7, and −10. This LMP-containing proteasome, known as the immunoproteasome because it plays a role in generating antigens as part of the immune response, is also the major proteasome isoform in hematopoietic-derived cells even in the absence of exogenous cytokines. Using purified preparations of the XYZ and LMP proteasomes, we identified a panel of peptidyl-aldehydes that preferentially inhibit the immunoproteasome with relative sparing of the constitutive isoform. Among these, the most immunoproteasome specific inhibitors (IPSI) included compounds 001 and 006. IPSI-001 demonstrated a Ki of 1.03 μM against the chymotryptic activity of the LMP proteasome but only a 105 μM Ki against the XYZ proteasome, while IPSI-006 demonstrated Kis of 8.4 μM and 460 μM, respectively. In contrast, other commonly used peptidyl aldehydes, such as MG-132 and the aldehyde version of bortezomib, showed no ability to discriminate between these two proteasomes. Using radiolabeled 3,4-dichloroisocoumarin as a probe, IPSIs were shown to bind only to LMP-2 of the immunoproteasome, but not to any subunits of the constitutive proteasome in vitro. Studies of cell lines expressing immunoproteasome subunits showed IPSI-001 inhibited the chymotryptic activity of the LMP proteasome, with relative sparing of this activity in XYZ proteasome-expressing cell lines. IPSI-001 was also able to induce apoptosis in LMP-proteasome-expressing cells, including IM-9 lymphoblastoid cells and ANBL-6 interleukin-(IL)-6-dependent and RPMI-8226 IL-6-independent multiple myeloma cells, while relatively sparing XYZ-proteasome-expressing cell lines. Bortezomib, in contrast, induced apoptosis indiscriminately in both LMP- and XYZ-proteasome expressing cells. Taken together, these studies suggest that immunoproteasome specific inhibitors represent a novel class of drugs with activity against hematologic malignancies that may have less toxicity by virtue of their ability to spare the proteasome in most other tissues in the body, including in neural tissues. These properties could lead to an improved therapeutic index and anti-tumor efficacy, providing a rationale for development of these agents into clinically relevant drug candidates.

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