RESUMO
Aim: To demonstrate the efficacy of pomalidomide for relapsed/refractory multiple myeloma (RRMM) following treatment in real-world, community practice using retrospective database analysis. Materials & methods: US-based community oncologists identified patients with RRMM treated with or without pomalidomide following first-line lenalidomide. Disease response (≥ very good partial response) and progression-free survival were compared. Results: Disease response was 78.6 and 51.7% for pomalidomide (n = 126) and nonpomalidomide cohorts (n = 174), respectively (p < 0.0001). Multivariate adjusted odds of response were 4.5-times greater for pomalidomide cohort (p < 0.0001). Median progression-free survival was not reached for pomalidomide cohort and 16.7 months for nonpomalidomide cohort (log-rank p < 0.01). Conclusion: Following lenalidomide induction in RRMM, pomalidomide is an effective treatment.
Plain language summary Treatment options have expanded in recent years for patients with relapsed/refractory multiple myeloma (RRMM) who received lenalidomide as their initial treatment and then either had a period of improvement before the disease worsened or did not respond to the medication at all. Pomalidomide is another MM treatment from the same drug class as lenalidomide. We analyzed the effect of a combination treatment containing pomalidomide versus a combination treatment without pomalidomide in patients with MM who had received routine initial treatment with lenalidomide. US-based community oncologists completed study forms to record patient characteristics and treatment response information. Results showed that patients who received pomalidomide in a combination treatment after initial lenalidomide treatment achieved higher rates of very good partial response or better and longer progression-free survival than those who did not. The results of this analysis suggest that switching to a different class of drugs following the initial treatment may not be warranted after first relapse and pomalidomide-containing combination treatments are a more effective treatment following lenalidomide for patients with RRMM.
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Inibidores da Angiogênese/uso terapêutico , Lenalidomida/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Talidomida/análogos & derivados , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Estudos Retrospectivos , Talidomida/uso terapêuticoRESUMO
In the phase III CASTOR trial, daratumumab, bortezomib and dexamethasone (D-Vd) significantly extended progression-free survival compared with bortezomib and dexamethasone (Vd) alone in patients with relapsed/refractory multiple myeloma (RRMM). Here, we present patient-reported outcomes (PROs) from the CASTOR trial. PROs were assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item (EORTC QLQ-C30) and the EuroQol 5-dimensional descriptive system questionnaire. Treatment effects through Cycle 8 were measured by a repeated measures mixed-effects model. After Cycle 8, PROs were only collected for patients in the D-Vd group who continued on daratumumab monotherapy. Compliance rates for PRO assessments were high and similar between treatment groups. Mean changes from baseline were generally similar between treatment groups for EORTC QLQ-C30 global health status (GHS), functioning and symptoms, and did not exceed 10 points for either treatment group. Subgroup analyses were consistent with the results observed in the overall population. There was no change in patients' health-related quality of life for the first eight cycles of therapy; thereafter, patients treated with daratumumab over the long-term reported improvements in GHS and pain. These results complement the significant clinical benefits observed with D-Vd in patients with RRMM and support its use in this patient population.
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Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Modelos Biológicos , Mieloma Múltiplo , Qualidade de Vida , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/administração & dosagem , Bortezomib/administração & dosagem , Dexametasona/administração & dosagem , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/mortalidade , Taxa de SobrevidaRESUMO
Combination treatment regimens including a proteasome inhibitor (PI), an immunomodulatory agent (IMiD) and a corticosteroid are standards of care for initial treatment of multiple myeloma (MM). We aimed to evaluate if a sequential treatment program using PI induction followed by IMiD based consolidation and maintenance could achieve similar outcomes with reduced toxicities. This phase 2 study was designed to assess the safety and efficacy of the Car-BiRd regimen: carfilzomib and dexamethasone (Kd) induction until maximum response, followed by lenalidomide, clarithromycin and dexamethasone (BiRd) consolidation until next maximum response, then lenalidomide maintenance in patients with newly diagnosed MM. Seventy-two patients, including both transplant eligible and ineligible patients, were enrolled and evaluated for response. The overall response rate to the Car-BiRd regimen was 94% with 83% of patients achieving a ≥ VGPR and 35% achieving a CR/sCR. The rate of CR/sCR increased from 7% with Kd induction to 21% with BiRd consolidation and 35% with lenalidomide maintenance. These results did not meet the study's target endpoint of a CR rate of 55%. The median PFS using this deferred transplant approach was 37.3 months (95% CI 27.9, 52.7) and median OS was not reached with a median follow-up of 60 months. Toxicities were primarily low grade and manageable. Hematologic toxicities were lower than those expected with a combination PI/IMiD protocol. The sequential Car-BiRd regimen is an effective and safe approach for the upfront treatment of MM including patients unfit for transplant.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Claritromicina/uso terapêutico , Dexametasona/uso terapêutico , Lenalidomida/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Oligopeptídeos/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Claritromicina/efeitos adversos , Dexametasona/efeitos adversos , Feminino , Humanos , Quimioterapia de Indução , Lenalidomida/efeitos adversos , Quimioterapia de Manutenção , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/diagnóstico , Oligopeptídeos/efeitos adversos , Resultado do TratamentoRESUMO
The revised International Staging System (R-ISS) combines ISS with genetic markers and lactate dehydrogenase and can prognosticate newly diagnosed multiple myeloma (MM). Early relapse (<24 months) after upfront autologous hematopoietic cell transplantation (AHCT) strongly predicts inferior overall survival (OS). We examined the ability of R-ISS in predicting early relapse and its independent prognostic effect on postrelapse survival after an early relapse. Using the Center for International Blood and Marrow Transplant Research database we identified MM patients receiving first AHCT within 18 months after diagnosis with available R-ISS stage at diagnosis (nâ¯=â¯628). Relative risks of relapse/progression, progression-free survival (PFS), and OS were calculated with the R-ISS group as a predictor in multivariate analysis. Among early relapsers, postrelapse survival was tested to identify factors affecting postrelapse OS. The cumulative incidence of early relapse was 23%, 39%, and 50% for R-ISS I, R-ISS II, and R-ISS III, respectively (P < .001). Shorter PFS and OS were seen with higher stage R-ISS. R-ISS was independently predictive for inferior postrelapse OS among early relapsers, as was the presence of ≥3 comorbidities and the use of ≥2 induction chemotherapy lines. R-ISS stage at diagnosis predicts early post-AHCT relapse and independently affects postrelapse survival among early relapsers.
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Transplante de Células-Tronco Hematopoéticas/métodos , Mieloma Múltiplo/terapia , Condicionamento Pré-Transplante/métodos , Transplante Autólogo/métodos , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/mortalidade , Estadiamento de Neoplasias , Prognóstico , RecidivaRESUMO
BACKGROUND: Daratumumab, a human IgGκ monoclonal antibody that targets CD38, induces direct and indirect antimyeloma activity and has shown substantial efficacy as monotherapy in heavily pretreated patients with multiple myeloma, as well as in combination with bortezomib in patients with newly diagnosed multiple myeloma. METHODS: In this phase 3 trial, we randomly assigned 498 patients with relapsed or relapsed and refractory multiple myeloma to receive bortezomib (1.3 mg per square meter of body-surface area) and dexamethasone (20 mg) alone (control group) or in combination with daratumumab (16 mg per kilogram of body weight) (daratumumab group). The primary end point was progression-free survival. RESULTS: A prespecified interim analysis showed that the rate of progression-free survival was significantly higher in the daratumumab group than in the control group; the 12-month rate of progression-free survival was 60.7% in the daratumumab group versus 26.9% in the control group. After a median follow-up period of 7.4 months, the median progression-free survival was not reached in the daratumumab group and was 7.2 months in the control group (hazard ratio for progression or death with daratumumab vs. control, 0.39; 95% confidence interval, 0.28 to 0.53; P<0.001). The rate of overall response was higher in the daratumumab group than in the control group (82.9% vs. 63.2%, P<0.001), as were the rates of very good partial response or better (59.2% vs. 29.1%, P<0.001) and complete response or better (19.2% vs. 9.0%, P=0.001). Three of the most common grade 3 or 4 adverse events reported in the daratumumab group and the control group were thrombocytopenia (45.3% and 32.9%, respectively), anemia (14.4% and 16.0%, respectively), and neutropenia (12.8% and 4.2%, respectively). Infusion-related reactions that were associated with daratumumab treatment were reported in 45.3% of the patients in the daratumumab group; these reactions were mostly grade 1 or 2 (grade 3 in 8.6% of the patients), and in 98.2% of these patients, they occurred during the first infusion. CONCLUSIONS: Among patients with relapsed or relapsed and refractory multiple myeloma, daratumumab in combination with bortezomib and dexamethasone resulted in significantly longer progression-free survival than bortezomib and dexamethasone alone and was associated with infusion-related reactions and higher rates of thrombocytopenia and neutropenia than bortezomib and dexamethasone alone. (Funded by Janssen Research and Development; ClinicalTrials.gov number, NCT02136134.).
Assuntos
ADP-Ribosil Ciclase 1/antagonistas & inibidores , Anticorpos Monoclonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bortezomib/administração & dosagem , Dexametasona/administração & dosagem , Mieloma Múltiplo/tratamento farmacológico , Adulto , Idoso , Anticorpos Monoclonais/efeitos adversos , Bortezomib/efeitos adversos , Dexametasona/efeitos adversos , Intervalo Livre de Doença , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , RecidivaRESUMO
Carfilzomib and dexamethasone (Kd) has significant activity in relapsed and refractory multiple myeloma. Kd has not previously been evaluated in newly diagnosed multiple myeloma (NDMM). We report a single-arm phase 2 study of 72 patients with NDMM to evaluate the efficacy and tolerability of Kd induction. Carfilzomib was administered in two dosing cohorts with dosing of 20/45 mg/m2 in the first 25 patients and 20/56 mg/m2 in the subsequent 47 patients. Carfilzomib was administered on days 1, 2, 8, 9, 15 and 16 of a 28-day cycle, dexamethasone 20 mg was administered orally on days 1, 2, 8, 9, 15, 16, 22 and 23. Treatment was continued to maximum response, progression of disease, or regimen intolerability. Endpoints included overall response rate (ORR), regimen toxicity and impact of carfilzomib on CD34+ stem cell collection yield. Sixty-five pts achieved at least a partial response (PR) for an ORR of 90%. The maximum response achieved was complete response or better in 5 (7%), very good partial response (VGPR) in 42 (58%), PR in 18 (25%) and stable disease in 7 pts (10%). Toxicities were predominantly low grade with 547 grade 1/2 adverse events and 44 grade ≥3 events. The rate of grade ≥3 cardiovascular adverse events was 11.1% with eight observed events. The activity of Kd described represents the highest rate of overall response and ≥VGPR for any 2-agent combination in NDMM reported to date. Kd demonstrated a safety profile consistent with previously reported carfilzomib studies.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Dexametasona/efeitos adversos , Mieloma Múltiplo/tratamento farmacológico , Oligopeptídeos/efeitos adversos , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Dexametasona/administração & dosagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Oligopeptídeos/administração & dosagemRESUMO
Administration of granulocyte colony-stimulating factor (G-CSF) after autologous peripheral blood stem cell transplantation (PBSCT) is generally recommended to reduce the duration of severe neutropenia; however, data regarding the optimal timing of G-CSFs post-transplantation are limited and conflicting. This retrospective study was performed at NewYork-Presbyterian/Weill Cornell Medical Center between November 5, 2013, and August 9, 2016, of adult inpatient autologous PBSCT recipients who received G-CSF empirically starting on day +5 (early) versus on those who received G-CSF on day +12 only if absolute neutrophil count (ANC) was <0.5 × 109/L (ANC-driven). G-CSF was dosed at 300 µg in patients weighing <75 kg and 480 µg in those weighing ≥75 kg. One hundred consecutive patients underwent autologous PBSCT using either the early (n = 50) or ANC-driven (n = 50) G-CSF regimen. Patient and transplantation characteristics were comparable in the 2 groups. In the ANC-driven group, 24% (n = 12) received G-CSF on day +12 and 60% (n = 30) started G-CSF earlier due to febrile neutropenia or at the physician's discretion, 6% (n = 3) started after day +12 at the physician's discretion, and 10% (n = 5) did not receive any G-CSF. The median start day of G-CSF therapy was day +10 in the ANC-driven group versus day +5 in the early group (P < .0001). For the primary outcome, the median time to neutrophil engraftment was 12 days (interquartile range [IQR] 11-13 days) in the early group versus 13 days (IQR, 12-14 days) in the ANC-driven group (P = .07). There were no significant between-group differences in time to platelet engraftment, 1-year relapse rate, or 1-year overall survival. The incidence of febrile neutropenia was 74% in the early group versus 90% in the ANC-driven group (P = .04); however, there was no significant between-group difference in the incidence of positive bacterial cultures or transfer to the intensive care unit. The duration of G-CSF administration until neutrophil engraftment was 6 days in the early group versus 3 days in the ANC-driven group (P < .0001). The median duration of post-transplantation hospitalization was 15 days (IQR, 14-19 days) in the early group versus 16 days (IQR, 15-22 days) in the ANC-driven group (P = .28). Our data show that early initiation of G-CSF (on day +5) and ANC-driven initiation of G-CSF following autologous PBSCT were associated with a similar time to neutrophil engraftment, length of stay post-transplantation, and 1-year overall survival.
Assuntos
Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Transplante de Células-Tronco de Sangue Periférico/métodos , Idoso , Feminino , Sobrevivência de Enxerto , Humanos , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Neutrófilos/citologia , Transplante de Células-Tronco de Sangue Periférico/mortalidade , Estudos Retrospectivos , Taxa de Sobrevida , Fatores de Tempo , Transplante Autólogo/métodos , Transplante Autólogo/mortalidadeRESUMO
We compared postrelapse overall survival (OS) after autologous/allogeneic (auto/allo) versus tandem autologous (auto/auto) hematopoietic cell transplantation (HCT) in patients with multiple myeloma (MM). Postrelapse survival of patients receiving an auto/auto or auto/allo HCT for MM and prospectively reported to the Center for International Blood and Marrow Transplant Research between 2000 and 2010 were analyzed. Relapse occurred in 404 patients (72.4%) in the auto/auto group and in 178 patients (67.4%) in the auto/allo group after a median follow-up of 8.5 years. Relapse occurred before 6 months after a second HCT in 46% of the auto/allo patients, compared with 26% of the auto/auto patients. The 6-year postrelapse survival was better in the auto/allo group compared with the auto/auto group (44% versus 35%; P = .05). Mortality due to MM was 69% (n = 101) in the auto/allo group and 83% (n = 229) deaths in auto/auto group. In multivariate analysis, both cohorts had a similar risk of death in the first year after relapse (hazard ratio [HR], .72; P = .12); however, for time points beyond 12 months after relapse, overall survival was superior in the auto/allo cohort (HR for death in auto/auto =1.55; P = .005). Other factors associated with superior survival were enrollment in a clinical trial for HCT, male sex, and use of novel agents at induction before HCT. Our findings shown superior survival afterrelapse in auto/allo HCT recipients compared with auto/auto HCT recipients. This likely reflects a better response to salvage therapy, such as immunomodulatory drugs, potentiated by a donor-derived immunologic milieu. Further augmentation of the post-allo-HCT immune system with new immunotherapies, such as monoclonal antibodies, checkpoint inhibitors, and others, merit investigation.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/terapia , Adulto , Idoso , Aloenxertos , Autoenxertos , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva , Fatores de Risco , Fatores Sexuais , Taxa de SobrevidaRESUMO
The Revised International Staging System (R-ISS) and the International Myeloma Working Group 2014 (IMWG 2014) are newer staging systems used to prognosticate multiple myeloma (MM) outcomes. We hypothesized that these would provide better prognostic differentiation for newly diagnosed multiple myeloma (MM) compared with ISS. We analyzed the Center for International Blood and Marrow Transplant Research database from 2008 to 2014 to compare the 3 systems (Nâ¯=â¯628) among newly diagnosed MM patients undergoing upfront autologous hematopoietic cell transplantation (AHCT). The median follow-up of survivors was 48 (range, 3 to 99) months. The R-ISS provided the greatest differentiation between survival curves for each stage (for overall survival [OS], the differentiation was 1.74 using the R-ISS, 1.58 using ISS, and 1.60 using the IMWG 2014) . Univariate analyses at 3 years for OS showed R-ISS I at 88% (95% confidence interval [CI], 83% to 93%), II at 75% (95% CI, 70% to 80%), and III at 56% (95% CI, 3% to 69%; P < .001). An integrated Brier score function demonstrated the R-ISS had the best prediction for PFS, though all systems had similar prediction for OS. Among available systems, the R-ISS is the most optimal among available prognostic tools for newly diagnosed MM undergoing AHCT. We recommend that serum lactate dehydrogenase and cytogenetic data be performed on every MM patient at diagnosis to allow accurate prognostication.
Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Mieloma Múltiplo/diagnóstico , Transplante Autólogo/métodos , Adulto , Idoso , Diferenciação Celular , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/patologia , Estadiamento de Neoplasias , Estudos ProspectivosRESUMO
BACKGROUND: Daratumumab is a human CD38-directed monoclonal antibody indicated for the treatment of relapsed and refractory multiple myeloma (MM). METHODS: A multicenter, open-label treatment protocol provided early access to daratumumab for patients who had progressive MM after they received ≥3 prior lines of therapy that included a proteasome inhibitor and an immunomodulatory agent or if they were refractory to both a proteasome inhibitor and an immunomodulatory agent. Patients received daratumumab 16 mg/kg weekly for 8 weeks, every other week for 16 weeks, and monthly until they developed disease progression, unacceptable toxicity, or 60 days after the drug gained US approval. Treatment-emergent grade ≥3 adverse events (AEs), serious AEs, and AEs of special interest were collected. RESULTS: Three hundred forty-eight patients were enrolled at 39 US sites between June and December 2015. Patients received study therapy for a median of 1.9 months (range, 0.03-6.0 months). Fifty-two percent of patients transitioned to commercially-available daratumumab and 37% discontinued because of progressive disease. Grade ≥3 AEs occurred in 50% of patients, including thrombocytopenia (15%) and anemia (14%). Serious AEs occurred in 35% of patients (12% were drug-related), including infections (11%). Infusion reactions occurred in 56%, 2%, and 2% of patients during the first, second, and all subsequent infusions, respectively; respiratory symptoms (cough, dyspnea, throat irritation, nasal congestion) were common. The infusion reaction rate for the first infusion was 38% in 50 patients at 2 sites who received montelukast as premedication for their first infusion and 59% in patients who did not receive montelukast. CONCLUSIONS: The current findings are consistent with previously reported trials and confirm the safety profile of daratumumab in heavily pretreated US patients who have relapsed or refractory MM. Cancer 2018;124:000-000.
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Anticorpos Monoclonais/administração & dosagem , Antineoplásicos Imunológicos/administração & dosagem , Mieloma Múltiplo/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Acetatos/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/efeitos adversos , Antineoplásicos Imunológicos/efeitos adversos , Ciclopropanos , Esquema de Medicação , Aprovação de Drogas , Feminino , Humanos , Infusões Intravenosas , Reação no Local da Injeção/prevenção & controle , Masculino , Pessoa de Meia-Idade , Quinolinas/administração & dosagem , Sulfetos , Análise de Sobrevida , Resultado do Tratamento , Estados UnidosRESUMO
Daratumumab, a CD38 human monoclonal antibody, demonstrated significant clinical activity in combination with bortezomib and dexamethasone versus bortezomib and dexamethasone alone in the primary analysis of CASTOR, a phase 3 study in relapsed and/or refractory multiple myeloma. A post hoc analysis based on treatment history and longer follow up is presented. After 19.4 (range: 0-27.7) months of median follow up, daratumumab plus bortezomib and dexamethasone prolonged progression-free survival (median: 16.7 versus 7.1 months; hazard ratio, 0.31; 95% confidence interval, 0.24-0.39; P<0.0001) and improved the overall response rate (83.8% versus 63.2%; P<0.0001) compared with bortezomib and dexamethasone alone. The progression-free survival benefit of daratumumab plus bortezomib and dexamethasone was most apparent in patients with 1 prior line of therapy (median: not reached versus 7.9 months; hazard ratio, 0.19; 95% con fidence interval, 0.12-0.29; P<0.0001). Daratumumab plus bortezomib and dexamethasone was also superior to bortezomib and dexamethasone alone in subgroups based on prior treatment exposure (bortezomib, thalidomide, or lenalidomide), lenalidomide-refractory status, time since last therapy (≤12, >12, ≤6, or >6 months), or cytogenetic risk. Minimal residual disease-negative rates were >2.5-fold higher with daratumumab across subgroups. The safety profile of daratumumab plus bortezomib and dexamethasone remained consistent with longer follow up. Daratumumab plus bortezomib and dexamethasone demonstrated significant clinical activity across clinically relevant subgroups and provided the greatest benefit to patients treated at first relapse. Trial registration: clinicaltrials.gov identifier: 02136134.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Neoplasia Residual/diagnóstico , Avaliação de Resultados em Cuidados de Saúde/estatística & dados numéricos , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/administração & dosagem , Bortezomib/administração & dosagem , Dexametasona/administração & dosagem , Resistencia a Medicamentos Antineoplásicos , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/patologia , Recidiva Local de Neoplasia , Avaliação de Resultados em Cuidados de Saúde/métodosRESUMO
Autologous stem cell transplantation (ASCT) conditioned with high-dose chemotherapy has long been established as the standard of care for eligible patients with newly diagnosed multiple myeloma. Despite recent therapeutic advances, high-dose melphalan (HDM) remains the chemotherapy regimen of choice in this setting. Lenalidomide (LEN) in combination with low-dose dexamethasone is recognized as a standard of care for patients with relapsed or refractory multiple myeloma (RRMM), and there is growing support for the administration of LEN as maintenance therapy post-ASCT. In view of the above, the present phase I clinical trial was designed to evaluate the safety and tolerability of high-dose LEN (HDLEN) in patients with RRMM, and to determine the maximum tolerated dose of HDLEN when added to HDM before ASCT. Despite administering HDLEN at doses of up to 350 mg/day, the maximum tolerated dose could not be determined, owing to an insufficient number of dose-limiting toxicities in the 21 patients enrolled in the trial. Conditioning with HDLEN plus HDM was associated with a favorable tolerability profile. Adverse events following ASCT were as expected with HDM. Median progression-free and overall survival were 10 months and 22 months, respectively, in this population of heavily pretreated patients. Our findings suggest that HDLEN in combination with HDM may offer significant potential as a conditioning regimen before ASCT in patients with RRMM. These preliminary findings are now being evaluated further in an ongoing phase II clinical trial.
Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Melfalan/administração & dosagem , Mieloma Múltiplo/terapia , Terapia de Salvação/métodos , Talidomida/análogos & derivados , Condicionamento Pré-Transplante/métodos , Adulto , Idoso , Feminino , Humanos , Lenalidomida , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Mieloma Múltiplo/mortalidade , Análise de Sobrevida , Talidomida/administração & dosagem , Condicionamento Pré-Transplante/mortalidade , Transplante AutólogoRESUMO
Waldenström macroglobulinemia/lymphoplasmacytic lymphoma (WM/LPL) is characterized by lymphoplasmacytic proliferation, lymph node and spleen enlargement, bone marrow involvement, and IgM production. Treatment varies based on the extent and biology of disease. In some patients, the use of allogeneic hematopoietic cell transplantation (alloHCT) may have curative potential. We evaluated long-term outcomes of 144 patients who received adult alloHCT for WM/LPL. Data were obtained from the Center for International Blood and Marrow Transplant Research database (2001 to 2013). Patients received myeloablative(n = 67) or reduced-intensity conditioning (RIC; n = 67). Median age at alloHCT was 53 years, and median time from diagnosis to transplantation was 41 months. Thirteen percent (n = 18) failed prior autologous HCT. About half (n = 82, 57%) had chemosensitive disease at the time of transplantation, whereas 22% had progressive disease. Rates of progression-free survival, overall survival, relapse, and nonrelapse mortality at 5 years were 46%, 52%, 24%, and 30%, respectively. Patients with chemosensitive disease and better pretransplant disease status experienced significantly superior overall survival. There were no significant differences in progression-free survival based on conditioning (myeloablative, 50%, versus RIC, 41%) or graft source. Conditioning intensity did not impact treatment-related mortality or relapse. The most common causes of death were primary disease and graft-versus-host disease (GVHD). AlloHCT yielded durable survival in select patients with WM/LPL. Strategies to reduce mortality from GVHD and post-transplant relapse are necessary to improve this approach.
Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Linfoma/terapia , Macroglobulinemia de Waldenstrom/terapia , Adulto , Idoso , Bases de Dados Factuais , Doença Enxerto-Hospedeiro/mortalidade , Transplante de Células-Tronco Hematopoéticas/mortalidade , Humanos , Linfoma/mortalidade , Pessoa de Meia-Idade , Recidiva , Análise de Sobrevida , Tempo para o Tratamento , Condicionamento Pré-Transplante/métodos , Condicionamento Pré-Transplante/mortalidade , Transplante Homólogo , Resultado do Tratamento , Macroglobulinemia de Waldenstrom/mortalidade , Adulto JovemRESUMO
Bortezomib (V), lenalidomide (R), cyclophosphamide (C), and dexamethasone (D) are components of the most commonly used modern doublet (RD, VD) or triplet (VRD, CVD) initial induction regimens before autologous hematopoietic cell transplantation (AHCT) for multiple myeloma (MM) in the United States. In this study we evaluated 693 patients receiving "upfront" AHCT after initial induction therapy with modern doublet or triplet regimens using data reported to the Center for International Blood and Marrow Transplant Research from 2008 to 2013. Analysis was limited to those receiving a single AHCT after 1 line of induction therapy within 12 months from treatment initiation for MM. In multivariate analysis, progression-free survival (PFS) and overall survival were similar irrespective of induction regimen. However, high-risk cytogenetics and nonreceipt of post-transplant maintenance/consolidation therapy were associated with higher risk of relapse. Patients receiving post-transplant therapy had significantly improved 3-year PFS versus no post-transplant therapy (55% versus 39%, P = .0001). This benefit was most evident in patients not achieving at least a complete response post-AHCT (P = .005). In patients receiving upfront AHCT, the choice of induction regimen (doublet or triplet therapies) appears to be of lower impact than use of post-transplant therapy.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transplante de Células-Tronco Hematopoéticas , Mieloma Múltiplo/tratamento farmacológico , Adolescente , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Causas de Morte , Terapia Combinada , Bases de Dados Factuais , Intervalo Livre de Doença , Feminino , Humanos , Fatores Imunológicos/administração & dosagem , Hibridização in Situ Fluorescente , Estimativa de Kaplan-Meier , Quimioterapia de Manutenção , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/genética , Mieloma Múltiplo/terapia , Segunda Neoplasia Primária/mortalidade , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Inibidores de Proteassoma/administração & dosagem , Indução de Remissão , Estudos Retrospectivos , Transplante Autólogo , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: Race/ethnicity remains an important barrier in clinical care. The authors investigated differences in the receipt of autologous hematopoietic cell transplantation (AHCT) among patients with multiple myeloma (MM) and outcomes based on race/ethnicity in the United States. METHODS: The Center for International Blood and Marrow Transplant Research database was used to identify 28,450 patients who underwent AHCT for MM from 2008 through 2014. By using data from the National Cancer Institute's Surveillance, Epidemiology, and End Results 18 registries, the incidence of MM was calculated, and a stem cell transplantation utilization rate (STUR) was derived. Post-AHCT outcomes were analyzed among patients ages 18 to 75 years who underwent melphalan-conditioned peripheral cell grafts (N = 24,102). RESULTS: The STUR increased across all groups from 2008 to 2014. The increase was substantially lower among Hispanics (range, 8.6%-16.9%) and non-Hispanic blacks (range, 12.2%-20.5%) compared with non-Hispanic whites (range, 22.6%-37.8%). There were 18,046 non-Hispanic whites, 4123 non-Hispanic blacks, and 1933 Hispanic patients. The Hispanic group was younger (P < .001). Fewer patients older than 60 years underwent transplantation among Hispanics (39%) and non-Hispanic blacks (42%) compared with non-Hispanic whites (56%). A Karnofsky score <90% and a hematopoietic cell transplantation comorbidity index score >3 were more common in non-Hispanic blacks compared with Hispanic and non-Hispanic whites (P < .001). More Hispanics (57%) versus non-Hispanic blacks (54%) and non-Hispanic whites (52%; P < .001) had stage III disease. More Hispanics (48%) versus non-Hispanic blacks (45%) and non-Hispanic whites (44%) had a very good partial response or better before transplantation (P = .005). Race/ethnicity did not impact post-AHCT outcomes. CONCLUSIONS: Although the STUR increased, it remained low and was significantly lower among Hispanics followed by non-Hispanic blacks compared with non-Hispanic whites. Race/ethnicity did not impact transplantation outcomes. Efforts to increase the rates of transplantation for eligible patients who have MM, with an emphasis on groups that underuse transplantation, are warranted. Cancer 2017;123:3141-9. © 2017 American Cancer Society.
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Disparidades em Assistência à Saúde/etnologia , Transplante de Células-Tronco Hematopoéticas/estatística & dados numéricos , Hispânico ou Latino/estatística & dados numéricos , Mieloma Múltiplo/terapia , Sistema de Registros , Transplante Autólogo/estatística & dados numéricos , Adolescente , Adulto , Negro ou Afro-Americano/estatística & dados numéricos , Idoso , Etnicidade/estatística & dados numéricos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/patologia , Estadiamento de Neoplasias , Estados Unidos , População Branca/estatística & dados numéricos , Adulto JovemRESUMO
Conventional cytogenetics and interphase fluorescence in situ hybridization (FISH) identify high-risk multiple myeloma (HRM) populations characterized by poor outcomes. We analyzed these differences among HRM versus non-HRM populations after upfront autologous hematopoietic cell transplantation (autoHCT). Between 2008 and 2012, 715 patients with multiple myeloma identified by FISH and/or cytogenetic data with upfront autoHCT were identified in the Center for International Blood and Marrow Transplant Research database. HRM was defined as del17p, t(4;14), t(14;16), hypodiploidy (<45 chromosomes excluding -Y) or chromosome 1 p and 1q abnormalities; all others were non-HRM. Among 125 HRM patients (17.5%), induction with bortezomib and immunomodulatory agents (imids) was higher compared with non-HRM (56% versus 43%, P < .001) with similar pretransplant complete response (CR) rates (14% versus 16%, P .1). At day 100 post-transplant, at least a very good partial response was 59% in HRM and 61% in non-HRM (P = .6). More HRM patients received post-transplant therapy with bortezomib and imids (26% versus 12%, P = .004). Three-year post-transplant progression-free (PFS) and overall survival (OS) rates in HRM versus non-HRM were 37% versus 49% (P < .001) and 72% versus 85% (P < .001), respectively. At 3 years, PFS for HRM patients with and without post-transplant therapy was 46% (95% confidence interval [CI], 33 to 59) versus 14% (95% CI, 4 to 29) and in non-HRM patients with and without post-transplant therapy 55% (95% CI, 49 to 62) versus 39% (95% CI, 32 to 47); rates of OS for HRM patients with and without post-transplant therapy were 81% (95% CI, 70 to 90) versus 48% (95% CI, 30 to 65) compared with 88% (95% CI, 84 to 92) and 79% (95% CI, 73 to 85) in non-HRM patients with and without post-transplant therapy, respectively. Among patients receiving post-transplant therapy, there was no difference in OS between HRM and non-HRM (P = .08). In addition to HRM, higher stage, less than a CR pretransplant, lack of post-transplant therapy, and African American race were associated with worse OS. In conclusion, we show HRM patients achieve similar day 100 post-transplant responses compared with non-HRM patients, but these responses are not sustained. Post-transplant therapy appeared to improve the poor outcomes of HRM.
Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Mieloma Múltiplo/genética , Mieloma Múltiplo/terapia , Medição de Risco/métodos , Adulto , Idoso , Análise Citogenética , Bases de Dados Factuais , Feminino , Humanos , Hibridização in Situ Fluorescente , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/mortalidade , Estudos Retrospectivos , Análise de Sobrevida , Transplante Autólogo , Resultado do TratamentoRESUMO
Few studies have evaluated the role of antibacterial prophylaxis during neutropenia in patients with multiple myeloma undergoing autologous hematopoietic stem cell transplantation (HSCT). At our center, levofloxacin prophylaxis was initiated in June 2006 in patients with myeloma who were undergoing autologous HSCT. We compared the incidence of bloodstream infection (BSI) and fever and neutropenia (FN) within 30 days of transplantation before (January 2003 to May 2006) and after (June 2006 to April 2010) the initiation of levofloxacin prophylaxis in patients undergoing autologous HSCT for myeloma. We also compared rates of BSI and FN during the same time periods in autologous HSCT recipients with lymphoma who did not receive antibacterial prophylaxis during either time period. After the initiation of levofloxacin prophylaxis, the BSI rate decreased from 41.2% (49 of 119) to 14.7% (23 of 156) and the rate of FN decreased from 91.6% to 60.9% in patients with myeloma (P < .001, for each). In contrast, rates of BSI (43.1% versus 47.3%; P = .50) and FN (98.8% versus 97.1%; P = .63) did not change in patients with lymphoma. Levofloxacin prophylaxis was independently associated with decreased odds of BSI (odds ratio, .27; 95% confidence interval, .14 to .51; P < .001) and FN (odds ratio, .18; 95% confidence interval, .09 to .36; P < .001) in multivariate analysis. Patients with myeloma had a nonsignificant increase in the risk of BSI due to levofloxacin-resistant Enterobacteriaceae (5% versus 1%, P = .08) and Clostridium difficile infection (7% versus 3%, P = .12) after the initiation of levofloxacin prophylaxis but did not have higher rates of BSI due to other resistant bacteria. Levofloxacin prophylaxis is associated with decreased risk of BSI and FN in patients with myeloma undergoing autologous HSCT.
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Antibioticoprofilaxia , Bacteriemia/prevenção & controle , Neutropenia Febril/prevenção & controle , Transplante de Células-Tronco Hematopoéticas , Levofloxacino/uso terapêutico , Mieloma Múltiplo/terapia , Antifúngicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bacteriemia/epidemiologia , Bacteriemia/microbiologia , Clostridioides difficile/isolamento & purificação , Infecções por Clostridium/epidemiologia , Terapia Combinada , Resistência Microbiana a Medicamentos , Farmacorresistência Bacteriana Múltipla , Enterobacteriaceae/efeitos dos fármacos , Infecções por Enterobacteriaceae/epidemiologia , Infecções por Enterobacteriaceae/etiologia , Neutropenia Febril/tratamento farmacológico , Neutropenia Febril/epidemiologia , Neutropenia Febril/etiologia , Feminino , Filgrastim/uso terapêutico , Fidelidade a Diretrizes , Humanos , Hospedeiro Imunocomprometido , Incidência , Levofloxacino/administração & dosagem , Linfoma/terapia , Masculino , Melfalan/uso terapêutico , Pessoa de Meia-Idade , Mieloma Múltiplo/complicações , Mieloma Múltiplo/tratamento farmacológico , Guias de Prática Clínica como Assunto , Estudos Retrospectivos , Fatores de Risco , Condicionamento Pré-Transplante , Transplante AutólogoRESUMO
The combination of clarithromycin, lenalidomide, and dexamethasone (BiRd) was evaluated as therapy for treatment-naive symptomatic multiple myeloma (MM), with overall response at 2 years of 90%. We reviewed the long-term follow-up of initial BiRd therapy. Seventy-two patients were given dexamethasone 40 mg weekly, clarithromycin 500 mg twice daily, and lenalidomide 25 mg daily on days 1 to 21 of a 28-day cycle. After a median follow-up of 6.6 years, overall response rates were 93%, with a very good partial response or better of 68%. Median progression-free survival was 49 months. Evaluation for the development of second primary malignancies (SPMs) was conducted, and no increase in incidence was noted in our cohort of patients who received frontline immunomodulatory therapy. BiRd remains a highly potent and safe regimen for frontline therapy in patients with MM without apparent increase in risk of SPMs. This trial was registered at www.clinicaltrials.gov as #NCT00151203.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Claritromicina/administração & dosagem , Ensaios Clínicos Fase II como Assunto , Dexametasona/administração & dosagem , Mieloma Múltiplo/tratamento farmacológico , Talidomida/análogos & derivados , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Claritromicina/efeitos adversos , Dexametasona/efeitos adversos , Feminino , Seguimentos , Transplante de Células-Tronco Hematopoéticas , Humanos , Lenalidomida , Quimioterapia de Manutenção/métodos , Masculino , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/terapia , Terapia Neoadjuvante , Estudos Retrospectivos , Análise de Sobrevida , Talidomida/administração & dosagem , Talidomida/efeitos adversos , Transplante AutólogoRESUMO
BACKGROUND: The collection of autologous peripheral blood (PB) stem cells can be challenging in the subgroup of patients deemed "poor mobilizers" with granulocyte-colony-stimulating factor. Plerixafor, a CXCR-4 antagonist, is an alternative mobilizing agent, but is costly, and the optimal mobilization algorithm has yet to be determined. STUDY DESIGN AND METHODS: To address the question we developed a protocol measuring PB CD34 on Day 4 of mobilization. We examined 26 patients before initiating the protocol versus 24 patients after initiation. RESULTS: Significant differences (p ≤ 0.05) included fewer days of collection (1.25 days vs. 2.42 days), lower total blood volume processed (25.9 L vs. 57.2 L), lower total product volume (324 mL vs. 691 mL), lower RBC content (9 mL vs. 18 mL), and lower granulocyte percentage per collection (35% vs. 11%). There were no significant differences between the two groups in demographics, baseline platelet count, total CD34, or CD34/kg harvested. CONCLUSION: Use of a protocol to assess PB CD34 1 day before collection allows for preemptive administration of plerixafor to augment mobilization. Subsequently, days of collection and processed blood volume are reduced while there is less RBC and granulocyte contamination in the collected stem cell product.
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Algoritmos , Antígenos CD34/sangue , Mobilização de Células-Tronco Hematopoéticas/métodos , Compostos Heterocíclicos/administração & dosagem , Adulto , Idoso , Benzilaminas , Contagem de Células Sanguíneas/instrumentação , Separação Celular/instrumentação , Separação Celular/métodos , Protocolos Clínicos , Ciclamos , Sinergismo Farmacológico , Eritrócitos , Feminino , Citometria de Fluxo/instrumentação , Citometria de Fluxo/métodos , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Fator Estimulador de Colônias de Granulócitos/farmacologia , Granulócitos , Doenças Hematológicas/sangue , Doenças Hematológicas/terapia , Compostos Heterocíclicos/farmacologia , Humanos , Masculino , Pessoa de Meia-Idade , Transplante de Células-Tronco de Sangue Periférico , Estudos Retrospectivos , Neoplasias Testiculares/sangue , Neoplasias Testiculares/terapia , Fatores de Tempo , Transplante Autólogo , Adulto JovemRESUMO
Autologous stem cell transplantation is a standard treatment strategy for patients with multiple myeloma that requires effective mobilization and apheresis of peripheral blood progenitor cells; however, in the current era of novel myeloma induction therapies, the optimal mobilization regimen to enhance stem cell yield while limiting toxicity and resource utilization remains unknown. In this multicenter retrospective study, we assessed apheresis and transplant outcomes in myeloma patients mobilized with granulocyte colony stimulating factor (G-CSF) alone (n = 62), G-CSF with chemotherapy (n = 43), or G-CSF with the CXCR4 antagonist plerixafor (n = 417). Compared to patients treated with G-CSF alone, the plerixafor group required significantly fewer median apheresis sessions (1 vs 2, p = 0.0023) with higher CD34+ stem cell yield (9.9 vs 5.8 × 106 cells/kg, p < 0.001) and had significantly faster engraftment of neutrophils (HR 1.54, 95% CI 1.17-2.03) and platelets (HR 2.24, 95% CI 1.69-2.96) after transplant. Additionally, the plerixafor group showed a significantly better toxicity profile and lower adverse event rate than patients treated with G-CSF alone (p = 0.0028) or chemomobilization (p < 0.0001), with a trend toward reduced survival in chemomobilization patients. Taken together, these data support the routine use of plerixafor-based mobilization to increase apheresis efficiency and reduce toxicity in myeloma patients undergoing transplant.