pci-32765 and carfilzomib

Patients with multiple myeloma (MM) inevitably relapse on initial treatment regimens, and novel combination therapies are needed. Ibrutinib is a first-in-class, once-daily inhibitor of Bruton's tyrosine kinase, an enzyme implicated in growth and survival of MM cells. Preclinical data suggest supra-additivity or synergy between ibrutinib and proteasome inhibitors (PIs) against MM. This phase 1/2b study evaluated the efficacy and safety of ibrutinib plus the PI carfilzomib and dexamethasone in patients with relapsed/refractory MM (RRMM). In this final analysis, we report results in patients who received the recommended phase 2 dose (RP2D; ibrutinib 840 mg and carfilzomib 36 mg/m

Topics: Adenine; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Drug Resistance, Neoplasm; Female; Follow-Up Studies; Humans; Male; Middle Aged; Multiple Myeloma; Neoplasm Recurrence, Local; Oligopeptides; Piperidines; Prognosis; Pyrazoles; Pyrimidines; Salvage Therapy; Survival Rate

Topics: Adenine; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Humans; Lymphoma, Mantle-Cell; Middle Aged; Neoplasm Recurrence, Local; Oligopeptides; Piperidines; Pyrazoles; Pyrimidines

This phase 1, dose-finding study investigated ibrutinib and carfilzomib ± dexamethasone in patients with relapsed or relapsed/refractory multiple myeloma (≥2 lines of therapy including bortezomib and an immunomodulatory agent). Of 43 patients enrolled, 74% were refractory to bortezomib and 23% had high-risk cytogenetics. No dose-limiting toxicities were observed. The recommended phase 2 dose was ibrutinib 840 mg and carfilzomib 36 mg/m

Topics: Adenine; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Diarrhea; Disease-Free Survival; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Fatigue; Female; Humans; Male; Middle Aged; Multiple Myeloma; Neoplasm Recurrence, Local; Oligopeptides; Outcome Assessment, Health Care; Piperidines; Pyrazoles; Pyrimidines

Topics: Adenine; Aniline Compounds; COVID-19 Drug Treatment; Drug Repositioning; Hematologic Neoplasms; Humans; Imatinib Mesylate; Janus Kinases; Nitriles; Oligopeptides; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Quinolines

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bendamustine Hydrochloride; Cyclophosphamide; Dopamine D2 Receptor Antagonists; Doxorubicin; Drug Resistance, Neoplasm; Drug Substitution; Heterocyclic Compounds, 4 or More Rings; Humans; Imidazoles; Lymphocytes, Tumor-Infiltrating; Lymphoma, Mantle-Cell; Male; Molecular Targeted Therapy; Neoplasm Proteins; Oligopeptides; Piperidines; Prednisone; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Pyrimidines; Rituximab; Stress, Physiological; Vincristine

Topics: Adenine; Humans; Multiple Myeloma; Oligopeptides; Piperidines; Pyrazoles; Pyrimidines

Topics: Adenine; Aged; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Blotting, Western; Female; Humans; In Vitro Techniques; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Oligopeptides; Piperidines; Proteasome Inhibitors; Pyrazoles; Pyrimidines; Tumor Cells, Cultured

Waldenström macroglobulinemia (WM) is a B-cell neoplasm manifested by the accumulation of clonal immunoglobulin (Ig)M-secreting lymphoplasmacytic cells. MYD88 and CXCR4 warts, hypogammaglobulinemia, infections, myelokathexis syndrome-like somatic mutations are present in >90% and 30% to 35% of WM patients, respectively, and impact disease presentation, treatment outcome, and overall survival. Familial predisposition is common in WM. Asymptomatic patients should be observed. Patients with disease-related hemoglobin <10 g/L, platelets <100 × 10(9)/L, bulky adenopathy and/or organomegaly, symptomatic hyperviscosity, peripheral neuropathy, amyloidosis, cryoglobulinemia, cold-agglutinin disease, or transformed disease should be considered for therapy. Plasmapheresis should be used for patients with symptomatic hyperviscosity and before rituximab for those with high serum IgM levels to preempt a symptomatic IgM flare. Treatment choice should take into account specific goals of therapy, necessity for rapid disease control, risk of treatment-related neuropathy, immunosuppression and secondary malignancies, and planning for future autologous stem cell transplantation. Frontline treatments include rituximab alone or rituximab combined with alkylators (bendamustine and cyclophosphamide), proteasome inhibitors (bortezomib and carfilzomib), nucleoside analogs (fludarabine and cladribine), and ibrutinib. In the salvage setting, an alternative frontline regimen, ibrutinib, everolimus, or stem cell transplantation can be considered. Investigational therapies under development for WM include agents that target MYD88, CXCR4, BCL2, and CD27/CD70 signaling, novel proteasome inhibitors, and chimeric antigen receptor-modified T-cell therapy.

Topics: Adenine; Adult; Aged; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; B-Lymphocytes; Bendamustine Hydrochloride; Boronic Acids; Bortezomib; Cladribine; Cyclophosphamide; Everolimus; Gene Expression; Genetic Predisposition to Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunoglobulin M; Male; Middle Aged; Molecular Targeted Therapy; Myeloid Differentiation Factor 88; Nitrogen Mustard Compounds; Oligopeptides; Piperidines; Plasmapheresis; Pyrazines; Pyrazoles; Pyrimidines; Receptors, CXCR4; Rituximab; Sirolimus; Transplantation, Autologous; Vidarabine; Waldenstrom Macroglobulinemia

Proteasome-inhibiting drugs (PI) are gaining importance in hematologic oncology. The proteasome carries three proteolytically active subunits (β1, β2, β5). All established PI (bortezomib and carfilzomib), as well as experimental drugs in the field (dalanzomib, oprozomib, and ixazomib), by design target the rate-limiting β5 subunit. It is unknown whether β2-selective proteasome inhibition can also be exploited toward anticancer treatment. Combining PI with the pan B-cell-directed Bruton tyrosine kinase inhibitor ibrutinib appears a natural option for future improved treatment of multiple myeloma (MM) and B-cell lymphomas. However, bortezomib induces phosphorylation of IκB and activation of NF-κB in MM cells, while ibrutinib inhibits the IκB/NF-κB axis, suggesting antagonistic signaling. A β2-selective proteasome inhibitor may lack such antagonistic signaling effects.. We recently introduced LU-102, the first β2-selective PI available for preclinical testing. We here compare bortezomib with carfilzomib and LU-102 in MM and MCL in vitro with regard to their effects on pIκB/NF-κB signaling and their cytotoxic activity in combination with ibrutinib.. LU-102 reduced phosphorylation of IκB, in contrast to bortezomib and carfilzomib, and was a superior inhibitor of NF-κB activation in MM cells. This translated into highly synergistic cytotoxicity between LU-102 and ibrutinib, which was able to overcome BTZ resistance and CFZ resistance. By contrast, BTZ lacked consistent synergistic cytotoxicity with ibrutinib.. Ibrutinib is highly synergistic with β2-selective proteasome inhibition against MM and MCL in vitro. Novel β2-selective proteasome inhibitors may be exploited to overcome bortezomib/carfilzomib resistance and boost the activity of BTK inhibitors against B-cell-derived malignancies.

Topics: Adenine; Antineoplastic Agents; Boronic Acids; Bortezomib; Cell Line, Tumor; Drug Resistance, Neoplasm; Drug Synergism; Humans; I-kappa B Proteins; Lymphoma, Mantle-Cell; Multiple Myeloma; Oligopeptides; Phosphorylation; Piperidines; Proteasome Inhibitors; Pyrazines; Pyrazoles; Pyrimidines

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Antineoplastic Agents; Humans; Isoquinolines; Leukemia, Lymphocytic, Chronic, B-Cell; Molecular Targeted Therapy; Oligopeptides; Phosphoinositide-3 Kinase Inhibitors; Piperidines; Protein-Tyrosine Kinases; Proto-Oncogene Proteins c-bcl-2; Purines; Pyrazoles; Pyrimidines; Signal Transduction