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1.
N Engl J Med ; 389(11): 1009-1022, 2023 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-37646702

RESUMO

BACKGROUND: Despite recent progress, multiple myeloma remains incurable. Mezigdomide is a novel cereblon E3 ubiquitin ligase modulator with potent antiproliferative and tumoricidal activity in preclinical models of multiple myeloma, including those resistant to lenalidomide and pomalidomide. METHODS: In this phase 1-2 study, we administered oral mezigdomide in combination with dexamethasone to patients with relapsed and refractory myeloma. The primary objectives of phase 1 (dose-escalation cohort) were to assess safety and pharmacokinetics and to identify the dose and schedule for phase 2. In phase 2 (dose-expansion cohort), objectives included the assessment of the overall response (partial response or better), safety, and efficacy of mezigdomide plus dexamethasone at the dose and schedule determined in phase 1. RESULTS: In phase 1, a total of 77 patients were enrolled in the study. The most common dose-limiting toxic effects were neutropenia and febrile neutropenia. On the basis of the phase 1 findings, investigators determined the recommended phase 2 dose of mezigdomide to be 1.0 mg, given once daily in combination with dexamethasone for 21 days, followed by 7 days off, in each 28-day cycle. In phase 2, a total of 101 patients received the dose identified in phase 1 in the same schedule. All patients in the dose-expansion cohort had triple-class-refractory multiple myeloma, 30 patients (30%) had received previous anti-B-cell maturation antigen (anti-BCMA) therapy, and 40 (40%) had plasmacytomas. The most common adverse events, almost all of which proved to be reversible, included neutropenia (in 77% of the patients) and infection (in 65%; grade 3, 29%; grade 4, 6%). No unexpected toxic effects were encountered. An overall response occurred in 41% of the patients (95% confidence interval [CI], 31 to 51), the median duration of response was 7.6 months (95% CI, 5.4 to 9.5; data not mature), and the median progression-free survival was 4.4 months (95% CI, 3.0 to 5.5), with a median follow-up of 7.5 months (range, 0.5 to 21.9). CONCLUSIONS: The all-oral combination of mezigdomide plus dexamethasone showed promising efficacy in patients with heavily pretreated multiple myeloma, with treatment-related adverse events consisting mainly of myelotoxic effects. (Funded by Celgene, a Bristol-Myers Squibb Company; CC-92480-MM-001 ClinicalTrials.gov number, NCT03374085; EudraCT number, 2017-001236-19.).


Assuntos
Antineoplásicos , Dexametasona , Mieloma Múltiplo , Ubiquitina-Proteína Ligases , Humanos , Anticorpos , Dexametasona/administração & dosagem , Dexametasona/efeitos adversos , Dexametasona/uso terapêutico , Lenalidomida/efeitos adversos , Mieloma Múltiplo/tratamento farmacológico , Neutropenia/induzido quimicamente , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Administração Oral , Recidiva
2.
Blood ; 2024 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-39321347

RESUMO

Dexamethasone is a key component of induction for newly diagnosed multiple myeloma (NDMM) despite common toxicities including hyperglycemia and insomnia. In the randomized ECOG E4A03 trial, dexamethasone 40 milligrams (mg) once weekly was associated with lower mortality than higher doses of dexamethasone. However, the performance of dexamethasone dose reductions below this threshold with regard to progression-free survival (PFS) and overall survival (OS) in NDMM have not been fully characterized. We conducted a secondary pooled analysis of the S0777 and S1211 SWOG studies of NDMM, which employed lenalidomide-dexamethasone (Rd) alone with or without bortezomib (VRd) and with or without elotuzumab (Elo-VRd). Planned dexamethasone intensity was 40-60 mg weekly in all arms. Patients were categorized into FD-DEX (full-dose dexamethasone maintained throughout induction) or LD-DEX (lowered-dose dexamethasone or discontinuation; only permitted for Grade 3+ toxicities per both study protocols). Of 541 evaluated patients, the LD-DEX group comprised 373 patients (69%). There was no difference in PFS or OS between the FD-DEX or LD-DEX groups, which were balanced in terms of age, stage, and performance status. Predictors of PFS and OS in multivariate models were treatment arm, age ≥70, and thrombocytopenia; FD-DEX did not significantly improve either outcome. Our study suggests that dexamethasone dose reductions are common in multiple myeloma, even within clinical trials. Given dexamethasone's many toxicities and unclear benefit in the era of modern treatment regimens, dexamethasone dose reduction during NDMM induction warrants further prospective study. NCT00644228, NCT01668719.

3.
Blood ; 143(25): 2612-2626, 2024 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-38551812

RESUMO

ABSTRACT: Immunogenic cell death (ICD) is a form of cell death by which cancer treatments can induce a clinically relevant antitumor immune response in a broad range of cancers. In multiple myeloma (MM), the proteasome inhibitor bortezomib is an ICD inducer and creates durable therapeutic responses in patients. However, eventual relapse and resistance to bortezomib appear inevitable. Here, by integrating patient transcriptomic data with an analysis of calreticulin (CRT) protein interactors, we found that GABA type A receptor-associated protein (GABARAP) is a key player whose loss prevented tumor cell death from being perceived as immunogenic after bortezomib treatment. GABARAP is located on chromosome 17p, which is commonly deleted in patients with high risk MM. GABARAP deletion impaired the exposure of the eat-me signal CRT on the surface of dying MM cells in vitro and in vivo, thus reducing tumor cell phagocytosis by dendritic cells and the subsequent antitumor T-cell response. Low GABARAP was independently associated with shorter survival in patients with MM and reduced tumor immune infiltration. Mechanistically, we found that GABARAP deletion blocked ICD signaling by decreasing autophagy and altering Golgi apparatus morphology, with consequent defects in the downstream vesicular transport of CRT. Conversely, upregulating autophagy using rapamycin restored Golgi morphology, CRT exposure, and ICD signaling in GABARAPKO cells undergoing bortezomib treatment. Therefore, coupling an ICD inducer, such as bortezomib, with an autophagy inducer, such as rapamycin, may improve patient outcomes in MM, in which low GABARAP in the form of del(17p) is common and leads to worse outcomes.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal , Proteínas Reguladoras de Apoptose , Resistencia a Medicamentos Antineoplásicos , Proteínas Associadas aos Microtúbulos , Mieloma Múltiplo , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/patologia , Mieloma Múltiplo/imunologia , Mieloma Múltiplo/genética , Humanos , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Camundongos , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Bortezomib/farmacologia , Bortezomib/uso terapêutico , Calreticulina/metabolismo , Calreticulina/genética , Morte Celular Imunogênica/efeitos dos fármacos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Autofagia/efeitos dos fármacos
4.
Cell ; 146(6): 904-17, 2011 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-21889194

RESUMO

MYC contributes to the pathogenesis of a majority of human cancers, yet strategies to modulate the function of the c-Myc oncoprotein do not exist. Toward this objective, we have targeted MYC transcription by interfering with chromatin-dependent signal transduction to RNA polymerase, specifically by inhibiting the acetyl-lysine recognition domains (bromodomains) of putative coactivator proteins implicated in transcriptional initiation and elongation. Using a selective small-molecule bromodomain inhibitor, JQ1, we identify BET bromodomain proteins as regulatory factors for c-Myc. BET inhibition by JQ1 downregulates MYC transcription, followed by genome-wide downregulation of Myc-dependent target genes. In experimental models of multiple myeloma, a Myc-dependent hematologic malignancy, JQ1 produces a potent antiproliferative effect associated with cell-cycle arrest and cellular senescence. Efficacy of JQ1 in three murine models of multiple myeloma establishes the therapeutic rationale for BET bromodomain inhibition in this disease and other malignancies characterized by pathologic activation of c-Myc.


Assuntos
Antineoplásicos/farmacologia , Descoberta de Drogas , Mieloma Múltiplo/tratamento farmacológico , Proteínas Proto-Oncogênicas c-myc/antagonistas & inibidores , Animais , Antineoplásicos/química , Azepinas/química , Azepinas/farmacologia , Benzodiazepinas/química , Benzodiazepinas/farmacologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Humanos , Camundongos , Proteínas Nucleares/química , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Estrutura Terciária de Proteína , Proteínas Proto-Oncogênicas c-myc/genética , Ativação Transcricional/efeitos dos fármacos , Triazóis/química , Triazóis/farmacologia
5.
N Engl J Med ; 387(2): 132-147, 2022 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-35660812

RESUMO

BACKGROUND: In patients with newly diagnosed multiple myeloma, the effect of adding autologous stem-cell transplantation (ASCT) to triplet therapy (lenalidomide, bortezomib, and dexamethasone [RVD]), followed by lenalidomide maintenance therapy until disease progression, is unknown. METHODS: In this phase 3 trial, adults (18 to 65 years of age) with symptomatic myeloma received one cycle of RVD. We randomly assigned these patients, in a 1:1 ratio, to receive two additional RVD cycles plus stem-cell mobilization, followed by either five additional RVD cycles (the RVD-alone group) or high-dose melphalan plus ASCT followed by two additional RVD cycles (the transplantation group). Both groups received lenalidomide until disease progression, unacceptable side effects, or both. The primary end point was progression-free survival. RESULTS: Among 357 patients in the RVD-alone group and 365 in the transplantation group, at a median follow-up of 76.0 months, 328 events of disease progression or death occurred; the risk was 53% higher in the RVD-alone group than in the transplantation group (hazard ratio, 1.53; 95% confidence interval [CI], 1.23 to 1.91; P<0.001); median progression-free survival was 46.2 months and 67.5 months. The percentage of patients with a partial response or better was 95.0% in the RVD-alone group and 97.5% in the transplantation group (P = 0.55); 42.0% and 46.8%, respectively, had a complete response or better (P = 0.99). Treatment-related adverse events of grade 3 or higher occurred in 78.2% and 94.2%, respectively; 5-year survival was 79.2% and 80.7% (hazard ratio for death, 1.10; 95% CI, 0.73 to 1.65). CONCLUSIONS: Among adults with multiple myeloma, RVD plus ASCT was associated with longer progression-free survival than RVD alone. No overall survival benefit was observed. (Funded by the National Heart, Lung, and Blood Institute and others; DETERMINATION ClinicalTrials.gov number, NCT01208662.).


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Quimioterapia de Manutenção , Mieloma Múltiplo , Transplante de Células-Tronco , Adulto , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bortezomib/administração & dosagem , Bortezomib/efeitos adversos , Dexametasona/administração & dosagem , Dexametasona/efeitos adversos , Progressão da Doença , Intervalo Livre de Doença , Humanos , Lenalidomida/administração & dosagem , Lenalidomida/efeitos adversos , Quimioterapia de Manutenção/métodos , Melfalan/administração & dosagem , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/cirurgia , Transplante Autólogo
6.
Blood ; 141(14): 1724-1736, 2023 04 06.
Artigo em Inglês | MEDLINE | ID: mdl-36603186

RESUMO

High-dose melphalan (HDM) improves progression-free survival in multiple myeloma (MM), yet melphalan is a DNA-damaging alkylating agent; therefore, we assessed its mutational effect on surviving myeloma cells by analyzing paired MM samples collected at diagnosis and relapse in the IFM 2009 study. We performed deep whole-genome sequencing on samples from 68 patients, 43 of whom were treated with RVD (lenalidomide, bortezomib, and dexamethasone) and 25 with RVD + HDM. Although the number of mutations was similar at diagnosis in both groups (7137 vs 7230; P = .67), the HDM group had significantly more mutations at relapse (9242 vs 13 383, P = .005). No change in the frequency of copy number alterations or structural variants was observed. The newly acquired mutations were typically associated with DNA damage and double-stranded breaks and were predominantly on the transcribed strand. A machine learning model, using this unique pattern, predicted patients who would receive HDM with high sensitivity, specificity, and positive prediction value. Clonal evolution analysis showed that all patients treated with HDM had clonal selection, whereas a static progression was observed with RVD. A significantly higher percentage of mutations were subclonal in the HDM cohort. Intriguingly, patients treated with HDM who achieved complete remission (CR) had significantly more mutations at relapse yet had similar survival rates as those treated with RVD who achieved CR. This similarity could have been due to HDM relapse samples having significantly more neoantigens. Overall, our study identifies increased genomic changes associated with HDM and provides rationale to further understand clonal complexity.


Assuntos
Mieloma Múltiplo , Humanos , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/genética , Mieloma Múltiplo/diagnóstico , Melfalan/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/genética , Bortezomib/uso terapêutico , Lenalidomida/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Doença Crônica , Transplante Autólogo , Dexametasona/uso terapêutico
7.
Br J Haematol ; 205(3): 780-797, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39031440

RESUMO

The growing use of frontline lenalidomide treatment in multiple myeloma (MM) is increasing the proportion of lenalidomide-refractory patients, which may limit the efficacy of subsequent lines of treatment (LOT). This systematic literature review (January 2008-October 2023) of clinical trials (CT) and real-world studies (RW) assessed treatment outcomes in adults with relapsed/refractory MM (RRMM) who were previously treated with ≥1 LOT, progressed and were lenalidomide-refractory. Medline, EMBASE and additional electronic databases were searched for articles published in English. Primary outcomes included progression-free survival (PFS), overall survival (OS) and overall/objective response rate (ORR); 24 CT and 19 RW were included. For CT, the population-weighted mean of median PFS (CT = 14) and OS (CT = 6) were shorter in the lenalidomide-refractory cohort (months: 8.8 [n = 2699] and 21.7 [n = 1066], respectively) than the intent-to-treat population (months: 13.8 [n = 5380] and 35.9 [n = 2264], respectively); the population-weighted (N = 2142) mean ORR for lenalidomide-refractory patients (CT = 18) was 56.0%. RW reported considerable variation in PFS (RW = 7), OS (RW = 8) and ORR (RW = 8); and median PFS (RW = 2; months) was lower in lenalidomide/bortezomib-refractory (5.5/5.5; n = 81/n = 25) versus lenalidomide-refractory (7.3/8.0; n = 81/n = 61) patients. These data provide evidence that clinical trials and real-world outcomes are suboptimal in lenalidomide-refractory patients with RRMM, highlighting the need to improve treatment options for this population.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Lenalidomida , Mieloma Múltiplo , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/mortalidade , Lenalidomida/uso terapêutico , Lenalidomida/administração & dosagem , Humanos , Ensaios Clínicos como Assunto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico
8.
Br J Haematol ; 204(6): 2227-2232, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38504552

RESUMO

Due in part to racial disparities and underrepresentation in clinical studies, optimal therapies for Black patients with multiple myeloma remain undefined. This final analysis of GRIFFIN by race showed that the addition of daratumumab (D) to lenalidomide/bortezomib/dexamethasone (RVd) provides clinical benefit among both Black and White transplant-eligible newly diagnosed patients compared with RVd alone. However, Black patients were more likely to discontinue ≥1 drug due to treatment-emergent adverse events. In summary, these findings suggest a benefit of D-RVd front-line therapy among Black and White patients and underscore the importance of equitable treatment access for all patients.


Assuntos
Anticorpos Monoclonais , Protocolos de Quimioterapia Combinada Antineoplásica , Bortezomib , Dexametasona , Lenalidomida , Mieloma Múltiplo , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Negro ou Afro-Americano , Bortezomib/administração & dosagem , Bortezomib/efeitos adversos , Bortezomib/uso terapêutico , Dexametasona/administração & dosagem , Dexametasona/efeitos adversos , Dexametasona/uso terapêutico , Lenalidomida/administração & dosagem , Lenalidomida/efeitos adversos , Lenalidomida/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Brancos
9.
Haematologica ; 109(8): 2585-2593, 2024 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-38426294

RESUMO

TOURMALINE-MM1, the only blinded randomized study in patients with relapsed and/or refractory multiple myeloma (RRMM; ≥1 prior therapy) in the last 10 years, investigated ixazomib + lenalidomide + dexamethasone (IRd) versus lenalidomide + dexamethasone (Rd). Final overall survival (OS) data were based on a median follow-up of 85 months. In RRMM trials where patients have had 1-3 relapses after initial treatment, a high proportion receive subsequent therapy. Application of salvage therapies in blinded trials and newer modes of therapy can increasingly complicate the interpretation of OS. This analysis explores the impact of subsequent therapies on OS outcomes in TOURMALINE-MM1. The inverse probability of censoring weights (IPCW) method, marginal structural model (MSM), and rank-preserving structural failure time model (RPSFTM) were utilized to adjust for confounding on OS, introduced by subsequent therapies. Analyses were conducted for the intent-totreat (ITT) population and ≥2 prior lines subgroup. Unadjusted hazard ratio (HR) for IRd versus Rd was 0.94 (95% confidence interval [CI]: 0.78-1.13) in the ITT population. After adjusting for the impact of subsequent therapies by the RPSFTM method, estimated HR for IRd versus Rd in the ITT population was 0.89 (95% CI: 0.74-1.07). Adjusting with IPCW and MSM methods also showed an improvement in HR, favoring IRd. IRd may be particularly beneficial in patients with ≥2 prior lines of therapy (IPCW and MSM HR=0.52, 95% CI: 0.30-0.88; RPSFTM HR=0.68, 95% CI: 0.51-0.91). These analyses highlight the growing challenge of demonstrating OS benefit in MM patients and the importance of assessing confounding introduced by subsequent therapies when interpreting OS.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Compostos de Boro , Dexametasona , Glicina , Lenalidomida , Mieloma Múltiplo , Humanos , Glicina/análogos & derivados , Glicina/uso terapêutico , Glicina/administração & dosagem , Lenalidomida/administração & dosagem , Lenalidomida/uso terapêutico , Dexametasona/administração & dosagem , Dexametasona/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/mortalidade , Compostos de Boro/administração & dosagem , Compostos de Boro/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Feminino , Masculino , Idoso , Pessoa de Meia-Idade , Resultado do Tratamento
10.
Haematologica ; 109(3): 867-876, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-37646657

RESUMO

Melphalan flufenamide (melflufen), a first-in-class, alkylating peptide-drug conjugate, demonstrated clinical benefit in combination with dexamethasone in triple-class refractory multiple myeloma (MM). The phase I/IIa ANCHOR study evaluated melflufen (30 or 40 mg) and dexamethasone (40 mg with daratumumab; 20 mg followed by 40 mg with bortezomib; dose reduced if aged ≥75 years) in triplet combination with daratumumab (16 mg/kg; daratumumab arm) or bortezomib (1.3 mg/m2; bortezomib arm) in patients with relapsed/refractory MM refractory to an immunomodulatory agent and/or a proteasome inhibitor and who had received one to four prior lines of therapy. Primary objectives were to determine the optimal dose of melflufen in triplet combination (phase I) and overall response rate (phase IIa). In total, 33 patients were treated in the daratumumab arm and 23 patients received therapy in the bortezomib arm. No dose-limiting toxicities were reported at either melflufen dose level with either combination. With both triplet regimens, the most common grade ≥3 treatment-emergent adverse events were thrombocytopenia and neutropenia; thrombocytopenia was the most common treatment-emergent adverse event leading to treatment discontinuation. In the daratumumab arm, patients receiving melflufen 30 mg remained on treatment longer than those receiving the 40-mg dose. In the daratumumab arm, the overall response rate was 73% and median progression-free survival was 12.9 months. Notably, in the bortezomib arm, the overall response rate was 78% and median progression-free survival was 14.7 months. Considering the totality of the data, melflufen 30 mg was established as the recommended dose for use with dexamethasone and daratumumab or bortezomib for future studies in relapsed/refractory MM.


Assuntos
Anticorpos Monoclonais , Melfalan , Mieloma Múltiplo , Neoplasias de Plasmócitos , Neutropenia , Fenilalanina , Trombocitopenia , Humanos , Bortezomib/uso terapêutico , Dexametasona/uso terapêutico , Melfalan/análogos & derivados , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/tratamento farmacológico , Neutropenia/induzido quimicamente , Fenilalanina/análogos & derivados , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos
11.
Haematologica ; 109(3): 895-905, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-37646660

RESUMO

Melphalan flufenamide (melflufen), a first-in-class alkylating peptide-drug conjugate, plus dexamethasone was approved in Europe for use in patients with triple-class refractory relapsed/refractory multiple myeloma (RRMM) with ≥3 prior lines of therapy and without prior autologous stem cell transplantation (ASCT) or with a time to progression >36 months after prior ASCT. The randomized LIGHTHOUSE study (NCT04649060) assessed melflufen plus daratumumab and dexamethasone (melflufen group) versus daratumumab in patients with RRMM with disease refractory to an immunomodulatory agent and a proteasome inhibitor or who had received ≥3 prior lines of therapy including an immunomodulatory agent and a proteasome inhibitor. A partial clinical hold issued by the US Food and Drug Administration for all melflufen studies led to financial constraints and premature study closure on February 23rd 2022 (data cut-off date). In total, 54 of 240 planned patients were randomized (melflufen group, N=27; daratumumab group, N=27). Median progression-free survival (PFS) was not reached in the melflufen group versus 4.9 months in the daratumumab group (Hazard Ratio: 0.18 [95% Confidence Interval, 0.05-0.65]; P=0.0032) at a median follow-up time of 7.1 and 6.6 months, respectively. Overall response rate (ORR) was 59% in the melflufen group versus 30% in the daratumumab group (P=0.0300). The most common grade ≥3 treatment-emergent adverse events in the melflufen group versus daratumumab group were neutropenia (50% vs. 12%), thrombocytopenia (50% vs. 8%), and anemia (32% vs. 19%). Melflufen plus daratumumab and dexamethasone demonstrated superior PFS and ORR versus daratumumab in RRMM and a safety profile comparable to previously published melflufen studies.


Assuntos
Anticorpos Monoclonais , Transplante de Células-Tronco Hematopoéticas , Melfalan , Mieloma Múltiplo , Neoplasias de Plasmócitos , Neutropenia , Fenilalanina , Humanos , Dexametasona/uso terapêutico , Melfalan/análogos & derivados , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/tratamento farmacológico , Fenilalanina/análogos & derivados , Inibidores de Proteassoma , Transplante Autólogo , Estados Unidos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos
12.
Haematologica ; 109(10): 3261-3268, 2024 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-38779740

RESUMO

The coronavirus disease 2019 (COVID-19) pandemic led to an unprecedented burden on healthcare systems around the world and a severe global socioeconomic crisis, with more than 750 million confirmed cases and at least 7 million deaths reported by December 31, 2023. The DEFI-VID19 study (clinicaltrials gov. Identifier: NCT04335201), a phase II, single-arm, multicenter, open-label trial was designed in mid-2020 to assess the safety and efficacy of defibrotide in treating patients with COVID-19 pneumonia. Defibrotide was administered at a dose of 25 mg/kg intravenously, divided into four daily doses over a planned 14-day period for patients with COVID-19 pneumonia receiving non-invasive ventilation. The primary endpoint was respiratory failure-free survival (RFFS). Overall survival (OS), the number of post-recovery days, and adverse events were the secondary endpoints. For comparison, a contemporaneous control cohort receiving standard of care only was retrospectively selected by applying the eligibility criteria of the DEFI-VID19 trial. To adjust for the imbalance between the two cohorts in terms of baseline variable distributions, an outcome regression analysis was conducted. In adjusted analysis, patients receiving defibrotide reported a trend towards higher RFFS (hazard ratio [HR]=0.71; 95% confidence interval [CI]: 0.34-1.29; P=0.138) and OS (HR=0.78; 95% CI: 0.33-1.53; P=0.248]) and showed a significantly increased number of post-recovery days (difference in means =3.61; 95% CI: 0.97-6.26; P=0.0037). Despite concomitant thromboprophylaxis with low molecular weight heparin, the safety profile of defibrotide proved to be favorable. Taken together, our findings suggest that defibrotide may represent a valuable addition to the COVID-19 therapeutic options.


Assuntos
Tratamento Farmacológico da COVID-19 , COVID-19 , Polidesoxirribonucleotídeos , SARS-CoV-2 , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , COVID-19/mortalidade , COVID-19/complicações , COVID-19/epidemiologia , Polidesoxirribonucleotídeos/uso terapêutico , Resultado do Tratamento , Adulto , Idoso de 80 Anos ou mais , Estudos de Coortes , Estudos Retrospectivos
13.
Haematologica ; 109(7): 2239-2249, 2024 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-38299578

RESUMO

The primary and prespecified updated analyses of ICARIA-MM (clinicaltrial gov. Identifier: NCT02990338) demonstrated improved progression-free survival (PFS) and a benefit in overall survival (OS) was reported with the addition of isatuximab, an anti-CD38 monoclonal antibody, to pomalidomide-dexamethasone (Pd) in patients with relapsed/refractory multiple myeloma. Here, we report the final OS analysis. This multicenter, randomized, open-label, phase III study included patients who had received and failed ≥2 previous therapies, including lenalidomide and a proteasome inhibitor. Between January 10, 2017, and February 2, 2018, 307 patients were randomized (1:1) to isatuximab-pomalidomide-dexamethasone (Isa-Pd; N=154) or Pd (N=153), stratified based on age (<75 vs. ≥75 years) and number of previous lines of therapy (2-3 vs. >3). At data cutoff for the final OS analysis after 220 OS events (January 27, 2022), median follow-up duration was 52.4 months. Median OS was 24.6 months (95% confidence interval [CI]: 20.3-31.3) with Isa-Pd and 17.7 months (95% CI: 14.4- 26.2) with Pd (hazard ratio=0.78; 95% CI: 0.59-1.02; 1-sided P=0.0319). Despite subsequent daratumumab use in the Pd group and its potential benefit on PFS in the first subsequent therapy line, median PFS2 was significantly longer with Isa-Pd versus Pd (17.5 vs. 12.9 months; log-rank 1-sided P=0.0091). In this analysis, Isa-Pd continued to be efficacious and well tolerated after follow-up of approximately 52 months, contributing to a clinically meaningful, 6.9-month improvement in median OS in patients with relapsed/refractory multiple myeloma.


Assuntos
Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Dexametasona , Mieloma Múltiplo , Talidomida , Humanos , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Dexametasona/administração & dosagem , Talidomida/análogos & derivados , Talidomida/administração & dosagem , Masculino , Idoso , Feminino , Pessoa de Meia-Idade , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/uso terapêutico , Idoso de 80 Anos ou mais , Adulto , Resistencia a Medicamentos Antineoplásicos , Resultado do Tratamento , Recidiva , Análise de Sobrevida
14.
Eur J Haematol ; 112(3): 402-411, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-37968873

RESUMO

Melphalan flufenamide (melflufen), a first-in-class alkylating peptide-drug conjugate, plus dexamethasone demonstrated superior progression-free survival (PFS), but not overall survival (OS), versus pomalidomide plus dexamethasone in relapsed/refractory multiple myeloma in the OCEAN study. Time to progression (TTP) <36 months after a prior autologous stem cell transplantation (ASCT) was a negative prognostic factor for OS with melflufen. This post hoc exploratory analysis evaluated patients refractory to prior alkylators (e.g., cyclophosphamide and melphalan) in OCEAN. In 153 patients refractory to prior alkylators (melflufen, n = 78; pomalidomide, n = 75), the melflufen and pomalidomide arms had similar median PFS (5.6 months [95% CI, 4.2-8.3] vs. 4.7 months [95% CI, 3.1-7.3]; hazard ratio [HR], 0.92 [95% CI, 0.63-1.33]) and OS (23.4 months [95% CI, 14.4-31.7] vs. 20.0 months [95% CI, 12.0-28.7]; HR, 0.92 [95% CI, 0.62-1.38]). Among alkylator-refractory patients with a TTP ≥ 36 months after a prior ASCT or no prior ASCT (melflufen, n = 54; pomalidomide, n = 53), the observed median PFS and OS were longer in the melflufen arm than the pomalidomide arm. The safety profile of melflufen was consistent with previous reports. These results suggest that melflufen is safe and effective in patients with alkylator-refractory disease, suggesting differentiated activity from other alkylators.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Melfalan/análogos & derivados , Mieloma Múltiplo , Fenilalanina/análogos & derivados , Talidomida/análogos & derivados , Humanos , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/tratamento farmacológico , Melfalan/uso terapêutico , Alquilantes/uso terapêutico , Dexametasona/efeitos adversos , Transplante Autólogo , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos
15.
Eur J Haematol ; 113(2): 242-252, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38693052

RESUMO

OBJECTIVES: To analyze the impact of prior therapies on outcomes with selinexor, bortezomib, and dexamethasone (SVd) versus bortezomib and dexamethasone (Vd) in 402 patients with relapsed/refractory multiple myeloma (RRMM) in the phase 3 BOSTON trial. METHODS: Post hoc analysis of progression-free survival (PFS), overall survival (OS), and safety for lenalidomide-refractory, proteasome inhibitor (PI)-naïve, bortezomib-naïve, and one prior line of therapy (1LOT) patient subgroups. RESULTS: At a median follow-up of over 28 months, clinically meaningful improvements in PFS were noted across all groups with SVd. The median SVd PFS was longer in all subgroups (lenalidomide-refractory: 10.2 vs. 7.1 months, PI-naïve: 29.5 vs. 9.7; bortezomib-naïve: 29.5 vs. 9.7; 1LOT: 21.0 vs. 10.7; p < .05). The lenalidomide-refractory subgroup had longer OS with SVd (26.7 vs. 18.6 months; HR 0.53; p = .015). In all subgroups, overall response and ≥very good partial response rates were higher with SVd. The manageable safety profile of SVd was similar to the overall patient population. CONCLUSIONS: With over 2 years of follow-up, these clinically meaningful outcomes further support the use of SVd in patients who are lenalidomide-refractory, PI-naïve, bortezomib-naïve, or who received 1LOT (including a monoclonal antibody) and underscore the observed synergy between selinexor and bortezomib.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Bortezomib , Dexametasona , Hidrazinas , Mieloma Múltiplo , Triazóis , Humanos , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/diagnóstico , Bortezomib/administração & dosagem , Bortezomib/uso terapêutico , Hidrazinas/uso terapêutico , Hidrazinas/administração & dosagem , Hidrazinas/efeitos adversos , Dexametasona/administração & dosagem , Dexametasona/uso terapêutico , Dexametasona/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Triazóis/uso terapêutico , Triazóis/administração & dosagem , Masculino , Feminino , Idoso , Pessoa de Meia-Idade , Seguimentos , Resistencia a Medicamentos Antineoplásicos , Resultado do Tratamento , Adulto , Idoso de 80 Anos ou mais , Recidiva , Retratamento
16.
Eur J Haematol ; 113(5): 593-605, 2024 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-38993150

RESUMO

OBJECTIVES: Cluster of differentiation 38 (CD38) is a key target on multiple myeloma (MM) cells. This multi-centre, Phase 1, single-agent study (NCT04000282) investigated SAR442085, a novel fragment crystallisable (Fc)-modified anti-CD38 monoclonal antibody (mAb), with enhanced affinity towards Fc-gamma receptor on effector cells in patients with relapsed and/or refractory (RR) MM. METHODS: This study comprised two parts: Part-A (dose-escalation involving anti-CD38 mAb pre-treated and naïve patients) and Part-B (dose expansion). Primary endpoints were maximum tolerated dose and recommended Phase 2 dose (RP2D). RESULTS: Thirty-seven heavily pre-treated patients were treated in Part A. Part-B (dose-expansion) was not studied. Seven dose-limiting toxicities were reported at DL3, DL5, DL6, and DL7. RP2D was determined to be 5-7·5 mg/kg. Most common treatment-emergent adverse events were infusion-related reactions in 70·3% (26/37) patients. Grade ≥3 thrombocytopenia was reported in 48·6% (18/37). Overall response rate was 70% in anti-CD38 mAb naïve and 4% in anti-CD38 pre-treated patients, with a median progression-free survival of 7·62 (95%CI: 2·858; not calculable) months and 2·79 (95%CI: 1·150; 4·172) months and, respectively. CONCLUSIONS: The efficacy of SAR442085 was promising in anti-CD38 mAb naïve patients but did not extend to the larger cohort of anti-CD38 mAb pre-treated patients. This observation, along with transient high-grade thrombocytopenia, could potentially limit its clinical use.


Assuntos
Mieloma Múltiplo , Humanos , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/mortalidade , Masculino , Idoso , Feminino , Pessoa de Meia-Idade , Resultado do Tratamento , Dose Máxima Tolerável , Resistencia a Medicamentos Antineoplásicos , Adulto , Idoso de 80 Anos ou mais , ADP-Ribosil Ciclase 1/antagonistas & inibidores , ADP-Ribosil Ciclase 1/imunologia , Recidiva , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais/efeitos adversos
17.
Am J Hematol ; 99(7): 1257-1268, 2024 07.
Artigo em Inglês | MEDLINE | ID: mdl-38622840

RESUMO

In the phase 2 GRIFFIN trial (ClinicalTrials.gov identifier: NCT02874742), daratumumab added to lenalidomide, bortezomib, and dexamethasone (D-RVd) improved depth of response and progression-free survival (PFS) versus lenalidomide, bortezomib, and dexamethasone (RVd) alone in transplant-eligible (TE) patients with newly diagnosed multiple myeloma (NDMM). Here, we present patient-reported outcomes (PROs) collected using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30-item (QLQ-C30), EORTC Quality of Life Questionnaire Multiple Myeloma Module 20-item (QLQ-MY20), and EuroQol 5-Dimension 5-Level (EQ-5D-5L) tools on day 1 of cycles 1, 2, and 3; on day 21 of cycle 4 (end of induction therapy); on day 1 of cycle 5; on day 21 of cycle 6 (end of posttransplant consolidation therapy); and at months 6, 12, 18, and 24 of maintenance therapy. Meaningful improvements from baseline were seen in most of the PRO scales with both treatments after consolidation and were sustained for at least 2 years of maintenance treatment. Large reductions from baseline (~20 points) were especially observed in pain symptoms for both treatment groups, although these were numerically higher for patients receiving D-RVd during the majority of the time points. In addition, improvements in key scales, such as global health status, fatigue symptoms, and physical functioning, were also seen with both D-RVd and RVd. These improvements in health-related quality of life contribute to the totality of evidence supporting the improvement in clinical outcomes such as response rates and PFS with D-RVd in induction, consolidation, and maintenance therapy in TE patients with NDMM.


Assuntos
Anticorpos Monoclonais , Protocolos de Quimioterapia Combinada Antineoplásica , Bortezomib , Dexametasona , Lenalidomida , Mieloma Múltiplo , Medidas de Resultados Relatados pelo Paciente , Qualidade de Vida , Humanos , Mieloma Múltiplo/tratamento farmacológico , Bortezomib/administração & dosagem , Bortezomib/uso terapêutico , Dexametasona/administração & dosagem , Dexametasona/uso terapêutico , Lenalidomida/administração & dosagem , Lenalidomida/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais/administração & dosagem , Adulto
18.
Future Oncol ; : 1-25, 2024 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-39452950

RESUMO

WHAT IS THIS SUMMARY ABOUT?: This summary describes the final analysis of the GRIFFIN study. In this study, participants were newly diagnosed with a type of blood and bone marrow cancer called multiple myeloma, had never received any treatment, and were able to undergo an autologous stem cell transplant. The GRIFFIN study looked at adding the drug daratumumab (D) to a combination of standard treatments called RVd (lenalidomide [R], bortezomib [V], and dexamethasone [d]) during the treatment phases induction and consolidation, followed by daratumumab and lenalidomide (D-R) maintenance. Participants also received an autologous stem cell transplant to further help reduce multiple myeloma. The GRIFFIN study looked at whether D-RVd followed by D-R maintenance was better at killing multiple myeloma cells compared with RVd on its own followed by R maintenance on its own, and if treatments were safe. This summary also describes results from 2 other GRIFFIN publications: one that looked at participants with certain multiple myeloma characteristics or demographic factors that are associated with worse outcomes, and another that looked at how treatments impacted the participants' quality of life. WHAT WERE THE RESULTS?: At the time of the final analysis of GRIFFIN, participants who were treated with D-RVd followed by D-R maintenance had very low (undetectable) levels of multiple myeloma cells and multiple myeloma markers (biological signs) and were more likely to be alive without the multiple myeloma getting worse or coming back compared with participants who received standard RVd treatment followed by R maintenance. There was also a pattern of similar benefits achieved by participants who were at risk for worse outcomes. Additionally, participants who received D-RVd treatment followed by D-R maintenance reported less pain, less fatigue (extreme tiredness), and greater improvements in their ability to conduct daily physical activities. While some side effects (unwanted or unexpected effects of treatment) were higher with D-RVd, side effects in both groups were as expected, and adding daratumumab did not reduce a participant's ability to handle treatment. WHAT DO THE RESULTS OF THE STUDY MEAN?: Results of the GRIFFIN study showed that D-RVd treatment followed by D-R maintenance was better at treating multiple myeloma than the standard treatment of RVd followed by R maintenance in adults with a new diagnosis of multiple myeloma who were able to receive an autologous stem cell transplant, with no unexpected side effects of treatment.Clinical Trial Registration: NCT02874742 (GRIFFIN) (ClinicalTrials.gov).

19.
Cancer ; 129(23): 3746-3760, 2023 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-37622738

RESUMO

BACKGROUND: Patients with relapsed/refractory multiple myeloma (RRMM) have a high unmet treatment need. Belantamab mafodotin (belamaf), a first-in-class, B-cell maturation antigen-binding antibody-drug conjugate, eliminates myeloma cells through direct cell killing and an anti-myeloma immune response. METHODS: DREAMM-2 (NCT03525678) was a phase 2, two-arm, open-label trial in patients with heavily pretreated RRMM who had three or more prior therapies, were refractory to an immunomodulatory agent and a proteasome inhibitor, and refractory or intolerant to an anti-CD38 monoclonal antibody. Belamaf was given at 2.5 or 3.4 mg/kg every 3 weeks. The primary end point was overall response rate (ORR); secondary end points included progression-free survival (PFS), overall survival (OS), safety, ocular symptoms, and health-related quality of life (HRQOL). RESULTS: This final analysis (cutoff date, March 31, 2022), N = 223, with median follow-up of 12.5 and 13.8 months, demonstrated an ORR of 32% and 35%, median PFS of 2.8 and 3.9 months, and median OS of 15.3 and 14.0 months in the 2.5 mg/kg and 3.4 mg/kg cohorts, respectively. Median duration of response was 12.5 and 6.2 months. No new safety signals were observed; the most common Grade 3 and 4 adverse events were keratopathy (29% vs. 25%), thrombocytopenia (22% vs. 29%), and anemia (21% vs. 28%). HRQOL outcomes suggest that overall global health status/quality of life, physical and role functioning, and overall disease symptoms were maintained or improved during treatment. CONCLUSIONS: This final analysis of DREAMM-2 confirms that in patients with triple-class refractory RRMM, single-agent belamaf results in durable and clinically meaningful responses with a manageable safety profile.


Assuntos
Mieloma Múltiplo , Humanos , Qualidade de Vida , Resultado do Tratamento , Anticorpos Monoclonais Humanizados/uso terapêutico
20.
Blood ; 137(26): 3616-3628, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-33763699

RESUMO

Continuous lenalidomide-dexamethasone (Rd)-based regimens are among the standards of care in transplant-ineligible newly diagnosed multiple myeloma (NDMM) patients. The oral proteasome inhibitor ixazomib is suitable for continuous dosing, with predictable, manageable toxicities. In the double-blind, placebo-controlled TOURMALINE-MM2 trial, transplant-ineligible NDMM patients were randomized to ixazomib 4 mg (n = 351) or placebo (n = 354) plus Rd. After 18 cycles, dexamethasone was discontinued and treatment was continued using reduced-dose ixazomib (3 mg) and lenalidomide (10 mg) until progression/toxicity. The primary endpoint was progression-free survival (PFS). Median PFS was 35.3 vs 21.8 months with ixazomib-Rd vs placebo-Rd, respectively (hazard ratio [HR], 0.830; 95% confidence interval, 0.676-1.018; P = .073; median follow-up, 53.3 and 55.8 months). Complete (26% vs 14%; odds ratio [OR], 2.10; P < .001) and ≥ very good partial response (63% vs 48%; OR, 1.87; P < .001) rates were higher with ixazomib-Rd vs placebo-Rd. In a prespecified high-risk cytogenetics subgroup, median PFS was 23.8 vs 18.0 months (HR, 0.690; P = .019). Overall, treatment-emergent adverse events (TEAEs) were mostly grade 1/2. With ixazomib-Rd vs placebo-Rd, 88% vs 81% of patients experienced grade ≥3 TEAEs, 66% vs 62% serious TEAEs, and 35% vs 27% TEAEs resulting in regimen discontinuation; 8% vs 6% died on study. Addition of ixazomib to Rd was tolerable with no new safety signals and led to a clinically meaningful PFS benefit of 13.5 months. Ixazomib-Rd is a feasible option for certain patients who can benefit from an all-oral triplet combination. This trial was registered at www.clinicaltrials.gov as #NCT01850524.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Mieloma Múltiplo , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Compostos de Boro/administração & dosagem , Compostos de Boro/efeitos adversos , Dexametasona/administração & dosagem , Dexametasona/efeitos adversos , Intervalo Livre de Doença , Método Duplo-Cego , Feminino , Seguimentos , Glicina/administração & dosagem , Glicina/efeitos adversos , Glicina/análogos & derivados , Humanos , Lenalidomida/administração & dosagem , Lenalidomida/efeitos adversos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/mortalidade , Taxa de Sobrevida
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