The Multiple Myeloma Drug Pipeline—2018: A Review of Small Molecules and Their Therapeutic Targets

Abramson, H. N.

doi:10.1016/j.clml.2018.06.015

Cited by 51 publications

(40 citation statements)

References 116 publications

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“…Previously dependent on alkylating agents, corticosteroids, and autologous stem cell transplantation, the treatment of MM has changed significantly in the last two decades. The introduction of immunomodulatory drugs, proteasome inhibitors, and histone deacetylase blockers, as well as the approval of antibody‐based immunotherapies by the Food and Drug Administration have all resulted in higher complete response rates and dramatically extended the 5‐year survival rate of patients with MM (Abramson, ; Moreau, Attal, & Facon, ). While the advances in therapeutic options have transformed the disease from being rapidly fatal to one resembling a chronic disease, MM remains largely incurable as most patients eventually develop resistance to their treatment and relapse (Barlogie et al, ).…”

Section: Introductionmentioning

confidence: 99%

Methodological considerations for the high sensitivity detection of multiple myeloma measurable residual disease

Soh

Tario

Hahn

et al. 2019

Cytometry Part B Clinical

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Background Recent advances in therapeutic interventions have dramatically improved complete response rates in patients with multiple myeloma (MM). The ability to identify residual myeloma cells (e.g., measurable residual disease [MRD]) can provide valuable information pertaining to patient's depth of response to therapy and risk of relapse. Multiparametric flow cytometry is an excellent technique to monitor MRD and has been demonstrated to correlate with patient outcome post‐treatment. To achieve the high sensitivity (one abnormal cell in 105–106 cells) required for MRD evaluation, millions of cells have to be acquired and conventional immunophenotyping protocols are unable to attain these numbers, indicating the needs for alternative flow cytometric staining procedures. A bulk, “Pre‐lysis” method is the consensus approach for staining large number of cells, requires two red blood cell lysis steps, and can adversely affect epitope density. In this study, we tested the “Pooled‐tube” and “Dextran Sedimentation” staining procedures and correlated them with the “Pre‐lysis” method as potential alternative approaches. Methods A total of 22 bone marrow aspirates from patients with plasma cell (PC) dyscrasia were processed in parallel using the “Pre‐lysis,” “Pooled‐tube,” and “Dextran Sedimentation” techniques. Stain indices were calculated and compared to assess their impacts on staining performance for each antibody used in the consensus panel. The recovery of normal and abnormal PCs, mast cells, and B cell precursors was enumerated and compared after their counts were normalized using fluorescent beads. The limit of blank, limit of detection, and lower limit of quantification were established using serial dilution experiments. Results The staining performances of CD19 PECy7, CD27 BV510, CD81 APCH7, and CD138 BV421 were improved using the “Pooled‐tube” method when compared to “Pre‐lysis.” “Pre‐lysis” was better at resolving CD56 using clone C5.9 but our results demonstrated similar improvement can also be achieved by “Pooled‐tube” when alternative CD56 PE clones were used. “Dextran sedimentation” yielded similar staining results when compared to “Pre‐lysis” for all the markers analyzed. The “Pooled‐tube” method, when normalized to “Pre‐lysis,” recovered higher numbers of total PCs (1.2 ± 0.2 times higher; p = .049), normal PCs (1.4 ± 0.26; p = .007), mast cells (1.46 ± 0.27; p = .003), and B cell precursors (1.42 ± 0.3; p = .011), but not abnormal PCs (1.09 ± 0.2; p = .352). There was no evidence that the recovery of cells was different between “Pre‐lysis” versus “Dextran Sedimentation.” All three flow cytometric assays achieved a minimum sensitivity of 10−5 and approached that of 10−6 for detecting rare events. Conclusion Both “Pooled‐tube” and “Dextran Sedimentation” staining procedures were comparable to the “Pre‐lysis” method and are suitable high sensitivity flow cytometric approaches that can be used to process bone marrow samples for MM MRD testing.

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Section: Introductionmentioning

confidence: 99%

Methodological considerations for the high sensitivity detection of multiple myeloma measurable residual disease

Soh

Tario

Hahn

et al. 2019

Cytometry Part B Clinical

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“…Selinexor is a first-in-class selective inhibitor of nuclear export that provides an additional therapeutic option for those with triplerefractory disease. 36 Selinexor has been studied in patients with quad-and penta-refractory disease because of their exposure to, and having become refractory to the 5 key agents used in this patient population (ie, bortezomib, lenalidomide, carfilzomib, pomalidomide, daratumumab). Selinexor is currently being evaluated as a component of combination regimens in a number of phase II and III clinical trials in patients with RRMM.…”

Section: Selinexormentioning

confidence: 99%

“…Selinexor is currently being evaluated as a component of combination regimens in a number of phase II and III clinical trials in patients with RRMM. 36 In the STORM (Selinexor Treatment of Refractory Myeloma) study (ClinicalTrials.gov identifier, NCT02336815), selinexor is being used in combination with low-dose dexamethasone. The first part of the phase II trial evaluated selinexor and dexamethasone in patients with MM refractory to bortezomib, carfilzomib, lenalidomide, and pomalidomide and a small subset of patients with penta-refractory disease, who were also refractory to an anti-CD38 antibody.…”

Section: Selinexormentioning

confidence: 99%

Treatment Options for Triple-class Refractory Multiple Myeloma

Mıkhael

2020

Clinical Lymphoma Myeloma and Leukemia

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The advent of new, more effective, and less toxic therapies has revolutionized the management of multiple myeloma in the past decade. Despite the availability of new treatments, most patients with multiple myeloma will become refractory to the therapies that currently comprise the hematologic standard of care for the malignancy, including proteasome inhibitors, immunomodulatory agents, and monoclonal antibodies. Moreover, in recent years, a new subset of patients with multiple myeloma refractory to all 3 of these agents has emerged. This population, for whom a clear treatment paradigm has remained undefined, has been characterized by poor survival outcomes. The current approaches to the treatment of triple-class refractory disease are limited and include conventional chemotherapy, salvage autologous stem cell transplantation, and recycling previous regimens, each of which have generally had short-lived efficacy. It is anticipated that additional agents will be available for triple-refractory disease in the near future, including selinexor, chimeric antigen receptor T-cell therapy, and next-generation monoclonal antibodies. The development and further refinement of novel treatments for this subset of patients should be considered a key clinical and research priority.

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“…The 5-year survival rate of MM is approximately 50% 7 , which is nearly double what it was in the late 1980s. 8 The reason for the improved outcomes is a series of therapeutic advances that include the introduction of autologous stem cell transplants (ASCT), immunomodulatory drugs (IMiDs), and proteasome inhibitors (PIs), all of which are now first-line therapies. 7–9 Despite the success of these treatments in extending the overall survival (OS) by 6-10 years, depending upon age at diagnosis, most patients eventually relapse and become refractory to the therapies that they had received.…”

Section: Introductionmentioning

confidence: 99%

“…3,13–15 Nonetheless, many new therapeutics with diverse mechanisms of action are under development and showing promise in clinical trials against relapse refractory multiple myeloma (RRMM). 8 These include next-generation IMiDs and PIs, as well as histone deacetylase (HDAC) inhibitors, monoclonal antibodies (mAbs), and immunotherapies. Currently, the optimal combination and sequence of these therapies is unknown, both at baseline and relapse.…”

Section: Introductionmentioning

confidence: 99%

Genetic program activity delineates risk, relapse, and therapy responsiveness in Multiple Myeloma

Wall

Turkarslan

et al. 2020

Preprint

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38Despite recent advancements in the treatment of multiple myeloma (MM), nearly all patients 39 ultimately relapse and many become refractory to their previous therapies. Although many 40 therapies exist with diverse mechanisms of action, it is not yet clear how the differences in MM 41 biology across patients impacts the likelihood of success for existing therapies and those in the 42 pipeline. Therefore, we not only need the ability to predict which patients are at high risk for 43 disease progression, but also a means to understand the mechanisms underlying their risk. We 44 hypothesized that knowledge of the biological networks that give rise to MM, specifically the 45 transcriptional regulatory network (TRN) and the mechanisms by which mutations impact gene 46 regulation, would enable improved predictions of disease progression and actionable insights for 47 treatment. Here we present a method to infer TRNs from multi-omics data and apply it to the 48 generation of a MM TRN that links chromosomal abnormalities and somatic mutations to 49 downstream effects on gene expression via perturbation of transcriptional regulators. We find that 50 141 genetic programs underlie the disease and that the activity profile of these programs fall into 51 one of 25 distinct transcriptional states. These transcriptional signatures prove to be more 52 predictive of outcomes than do mutations and reveal plausible mechanisms for relapse, including 53 the establishment of an immuno-suppressive microenvironment. Moreover, we observe subtype-54 specific vulnerabilities to interventions with existing drugs and motivate the development of new 55 targeted therapies that appear especially promising for relapsed refractory MM. 56 57 Introduction 58 59 Multiple Myeloma (MM) is a cancer of malignant plasma cells in the bone marrow (BM) that has 60 a prevalence of approximately 86,000 new cases per year. 1 Several clinical subtypes of MM have 61 been established on the basis of characteristic cytogenetic features, including various 62 translocations, gain or loss of chromosomal arms, deletion of specific chromosomes, and 63 hyperdiploidy. 2-4 Accordingly, MM is a complex disease of great heterogeneity that exhibits64 subtype-specific drivers of progression. 5,6 Efforts to better characterize the biology and 65 therapeutic vulnerabilities of MM have increased exponentially in recent years, as can be seen 66 from the number of research articles, clinical trials, and public availability of matched genomic, 67 transcriptomic, and patient data. However, the myriad combinations of chromosomal aberrations 68 and somatic mutations, coupled with the complex dependence of MM progression on the BM 69 microenvironment, have precluded a mechanistic understanding of the disease on a patient-70 specific level. 72The 5-year survival rate of MM is approximately 50% 7 , which is nearly double what it was in the 73 late 1980s. 8 The reason for the improved outcomes is a series of therapeutic advances that 74 include the introduction of autologous stem cell t...

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The Multiple Myeloma Drug Pipeline—2018: A Review of Small Molecules and Their Therapeutic Targets

Cited by 51 publications

References 116 publications

Methodological considerations for the high sensitivity detection of multiple myeloma measurable residual disease

Methodological considerations for the high sensitivity detection of multiple myeloma measurable residual disease

Treatment Options for Triple-class Refractory Multiple Myeloma

Genetic program activity delineates risk, relapse, and therapy responsiveness in Multiple Myeloma

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