Low-dose thalidomide with pegylated liposomal doxorubicin and high-dose dexamethasone for relapsed/refractory multiple myeloma: a prospective, multicenter, phase II study

The aim of this prospective, multicenter, phase II study was to investigate the combination of pegylated liposomal doxorubicin (Caelyx) 40 mg/m2 on day 1 every 28 days, dexamethasone 40 mg p.o. on days 1-4 and 9-12 and thalidomide 100 mg daily in 50 patients with advanced multiple myeloma. Twenty-six percent of patients achieved a complete response, 6% a near complete response, 6% a very good partial response, 38% a partial response, 16% a minor response and 8% progressed, for an overall response rate of 92%. The median event-free survival was 17 months and the median overall survival was not reached. Grade 3 non-hematologic toxicity occurred in 12% of patients, thromboembolic disease in 12% and severe infection in 16%. The combination of pegylated liposomal doxorubicin, dexamethasone an thalidomide is safe and very effective in advanced multiple myeloma.     

A phase I study of bortezomib in combination with doxorubicin and intermediate-dose dexamethasone (iPAD therapy) for relapsed or refractory multiple myeloma

Bortezomib and doxorubicin have synergistic activity against myeloma cells in vitro. We underwent a dose finding study of bortezomib in combination with a fixed dose of doxorubicin and intermediate-dose dexamethasone (iPAD therapy) in patients with relapsed or refractory myeloma. Bortezomib was administered on days 1, 4, 8 and 11 at a dose of 1.0 and 1.3 mg/m² in cohorts 1 and 2, respectively. Doxorubicin 9 mg/m² was given by rapid intravenous infusion on days 1–4, and dexamethasone 20 mg on days 1–2, 4–5, 8–9 and 11–12. Treatment was repeated at a 3-week interval and the dose-limiting toxicity (DLT), defined as grade 4 hematological toxicity lasting more than 5 days and/or grade 3 or higher non-hematological toxicity, was evaluated. In cohort 1, 2 of 6 patients developed DLTs including grade 4 hyponatremia and grade 3 infection with appropriate neutrophil counts. No DLT was observed in the remaining 4 patients, indicating this dose was tolerable. In cohort 2, 3 of 5 patients developed DLTs including grade 4 thrombocytopenia lasting more than 5 days, grade 3 hepatic transaminase elevation and grade 3 ileus, indicating this dose was intolerable. It is concluded that bortezomib at the dose of 1.0 mg/m² is recommended in combination with doxorubicin and intermediate-dose dexamethasone.     

Bendamustine,lenalidomide and dexamethasone (BRd) has high activity as 2nd‐line therapy for relapsed and refractory multiple myeloma – a phase II trial

The combination of lenalidomide (Revlimid^®, R) and dexamethasone (d) is a standard regimen for patients with relapsed/refractory multiple myeloma (rrMM ). With this regimen, only a small fraction of patients will achieve high quality responses [≥ very good partial response (VGPR )]. The combination of bendamustine (B), lenalidomide and dexamethasone (BR d) has shown high efficacy in patients with advanced rrMM . However, dose‐limiting haematotoxicity restricted its use in extensively pre‐treated patient populations. This prospective, multicentre Phase II study evaluated the efficacy and safety of BR d in rrMM patients with one prior line of therapy. Fifty patients were enrolled (median age 68·5 years [range 46–83]) and were treated with B 75 mg/m² days 1, 2; R 25 mg days 1–21 and d (40/20 mg) days 1, 8, 15 and 22, for 6 28‐day induction cycles, followed by 12 cycles with Rd alone. Pegfilgrastim was administered according to protocol‐defined criteria. The study aimed to demonstrate a complete response (CR )/VGPR rate of >40% after induction therapy. Of 45 evaluable patients, 23 (51%) achieved a CR /VGPR . Grade 4 neutropenia or thrombocytopenia occurred in 17 (34%) and 8 (16%) of patients, respectively. BR d is a safe and efficacious regimen as a second line treatment for rrMM , leading to high quality responses in a considerable proportion of patients.     

Low-dose lenalidomide and dexamethasone combination treatment in elderly patients with relapsed and refractory multiple myeloma

Objective: This study investigated the efficacy and safety of low-dose lenalidomide combined with dexamethasone in elderly patients with relapsed and refractory multiple myeloma (MM).

Methods: Thirty-two elderly patients with refractory and recurrent MM (median age: 64 years) were treated with low-dose lenalidomide (LD-R) combined with dexamethasone (D). LD-R (10?mg/d) was administered orally for 21 days and D (40?mg/d) was administered twice a day on days 1–4, 9–12, and 17–20. The treatment lasted 2–8 28-day cycles.

Results: After two cycles, the complete, very good partial, and partial remission rates were 12.5% (4/32), 25.0% (8/32), and 34.4% (11/32), respectively. The overall response rate was 71.9% (23/32). After a 24-month follow-up, 23 patients responded to therapy, three were in complete remission, four were stable, and 16 exhibited disease progression. In addition, median time-to-progression was 13 months. Observed side effects were hypodynamia, gastrointestinal reaction, peripheral neuritis, and mild hypocytosis.

Conclusion: Low-dose lenalidomide in combination with dexamethasone is an effective and safe treatment for relapsed and refractory MM in elderly patients.     

The addition of cyclophosphamide to lenalidomide and dexamethasone in multiply relapsed/refractory myeloma patients; a phase I/II study

We report the results of a Phase I/II dose escalation study to determine the maximum tolerated dose (MTD) of cyclophosphamide when combined with lenalidomide and dexamethasone in relapsed/refractory myeloma. Thirty‐one patients were enrolled in cohorts of 3, at five dose levels of cyclophosphamide to a maximum of 700 mg on days 1 and 8 of a 28‐d cycle. Patients received lenalidomide 25 mg days 1–21 and dexamethasone 20 mg orally days 1–4 and 8–11. The MTD was 600 mg cyclophosphamide, days 1 and 8. Grade 3/4 haematological complications occurred in 26% of patients, grade 3/4 infection in 3% (both at 700 mg cyclophosphamide), with thromboembolic complications in 6% of patients. Overall complete response (CR) rate was 29%, very good partial response rate 7% and partial response rate 45% giving an overall response rate of 81%. After 21 months median follow‐up, projected 2‐year progression‐free survival was 56%, with 80% overall survival at 30 months. Ten further patients were treated at MTD with a 40% CR rate. No dose reductions for any study drugs or deaths occurred during cycles 1–9. Lenalidomide, cyclophosphamide and dexamethasone is a safe, effective combination in relapsed myeloma inducing a high response rate, warranting further investigation in phase III trials.     

Ibrutinib alone or with dexamethasone for relapsed or relapsed and refractory multiple myeloma: phase 2 trial results

Novel therapies with unique new targets are needed for patients who are relapsed/refractory to current treatments for multiple myeloma. Ibrutinib is a first‐in‐class, once‐daily, oral covalent inhibitor of Bruton tyrosine kinase, which is overexpressed in the myeloma stem cell population. This study examined various doses of ibrutinib ± low‐dose dexamethasone in patients who received ≥2 prior lines of therapy, including an immunomodulatory agent. Daily ibrutinib ± weekly dexamethasone 40 mg was assessed in 4 cohorts using a Simon 2‐stage design. The primary objective was clinical benefit rate (CBR; ≥minimal response); secondary objectives included safety. Patients (n = 92) received a median of 4 prior regimens. Ibrutinib + dexamethasone produced the highest CBR (28%) in Cohort 4 (840 mg + dexamethasone; n = 43), with median duration of 9·2 months (range, 3·0–14·7). Progression‐free survival was 4·6 months (range, 0·4–17·3). Grade 3–4 haematological adverse events included anaemia (16%), thrombocytopenia (11%), and neutropenia (2%); grade 3–4 non‐haematological adverse events included pneumonia (7%), syncope (3%) and urinary tract infection (3%). Ibrutinib + dexamethasone produced notable responses in this heavily pre‐treated population. The encouraging efficacy, coupled with the favourable safety and tolerability profile of ibrutinib, supports its further evaluation as part of combination treatment.     

A systematic review of phase II trials of thalidomide/dexamethasone combination therapy in patients with relapsed or refractory multiple myeloma

Thalidomide monotherapy in relapsed/refractory multiple myeloma (MM) has a response rate of 30%. The combination of thalidomide with dexamethasone (Thal/Dex) is expected to improve responses, but it is unknown if the combination increases the rate of adverse events. Here, we conducted a systematic review of studies evaluating Thal/Dex in relapsed/refractory MM. Twelve studies were included, comprising 451 patients. The response rate (CR and PR) was 46% (95% CI 42-51%). Therapy-related toxicity was comparable to thalidomide monotherapy and included somnolence (26%, 95% CI 22-31%), constipation (37%, 95% CI 32-42%) and peripheral neuropathy (27%, 95% CI 23-32%). Only venous thromboembolism appeared to occur more often with Thal/Dex (5%, 95% CI 3-8%). Thus, using Thal/Dex results in an improved response rate in relapsed/refractory MM, with a toxicity rate comparable to thalidomide monotherapy.     

CTD方案治疗难治或复发多发性骨髓瘤

目的应用环磷酰胺、沙立度胺及地塞米松(CTD)方案治疗难治或复发多发性骨髓瘤(MM)。方法20例难治或复发MM患者接受沙立度胺,100~200mg/d,口服持续应用;环磷酰胺,200~300mg.m-2.d-1,1~4d,静脉注射;地塞米松,20~40mg/d,1~4d,口服。4周为1个疗程。3个疗程后,若出现疗效或病情稳定则再连续应用3个疗程;若病情进展,则停止治疗。结果3个疗程后,13例(65%)患者显示治疗反应,其中9例患者获部分缓解,4例患者获微小缓解。而5例患者病情稳定,2例进展。对病情未进展的18例患者继续治疗3个疗程后再次评价,则部分缓解13例(65%),获微小缓解5例。结论CTD是一个具有较好治疗前景的方案。     

Phase II study of pegylated liposomal doxorubicin,low‐dose dexamethasone,and lenalidomide in patients with newly diagnosed multiple myeloma

Our previous phase I/II trial of pegylated liposomal doxorubicin (PLD), low‐dose dexamethasone, and lenalidomide in patients with relapsed and refractory myeloma showed an overall response rate of 75%, with 29% achieving ≥ VGPR. Here, we investigated this combination (PLD 30 or 40 mg/m² intravenously, day 1; dexamethasone 40 mg orally, days 1–4; lenalidomide 25 mg orally, days 1–21; administered every 28 days) in a phase II study in patients with newly diagnosed symptomatic multiple myeloma to determine its efficacy and tolerability ( ClinicalTrials.gov NCT00617591). At best response, patients could proceed with high‐dose melphalan or with maintenance lenalidomide and dexamethasone. In 57 patients, we found that the overall response rate and rate of very good partial response and better on intent‐to‐treat, our primary endpoints, were 77.2% and 42.1%, respectively, with responses per the International Myeloma Working Group. Median progression‐free survival was 28 months (95% CI 18.1–34.8), with 1‐ and 2‐year overall survival rates of 98.1 and 79.6%. During induction, grade 3/4 toxicities were neutropenia (49.1%), anemia (15.8%), thrombocytopenia (7%), fatigue (14%), febrile neutropenia (8.8%), and venous thromboembolic events (8.8%). During maintenance, grade 3/4 toxicities were mainly hematologic. We found this combination to be active in patients with newly diagnosed myeloma, with results comparable to other lenalidomide‐based induction strategies without proteasome inhibition. In addition, maintenance therapy with lenalidomide was well tolerated. Am. J. Hematol. 89:62–67, 2014. © 2013 Wiley Periodicals, Inc.     

Melphalan, prednisone, thalidomide and defibrotide in relapsed/refractory multiple myeloma: results of a multicenter phase I/II trial

Background

Defibrotide is a novel orally bioavailable polydisperse oligonucleotide with anti-thrombotic and anti-adhesive effects. In SCID/NOD mice, defibrotide showed activity in human myeloma xenografts. This phase I/II study was conducted to identify the most appropriate dose of defibrotide in combination with melphalan, prednisone and thalidomide in patients with relapsed and relapsed/refractory multiple myeloma, and to determine its safety and tolerability as part of this regimen.

Design and Methods

This was a phase I/II, multicenter, dose-escalating, non-comparative, open label study. Oral melphalan was administered at a dose of 0.25 mg/kg on days 1–4, prednisone at a dose of 1.5 mg/kg also on days 1–4 and thalidomide at a dose of 50–100 mg/day continuously. Defibrotide was administered orally at three dose-levels: 2.4, 4.8 or 7.2 g on days 1–4 and 1.6, 3.2, or 4.8 g on days 5–35.

Results

Twenty-four patients with relapsed/refractory multiple myeloma were enrolled. No dose-limiting toxicity was observed. In all patients, the complete response plus very good partial response rate was 9%, and the partial response rate was 43%. The 1-year progression-free survival and 1-year overall survival rates were 34% and 90%, respectively. The most frequent grade 3–4 adverse events included neutropenia, thrombocytopenia, anemia and fatigue. Deep vein thrombosis was reported in only one patient.

Conclusions

This combination of melphalan, prednisone and thalidomide together with defibrotide showed anti-tumor activity with a favorable tolerability. The maximum tolerated dose of defibrotide was identified as 7.2 g p.o. on days 1–4 followed by 4.8 g p.o. on days 5–35. Further trials are needed to confirm the role of this regimen and to evaluate the combination of defibrotide with new drugs (ClinicalTrials.gov Identifier: NCT00406978).     

Weekly carfilzomib,lenalidomide, and dexamethasone in relapsed or refractory multiple myeloma: A phase 1b study

Twice-weekly carfilzomib (27 mg/m²) with lenalidomide-dexamethasone (KRd) is a standard-of-care in relapsed or refractory multiple myeloma (RRMM). This phase 1b study evaluated KRd with once-weekly carfilzomib in RRMM. Patients received carfilzomib (30-minute infusion; 56 or 70mg/m²) on days 1, 8, and 15; lenalidomide 25 mg on days 1-21; and dexamethasone 40 mg on days 1, 8, 15, and 22 (day 22 omitted for cycles 9+) of 28-day cycles. Primary objective was safety/tolerability; efficacy was a secondary objective. Fifty-six RRMM patients enrolled: 22 during dose evaluation (56-mg/m², n = 10; 70-mg/m², n = 12) and 34 during dose expansion (all initiated dosing at 70 mg/m²). After 2 fatal adverse events (AEs) during 70-mg/m² dose expansion, dosage reduction to 56 mg/m² was permitted. Results are presented for carfilzomib 56-mg/m² (n = 10) and 70-mg/m² groups (dose evaluation/expansion; n = 46). Median carfilzomib dose was 53.2 mg/m² (56-mg/m² group) and 62.4 mg/m² (70-mg/m² group). Grade ≥3 AE rates were 70.0% (56 mg/m²) and 69.6% (70 mg/m²). Overall response rates were 90.0% (56 mg/m²) and 89.1% (70 mg/m²); ≥very good partial response rates were 50.0% (56 mg/m²) and 73.9% (70 mg/m²). Once-weekly KRd was active with acceptable toxicity in RRMM, supporting further evaluation of this regimen.     

Safety and efficacy of pomalidomide,dexamethasone and pegylated liposomal doxorubicin for patients with relapsed or refractory multiple myeloma

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.     

DVd(T)方案治疗多发性骨髓瘤17例临床疗效分析

目的:观察脂质体阿霉素(PLD)联合长春新碱(VCR)、地塞米松(Dex)士沙利度胺(Thal)治疗多发性骨髓瘤(MM)患者的疗效及毒副反应.方法:17例初治或复发难治MM患者接受DVd(PLD 40 mg·m-2d1、VCR 2 mg d1、Dex 40 mg d1～4)或DVdT(PLD及VCR用法用量同上,Dex:40 mg,d1～4、d9～12;Thal:100 mg,d1～21)治疗,按照EBMT标准评价疗效、WHO标准判断毒副反应.结果:①17例患者共完成了34个周期的治疗,总有效率(ORR=CR+nCR+VGPR+PR)为58.8%,与国外文献报道接近,与历史上我院采用的VAD及其类似方案相比疗效也接近.②采用DVd方案治疗的11例患者的ORR为4/11(36.4%).其中6例初治患者的ORR为2/6(33.3%).采用DVdT方案化疗的6例患者均为初治病例,其ORR为6/6(100%).对于初治患者.DVdT方案的ORR显著好于DVd方案.③多数治疗相关毒副反应为1～2级且可耐受.17例患者中有13例在接受DVd(T)化疗前心电图或心脏B超示不同程度的心律失常或左室舒张功能降低,但均未因化疗增加心脏毒性.DVd组与DVdT组的毒副反应接近.结论:DVd方案具有较好的耐受性,适当延长Dex用量并加入Thal可以在不增加化疗相关毒性的同时显著提高DVd方案疗效.     

Bortezomib, doxorubicin, and dexamethasone combination therapy followed by thalidomide and dexamethasone consolidation as a salvage treatment for relapsed or refractory multiple myeloma: analysis of efficacy and safety

We conducted a phase 2 study with bortezomib, doxorubicin, and dexamethasone (PAD) followed by thalidomide and dexamethasone (TD) in patients with relapsed multiple myeloma (MM). Forty patients were enrolled between November 2005 and October 2007, with follow-up continuing until January 2009. Efficacy could be assessed in 37 patients. The overall response rate to PAD followed by TD was 83.6%: complete response 51.4%, near-complete response 13.4%, very good partial remission 5.4%, and partial response 13.4%. The median follow-up was 27 months (range 13–39). The median progression-free survival (PFS) from the start of treatment was 18 months (95% CI, 9.7–26.2 months), with a 1-year PFS rate of 56.9% and 3-year PFS rate of 25.7%. Median overall survival was 35.1 months (95% CI, 18.5–51.7), with a 1-year survival rate of 75% and 3-year survival rate of 27.3%. One hundred seventy-eight PAD cycles (median 6, range 1–6) in 38 patients were assessable for safety. The most common hematologic toxicity was thrombocytopenia, with grade 3–4 in 35.8%. Sensory neuropathy occurred at grade 2 in 26.3% and grade 3 in 10.3%. Two hundred TD treatment cycles (median 4, range 0–12 cycles) were administered. Most adverse events were of mild degree and manageable. PAD followed by TD in patients with relapsed MM is very effective and tolerable.     

Perifosine plus lenalidomide and dexamethasone in relapsed and relapsed/refractory multiple myeloma: a Phase I Multiple Myeloma Research Consortium study

The combination of lenalidomide-dexamethasone is active in multiple myeloma (MM). Preclinical data showed that the Akt inhibitor, perifosine, sensitized MM cells to lenalidomide and dexamethasone, providing the rationale for this Phase I, multicentre, single-arm study to assess the safety and determine the maximum-tolerated dose (MTD) of perifosine-lenalidomide-dexamethasone in relapsed and relapsed/refractory MM. Patients received escalating doses of perifosine 50-100 mg daily and lenalidomide 15-25 mg once daily on days 1-21 of each 28-d cycle, plus dexamethasone 20-40 mg weekly thereafter, as indicated. Thirty-two patients were enrolled across four dose cohorts. MTD was not reached, with 31 patients evaluable for safety/tolerability. The most common all-causality grade 1-2 adverse events were fatigue (48%) and diarrhoea (45%), and grade 3-4 neutropenia (26%), hypophosphataemia (23%), thrombocytopenia (16%), and leucopenia (13%). Among 30 evaluable patients, 73% (95% confidence interval, 57·5-89·2%) achieved a minimal response or better, including 50% with a partial response or better. Median progression-free survival was 10·8 months and median overall survival 30·6 months. Response was associated with phospho-Akt in pharmacodynamic studies. Perifosine-lenalidomide-dexamethasone was well tolerated and demonstrated encouraging clinical activity in relapsed and relapsed/refractory MM.