abt-199 and carfilzomib

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

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

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

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