RESUMEN
BACKGROUND: There is a small but growing number of thrombotic thrombocytopenic purpura (TTP) cases attributed to immune checkpoint inhibitor therapy, with nivolumab and ipilimumab therapy being the most frequently described in the literature. STUDY DESIGN AND METHODS: This report evaluates the course of a patient with a history of metastatic adenocarcinoma of the lung who developed TTP following treatment with the PD-1 inhibitor Pembrolizumab. The patient was treated with six sessions of therapeutic plasma exchange and appeared to be in remission. Exacerbation occurred 4 days later, and seven more sessions of plasma exchange were performed along with four total doses of Rituximab, and a steroid taper with monitoring of platelet counts and ADAMTS13 activity. RESULTS: His platelet count recovered to a peak of 318,000 UL with an ADAMTS13 activity of 77% at the time of discharge. The patient has been following up regularly for outpatient testing with no TTP relapse as of the completion of this report. DISCUSSION: This is one of a few cases of Pembrolizumab-associated TTP reported in the literature with successful complete remission following treatment. Plasma exchange in this setting may be an especially beneficial therapeutic intervention because of the removal of both the anti-ADAMTS13 antibody as well as the immune system upregulating anti-PDL1 monoclonal antibody with replacement of ADAMTS13 from donor plasma. Longer duration of plasma exchange and monitoring for normalization of ADAMTS13 levels in addition to platelet count before cessation of treatment may improve durable remission rates in this entity.
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Púrpura Trombocitopénica Trombótica , Humanos , Púrpura Trombocitopénica Trombótica/inducido químicamente , Púrpura Trombocitopénica Trombótica/tratamiento farmacológico , Proteínas ADAM/uso terapéutico , Recurrencia Local de Neoplasia/terapia , Rituximab/uso terapéutico , Intercambio Plasmático/efectos adversos , Proteína ADAMTS13Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma Neuroendocrino/tratamiento farmacológico , Vesícula Biliar/efectos de los fármacos , Carboplatino/administración & dosificación , Carcinoma Neuroendocrino/genética , Carcinoma Neuroendocrino/metabolismo , Etopósido/administración & dosificación , Femenino , Vesícula Biliar/metabolismo , Vesícula Biliar/patología , Humanos , Ipilimumab/administración & dosificación , Antígeno Ki-67/análisis , Persona de Mediana Edad , Mutación , Clasificación del Tumor , Metástasis de la Neoplasia , Nivolumab/administración & dosificación , Proteínas de Unión a Retinoblastoma/genética , Resultado del Tratamiento , Proteína p53 Supresora de Tumor/genética , Ubiquitina-Proteína Ligasas/genéticaRESUMEN
Immunomodulatory drugs including thalidomide, lenalidomide (LEN) and pomalidomide (POM), are effective for treating multiple myeloma (MM). POM has shown enhanced efficacy with dexamethasone (DEX). Pegylated liposomal doxorubicin (PLD) with bortezomib is US Food and Drug Administration-approved for treating MM. PLD with LEN or thalidomide has shown efficacy for MM patients. LEN with DEX, PLD and bortezomib achieves high response rates. We evaluated the combination of POM with DEX 40 mg and PLD 5 mg/m2 with the latter two drugs administered on days 1, 4, 8 and 11 on a 28-day cycle for the treatment of relapsed/refractory MM patients. During Phase 1, the maximum tolerated dose of POM was 4 mg, and was used in Phase 2, which also required patients to be refractory to LEN. However, neutropenia ≥ grade 3 was observed in 10/17 (59%) patients, and the dose was lowered to 3 mg. Median PFS was 5·4 months (range, 0·3-29·0 + months). Overall response rates for patients in Phase 2 were 39% and 31% among subjects receiving POM at 3 mg and 4 mg, respectively, and clinical benefit rates were 51% and 44%, respectively. POM, PLD and DEX is a treatment option for relapsed/refractory MM patients including those who are refractory to LEN.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/patología , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Dexametasona/administración & dosificación , Doxorrubicina/administración & dosificación , Doxorrubicina/análogos & derivados , Resistencia a Antineoplásicos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mieloma Múltiple/mortalidad , Polietilenglicoles/administración & dosificación , Recurrencia , Retratamiento , Análisis de Supervivencia , Talidomida/administración & dosificación , Talidomida/análogos & derivados , Resultado del TratamientoRESUMEN
OBJECTIVE: Neuropathy is an important complication that may limit treatment options for patients with multiple myeloma. Previous studies have focused on treatment efficacy and have shown that retreatment with bortezomib (BTZ) is an effective treatment option. The goal of this study was to focus on the clinical manifestations of peripheral neuropathy (PN) and to retrospectively compare the incidence and severity of PN between the initial BTZ regimen and upon retreatment. Furthermore, this study evaluated how certain factors affect BIPN, which will help determine what conditions should be considered prior to retreatment. METHODS: Charts were reviewed from 93 patients who were retreated with a BTZ-containing regimen after previously being treated with this drug. RESULTS: Among the patients who developed PN, most patients in the study had low-grade neuropathy during the initial BTZ treatment (n = 52, 68%). The results showed no evidence of cumulative toxicity, and there was no significant difference in the incidence and severity of PN upon retreatment. Factors such as the presence of baseline PN, number of prior treatments, dose of BTZ, and comorbidities did not increase the severity of PN upon retreatment. The lapse of time between the two regimens also did not affect the severity of PN. CONCLUSION: The results suggest that retreatment with BTZ may be a feasible option, without additional risks of PN, for MM patients even with peripheral neuropathy during their initial treatment with this drug.
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Antineoplásicos/efectos adversos , Bortezomib/efectos adversos , Mieloma Múltiple/tratamiento farmacológico , Enfermedades del Sistema Nervioso Periférico/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/administración & dosificación , Bortezomib/administración & dosificación , Femenino , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Mieloma Múltiple/complicaciones , Mieloma Múltiple/epidemiología , Enfermedades del Sistema Nervioso Periférico/epidemiología , Enfermedades del Sistema Nervioso Periférico/etiología , Enfermedades del Sistema Nervioso Periférico/patología , Recurrencia , Retratamiento , Estudios Retrospectivos , Factores de Riesgo , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
New classes of drugs including the proteasome inhibitors (PI) bortezomib and, more recently, carfilzomib and the immunomodulatory agent lenalidomide have shown improved outcomes for multiple myeloma (MM) patients during the past decade. However, most of the studies reporting outcomes for patients receiving these drugs have relied on older data sets derived from large institutions that included patients not receiving their treatment at those facilities and represented only those eligible for clinical trials or were from sites where treatment options were limited. We have analyzed data from 258 MM patients who have received treatment with at least one of three agents: bortezomib, carfilzomib, and lenalidomide in a single clinic specializing in MM with respect to their responses and other outcomes to treatment regimens including these agents. Response rates were similar between these three drugs when used for the first time and again during subsequent treatment regimens. As expected, the clinical benefit rates (CBRs) were better for patients receiving their first treatment when compared to their use in subsequent treatment regimens. The CBRs were similar during their 2nd, 3rd, and 4th treatments containing these agents. Many patients refractory to these agents showed responses to regimens containing these same drugs when used in different combinations. In addition, patients refractory to one PI often responded to the other PI. The results of this study demonstrate that novel agents can be used repeatedly in novel combinations with significant clinical benefit for patients with MM.
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Antineoplásicos/administración & dosificación , Bortezomib/administración & dosificación , Mieloma Múltiple/diagnóstico , Mieloma Múltiple/tratamiento farmacológico , Oligopéptidos/administración & dosificación , Talidomida/análogos & derivados , Adulto , Anciano , Anciano de 80 o más Años , Inhibidores de la Angiogénesis/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Estudios de Cohortes , Femenino , Humanos , Lenalidomida , Masculino , Persona de Mediana Edad , Mieloma Múltiple/mortalidad , Estudios Retrospectivos , Tasa de Supervivencia/tendencias , Talidomida/administración & dosificación , Resultado del TratamientoRESUMEN
Despite recent advances made in its treatment, multiple myeloma (MM) remains an incurable B cell malignancy. Thus, the objective for treating these patients is to prolong overall survival (OS) and preserve patients' quality of life. We have analyzed data from 264 consecutive MM patients who had their initial visit between July 1, 2004 and December 1, 2014 and have received treatment in a single clinic specializing in MM. We determined their progression-free survival (PFS, OS, and 5-year OS). The PFS for frontline (n = 165 treatments), salvage (n = 980), and all treatments (n = 1145) were 13.9, 4.6, and 5.5 months, respectively. The median OS of all patients was 98 months with a 5-year survival of 74%. The results of this study show a marked improvement in OS for unselected MM patients compared with historical data. There were no significant differences in OS between patients with different International Staging System (ISS) stages. Younger patients (<65 years old) showed a longer OS. The results of this study should help physicians predict outcomes for MM patients and be encouraging for patients with this B cell malignancy.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Mieloma Múltiple/diagnóstico , Mieloma Múltiple/tratamiento farmacológico , Servicio Ambulatorio en Hospital/tendencias , Adulto , Anciano , Anciano de 80 o más Años , Bortezomib/administración & dosificación , Femenino , Estudios de Seguimiento , Humanos , Lenalidomida , Masculino , Persona de Mediana Edad , Mieloma Múltiple/mortalidad , Oligopéptidos/administración & dosificación , Estudios Retrospectivos , Tasa de Supervivencia/tendencias , Talidomida/administración & dosificación , Talidomida/análogos & derivadosRESUMEN
PURPOSE: Fatigue is a common problem among multiple myeloma (MM) patients. Armodafinil is a drug known to promote wakefulness, which is related to modafinil, a compound that improves fatigue in some cancer patients treated with chemotherapeutic agents. We investigated whether armodafinil could reduce cancer-related fatigue in MM patients. METHODS: This double-blind, placebo-controlled phase 3 trial evaluated the efficacy of armodafinil in MM patients with evidence of moderate fatigue. Patients were randomized to one of two arms: treatment-only, with armodafinil given at 150 mg/daily for 56 days, or placebo-first, with placebo given on days 1-28, followed by armodafinil administered at 150 mg daily on days 29-56. Fatigue was measured on days 1 (pre-dose: baseline), 15, 28, 43, and 56 using seven separate assessments, including four patient-reported outcomes of fatigue and related quality of life measures, as well as three objective measures of cognitive function. RESULTS: Overall toxicities were similar between treatment groups. No significant differences were observed between the placebo-first and the treatment-only arms after 28 days. Treatment with armodafinil for 28 additional days did not produce responses. Both placebo-first and treatment-only patients showed similar significant improvements in three patient-reported measures and one objective task at day 28 compared to baseline. Placebo-first patients improved on eight additional measures (one patient-reported measure, six subscales, and one objective task), suggesting a strong placebo effect in this patient population. CONCLUSIONS: Evaluation and treatment of cancer-related fatigue continues to be challenging; a clear definition of this symptom and better assessment tools are needed.
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Compuestos de Bencidrilo/uso terapéutico , Fatiga/tratamiento farmacológico , Fatiga/etiología , Mieloma Múltiple/complicaciones , Promotores de la Vigilia/uso terapéutico , Adulto , Anciano , Compuestos de Bencidrilo/efectos adversos , Estudios Cruzados , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Modafinilo , Mieloma Múltiple/tratamiento farmacológico , Efecto Placebo , Calidad de Vida , Vigilia/efectos de los fármacosRESUMEN
Panobinostat is a histone deacetylase inhibitor that has shown synergistic preclinical anti-myeloma activity when combined with other agents, recently exhibiting synergy with the alkylating agent melphalan (Sanchez et al., Leuk Res 35(3):373-379, 2011). This phase 1/2 trial investigated the safety and efficacy of panobinostat in combination with melphalan for relapsed/refractory multiple myeloma patients. There were four different trial treatment schedules due to tolerability issues, with the final treatment schedule (treatment schedule D) consisting of panobinostat (15 or 20 mg) and melphalan (0.05 or 0.10 mg/kg), both administered on days 1, 3, and 5 of a 28-day cycle. A total of 40 patients were enrolled; 3 in treatment schedule A, 9 in schedule B, 7 in schedule C, and finally 21 schedule D. Patients had been treated with a median of four regimens (range, 1-16) and two prior bortezomib-containing regimens (range, 0-9). Maximum-tolerated dose was established at 20 mg panobinostat and 0.05 mg/kg melphalan in treatment schedule D. Overall, 3 patients (7.5 %) achieved ≥partial response (two very good PRs and one PR) while 23 exhibited stable disease and 14 showed progressive disease. All three responders were enrolled in cohort 2 of treatment schedule B (panobinostat 20 mg thrice weekly continuously with melphalan 0.05 mg/kg on days 1, 3, and 5). Neutropenia and thrombocytopenia were common, with 30.8 and 23.1 % of patients exhibiting ≥grade 3, respectively. Panobinostat + melphalan appears to have tolerability issues in a dosing regimen capable of producing a response. Care must be taken to balance tolerability and efficacy with this combination.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Mieloma Múltiple/tratamiento farmacológico , Administración Oral , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Progresión de la Enfermedad , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Enfermedades Gastrointestinales/inducido químicamente , Enfermedades Hematológicas/inducido químicamente , Humanos , Ácidos Hidroxámicos/administración & dosificación , Ácidos Hidroxámicos/efectos adversos , Indoles/administración & dosificación , Indoles/efectos adversos , Infecciones/etiología , Estimación de Kaplan-Meier , Masculino , Dosis Máxima Tolerada , Melfalán/administración & dosificación , Melfalán/efectos adversos , Persona de Mediana Edad , Panobinostat , Recurrencia , Terapia RecuperativaRESUMEN
Bendamustine, active in multiple myeloma (MM), is a bifunctional mechlorethamine derivative with alkylating properties. Bortezomib, approved to treat MM, is effective in combination with alkylators. The tolerability and efficacy of bendamustine plus bortezomib in relapsed/refractory MM was assessed in an open-label, dose-escalating, phase I/II study. Patients aged ≥18 years received intravenous bendamustine 50, 70, or 90 mg/m(2) (days 1 and 4) plus bortezomib 1·0 mg/m(2) (days 1, 4, 8, and 11) for up to eight 28-day cycles. No dose-limiting toxicity was observed after cycle 1; bendamustine 90 mg/m(2) plus bortezomib 1·0 mg/m(2) was designated the maximum tolerated dose (MTD). The most common grade 3/4 adverse events were leucopenia (58%), neutropenia (50%), lymphopenia (45%), and thrombocytopenia (30%). Primary efficacy measure was overall response rate (ORR), which was the combined complete response (CR), very good partial response (VGPR), partial response (PR), and minimal response (MR). ORR was 48% (one CR, two VGPR, nine PR, and seven MR) for all 40 enrolled patients, 52% (16/31) at the MTD (90 mg/m(2) ), and 42% and 46% for prior use of bortezomib (n = 31) or alkylators (n = 28) respectively. Bendamustine plus bortezomib was well tolerated with promising efficacy in this heavily pretreated population.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Mieloma Múltiple/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Clorhidrato de Bendamustina , Ácidos Borónicos/administración & dosificación , Bortezomib , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mieloma Múltiple/mortalidad , Mieloma Múltiple/patología , Estadificación de Neoplasias , Compuestos de Mostaza Nitrogenada/administración & dosificación , Pirazinas/administración & dosificación , Recurrencia , Resultado del TratamientoRESUMEN
The combination of pegylated liposomal doxorubicin (PLD), bortezomib and dexamethasone has shown efficacy in the treatment of multiple myeloma (MM) patients. Our earlier retrospective study suggested that modification of the doses, schedules and route of administration of these drugs appears to reduce toxicity without compromising anti-MM activity. As a result, we evaluated this modified drug combination in the frontline setting in a prospective multicentre phase II trial. Thirty-five previously untreated MM patients were enrolled. Dexamethasone IV 40 mg, bortezomib 1 mg/m(2) and PLD 5 mg/m(2) were administered on days 1, 4, 8 and 11 of a 4-week cycle. Patients were treated to their maximum response plus two additional cycles. The treatment regimen was discontinued after a maximum of eight cycles. Our modified schedule and dosing regimen achieved a high overall response rate of 86%, while showing a marked decrease in the incidence and severity of peripheral neuropathy, palmar-plantar erythrodysesthesia and myelosuppression compared to the standard dosing on a 3-week cycle using these drugs. This modified regimen of dexamethasone, bortezomib and PLD shows improved tolerability and safety while maintaining a high response rate when compared to standard treatment with these agents in the frontline setting.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Mieloma Múltiple/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Ácidos Borónicos/administración & dosificación , Ácidos Borónicos/efectos adversos , Bortezomib , Dexametasona/administración & dosificación , Dexametasona/efectos adversos , Supervivencia sin Enfermedad , Doxorrubicina/administración & dosificación , Doxorrubicina/efectos adversos , Doxorrubicina/análogos & derivados , Esquema de Medicación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Polietilenglicoles/administración & dosificación , Polietilenglicoles/efectos adversos , Estudios Prospectivos , Pirazinas/administración & dosificación , Pirazinas/efectos adversosRESUMEN
Few studies have evaluated prognostic factors among patients with multiple myeloma (MM) since new therapies have become available. Monthly zoledronic acid (ZOL) has been incorporated into many treatment regimens to reduce skeletal-related events (SREs), but outcomes among patients receiving this bisphosphonate have not been well-defined. The aim of this retrospective study was to determine baseline and on-treatment prognostic factors in these patients. Data were collected from the date of diagnosis on 300 consecutive MM patients treated with ZOL. Median duration of ZOL was 18 months (range 1-121 months). The skeletal morbidity rate was 0.116 events per patient year. Five-year overall survival (OS) was 69%. Risk factors for shortened OS included SREs, increased serum creatinine, and International Staging System (ISS) Stage II or III. Thirty-four (11%) patients showed worsening renal function. In 28 of these patients, ZOL was discontinued and restarted in half of these patients following a brief delay. Only 5 of the 34 patients showed worsening of their renal function. Fourteen patients (4.7%) developed osteonecrosis of the jaw (ONJ). All patients with ONJ are in remission or with stable disease except one patient who died of a myocardial infarction while in remission. Only two patients showed some worsening of ONJ despite of ongoing monthly ZOL. Overall, these results suggest that skeletal complications are an important prognostic factor for MM. Although ONJ and renal deterioration may infrequently occur with ZOL, most patients do not experience worsening of these conditions with ongoing treatment with this bisphosphonate.
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Difosfonatos/efectos adversos , Imidazoles/efectos adversos , Enfermedades Maxilomandibulares/inducido químicamente , Enfermedades Renales/inducido químicamente , Mieloma Múltiple/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Difosfonatos/uso terapéutico , Femenino , Humanos , Imidazoles/uso terapéutico , Enfermedades Maxilomandibulares/patología , Masculino , Persona de Mediana Edad , Mieloma Múltiple/patología , Pronóstico , Estudios Retrospectivos , Factores de Riesgo , Ácido ZoledrónicoRESUMEN
BACKGROUND: We conducted a single-arm, multicentre phase 2 study to evaluate bortezomib, ascorbic acid and melphalan (BAM) for patients with newly diagnosed multiple myeloma (MM). METHODS: Induction consisted of up to eight 28-d cycles of bortezomib 1.0 mg/m(2) on days 1, 4, 8 and 11, plus oral ascorbic acid 1 g and oral melphalan 0.1 mg/kg on days 1-4, followed by maintenance bortezomib 1.3 mg/m(2) every 2 wk until progression. RESULTS: Among 35 patients enrolled (median age 70 yr), responses occurred in 23/31 evaluable patients (74%) including five (16%) complete, three (10%) very good partial, six (19%) partial and nine (29%) minimal responses. Six patients (19%) had stable disease. Thus, disease control was achieved in 29 (94%) patients. Median times to first and best responses were 2 and 3 months (ranges 1-5 and 1-7), respectively. Median time to progression was 19 months and median overall survival has not been reached (range 2-23+ months). Grade 3 and 4 adverse events occurred in 17 and 5 patients, respectively; the most common were neutropenia, neuropathy and thrombocytopenia. CONCLUSIONS: BAM is an efficacious, well-tolerated and steroid- and immunomodulatory drug (IMiD)-free frontline treatment regimen for MM patients.
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Ácido Ascórbico/administración & dosificación , Ácidos Borónicos/administración & dosificación , Melfalán/administración & dosificación , Mieloma Múltiple/tratamiento farmacológico , Pirazinas/administración & dosificación , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/toxicidad , Bortezomib , Humanos , Persona de Mediana Edad , Mieloma Múltiple/mortalidad , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
PURPOSE: This open-label, phase I dose-escalation study assessed the safety, tolerability, and initial efficacy of Samariam 153 (153Sm)-lexidronam/bortezomib combination therapy for patients with relapsed/refractory multiple myeloma. EXPERIMENTAL DESIGN: Patients were enrolled in six cohorts and given bortezomib (1.0 or 1.3 mg/m2) on days 1, 4, 8, and 11 and 153Sm-lexidronam (0.25, 0.5, or 1.0 mCi/kg) on day 3 of a 56-day cycle (maximum of four cycles). The primary endpoints were safety and tolerability of the 153Sm-lexidronam/bortezomib regimen. RESULTS: Twenty-four patients were enrolled. Median values for age, time since diagnosis, and number of prior treatments were 63 years, 29 months, and three regimens, respectively. The most common toxicities were hematologic; during the first cycle, median neutrophil and platelet nadirs were 1,000/mm3 and 98,500/mm3, respectively, and observed generally 3 to 4 weeks post-treatment. The incidences of grade 4 neutropenia and thrombocytopenia were 12.5% and 8.3%, respectively, during treatment cycle 1. Dose-limiting toxicity, reached in cohort 6 as a result of hematologic toxicity, defined the maximum tolerated dose as 0.5 mCi/kg 153Sm-lexidronam in combination with 1.3 mg/m2 bortezomib. The maximum tolerated dose for 153Sm-lexidronam in combination with the 1.0 mg/m2 bortezomib was not reached. No nonhematologic dose-limiting toxicities were observed; both the incidence and the severity of peripheral neuropathy were low. Responses occurred in 5 (21%) patients, including 3 (12.5%) complete and 2 (8.3%) minimal responses. CONCLUSIONS: Bortezomib combined with 153Sm-lexidronam appears to be a well-tolerated regimen, which showed clinical activity in this phase I trial for patients with relapsed or refractory multiple myeloma.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Ácidos Borónicos/administración & dosificación , Etilenodiaminas/administración & dosificación , Mieloma Múltiple/terapia , Organofosfonatos/administración & dosificación , Pirazinas/administración & dosificación , Radioisótopos/administración & dosificación , Samario/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bortezomib , Terapia Combinada , Esquema de Medicación , Humanos , Dosis Máxima Tolerada , Recuento de Plaquetas , RecurrenciaRESUMEN
PURPOSE: Patients with monoclonal gammopathy of undetermined significance (MGUS) have increased rates of bone resorption, osteopenia, osteoporosis, and risk of fractures. This study was undertaken to determine the efficacy and safety of zoledronic acid for patients with MGUS and enhanced bone loss. EXPERIMENTAL DESIGN: In this phase II open-label study, 54 patients with MGUS and osteopenia or osteoporosis were administered zoledronic acid 4 mg i.v. at 0, 6, and 12 months. The primary efficacy end point was bone mineral density, assessed using a dual-energy X-ray absorptiometry scan in the lumbar (L)-spine done at screening and at 13 months (1 month after the final zoledronic acid infusion). RESULTS: At study end for all patients (N = 54), L-spine T-scores improved by a median of +0.27 (range, -0.38 to +3.91), corresponding to a median increase in bone mineral density of +15.0% (range, -18.0% to +1,140.0%; P < 0.0001). Hip T-scores improved by a median of +0.10 (range, -2.40 to +2.03), corresponding to a median increase of +6.0% (range, -350.0% to +165.0%). During the study, no new fractures, osteonecrosis of the jaw, or significant renal adverse events were reported. CONCLUSIONS: Zoledronic acid administered i.v. at a dosage of 4 mg every 6 months for three doses total was well-tolerated and substantially improved bone mineral density for patients with MGUS and bone loss. Zoledronic acid may be effective for the prevention of new fractures in this high-risk population.
Asunto(s)
Conservadores de la Densidad Ósea/farmacología , Densidad Ósea , Enfermedades Óseas/tratamiento farmacológico , Difosfonatos/farmacología , Imidazoles/farmacología , Gammopatía Monoclonal de Relevancia Indeterminada/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Vértebras Lumbares/diagnóstico por imagen , Vértebras Lumbares/efectos de los fármacos , Masculino , Persona de Mediana Edad , Osteonecrosis , Radiografía , Factores de Tiempo , Rayos X , Ácido ZoledrónicoRESUMEN
Bortezomib synergizes with melphalan in preclinical and early clinical studies. Updated data from our phase 1/2 study assessing the safety and efficacy of bortezomib plus melphalan in relapsed/refractory multiple myeloma (MM) are presented. Bortezomib (0.7, 1.0, or 1.3 mg/m(2)) on days 1, 4, 8, and 11 and oral melphalan (0.025-0.25 mg/kg) on days 1-4 of a 28-day cycle were administered. Hematologic toxicities defined the maximum tolerated dose as bortezomib 1.0 mg/m(2) and melphalan 0.10 mg/kg. Because dose-limiting toxicities were attributed to the more myelosuppressive melphalan, cohorts 9 and 10 with higher bortezomib (1.3 mg/m(2)) and lower melphalan (0.025 and 0.10 mg/kg) doses were added. Responses occurred in 32/46 (70%) evaluable patients: two complete (4%), five near-complete (11%), 16 partial (35%), and nine minimal (20%). Complete and near-complete responses were observed only with higher bortezomib doses. Response rates were similar in patients with prior melphalan or bortezomib. Median progression-free survival was 9 months (range, 1-24), and overall survival was 32 months (range, 1-54). The most common grade 3/4 hematologic adverse events (AEs) were neutropenia (31%/0%), thrombocytopenia (25%/2%), and anemia (13%/0%). Grade 4 tumor lysis syndrome was reported in one patient. Fewer grade 3/4 hematologic AEs were reported in cohorts 9 and 10 than in cohorts receiving lower bortezomib and higher melphalan doses. In conclusion, bortezomib plus melphalan is a steroid- and immunomodulatory drug-free regimen that may provide a treatment alternative for elderly patients and patients with significant comorbidity.