abt-199 and Multiple-Myeloma

Multiple myeloma (MM) is an incurable malignancy. Venetoclax (VEN) shows a meaningful effect in MM patients who are relapsed or refractory (RR) to previous standard therapies.. This study aimed to assess the efficacy and safety of VEN-based treatments in RR MM patients.. Comprehensive studies were searched in PubMed, Embase, Web of Science and Cochrane library. Efficacy was assessed by overall response rate (ORR), strict complete response rate (sCR), complete response rate (CR), very good partial response rate (VGPR) and partial response rate (PR).. Seven studies containing 482 subjests were included. The pooled ORR, ≥ CR (sCR + CR), VGPR and PR were 68% (51%-85%), 24% (13%-35%), 25% (17%-34%) and 17% (11%-24%) respectively. Multi-drug treatments were superior to VEN ± dexamethasone (Dex) treatments in ORR (82% vs 42%,. VEN-containing regimens could be suggested as effective and safe treatments to RR MM patients with t(11;14) or high BCL-2 levels.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Humans; Multiple Myeloma; Prospective Studies

Venetoclax is clinically active in treating relapsed/refractory multiple myeloma (RRMM). This study evaluated the efficacy and safety of venetoclax or venetoclax with other agents in treating RRMM.. PubMed, Web of Science, Embase, and Cochrane Library were comprehensively searched. We included studies investigating the efficacy and safety of venetoclax or venetoclax with other agents in treating RRMM. Overall response rates (ORR), stringent complete response rates (sCR), complete response rates (CR), very good partial response rates (VGPR), partial response rates (PR), stable disease (SD), progressive disease (PD) and adverse events were synthesized using either a random-effects model or a fixed-effects model.. A total of 7 clinical trials with 482 patients with RRMM were included. Concerning venetoclax with other agents, the pooled ORR, sCR, CR, VGPR, PR, SD, and PD were 0.76 (95% CIs: 0.62, 0.87), 0.11 (95% CIs: 0.04, 0.21), 0.18 (95% CIs: 0.11, 0.26), 0.16 (95% CIs: 0.12, 0.25), 0.29 (95% CIs: 0.25, 0.34), 0.07 (95% CIs: 0.05, 0.10), and 0.11 (95% CIs: 0.04, 0.23). The overall rate of adverse events ≥ Grade 3 was 0.84 (95% CIs: 0.77, 0.91). The most common non-hematologic adverse events were nausea, diarrhea, fatigue, back pain, and vomiting; hematologic adverse events included thrombocytopenia, neutropenia, anemia, leukopenia, and lymphopenia.. This study indicates that venetoclax alone or in combination with other agents reveals favorable treatment responses and acceptable adverse events in treating RRMM.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Dexamethasone; Humans; Multiple Myeloma; Treatment Outcome

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

BH3-mimetics are a novel drug class of small molecule inhibitors of BCL2 family proteins which restore apoptosis in malignant cells. The only currently approved BH3-mimetic, the selective BCL2 inhibitor venetoclax, is highly efficacious in chronic lymphocytic leukemia and has rapidly advanced to an approved standard of care in frontline and relapsed disease in combination with anti-CD20 monoclonal antibodies. In this context, tumour lysis syndrome and myelosuppression are the most commonly encountered toxicities and are readily manageable with established protocols. Venetoclax is active in other lymphoid malignancies including several B cell non-Hodgkin lymphomas, acute lymphoblastic leukemia and multiple myeloma, with the highest intrinsic sensitivity observed in mantle cell lymphoma and Waldenstrom macroglobulinemia. Venetoclax combination with standard regimens in follicular lymphoma, multiple myeloma and aggressive B cell neoplasms has shown some promise, but further studies are required to optimize dose and scheduling to mitigate increased myelosuppression and infection risk, and to find validated biomarkers of venetoclax sensitivity. Future research will focus on overcoming venetoclax resistance, targeting other BCL2 family members and the rational design of synergistic combinations.

Topics: Adult; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Humans; Lymphoma, B-Cell; Multiple Myeloma; Proto-Oncogene Proteins c-bcl-2; Sulfonamides

Multiple myeloma has witnessed significant advances due to the approval of many novel agents. However, in spite of all these new developments, multiple myeloma remains an incurable disease with inevitable relapse in the majority of patients. Venetoclax is a selective antiapoptotic protein B-cell lymphoma 2 inhibitor that induces cell death in multiple myeloma cells, particularly in those harboring t(11,14)(q13;q32). We report two cases of patients with multiple myeloma with t(11,14)(q13;q32) who were treated with venetoclax/carfilzomib/dexamethasone with rapid initial response; however, the response was short-lived.. Patient 1 was a 50-year-old Saudi man with International Staging System stage III kappa light chain multiple myeloma with normal karyotype diagnosed in May 2013. He received bortezomib/thalidomide/dexamethasone treatment and underwent autologous hematopoietic stem cell transplant. Three years later, he presented with disease progression and received multiple lines of chemotherapy, including carfilzomib/lenalidomide/dexamethasone. Venetoclax/carfilzomib/dexamethasone was started after acquiring t(11,14)(q13;q32) 5 years into his disease course. He achieved complete remission, with disease progression after cycle 6. Patient 2 was a 48-year-old Saudi man with International Staging System stage III immunoglobulin G kappa multiple myeloma with t(11,14)(q13;q32) diagnosed in May 2017. He received bortezomib/thalidomide/dexamethasone treatment and underwent autologous hematopoietic stem cell transplant. Eighteen months later, he had disease progression, and he received multiple lines of chemotherapy, including carfilzomib/dexamethasone. He was shifted to venetoclax/carfilzomib/dexamethasone in April 2019 and had an initial clinical response; two months later, he progressed to plasma cell leukemia with rapid deterioration to multiorgan failure.. Acquired t(11;14)(q13;q32) is unreported in the multiple myeloma literature. In the era of targeted therapy, it is essential to repeat the cytogenetic and multiple myeloma fluorescence in situ hybridization panel with each disease progression. Multiple myeloma remains a challenging hematological malignancy despite advances in personalized/precision medicine.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Dexamethasone; Fatal Outcome; Hematopoietic Stem Cell Transplantation; Humans; Male; Middle Aged; Multiple Myeloma; Neoplasm Recurrence, Local; Oligopeptides; Remission Induction; Sulfonamides

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Biomarkers; Bridged Bicyclo Compounds, Heterocyclic; Clinical Trials, Phase I as Topic; Drug Evaluation, Preclinical; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Humans; Molecular Targeted Therapy; Multiple Myeloma; Mutation; Protein Binding; Protein Interaction Domains and Motifs; Proto-Oncogene Proteins c-bcl-2; Signal Transduction; Sulfonamides; Treatment Outcome

Despite significant progress in our understanding and the development of novel therapies, most patients with multiple myeloma will experience relapse of their disease. Therapy of relapsed myeloma has improved due to the availability of novel agents that are highly active against the disease. However, the selection of therapy can be challenging due to the emergence of toxicities, comorbidities and frailty. In the following we discuss our approach to the treatment of the patient with relapsed myeloma.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Clinical Trials, Phase III as Topic; Decision Making; Gene Expression Profiling; Humans; Hydrazines; Immunotherapy; In Situ Hybridization, Fluorescence; Multiple Myeloma; Neoplasm Recurrence, Local; Stem Cell Transplantation; Sulfonamides; Symptom Assessment; Transplantation, Autologous; Triazoles; Watchful Waiting

Mitogen-activated protein kinase pathway mutations are present in >50% of patients with relapsed/refractory (R/R) multiple myeloma (MM). MEK inhibitors show limited single-agent activity in R/R MM; combination with B-cell lymphoma-2 (BCL-2) and programmed death-ligand 1 inhibition may improve efficacy. This phase Ib/II trial (NCT03312530) evaluated safety and efficacy of cobimetinib (cobi) alone and in combination with venetoclax (ven) with/without atezolizumab (atezo) in patients with R/R MM.. Forty-nine patients were randomized 1:2:2 to cobi 60 mg/day on days 1-21 (n = 6), cobi 40 mg/day on days 1-21 + ven 800 mg/day on days 1-28 with/without atezo 840 mg on days 1 and 15 of 28-day cycles (cobi-ven, n = 22; cobi-ven-atezo, n = 21). Safety run-in cohorts evaluated cobi-ven and cobi-ven-atezo dose levels.. Any-grade common adverse events (AEs) with cobi, cobi-ven, and cobi-ven-atezo, respectively, included diarrhea (33.3%, 81.8%, 90.5%) and nausea (16.7%, 50.0%, 66.7%); common grade ≥3 AEs included anemia (0%, 22.7%, 23.8%), neutropenia (0%, 13.6%, 38.1%), and thrombocytopenia (0%, 18.2%, 23.8%). The overall response rate for all-comers was 0% (cobi), 27.3% (cobi-ven), and 28.6% (cobi-ven-atezo), and 0%, 50.0%, and 100%, respectively, in patients with t(11;14)+. Biomarker analysis demonstrated non-t(11;14) patient selection with NRAS/KRAS/BRAF mutation or high BCL-2/BCL-2-L1 ratio (>52% of the study population) could enrich for responders to the cobi-ven combination.. Cobi-ven and cobi-ven-atezo demonstrated manageable safety with moderate activity in all-comers, and higher activity in patients with t(11;14)+ MM, supporting a biomarker-driven approach for ven in MM.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Humans; Multiple Myeloma; Proto-Oncogene Proteins c-bcl-2

Proteins in the antiapoptotic B-cell lymphoma 2 (BCL-2) family play a role in the pathophysiology of multiple myeloma (MM). Venetoclax is a highly selective, potent, oral BCL-2 inhibitor that induces apoptosis of MM cells, and its efficacy may be potentiated through combination with agents that increase BCL-2 dependency or have complementary mechanisms of action. The safety, tolerability, pharmacokinetics, and antitumor activity of venetoclax in combination with carfilzomib and dexamethasone (VenKd) in adults with relapsed/refractory MM (RRMM) were investigated in this phase 2 dose-escalation study. Oral venetoclax (400 or 800 mg) was administered daily in combination with intravenous carfilzomib (27, 56, or 70 mg/m2) and oral dexamethasone (20 or 40 mg) in 4 dose-finding cohorts. The expansion cohort received venetoclax 800 mg, carfilzomib 70 mg/m2, and dexamethasone 40 mg. Forty-nine patients received treatment. Median prior lines of therapy was 1 (range, 1-3), and median time in the study was 27 months. The most common treatment-emergent adverse events were diarrhea (65%), fatigue (47%), nausea (47%), and lymphopenia (35%). Serious adverse events occurred in 26 (53%) patients. Of 3 treatment-emergent deaths, 1 was considered treatment related. The overall response rate was 80% in all patients, 92% in patients with t(11;14) (n = 13), and 75% in patients without (n = 36). The rate of complete response or better was 41%. Median progression-free survival was 22.8 months. Treatment with VenKd was well tolerated and showed promising response rates in this RRMM patient population, with greater responses observed in patients with t(11;14). This trial is registered at www.clinicaltrials.gov as #NCT02899052.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Dexamethasone; Humans; Multiple Myeloma; Oligopeptides; Sulfonamides

Venetoclax is a selective BCL-2 inhibitor with clinical activity in relapsed/refractory multiple myeloma (RRMM). Combinations of venetoclax with agents that have complementary mechanisms of action may improve venetoclax efficacy in RRMM. This study evaluated venetoclax with pomalidomide and dexamethasone (VenPd) in RRMM.. This phase II open label study (NCT03567616) evaluated VenPd in patients with RRMM who had received ≥ 1 prior therapy and were refractory to lenalidomide. Venetoclax was administered orally daily for days 1 to 28, pomalidomide was administered orally daily for days 1 to 21, and dexamethasone was administered weekly for each 28-day cycle. The primary objective was to characterize the safety and tolerability of VenPd. The secondary objectives were to evaluate the efficacy and pharmacokinetics. The study was terminated early due to partial clinical hold and decision to pursue biomarker driven strategy.. Eight patients were enrolled. Patients had a median age of 67.5 years. All patients received 400 mg venetoclax; 4 patients experienced dose-limiting toxicities and the dose was not escalated. All patients had a grade ≥ 3 adverse event, and the most common was neutropenia (n = 6); cytopenias were the most prevalent adverse events. Five patients (63%) had a confirmed response, and the median duration of response was 12.9 months. The median progression-free survival was 10.5 months.. Given the limited enrollment, no clear safety or efficacy conclusions about VenPd can be drawn. Preliminary safety data, particularly the occurrence of cytopenias, can be used to guide dosing strategies for future combinations of venetoclax with immunomodulatory agents.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Dexamethasone; Female; Humans; Male; Multiple Myeloma; Progression-Free Survival; Sulfonamides; Thalidomide

Topics: Aged; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; bcl-X Protein; Bone Marrow; Bridged Bicyclo Compounds, Heterocyclic; Chromosomes, Human, Pair 11; Chromosomes, Human, Pair 14; Combined Modality Therapy; Dexamethasone; Female; Follow-Up Studies; Genes, bcl-2; Hematologic Diseases; Hematopoietic Stem Cell Transplantation; Humans; Infections; Kaplan-Meier Estimate; Male; Middle Aged; Multiple Myeloma; Neoplasm Proteins; Proto-Oncogene Proteins c-bcl-2; Recurrence; Salvage Therapy; Signal Transduction; Sulfonamides; Translocation, Genetic

Venetoclax is an oral BCL-2 inhibitor with single-agent activity in patients with relapsed or refractory multiple myeloma (RRMM) with t(11;14) translocation. Venetoclax efficacy in RRMM may be potentiated through combination with agents including bortezomib, dexamethasone, and daratumumab.. This phase I study (NCT03314181) evaluated venetoclax with daratumumab and dexamethasone (VenDd) in patients with t(11;14) RRMM and VenDd with bortezomib (VenDVd) in cytogenetically unselected patients with RRMM. Primary objectives included expansion-phase dosing, safety, and overall response rate. Secondary objectives included further safety analysis, progression-free survival, duration of response, time to progression, and minimal residual disease negativity.. Forty-eight patients were enrolled, 24 each in parts 1 (VenDd) and 2 (VenDVd). There was one dose-limiting toxicity in part 1 (grade 3 febrile neutropenia, 800 mg VenDd). Common adverse events with VenDd and VenDVd included diarrhea (63% and 54%) and nausea (50% and 50%); grade ≥ 3 adverse events were observed in 88% in the VenDd group and 71% in the VenDVd group. One treatment-emergent death occurred in part 2 (sepsis) in the context of progressive disease, with no other infection-related deaths on study with medians of 20.9 and 20.4 months of follow-up in parts 1 and 2, respectively. The overall response rate was 96% with VenDd (all very good partial response or better [≥ VGPR]) and 92% with VenDVd (79% ≥ VGPR). The 18-month progression-free survival rate was 90.5% (95% CI, 67.0 to 97.5) with VenDd and 66.7% (95% CI, 42.5 to 82.5) with VenDVd.. VenDd and VenDVd produced a high rate of deep and durable responses in patients with RRMM. These results support continued evaluation of venetoclax with daratumumab regimens to treat RRMM, particularly in those with t(11;14).

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Australia; Bortezomib; Bridged Bicyclo Compounds, Heterocyclic; Chromosomes, Human, Pair 11; Chromosomes, Human, Pair 14; Dexamethasone; Europe; Female; Humans; Male; Middle Aged; Multiple Myeloma; Neoplasm, Residual; North America; Progression-Free Survival; Sulfonamides; Time Factors; Translocation, Genetic

The treatment for relapsed/refractory multiple myeloma (RRMM) continues to be challenging despite recent therapeutic advancements. Venetoclax, an inhibitor of the anti-apoptotic protein BCL-2, is a promising agent, especially in patients harbouring t(11;14). Our objective was to review our experience with venetoclax-based regimens at our institution. All ten RRMM patients treated with venetoclax were included and had a median of six prior lines of therapy. The overall response rate was 78% and one patient with cardiac amyloidosis and MM achieved a cardiac organ response. Haematologic toxicities requiring red blood cell and platelet transfusion and non-haematologic toxicities, most commonly gastrointestinal upset, were observed.

Topics: Adult; Bridged Bicyclo Compounds, Heterocyclic; Chromosomes, Human, Pair 11; Chromosomes, Human, Pair 14; Erythrocyte Transfusion; Female; Humans; Male; Multiple Myeloma; Platelet Transfusion; Proto-Oncogene Proteins c-bcl-2; Sulfonamides; Translocation, Genetic

Venetoclax is a highly selective, potent, oral BCL-2 inhibitor, which induces apoptosis in multiple myeloma cells. Venetoclax plus bortezomib and dexamethasone has shown encouraging clinical efficacy with acceptable safety and tolerability in a phase 1 trial. The aim of this study was to evaluate venetoclax plus bortezomib and dexamethasone in patients with relapsed or refractory multiple myeloma.. In this randomised, double-blind, multicentre, phase 3 trial, patients aged 18 years or older with relapsed or refractory multiple myeloma, an Eastern Cooperative Oncology Group performance status of 2 or less, who had received one to three previous therapies were enrolled from 90 hospitals in 16 countries. Eligible patients were randomly assigned (2:1) centrally using an interactive response technology system and a block size of three to receive venetoclax (800 mg per day orally) or placebo with bortezomib (1·3 mg/m. Between July 19, 2016, and Oct 31, 2017, 291 patients were randomly assigned to receive venetoclax (n=194) or placebo (n=97). With a median follow-up of 18·7 months (IQR 16·6-21·0), median progression-free survival according to independent review committee was 22·4 months (95% CI 15·3-not estimable) with venetoclax versus 11·5 months (9·6-15·0) with placebo (hazard ratio [HR] 0·63 [95% CI 0·44-0·90]; p=0·010). The most common grade 3 or worse treatment-emergent adverse events were neutropenia (35 [18%] of 193 patients in the venetoclax group vs seven [7%] of 96 patients in the placebo group), pneumonia (30 [16%] vs nine [9%]), thrombocytopenia (28 [15%] vs 29 [30%]), anaemia (28 [15%] vs 14 [15%]), and diarrhoea (28 [15%] vs 11 [11%]). Serious treatment-emergent adverse events occurred in 93 (48%) patients in the venetoclax group and 48 (50%) patients in the placebo group, with eight (4%) treatment-emergent fatal infections reported in the venetoclax group and none reported in the placebo group. Three deaths in the venetoclax group (two from pneumonia and one from septic shock) were considered treatment-related; no deaths in the placebo group were treatment-related.. The primary endpoint was met with a significant improvement in independent review committee-assessed progression-free survival with venetoclax versus placebo plus bortezomib and dexamethasone. However, increased mortality was seen in the venetoclax group, mostly because of an increased rate of infections, highlighting the importance of appropriate selection of patients for this treatment option.. AbbVie and Genentech.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Bridged Bicyclo Compounds, Heterocyclic; Dexamethasone; Double-Blind Method; Female; Humans; Male; Middle Aged; Multiple Myeloma; Progression-Free Survival; Proteasome Inhibitors; Sulfonamides; Time Factors

Exposure-response analyses of venetoclax in combination with bortezomib and dexamethasone in previously treated patients with multiple myeloma (MM) were performed on a phase Ib venetoclax dose-ranging study. Logistic regression models were utilized to determine relationships, identify subpopulations with different responses, and optimize the venetoclax dosage that balanced both efficacy and safety. Bortezomib refractory status and number of prior treatments were identified to impact the efficacy response to venetoclax treatment. Higher venetoclax exposures were estimated to increase the probability of achieving a very good partial response (VGPR) or better through venetoclax doses of 1,200 mg. However, the probability of neutropenia (grade ≥3) was estimated to increase at doses >800 mg. Using a clinical utility index, a venetoclax dosage of 800 mg daily was selected to optimally balance the VGPR or better rates and neutropenia rates in MM patients administered 1-3 prior lines of therapy and nonrefractory to bortezomib.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Bridged Bicyclo Compounds, Heterocyclic; Dexamethasone; Dose-Response Relationship, Drug; Drug Dosage Calculations; Humans; Logistic Models; Maximum Tolerated Dose; Multiple Myeloma; Neutropenia; Sulfonamides

Topics: ADP-ribosyl Cyclase 1; Antibodies, Monoclonal; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Humans; Multiple Myeloma

Multiple myeloma is one of the most common hematologic malignancies, with approximately 400 patients diagnosed in Hungary annually. Novel therapies emerging in the last decade have made a great impact on most patients' survival, however, those responding poorly to standard first-line therapy and failing to proceed to stem cell transplantation face a dire prognosis. Venetoclax, a selective Bcl-2 inhibitor has been shown very effective in the treatment of relapsed/refractory t(11;14) patients, but there are only a few studies about its safety and efficacy when used as salvage in the second line.. The aim of our study was to analyze the data of t(11;14) patients treated with venetoclax salvage at our clinic and to evaluate its efficacy.. Between 2017 and 2021, 13 patients received venetoclax therapy at our clinic after suboptimal response to frontline treatment, whose data we analyzed retrospectively.. Adverse prognostic markers were very prevalent in our group, 4 of our patients had del(17p), 5 had amp(1q21) and 6 had stage 3. Nevertheless, all 13 patients responded well to venetoclax therapy, with 6 reaching very good partial response and 7 complete response. All eligible patients (10) could proceed to transplantation. After median 38 months follow up, neither median progression-free, nor median overall survival was reached, since only 3 patients progressed and 1 died.. We have shown that when salvage is needed for t(11;14) patients who respond suboptimally to standard frontline therapy, venetoclax is a remarkably good option. Orv Hetil. 2023; 164(23): 894-899.. Bevezetés: A myeloma multiplex az egyik leggyakoribb hematológiai malignitás, évi kb. 400 esettel Magyarországon. Az utóbbi évtizedben bevezetett új gyógyszerek sokat javítottak a legtöbb beteg túlélésén, azok azonban, akik az első vonalbeli kezelésre nem jól reagálnak, és nem juttathatók őssejt-transzplantációra, igen rossz prognózissal néznek szembe. A szelektív Bcl-2-inhibitor venetoclax rendkívül hatásosnak bizonyult relabált/refrakter betegekben, második vonalban, mentőkezelésként való alkalmazásáról azonban kevés az adat. Célkitűzés: Kutatásunk célja a Klinikánkon venetoclax mentőkezelésben részesült t(11;14)-betegek adatainak elemzése és a terápia hatékonyságának értékelése volt. Módszer: 2017 és 2021 között 13 beteg esetében alkalmaztunk a frontline kezelésre adott szuboptimális válasz miatt venetoclaxkezelést, adataikat retrospektíven elemeztük. Eredmények: Betegcsoportunkban nagyon gyakoriak voltak az adverz prognosztikai faktorok: del(17p) 4 betegnél, amp(1q21) 5 betegnél, míg 3. stádium 6 betegnél volt jelen. Ennek ellenére mind a 13 beteg kiválóan reagált a venetoclaxterápiára, 6 nagyon jó parciális választ, 7 pedig komplett választ ért el. Minden alkalmas beteget transzplantációra tudtunk juttatni. Medián 38 hónapos követés után sem a medián progressziómentes, sem a medián teljes túlélést nem értük el, csupán 3 beteg progrediált, és 1-et veszítettünk el. Következtetés: Vizsgálatunk azt mutatta, hogy a standard korai terápiára szuboptimálisan reagáló és mentőkezelésre szoruló t(11;14)-betegek esetében a venetoclax különösen jó kezelési opció. Orv Hetil. 2023; 164(23): 894–899.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Humans; Multiple Myeloma; Retrospective Studies; Salvage Therapy

Topics: Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Humans; Multiple Myeloma; Neoplasm Recurrence, Local; Retreatment; Treatment Outcome

Identification of novel vulnerabilities in the context of therapeutic resistance is emerging as a key challenge for cancer treatment. Recent studies have detected pervasive aberrant splicing in cancer cells, supporting its targeting for novel therapeutic strategies. Here, we evaluated the expression of several spliceosome machinery components in multiple myeloma (MM) cells and the impact of splicing modulation on tumor cell growth and viability. A comprehensive gene expression analysis confirmed the reported deregulation of spliceosome machinery components in MM cells, compared to normal plasma cells from healthy donors, with its pharmacological and genetic modulation resulting in impaired growth and survival of MM cell lines and patient-derived malignant plasma cells. Consistent with this, transcriptomic analysis revealed deregulation of BCL2 family members, including decrease of anti-apoptotic long form of myeloid cell leukemia-1 (MCL1) expression, as crucial for "priming" MM cells for Venetoclax activity in vitro and in vivo, irrespective of t(11;14) status. Overall, our data provide a rationale for supporting the clinical use of splicing modulators as a strategy to reprogram apoptotic dependencies and make all MM patients more vulnerable to BCL2 inhibitors.

Topics: Antineoplastic Agents; Apoptosis; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Humans; Multiple Myeloma; Myeloid Cell Leukemia Sequence 1 Protein; Proto-Oncogene Proteins c-bcl-2; Sulfonamides

Topics: Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Bridged Bicyclo Compounds, Heterocyclic; Dexamethasone; Humans; Hypocalcemia; Multiple Myeloma; Neoplasm Recurrence, Local; Sulfonamides

Plasma cell leukemia (PCL) is a rare but aggressive variant of multiple myeloma (MM) with a poor prognosis. Due to the limited number of prospective clinical trials studying PCL, treatment options are often extrapolated from data available for the treatment of MM. Venetoclax has recently demonstrated antimyeloma activity in patients with relapsed/refractory MM carrying the t(11;14) translocation. However, few cases have reported the analogous efficacy of venetoclax in PCL.. A 64-year-old Caucasian male developed relapsed PCL despite treatment with hyperCD (hyperfractionated cyclophosphamide and dexamethasone) and Dara-KRd (daratumumab, carfilzomib, lenalidomide, dexamethasone). Due to the refractory nature of his disease and the presence of a t(11:14) translocation, the patient was subsequently initiated on venetoclax 400 mg daily and dexamethasone 4 mg once weekly.. The patient achieved a complete response by International Myeloma Working Group criteria three months after initiating venetoclax-dexamethasone, including a repeat bone marrow biopsy that showed no abnormal plasma cells. He successfully underwent consolidation with melphalan-based autologous stem cell transplantation. He remains disease-free 9 months after venetoclax initiation.. Combination all-oral therapy with venetoclax and dexamethasone can induce deep hematologic responses in patients with relapsed/refractory PCL carrying the t(11;14) translocation.

Topics: Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Plasma Cell; Male; Middle Aged; Multiple Myeloma; Prospective Studies; Transplantation, Autologous

Despite the introduction of novel agents, multiple myeloma remains incurable for most patients, necessitating further therapeutic options. Venetoclax, a selective BCL-2 inhibitor, had shown promising results in patients with translocation t(11;14), but questions remain open about its optimal use. We have contacted all Hungarian haematology centers for their experience treating t(11;14) myeloma patients with venetoclax. 58 patients were reported. 37 received venetoclax in the relapsed/refractory setting with few or no other therapeutic options available. 21 patients started venetoclax as salvage after failing to achieve satisfactory response to first line therapy. In the relapsed/refractory setting objective response rate (ORR) was 94%, median progression-free survival (PFS) 10.0 months and median overall survival (OS) 14.6 months. In reinduction patients, ORR was 100%, median PFS and OS were not reached. Importantly, we found no adverse effect of high risk features such as deletion 17p or renal failure, in fact renal failure ameliorated in 42% of the cases, including three patients who became dialysis independent. Our study also reports the highest number of plasma cell leukemia cases successfully treated with venetoclax published in literature, with refractory plasma cell leukemia patients achieving a median PFS of 10.0 and a median OS of 12.2 months.

Topics: Bridged Bicyclo Compounds, Heterocyclic; Humans; Hungary; Multiple Myeloma; Sulfonamides

Topics: Bridged Bicyclo Compounds, Heterocyclic; Humans; Multiple Myeloma; Proto-Oncogene Proteins c-bcl-2; Sulfonamides

Multiple myeloma (MM) is the second most common hematologic malignancy with almost all patients eventually having relapse or refractory MM (RRMM), thus novel drugs or combination therapies are needed for improved prognosis. Chidamide and venetoclax, which target histone deacetylase and BCL2, respectively, are two promising agents for the treatment of RRMM.. Herein, we found that chidamide and venetoclax synergistically exert an anti-myeloma effect in vitro in human myeloma cell lines (HMCLs) with a combination index (CI) < 1. Moreover, the synergistic anti-myeloma effect of these two drugs was demonstrated in primary MM cells and MM xenograft mice. Mechanistically, co-exposure to chidamide and venetoclax led to cell cycle arrest at G0/G1 and a sharp increase in DNA double-strand breaks. In addition, the combination of chidamide and venetoclax resulted in BCL-X. In conclusion, these results proved the high therapeutic potential of venetoclax and chidamide combination in curing MM, representing a potent and alternative salvage therapy for the treatment of RRMM.

Topics: Aminopyridines; Animals; Apoptosis; Benzamides; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; DNA Methylation; Humans; Mice; Multiple Myeloma; Neoplasm Recurrence, Local; Sulfonamides

Proteasome inhibitors bortezomib and carfilzomib are the backbones of treatments of multiple myeloma, which remains incurable despite many recent advances. With many patients relapsing despite high initial response rates to proteasome inhibitor-containing regimens, it is critical to understand the process of acquired resistance. In vitro generated resistant cell lines are important tools in this process. The majority of previously developed bortezomib-resistant cell lines bear mutations in the proteasome PSMB5 sites, the prime target of bortezomib and carfilzomib, which are rarely observed in patients. Here we present a novel bortezomib-resistant derivative of the KMS-12-BM multiple myeloma cell line, KMS-12-BM-BPR. Unlike previously published bortezomib-resistant cell lines, it was created using clinically relevant twice-weekly pulse treatments with bortezomib instead of continuous incubation. It does not contain mutations in the PSMB5 site and retains its sensitivity to carfilzomib. Reduced load on proteasome due to decreased protein synthesis appears to be the main cause of resistance. In addition, KMS-12-BM-BPR cells are more sensitive to Bcl-2 inhibitor venetoclax. Overall, this study demonstrates the feasibility of creating a proteasome inhibitor resistant myeloma cell lines by using clinically relevant pulse treatments and provides a novel model of acquired resistance.

Topics: Antineoplastic Agents; Bortezomib; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Drug Resistance, Neoplasm; Humans; Multiple Myeloma; Mutation; Neoplasm Recurrence, Local; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Sulfonamides

The connections between metabolic state and therapy resistance in multiple myeloma (MM) are poorly understood. We previously reported that electron transport chain (ETC) suppression promotes sensitivity to the BCL-2 antagonist venetoclax. Here, we show that ETC suppression promotes resistance to proteasome inhibitors (PIs). Interrogation of ETC-suppressed MM reveals integrated stress response-dependent suppression of protein translation and ubiquitination, leading to PI resistance. ETC and protein translation gene expression signatures from the CoMMpass trial are down-regulated in patients with poor outcome and relapse, corroborating our in vitro findings. ETC-suppressed MM exhibits up-regulation of the cystine-glutamate antiporter

Topics: Antiporters; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Cystine; Glutamates; Humans; Multiple Myeloma; Proteasome Inhibitors; Proto-Oncogene Proteins c-bcl-2; Sulfonamides

Immunoglobulin light chain (AL) amyloidosis is an incurable hematologic disorder typically characterized by the production of amyloidogenic light chains by clonal plasma cells. These light chains misfold and aggregate in healthy tissues as amyloid fibrils, leading to life-threatening multi-organ dysfunction. Here we show that the clonal plasma cells in AL amyloidosis are highly primed to undergo apoptosis and dependent on pro-survival proteins MCL-1 and BCL-2. Notably, this MCL-1 dependency is indirectly targeted by the proteasome inhibitor bortezomib, currently the standard of care for this disease and the related plasma cell disorder multiple myeloma, due to upregulation of pro-apoptotic Noxa and its inhibitory binding to MCL-1. BCL-2 inhibitors sensitize clonal plasma cells to multiple front-line therapies including bortezomib, dexamethasone and lenalidomide. Strikingly, in mice bearing AL amyloidosis cell line xenografts, single agent treatment with the BCL-2 inhibitor ABT-199 (venetoclax) produces deeper remissions than bortezomib and triples median survival. Mass spectrometry-based proteomic analysis reveals rewiring of signaling pathways regulating apoptosis, proliferation and mitochondrial metabolism between isogenic AL amyloidosis and multiple myeloma cells that divergently alter their sensitivity to therapies. These findings provide a roadmap for the use of BH3 mimetics to exploit endogenous and induced apoptotic vulnerabilities in AL amyloidosis.

Topics: Amyloid; Animals; Antineoplastic Agents; Bortezomib; Bridged Bicyclo Compounds, Heterocyclic; Dexamethasone; Humans; Immunoglobulin Light Chains; Immunoglobulin Light-chain Amyloidosis; Lenalidomide; Mice; Multiple Myeloma; Myeloid Cell Leukemia Sequence 1 Protein; Proteasome Inhibitors; Proteomics; Proto-Oncogene Proteins c-bcl-2; Sulfonamides

The prognosis of multiple myeloma (MM) has drastically improved owing to the development of new drugs, such as proteasome inhibitors and immunomodulatory drugs. Nevertheless, MM is an extremely challenging disease, and many patients are still refractory to the existing therapies, thus requiring new treatment alternatives. Venetoclax is a selective, orally bioavailable inhibitor of BCL-2 that shows efficacy in MM not only as a single agent but also in combination therapy, especially for MM patients with translocation t(11;14). However, many patients are refractory to this drug. Here, we treated the MM cell lines KMS12PE and KMS27 with a combination treatment of venetoclax targeting BCL-2 and daratumumab targeting CD38 to evaluate the synergistic cytotoxicity of these drugs in vitro. MM cell lines were co-cultured with natural killer (NK) cells at an effector:target ratio of 0.3:1 in the presence of serial concentrations of daratumumab and venetoclax, and the resulting apoptotic MM cells were detected by flow cytometry using annexin V. These results indicated that the antibody-dependent cell-mediated NK cytotoxicity was enhanced in KMS12PE and KMS27 cells harboring t(11;14) with a high BCL-2 expression, suggesting that the combination treatment of venetoclax and daratumumab should be especially effective in patients with these characteristics.

Topics: Antibodies, Monoclonal; Antibody-Dependent Cell Cytotoxicity; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Bridged Bicyclo Compounds, Heterocyclic; Cell Proliferation; Drug Synergism; Gene Expression Regulation, Neoplastic; Humans; Killer Cells, Natural; Multiple Myeloma; Sulfonamides; Tumor Cells, Cultured

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Chromosomes, Human, Pair 11; Chromosomes, Human, Pair 14; Clinical Trials, Phase III as Topic; Drug Resistance, Neoplasm; Female; Follow-Up Studies; Humans; Male; Middle Aged; Molecular Targeted Therapy; Multiple Myeloma; Patient Selection; Prognosis; Progression-Free Survival; Proto-Oncogene Proteins c-bcl-2; Salvage Therapy; Sulfonamides; Translocation, Genetic

A 70-year-old man with medical history of IgG kappa multiple myeloma, initially diagnosed in 2017, underwent induction therapy with carfilzomib, lenalidomide and dexamethasone followed by autologous haematopoietic stem cell transplantation. Nine months following transplant, disease relapsed in the form of plasma cell leukaemia. Fluorescent in situ hybridisation of malignant plasma cells revealed t(11;14). A combination therapy including venetoclax was used based on efficacy data for Bcl-2 inhibitor venetoclax from available early-phase clinical trials in patients with relapsed multiple myeloma with t(11;14) and other published case studies. Unfortunately, the disease was primary refractory, and after further ineffective therapies, the patient did not have a successful outcome.

Topics: Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Dexamethasone; Hematopoietic Stem Cell Transplantation; Humans; In Situ Hybridization, Fluorescence; Lenalidomide; Leukemia, Plasma Cell; Male; Multiple Myeloma; Neoplasm Recurrence, Local; Oligopeptides; Oncogene Proteins, Fusion; Sulfonamides; Translocation, Genetic; Transplantation, Autologous; Treatment Failure

Venetoclax is a highly potent, selective BCL2 inhibitor capable of inducing apoptosis in cells dependent on BCL2 for survival. Most myeloma is MCL1-dependent; however, a subset of myeloma enriched for translocation t(11;14) is codependent on BCL2 and thus sensitive to venetoclax. The biology underlying this heterogeneity remains poorly understood. We show that knockdown of cyclin D1 does not induce resistance to venetoclax, arguing against a direct role for cyclin D1 in venetoclax sensitivity. To identify other factors contributing to venetoclax response, we studied a panel of 31 myeloma cell lines and 25 patient samples tested for venetoclax sensitivity. In cell lines, we corroborated our previous observation that BIM binding to BCL2 correlates with venetoclax response and further showed that knockout of BIM results in decreased venetoclax sensitivity. RNA-sequencing analysis identified expression of B-cell genes as enriched in venetoclax-sensitive myeloma, although no single gene consistently delineated sensitive and resistant cells. However, a panel of cell surface makers correlated well with ex vivo prediction of venetoclax response in 21 patient samples and may serve as a biomarker independent of t(11;14). Assay for transposase-accessible chromatin sequencing of myeloma cell lines also identified an epigenetic program in venetoclax-sensitive cells that was more similar to B cells than that of venetoclax-resistant cells, as well as enrichment for basic leucine zipper domain-binding motifs such as BATF. Together, these data indicate that remnants of B-cell biology are associated with BCL2 dependency and point to novel biomarkers of venetoclax-sensitive myeloma independent of t(11;14).

Topics: B-Lymphocytes; Basic-Leucine Zipper Transcription Factors; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Chromosomes, Human, Pair 11; Chromosomes, Human, Pair 14; Cyclin D1; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Humans; Multiple Myeloma; Proto-Oncogene Proteins c-bcl-2; Sulfonamides; Translocation, Genetic

Topics: Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Decitabine; Female; Humans; Leukemia, Myeloid, Acute; Middle Aged; Multiple Myeloma; Sulfonamides

BH3-mimetics targeting anti-apoptotic proteins such as MCL-1 (S63845) or BCL-2 (venetoclax) are currently being evaluated as effective therapies for the treatment of multiple myeloma (MM). Interleukin 6, produced by mesenchymal stromal cells (MSCs), has been shown to modify the expression of anti-apoptotic proteins and their interaction with the pro-apoptotic BIM protein in MM cells. In this study, we assess the efficacy of S63845 and venetoclax in MM cells in direct co-culture with MSCs derived from MM patients (pMSCs) to identify additional mechanisms involved in the stroma-induced resistance to these agents. MicroRNAs miR-193b-3p and miR-21-5p emerged among the top deregulated miRNAs in myeloma cells when directly co-cultured with pMSCs, and we show their contribution to changes in MCL-1 and BCL-2 protein expression and in the activity of S63845 and venetoclax. Additionally, direct contact with pMSCs under S63845 and/or venetoclax treatment modifies myeloma cell dependence on different BCL-2 family anti-apoptotic proteins in relation to BIM, making myeloma cells more dependent on the non-targeted anti-apoptotic protein or BCL-X

Topics: Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Drug Resistance, Neoplasm; Humans; Multiple Myeloma; Proto-Oncogene Proteins c-bcl-2; Pyrimidines; Sulfonamides; Thiophenes

Topics: Aged; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Bridged Bicyclo Compounds, Heterocyclic; Dexamethasone; Female; Humans; Male; Middle Aged; Multiple Myeloma; Neoplasm Recurrence, Local; Retrospective Studies; Sulfonamides; Treatment Outcome

Multiple myeloma (MM) remains an incurable disease despite incorporation of novel agents. Venetoclax, a B-cell lymphoma 2 (BCL-2) inhibitor is approved for some hematologic malignancies but not yet for MM, although clinical trials have shown efficacy in patients with MM, particularly those harboring t(11;14). We reviewed the medical records of relapsed and/or refractory MM patients to study the efficacy and safety of venetoclax used outside of clinical trials at Mayo Clinic between December, 2016 and March, 2019. The data cut-off date was August 06, 2020. We identified 56 patients of whom 42 (75%) harbored t(11;14). The median number of prior therapies was six (range 1-15) and 14% of patients had received ≥10 prior lines of therapy. Fifty-three (95%) patients were refractory to an immunomodulatory drug and proteasome inhibitor. Venetoclax was used as monotherapy or doublet, in combination with dexamethasone in 55% (n = 31) and a triplet or quadruplet in 45% of patients. No patient experienced tumor lysis syndrome. Overall response rate in 52 evaluable patients was 44%. The median time to best response was 2 months and median duration of response was 13.6 months. The median PFS for the entire cohort was 5.8 (95% CI 4.9-10.3) months and median OS was 28.4 (95% CI 14.6-not reached) months. The presence of t(11;14) was associated with improved PFS (median 9.7 months vs. 4.2 months, p = 0.019) and OS (median not reached vs. 10.8 9 months, p = 0.015). Venetoclax demonstrates encouraging activity in heavily-treated patients with relapsed/refractory MM, particularly the t(11;14) patient-population.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Dexamethasone; Female; Follow-Up Studies; Humans; Male; Middle Aged; Multiple Myeloma; Sulfonamides; Treatment Outcome

Topics: Adult; Aged; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Chromosomes, Human, Pair 11; Chromosomes, Human, Pair 14; Female; Follow-Up Studies; Genes, Immunoglobulin; Humans; Immunoglobulin Heavy Chains; In Situ Hybridization, Fluorescence; Kaplan-Meier Estimate; Male; Middle Aged; Multiple Myeloma; Progression-Free Survival; Proportional Hazards Models; Sulfonamides; Translocation, Genetic; Treatment Outcome; Young Adult

Topics: Bridged Bicyclo Compounds, Heterocyclic; Humans; Multiple Myeloma; Sulfonamides

Topics: Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Humans; Ikaros Transcription Factor; MTOR Inhibitors; Multiple Myeloma; Proto-Oncogene Proteins c-bcl-2; Sulfonamides; TOR Serine-Threonine Kinases; Up-Regulation

CD38 expression on myeloma cells is a critical factor affecting the early response to the anti-CD38 antibody daratumumab. However, factors affecting CD38 expression in untreated multiple myeloma are not fully elucidated. In this study, we found that CD38 expression was significantly lower in myeloma patients with the translocation t(11;14)-associated immature plasma cell phenotype, and particularly in those expressing B-cell-associated genes such as PAX5 and CD79A. CD138, a representative marker of plasmacytic differentiation, was also significantly lower in these patients, suggesting that CD38 expression may be associated with the differentiation and maturation stages of myeloma cells. Furthermore, the BCL2/BCL2L1 ratio, a response marker of the BCL2 inhibitor venetoclax, was significantly higher in patients with the immature phenotype expressing B-cell-associated genes. The BCL2/BCL2L1 ratio and CD38 expression were significantly negatively correlated. We also confirmed that patients with translocation t(11;14) expressing B-cell-associated genes were indeed less sensitive to daratumumab-mediated direct cytotoxicity but highly sensitive to venetoclax treatment in ex vivo assays. Moreover, all-trans-retinoic acid, which enhances CD38 expression and induces cell differentiation in myeloma cells, reduced B-cell marker expression and the BCL2/BCL2L1 ratio in myeloma cell lines, leading to reduced efficacy of venetoclax. Venetoclax specifically induces cell death in myeloma with t(11;14), although why patients with translocation t(11;14) show BCL2 dependence is unclear. These results suggest that BCL2 dependence, as well as CD38 expression, are deeply associated with the differentiation and maturation stages of myeloma cells. This study highlights the importance of examining t(11;14) and considering cell maturity in myeloma treatment strategies.

Topics: ADP-ribosyl Cyclase 1; Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Antineoplastic Agents; B-Lymphocytes; Bridged Bicyclo Compounds, Heterocyclic; Cell Differentiation; Cell Line, Tumor; Chromosomes, Human, Pair 11; Chromosomes, Human, Pair 14; Female; Humans; Male; Membrane Glycoproteins; Middle Aged; Multiple Myeloma; Phenotype; Proto-Oncogene Proteins c-bcl-2; Signal Transduction; Sulfonamides; Translocation, Genetic; Tretinoin

Topics: Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Dexamethasone; Doxorubicin; Humans; Male; Middle Aged; Multiple Myeloma; Neoplasm Recurrence, Local; Oligopeptides; Sulfonamides

Topics: Bridged Bicyclo Compounds, Heterocyclic; Humans; Multiple Myeloma; Renal Dialysis; Sulfonamides

Venetoclax, a small molecule inhibitor of BCL-2, has promising pre-clinical and early clinical activity in relapsed refractory multiple myeloma (RRMM). However, the clinical use of venetoclax remains under evaluation. We performed a single-center, retrospective analysis of patients with RRMM treated with off-label venetoclax. Forty-seven patients with a median of seven lines of prior therapy were identified. Most patients (87%) received venetoclax plus proteasome inhibitor, though there was heterogeneity in the venetoclax-containing regimen patients received, and 38% had known t(11;14). The overall response rate (ORR) was 39%, with 17% achieving ≥ very good partial response (VGPR). In the t(11;14) cohort, the ORR was 71%, with 24% achieving ≥ VGPR. The median progression-free survival was 2.1 months and overall survival was 15.6 months. One treatment-related death (related to infection) occurred. Venetoclax appears safe and efficacious in patients with RRMM, especially in those with t(11;14). Prospective trials are ongoing to further evaluate this treatment.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Cohort Studies; Humans; Multiple Myeloma; Neoplasm Recurrence, Local; Prospective Studies; Retrospective Studies; Sulfonamides; Treatment Outcome

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Bridged Bicyclo Compounds, Heterocyclic; Busulfan; Cell Line, Tumor; Cytotoxins; Deoxycytidine; DNA Fragmentation; Drug Screening Assays, Antitumor; Endoplasmic Reticulum Chaperone BiP; Endoplasmic Reticulum Stress; Gemcitabine; Humans; Melphalan; Membrane Potential, Mitochondrial; Multiple Myeloma; Neoplasm Proteins; Panobinostat; Signal Transduction; Sulfonamides

Topics: Biomarkers; Bridged Bicyclo Compounds, Heterocyclic; Humans; Multiple Myeloma; Sulfonamides

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Dexamethasone; Female; Humans; Male; Middle Aged; Multiple Myeloma; Neoplasm Recurrence, Local; Oligopeptides; Sulfonamides

Venetoclax, an orally available BCL2-selective inhibitor, has demonstrated promising single-agent anti-tumour activity in myeloma especially patients with t(11;14). Herein, whether venetoclax sensitivity could be enhanced or restored in combination with bortezomib or S63845, a novel MCL1-selective inhibitor, was examined in human myeloma cell lines (HMCLs), including bortezomib-resistant HMCLs.. Regardless of t(11;14), combination of venetoclax with S63845 is a promising strategy in enhancing venetoclax sensitivity or overcoming venetoclax resistance in myeloma therapy, hence warrant future clinical studies.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Chromosomes, Human, Pair 11; Chromosomes, Human, Pair 14; Drug Resistance, Neoplasm; Drug Synergism; Humans; Inhibitory Concentration 50; Multiple Myeloma; Myeloid Cell Leukemia Sequence 1 Protein; Proto-Oncogene Proteins c-bcl-2; Pyrimidines; Sulfonamides; Thiophenes; Translocation, Genetic

The BCL-2 antagonist venetoclax is highly effective in multiple myeloma (MM) patients exhibiting the 11;14 translocation, the mechanistic basis of which is unknown. In evaluating cellular energetics and metabolism of t(11;14) and non-t(11;14) MM, we determine that venetoclax-sensitive myeloma has reduced mitochondrial respiration. Consistent with this, low electron transport chain (ETC) Complex I and Complex II activities correlate with venetoclax sensitivity. Inhibition of Complex I, using IACS-010759, an orally bioavailable Complex I inhibitor in clinical trials, as well as succinate ubiquinone reductase (SQR) activity of Complex II, using thenoyltrifluoroacetone (TTFA) or introduction of SDHC R72C mutant, independently sensitize resistant MM to venetoclax. We demonstrate that ETC inhibition increases BCL-2 dependence and the 'primed' state via the ATF4-BIM/NOXA axis. Further, SQR activity correlates with venetoclax sensitivity in patient samples irrespective of t(11;14) status. Use of SQR activity in a functional-biomarker informed manner may better select for MM patients responsive to venetoclax therapy.

Topics: Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Chromosomes, Human, Pair 11; Chromosomes, Human, Pair 14; Drug Resistance, Neoplasm; Electron Transport; Electron Transport Complex I; Electron Transport Complex II; Gene Knockdown Techniques; Humans; Membrane Proteins; Mitochondria; Multiple Myeloma; Mutation; Oxidation-Reduction; Patient Selection; Prognosis; Proto-Oncogene Proteins c-bcl-2; Sulfonamides; Thenoyltrifluoroacetone; Translocation, Genetic

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Bridged Bicyclo Compounds, Heterocyclic; Chromosomes, Human, Pair 11; Chromosomes, Human, Pair 14; Dexamethasone; Female; Follow-Up Studies; Humans; Male; Middle Aged; Multiple Myeloma; Prognosis; Retrospective Studies; Sulfonamides; Survival Rate; Translocation, Genetic

Seventy-six FDA-approved oncology drugs and emerging therapeutics were evaluated in 25 multiple myeloma (MM) and 15 non-Hodgkin's lymphoma cell lines and in 113 primary MM samples. Ex vivo drug sensitivities were mined for associations with clinical phenotype, cytogenetic, genetic mutation, and transcriptional profiles. In primary MM samples, proteasome inhibitors, dinaciclib, selinexor, venetoclax, auranofin, and histone deacetylating agents had the broadest cytotoxicity. Of interest, newly diagnosed patient samples were globally less sensitive especially to bromodomain inhibitors, inhibitors of receptor tyrosine kinases or non-receptor kinases, and DNA synthesis inhibitors. Clustering demonstrated six broad groupings of drug sensitivity linked with genomic biomarkers and clinical outcomes. For example, our findings mimic clinical observations of increased venetoclax responsiveness in t(11;14) patients but also identify an increased sensitivity profile in untreated patients, standard genetic risk, low plasma cell S-Phase, and in the absence of Gain(1q) and t(4;14). In contrast, increased ex vivo responsiveness to selinexor was associated with biomarkers of poor prognosis and later relapse patients. This "direct to drug" screening resource, paired with functional genomics, has the potential to successfully direct appropriate individualized therapeutic approaches in MM and to enrich clinical trials for likely responders.

Topics: Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Drug Screening Assays, Antitumor; Humans; Hydrazines; Multiple Myeloma; Precision Medicine; Sulfonamides; Triazoles; Tumor Cells, Cultured

Topics: Adult; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Humans; Kidney Diseases; Kidney Transplantation; Male; Multiple Myeloma; Sulfonamides

Topics: Aged; Antibodies, Monoclonal; Antineoplastic Agents; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Chromosomes, Human, Pair 11; Chromosomes, Human, Pair 14; Combined Modality Therapy; Drug Resistance, Neoplasm; Female; Humans; Leukemia, Plasma Cell; Multiple Myeloma; Neoplasm Proteins; Neoplasms, Second Primary; Plasma Cells; Plasmapheresis; Progression-Free Survival; Proto-Oncogene Proteins c-bcl-2; Sulfonamides; Translocation, Genetic

Topics: Adult; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Humans; Male; Multiple Myeloma; Sulfonamides

Topics: Bortezomib; Bridged Bicyclo Compounds, Heterocyclic; Dexamethasone; Double-Blind Method; Humans; Multiple Myeloma; Sulfonamides

Topics: Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Humans; Multiple Myeloma; Myeloid Cell Leukemia Sequence 1 Protein; Proto-Oncogene Proteins c-bcl-2; Pyrimidines; Sulfonamides; Thiophenes

Multiple myeloma (MM) is the second most common haematological malignancy. Almost all patients with MM eventually relapse, and most recommended treatment protocols for the patients with relapsed refractory MM comprise a combination of drugs with different mechanisms of action. Therefore novel drugs are in urgent need in clinic. Bcl-2 inhibitors and HDAC inhibitors were proved their anti-MM effect in clinic or under clinical trials, and they were further discovered to have synergistic interactions. In this study, a series of Bcl-2/HDAC dual-target inhibitors were designed and synthesized. Among them, compounds 7e-7g showed good inhibitory activities against HDAC6 and high binding affinities to Bcl-2 protein simultaneously. They also displayed good growth inhibitory activities against human MM cell line RPMI-8226, which proved their potential value for the treatment of multiple myeloma.

Topics: Antineoplastic Agents; Cell Proliferation; Dose-Response Relationship, Drug; Drug Design; Drug Screening Assays, Antitumor; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Models, Molecular; Molecular Structure; Multiple Myeloma; Proto-Oncogene Proteins c-bcl-2; Structure-Activity Relationship

Topics: Antineoplastic Agents; Apoptosis; Biological Assay; Bridged Bicyclo Compounds, Heterocyclic; Drug Resistance, Neoplasm; Humans; Multiple Myeloma; Prognosis; Sulfonamides; Treatment Outcome; Tumor Cells, Cultured

Topics: Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Cellular Microenvironment; Drug Resistance, Neoplasm; Humans; Macrocyclic Compounds; Multiple Myeloma; Myeloid Cell Leukemia Sequence 1 Protein; Proto-Oncogene Proteins c-bcl-2; Sulfonamides

Potent MCL1 inhibitors are showing strong anticancer activity in preclinical models of hematologic cancers, especially when given in combination with other therapies. The drugs are now in phase I testing, with initial clinical results expected soon.

Topics: Animals; Antineoplastic Agents; Apoptosis; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Clinical Trials as Topic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Myeloid, Acute; Mice; Molecular Targeted Therapy; Multiple Myeloma; Myeloid Cell Leukemia Sequence 1 Protein; Proto-Oncogene Proteins c-bcl-2; Sulfonamides; Xenograft Model Antitumor Assays

Topics: Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Drug Approval; Drug Development; Health Services Needs and Demand; Humans; Multiple Myeloma; Patient Safety; Risk Assessment; Sulfonamides; Treatment Outcome; United States; United States Food and Drug Administration

Topics: Antineoplastic Combined Chemotherapy Protocols; Biomarkers; Bridged Bicyclo Compounds, Heterocyclic; Humans; Legislation, Drug; Multiple Myeloma; Randomized Controlled Trials as Topic; Research Design; Sulfonamides; Survival Analysis; Treatment Outcome

The BCL-2-specific BH3-mimetic ABT-199 (venetoclax) has been reported to be principally active against favourable-risk multiple myeloma (MM) cells, prompting efforts to extend its activity to include more resistant, higher-risk MM subsets.. Effects of the CDK9 inhibitor flavopiridol (FP; alvocidib) on responses to ABT-199 were examined in MM cells. Cell death and protein expression were evaluated by western blot and immunofluorescence. Xenograft models were used to study combination effects in vivo.. FP synergistically increased ABT-199 lethality in both ABT-199-sensitive and insensitive MM cells. FP blocked CDK9 activation/positive transcription elongation factor B phosphorylation, downregulated MCL-1, increased BCL-2/MCL-1 ratios, and upregulated BIM. MCL-1 ectopic expression or knockdown in MM cells significantly diminished or increased ABT-199 sensitivity, respectively. CDK9 knockdown triggered MCL-1 downregulation and increased ABT-199 activity, whereas BIM knockdown significantly reduced FP/ABT-199 lethality. FP also enhanced ABT-199 lethality in unfavourable prognosis primary MM cells. HS-5 cell co-culture failed to protect MM cells from the FP/ABT-199 regimen, suggesting circumvention of microenvironmental signals. Finally, FP/ABT-199 significantly increased survival in systemic xenograft and immune-competent MM models while exhibiting minimal toxicity.. These findings argue that CDK9 inhibitors, for example, FP may increase the antimyeloma activity of ABT-199, including in unfavourable-risk MM minimally responsive to ABT-199 alone.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Bcl-2-Like Protein 11; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Cyclin-Dependent Kinase 9; Down-Regulation; Drug Resistance, Neoplasm; Drug Synergism; Flavonoids; Gene Knockdown Techniques; Humans; Mice; Multiple Myeloma; Myeloid Cell Leukemia Sequence 1 Protein; Neoplasm Transplantation; Piperidines; Primary Cell Culture; Proto-Oncogene Proteins c-bcl-2; Risk Assessment; Sulfonamides; Up-Regulation

Topics: Aged; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Bridged Bicyclo Compounds, Heterocyclic; Dexamethasone; Female; Humans; Middle Aged; Multiple Myeloma; Prognosis; Remission Induction; Sulfonamides

Mcl-1 is a member of the Bcl-2 family of proteins that promotes cell survival by preventing induction of apoptosis in many cancers. High expression of Mcl-1 causes tumorigenesis and resistance to anticancer therapies highlighting the potential of Mcl-1 inhibitors as anticancer drugs. Here, we describe AZD5991, a rationally designed macrocyclic molecule with high selectivity and affinity for Mcl-1 currently in clinical development. Our studies demonstrate that AZD5991 binds directly to Mcl-1 and induces rapid apoptosis in cancer cells, most notably myeloma and acute myeloid leukemia, by activating the Bak-dependent mitochondrial apoptotic pathway. AZD5991 shows potent antitumor activity in vivo with complete tumor regression in several models of multiple myeloma and acute myeloid leukemia after a single tolerated dose as monotherapy or in combination with bortezomib or venetoclax. Based on these promising data, a Phase I clinical trial has been launched for evaluation of AZD5991 in patients with hematological malignancies (NCT03218683).

Topics: Animals; Antineoplastic Agents; Apoptosis; Bortezomib; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Crystallography, X-Ray; Humans; Leukemia, Myeloid, Acute; Mice; Mice, Inbred C57BL; Mice, SCID; Multiple Myeloma; Myeloid Cell Leukemia Sequence 1 Protein; Rats; Rats, Nude; Sulfonamides; Xenograft Model Antitumor Assays

Topics: Adult; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Cell Death; Chromosome Deletion; Chromosomes, Human, Pair 11; Chromosomes, Human, Pair 14; Chromosomes, Human, Pair 17; Compassionate Use Trials; Disease Progression; Drug Resistance, Neoplasm; Female; Humans; Leukocytes, Mononuclear; Multiple Myeloma; Sulfonamides; Translocation, Genetic; Treatment Outcome

Topics: Aged; Aged, 80 and over; Aniline Compounds; Antineoplastic Agents; bcl-X Protein; Biological Assay; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Cytochromes c; Female; Gene Expression Regulation, Neoplastic; Humans; Male; Middle Aged; Mitochondria; Multiple Myeloma; Myeloid Cell Leukemia Sequence 1 Protein; Organ Specificity; Peptides; Plasma Cells; Proto-Oncogene Proteins c-bcl-2; Recurrence; Sulfonamides

Multiple myeloma (MM) is a plasma cell malignancy that is largely incurable due to development of resistance to therapy-elicited cell death. Nutrients are intricately connected to maintenance of cellular viability in part by inhibition of apoptosis. We were interested to determine if examination of metabolic regulation of BCL-2 proteins may provide insight on alternative routes to engage apoptosis. MM cells are reliant on glucose and glutamine and withdrawal of either nutrient is associated with varying levels of apoptosis. We and others have demonstrated that glucose maintains levels of key resistance-promoting BCL-2 family member, myeloid cell leukemic factor 1 (MCL-1). Cells continuing to survive in the absence of glucose or glutamine were found to maintain expression of MCL-1 but importantly induce pro-apoptotic BIM expression. One potential mechanism for continued survival despite induction of BIM could be due to binding and sequestration of BIM to alternate pro-survival BCL-2 members. Our investigation revealed that cells surviving glutamine withdrawal in particular, enhance expression and binding of BIM to BCL-2, consequently sensitizing these cells to the BH3 mimetic venetoclax. Glutamine deprivation-driven sensitization to venetoclax can be reversed by metabolic supplementation with TCA cycle intermediate α-ketoglutarate. Inhibition of glucose metabolism with the GLUT4 inhibitor ritonavir elicits variable cytotoxicity in MM that is marginally enhanced with venetoclax treatment, however, targeting glutamine metabolism with 6-diazo-5-oxo-l-norleucine uniformly sensitized MM cell lines and relapse/refractory patient samples to venetoclax. Our studies reveal a potent therapeutic strategy of metabolically driven synthetic lethality involving targeting glutamine metabolism for sensitization to venetoclax in MM.

Topics: Antineoplastic Agents; Bcl-2-Like Protein 11; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Glucose Transporter Type 4; Glutamine; Humans; Multiple Myeloma; Proto-Oncogene Proteins c-bcl-2; Ritonavir; Sulfonamides

Venetoclax (ABT-199), a specific inhibitor of the anti-apoptotic protein Bcl-2, is currently in phase I clinical trials for multiple myeloma. The results suggest that venetoclax is only active in a small cohort of patients therefore we wanted to determine its efficacy when used in combination. Combining venetoclax with melphalan or carfilzomib produced additive or better cell death in four of the five cell lines tested. The most striking results were seen with dexamethasone (Dex). Co-treatment of human myeloma cell lines and primary patient samples, with Dex and venetoclax, significantly increased cell death over venetoclax alone in four of the five cell lines, and in all patient samples tested. The mechanism by which this occurs is an increase in the expression of both Bcl-2 and Bim upon addition of Dex. This results in alterations in Bim binding to anti-apoptotic proteins. Dex shifts Bim binding towards Bcl-2 resulting in increased sensitivity to venetoclax. These data suggest that knowledge of drug-induced alterations of Bim-binding patterns may help inform better combination drug regimens. Furthermore, the data indicate combining this novel therapeutic with Dex could be an effective therapy for a broader range of patients than would be predicted by single-agent activity.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Apoptosis Regulatory Proteins; Bcl-2-Like Protein 11; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Dexamethasone; Humans; Melphalan; Middle Aged; Multiple Myeloma; Oligopeptides; Protein Binding; Proto-Oncogene Proteins c-bcl-2; Sulfonamides; Tumor Cells, Cultured

BCL-2 family proteins dictate survival of human multiple myeloma cells, making them attractive drug targets. Indeed, multiple myeloma cells are sensitive to antagonists that selectively target prosurvival proteins such as BCL-2/BCL-XL (ABT-737 and ABT-263/navitoclax) or BCL-2 only (ABT-199/GDC-0199/venetoclax). Resistance to these three drugs is mediated by expression of MCL-1. However, given the selectivity profile of venetoclax it is unclear whether coexpression of BCL-XL also affects antitumor responses to venetoclax in multiple myeloma. In multiple myeloma cell lines (n = 21), BCL-2 is expressed but sensitivity to venetoclax correlated with high BCL-2 and low BCL-XL or MCL-1 expression. Multiple myeloma cells that coexpress BCL-2 and BCL-XL were resistant to venetoclax but sensitive to a BCL-XL-selective inhibitor (A-1155463). Multiple myeloma xenograft models that coexpressed BCL-XL or MCL-1 with BCL-2 were also resistant to venetoclax. Resistance to venetoclax was mitigated by cotreatment with bortezomib in xenografts that coexpressed BCL-2 and MCL-1 due to upregulation of NOXA, a proapoptotic factor that neutralizes MCL-1. In contrast, xenografts that expressed BCL-XL, MCL-1, and BCL-2 were more sensitive to the combination of bortezomib with a BCL-XL selective inhibitor (A-1331852) but not with venetoclax cotreatment when compared with monotherapies. IHC of multiple myeloma patient bone marrow biopsies and aspirates (n = 95) revealed high levels of BCL-2 and BCL-XL in 62% and 43% of evaluable samples, respectively, while 34% were characterized as BCL-2(High)/BCL-XL (Low) In addition to MCL-1, our data suggest that BCL-XL may also be a potential resistance factor to venetoclax monotherapy and in combination with bortezomib. Mol Cancer Ther; 15(5); 1132-44. ©2016 AACR.

Topics: Animals; Antineoplastic Agents; Bcl-2-Like Protein 11; bcl-X Protein; Bortezomib; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Disease Models, Animal; Drug Resistance, Neoplasm; Drug Therapy, Combination; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; Mice; Multiple Myeloma; Myeloid Cell Leukemia Sequence 1 Protein; Protein Binding; Proto-Oncogene Proteins c-bcl-2; Sulfonamides; Xenograft Model Antitumor Assays

As myeloma cells actively produce and secrete immunoglobulins, they are prone to ER stress, which if unresolved leads to apoptosis. We found that myeloma cell death induced by the ER stressor Thapsigargin was highly variable, ranging from 2 to 89%. Induction of ATF4 and CHOP was observed in myeloma cells under Thapsigargin independently of cell death. The decrease in Mcl-1 was associated with protein translation inhibition and identified as a crucial factor in Thapsigargin sensitivity, since it was the only Bcl-2 family protein differentially modified between sensitive and resistant myeloma cells. Bak but not Bax was found to contribute to Thapsigargin-induced apoptosis. Appropriately, a basal Mcl-1/Bak interaction was demonstrated in Thapsigargin-sensitive cells. Of note, the only pro-apoptotic protein freed from Mcl-1 under Thapsigargin was Bak, whereas Mcl-1/Noxa or Mcl-1/Bim complexes were simultaneously increased. Thus, the disruption of the basal Mcl-1/Bak complex in Thapsigargin-sensitive cells seemed to be an essential event in cell death induction, probably favored by the induced Noxa and Bim BH3-only proteins. These findings underscore the implication of the Mcl-1/Bak axis in myeloma cell death triggered by Thapsigargin.

Topics: Antineoplastic Agents; Apoptosis; bcl-2 Homologous Antagonist-Killer Protein; Bcl-2-Like Protein 11; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Dose-Response Relationship, Drug; Down-Regulation; Drug Resistance, Neoplasm; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Gene Expression Regulation, Neoplastic; Humans; Mitochondria; Multiple Myeloma; Myeloid Cell Leukemia Sequence 1 Protein; Protein Binding; Proto-Oncogene Proteins c-bcl-2; RNA Interference; Signal Transduction; Sulfonamides; Thapsigargin; Transfection

Bcl-2 inhibits apoptosis by two distinct mechanisms but only one is targeted to treat Bcl-2-positive malignancies. In this mechanism, the BH1-3 domains of Bcl-2 form a hydrophobic pocket, binding and inhibiting pro-apoptotic proteins, including Bim. In the other mechanism, the BH4 domain mediates interaction of Bcl-2 with inositol 1,4, 5-trisphosphate receptors (IP3Rs), inhibiting pro-apoptotic Ca2+ signals. The current anti-Bcl-2 agents, ABT-263 (Navitoclax) and ABT-199 (Venetoclax), induce apoptosis by displacing pro-apoptotic proteins from the hydrophobic pocket, but do not inhibit Bcl-2-IP3R interaction. Therefore, to target this interaction we developed BIRD-2 (Bcl-2 IP3 Receptor Disruptor-2), a decoy peptide that binds to the BH4 domain, blocking Bcl-2-IP3R interaction and thus inducing Ca2+-mediated apoptosis in chronic lymphocytic leukemia, multiple myeloma, and follicular lymphoma cells, including cells resistant to ABT-263, ABT-199, or the Bruton's tyrosine kinase inhibitor Ibrutinib. Moreover, combining BIRD-2 with ABT-263 or ABT-199 enhances apoptosis induction compared to single agent treatment. Overall, these findings provide strong rationale for developing novel therapeutic agents that mimic the action of BIRD-2 in targeting the BH4 domain of Bcl-2 and disrupting Bcl-2-IP3R interaction.

Topics: Aniline Compounds; Animals; Apoptosis; bcl-2-Associated X Protein; Bridged Bicyclo Compounds, Heterocyclic; Calcium Signaling; Cell Line, Tumor; Cell Survival; Drug Resistance, Neoplasm; HEK293 Cells; Humans; Hydrophobic and Hydrophilic Interactions; Immunohistochemistry; Inositol 1,4,5-Trisphosphate Receptors; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Follicular; Mice; Mice, Nude; Multiple Myeloma; Neoplasm Transplantation; NIH 3T3 Cells; Peptides; Protein Structure, Tertiary; Proto-Oncogene Proteins c-bcl-2; Sulfonamides

Topics: Adult; Aged; Aged, 80 and over; Bridged Bicyclo Compounds, Heterocyclic; Chromosomes, Human, Pair 11; Chromosomes, Human, Pair 14; Female; Humans; Male; Middle Aged; Multiple Myeloma; Proto-Oncogene Proteins c-bcl-2; Sulfonamides