arry-520 and Multiple-Myeloma

Multiple myeloma is currently incurable, and the incidence rate is increasing year by year worldwide. Although in recent years the combined treatment plan based on proteasome inhibitors and immunomodulatory drugs has greatly improved the treatment effect of multiple myeloma, most patients still relapse and become resistant to current treatments. To solve this problem, scientists are committed to developing drugs with higher specificity, such as iberdomide, which is highly specific to ikaros and aiolos. This review aims to focus on the small molecular agents that are being researched/clinically used for the treatment of multiple myeloma, including the target mechanism, structure-activity relationship and application prospects of small molecular agents.

Topics: Animals; Antineoplastic Agents; Biomarkers, Tumor; Combined Modality Therapy; Deubiquitinating Enzymes; Drug Development; Drug Resistance; Histone Deacetylases; Humans; Ikaros Transcription Factor; Immunomodulating Agents; Models, Molecular; Morpholines; Multiple Myeloma; Phthalimides; Piperidones; Proteasome Inhibitors; Treatment Outcome; Ubiquitin-Protein Ligases

Topics: Animals; Antimitotic Agents; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Drug Development; Humans; Kinesins; Multiple Myeloma; Thiadiazoles

Despite the availability of various anticancer agents, Multiple Myeloma (MM) remains incurable in most cases, along with high relapse rate in the patients treated with these agents. The year 2015 saw major advancements in our battle against multiple myeloma. In 2015, the U.S. Food and Drug Administration (FDA) approved three new therapies for multiple myeloma, namely Ixazomib (an oral proteasome inhibitor), Daratumumab and Elotuzumab (monoclonal antibodies against CD38 and SLAMF7 respectively). The purpose of this review is to provide a detailed analysis of these aforementioned breakthrough therapies and two other newer agents, Filanesib (kinesis spindle inhibitor) and selinexor (SINE inhibitor), presented at the 2015 annual meeting of American Society of Hematology (ASH). We also describe the role of agents targeting PD-1 axis and chimeric antigen receptor T (CAR-T) cells in the treatment of MM.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; Boron Compounds; Congresses as Topic; Glycine; Humans; Hydrazines; Molecular Targeted Therapy; Multiple Myeloma; Proteasome Inhibitors; Protein Kinase Inhibitors; Signal Transduction; Thiadiazoles; Treatment Outcome; Triazoles

Filanesib is a first-in-class kinesin spindle protein inhibitor which demonstrated safety and encouraging activity in combination with bortezomib and dexamethasone in relapsed/refractory multiple myeloma in a preliminary analysis of dose-escalation phase results. This multicenter study included first a dose-escalation phase to determine maximum tolerated dose of two schedules of filanesib, bortezomib, and dexamethasone and a subsequent dose-expansion phase using the maximum tolerated doses. In the dose-expansion phase, 28 patients were evaluable for safety and efficacy. The most common grade ≥3 adverse events were neutropenia (21%) and anemia (18%), which were noncumulative and reversible, and hypertension (18%). The overall response rate was 43% with median duration of response not yet reached (range, 2.8-23.7+ months) with median follow-up of 6.3 months. A post hoc analysis incorporated 29 dose-escalation phase patients who received therapeutic filanesib doses, with an overall response rate of 39% and median duration of response of 18.0 months among the 57 total patients with median progression-free survival of 8.5 months. Notably, the PFS of high risk patients was comparable at 8.5 months, driven by the patients with 1q21 gain, characterized by increased MCL-1 expression, with a PFS of 9.1 months versus 3.5 months for the remainder of high risk patients. Patients with t(11;14) also had an encouraging PFS of 15.0 months. The combination of filanesib, bortezomib, and dexamethasone continues to show safety and encouraging activity in relapsed/refractory multiple myeloma, particularly in those patients with 1q21 gain and t(11;14).

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Chromosome Aberrations; Chromosomes, Human, Pair 1; Dexamethasone; Dose-Response Relationship, Drug; Female; Humans; Male; Maximum Tolerated Dose; Middle Aged; Multiple Myeloma; Neoplasm Recurrence, Local; Progression-Free Survival; Thiadiazoles

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Female; Humans; Kinesins; Male; Middle Aged; Multiple Myeloma; Neoplasm Recurrence, Local; Orosomucoid; Spain; Thalidomide; Thiadiazoles; Treatment Outcome

Topics: Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Humans; Multiple Myeloma; Neoplasm Recurrence, Local; Oligopeptides; Progression-Free Survival; Thiadiazoles

Filanesib (ARRY-520) is a highly selective inhibitor of kinesin spindle protein, which has demonstrated preclinical antimyeloma activity.. This open-label Phase 1/2 study determined the maximum tolerated dose of Filanesib administered on Days 1 and 2 of 14-Day Cycles in patients with multiple myeloma (MM) and included expansion cohorts with and without dexamethasone (40 mg/week). Patients in the dose-escalation (N = 31) and Phase 2 single-agent (N = 32) cohorts had received prior bortezomib as well as prior thalidomide and/or lenalidomide. Patients in the Phase 2 Filanesib plus dexamethasone cohort (N = 55) had received prior alkylator therapy and had disease refractory to lenalidomide, bortezomib, and dexamethasone. Prophylactic filgrastim was incorporated during dose escalation and was used throughout Phase 2.. Patients in each cohort had received a median of ≥6 prior therapies. The most common dose-limiting toxicities were febrile neutropenia and mucosal inflammation. In Phase 2, Grade 3 and 4 cytopenias were reported in approximately 50% of patients. Nonhematologic toxicities were infrequent. Phase 2 response rates (partial responses or better) were 16% (single agent) and 15% (Filanesib plus dexamethasone). All responding patients had low baseline levels of α1-acid glycoprotein, a potential selective biomarker.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cohort Studies; Dexamethasone; Drug Resistance, Neoplasm; Female; Follow-Up Studies; Humans; Male; Maximum Tolerated Dose; Middle Aged; Multiple Myeloma; Neoplasm Recurrence, Local; Prognosis; Salvage Therapy; Survival Rate; Thiadiazoles

Kinesin spindle protein inhibition is known to be an effective therapeutic approach in several malignancies. Filanesib (ARRY-520), an inhibitor of this protein, has demonstrated activity in heavily pre-treated multiple myeloma patients. The aim of the work herein was to investigate the activity of filanesib in combination with pomalidomide plus dexamethasone backbone, and the mechanisms underlying the potential synergistic effect. The ability of filanesib to enhance the activity of pomalidomide plus dexamethasone was studied in several

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Cycle Checkpoints; Cells, Cultured; Dexamethasone; Drug Synergism; Humans; Kinesins; Mice; Multiple Myeloma; Thalidomide; Thiadiazoles; Treatment Outcome

Topics: Antineoplastic Combined Chemotherapy Protocols; Autografts; Cell Line, Tumor; Cell Proliferation; Combined Modality Therapy; Drug Administration Schedule; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Multiple Myeloma; Thiadiazoles; Transplantation Conditioning; Treatment Outcome

Kinesin spindle protein (KSP/Eg5) inhibitors are novel anticancer agents that have thus far shown only modest activity in the clinic. Understanding how to identify patients who may be most sensitive to treatment is clearly needed to improve the development of these molecules. We studied four multiple myeloma cell lines treated with the KSP inhibitor ARRY-520 to identify factors important for initiating apoptosis while cells are arrested in mitosis. The majority (three of four) of cell lines underwent mitotic arrest, with apoptosis occurring in mitosis within 24 to 30 hours. The remaining line (NCI H929) is temporally refractory to ARRY-520 treatment, undergoing mitotic slippage and subsequently peaking in apoptotic markers after 72 hours of treatment, while most cells are in interphase. Interestingly, loss of the antiapoptotic protein myeloid cell leukemia 1 (Mcl-1) coincided with mitotic cell death. Stabilization of Mcl-1 resulted in a delayed onset of apoptosis, whereas enforced downregulation of Mcl-1 increased cell death in response to KSP inhibition. Thus, variation in responses to KSP inhibition is governed by a balance between survival proteins and spindle checkpoint integrity. Cells relying on short-lived survival proteins during mitosis are more likely to undergo apoptosis in response to KSP inhibition. We propose that patients with hematologic malignancies, which rely on Mcl-1, would therefore be good candidates for treatment with KSP inhibitors.

Topics: Animals; Apoptosis; Blotting, Western; Caspase 3; Caspase 7; Cell Line, Tumor; Cell Survival; Enzyme Activation; Female; Humans; Kinesins; Mice; Mice, SCID; Mitosis; Multiple Myeloma; Myeloid Cell Leukemia Sequence 1 Protein; Proto-Oncogene Proteins c-bcl-2; RNA Interference; Thiadiazoles; Xenograft Model Antitumor Assays