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Rakesh Popat Heather Oakervee Catherine Williams Mark Cook Charles Craddock Supratik Basu Charles Singer Stephen Harding Nicola Foot Simon Hallam Liz Odeh Simon Joel Jamie Cavenagh 《British journal of haematology》2009,144(6):887-894
This multicenter phase I/II study investigated the maximum tolerated dose (MTD), safety, and efficacy of low dose intravenous (IV) melphalan in combination with bortezomib for patients with relapsed multiple myeloma (MM). Patients received bortezomib 1·3 mg/m2 on days 1, 4, 8, and 11 and escalating doses of IV melphalan (2·5–10·0 mg/m2 ) on day 2 of a 28-day cycle for a maximum of eight cycles. Dexamethasone 20 mg was added for progressive or stable disease. Fifty-three patients were enrolled. The MTD was defined at melphalan 7·5 mg/m2 and bortezomib 1·3 mg/m2 . The overall response rate (ORR) was 68% (23% complete or near-complete responses [CR/nCR]) whilst at the MTD ( n = 33) the ORR was 76% (34% CR/nCR). After median follow-up of 17 months, the median progression free survival was 10 months, rising to 12 months at the MTD ( P < 0·05 vs. non-MTD regimens). The median overall survival was 28 months, but was not yet reached at the MTD. Grade 3/4 adverse events included thrombocytopenia (62%), neutropenia (57%), infection (21%), and neuropathy (15%). Bortezomib and low-dose IV melphalan combination therapy is a safe and highly effective regimen for patients with relapsed MM. These data suggest further investigation of this combination is warranted. 相似文献
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Christine Chen Donna E. Reece David Siegel Ruben Niesvizky Ralph V. Boccia Edward A. Stadtmauer Rafat Abonour Paul Richardson Jeffrey Matous Shaji Kumar Nizar J. Bahlis Melissa Alsina Robert Vescio Steven E. Coutre Dennis Pietronigro Robert D. Knight Jerome B. Zeldis Vincent Rajkumar 《British journal of haematology》2009,146(2):164-170
Lenalidomide gained Food and Drug Administration (FDA) approval for treatment of patients with relapsed or refractory multiple myeloma (MM) in combination with dexamethasone in June 2006. In April 2005, the FDA and patient advocacy groups requested an expanded access programme to both provide lenalidomide to patients likely to benefit and obtain additional safety information. Relapsed/refractory MM patients received lenalidomide 25 mg/d (days 1–21) and dexamethasone 40 mg/d (days 1–4, 9–12, and 17–20 of cycles 1–4; days 1–4 only from cycle 5 onwards), in 4-week cycles until disease progression, study drug discontinuation, or lenalidomide approval. Of the 1438 patients enrolled, ∼60% were male, median age was 64 years, and 61·7% had Durie-Salmon stage III disease. Median time on study was 15·4 weeks (range: 0·1–49·1) and median dose was 25 mg. The most common adverse events (AEs) were haematological (49%), gastrointestinal (59%), and fatigue (55%). The most common grade ≥3 AEs were haematological (45%), fatigue (10%), and pneumonia (7%). The most common serious AEs were pneumonia (8%), pyrexia (4%), and deep-vein thrombosis (3%). Primary cause of death was disease progression (10%). Safety data confirmed known AEs of lenalidomide plus dexamethasone therapy in patients with relapsed/refractory MM. 相似文献
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Andrzej J. Jakubowiak Jagoda K. Jasielec Cara A. Rosenbaum Craig E. Cole Ajai Chari Joseph Mikhael Jennifer Nam Amanda McIver Erica Severson Leonor A. Stephens Kathryn Tinari Shaun Rosebeck Todd M. Zimmerman Tyler Hycner Agata Turowski Theodore Karrison Jeffrey A. Zonder 《British journal of haematology》2019,186(4):549-560
Selinexor, an oral Selective Inhibitor of Nuclear Export, targets Exportin 1 (XPO1, also termed CRM1). Non-clinical studies support combining selinexor with proteasome inhibitors (PIs) and corticosteroids to overcome resistance in relapsed/refractory multiple myeloma (RRMM). We conducted a phase I dose-escalation trial of twice-weekly selinexor in combination with carfilzomib and dexamethasone (SKd) to determine maximum tolerated dose in patients with RRMM (N = 21), with an expansion cohort to assess activity in carfilzomib-refractory disease and identify a recommended phase II dose (RP2D). During dose escalation, there was one dose-limiting toxicity (cardiac failure). The RP2D of twice-weekly SKd was selinexor 60 mg, carfilzomib 20/27 mg/m2 and dexamethasone 20 mg. The most common grade 3/4 treatment-emergent adverse events included thrombocytopenia (71%), anaemia (33%), lymphopenia (33%), neutropenia (33%) and infections (24%). Rates of ≥minimal response, ≥partial response and very good partial response were 71%, 48% and 14%, respectively; similar response outcomes were observed for dual-class refractory (PI and immunomodulatory drug)/quad-exposed (carfilzomib, bortezomib, lenalidomide and pomalidomide) patients (n = 17), and patients refractory to carfilzomib in last line of therapy (n = 13). Median progression-free survival was 3·7 months, and overall survival was 22·4 months in the overall population. SKd was tolerable and re-established disease control in RRMM patients, including carfilzomib-refractory patients. Registered at ClinicalTrials.gov (NCT02199665) 相似文献
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Jagannath S Barlogie B Berenson J Siegel D Irwin D Richardson PG Niesvizky R Alexanian R Limentani SA Alsina M Adams J Kauffman M Esseltine DL Schenkein DP Anderson KC 《British journal of haematology》2004,127(2):165-172
In a phase 2 open-label study of the novel proteasome inhibitor bortezomib, 54 patients with multiple myeloma who had relapsed after or were refractory to frontline therapy were randomized to receive intravenous 1.0 or 1.3 mg/m(2) bortezomib twice weekly for 2 weeks, every 3 weeks for a maximum of eight cycles. Dexamethasone was permitted in patients with progressive or stable disease after two or four cycles respectively. Responses were determined using modified European Group for Blood and Marrow Transplantation criteria. The complete response (CR) + partial response (PR) rate for bortezomib alone was 30% [90% confidence interval (CI), 15.7-47.1] and 38% (90% CI, 22.6-56.4) in the 1.0 mg/m(2) (8 of 27 patients) and 1.3 mg/m(2) (10 of 26 patients) groups respectively. The CR + PR rate for patients who received bortezomib alone or in combination with dexamethasone was 37% and 50% for the 1.0 and 1.3 mg/m(2) cohorts respectively. The most common grade 3 adverse events were thrombocytopenia (24%), neutropenia (17%), lymphopenia (11%) and peripheral neuropathy (9%). Grade 4 events were observed in 9% (five of 54 patients). Bortezomib alone or in combination with dexamethasone demonstrated therapeutic activity in patients with multiple myeloma who relapsed after frontline therapy. 相似文献
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Adverse event management in patients with relapsed and refractory multiple myeloma taking pomalidomide plus low‐dose dexamethasone: A pooled analysis
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Philippe Moreau Meletios A. Dimopoulos Paul G. Richardson David S. Siegel Michele Cavo Paolo Corradini Katja Weisel Michel Delforge Peter O'Gorman Kevin Song Christine Chen Nizar Bahlis Albert Oriol Markus Hansson Martin Kaiser Pekka Anttila Reinier Raymakers Cristina Joao Gordon Cook Lars Sternas Tsvetan Biyukov Ana Slaughter Kevin Hong Jennifer Herring Xin Yu Mohamed Zaki Jesus San‐Miguel 《European journal of haematology》2017,99(3):199-206
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von Lilienfeld-Toal M Hahn-Ast C Furkert K Hoffmann F Naumann R Bargou R Cook G Glasmacher A 《European journal of haematology》2008,81(4):247-252
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. 相似文献
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Bortezomib in combination with intermediate-dose dexamethasone and continuous low-dose oral cyclophosphamide for relapsed multiple myeloma 总被引:5,自引:1,他引:4
Kropff M Bisping G Schuck E Liebisch P Lang N Hentrich M Dechow T Kröger N Salwender H Metzner B Sezer O Engelhardt M Wolf HH Einsele H Volpert S Heinecke A Berdel WE Kienast J;Deutsche Studiengruppe Multiples Myelom 《British journal of haematology》2007,138(3):330-337
A phase 2 trial was performed to study the combination of bortezomib (VELCADE) with intermediate-dose dexamethasone (DEX), and continuous low-dose oral cyclophosphamide (CY) in patients with relapsed multiple myeloma (MM). Fifty-four patients with advanced MM were enroled to receive eight 3-week treatment cycles with bortezomib 1.3 mg/m(2) on days 1, 4, 8, and 11, followed by three 5-week cycles with bortezomib 1.3 mg/m(2) on days 1, 8, 15, and 22. Within all cycles, DEX 20 mg/d was given orally on the day of bortezomib injection and the day thereafter. In addition, patients received CY continuous oral treatment at a dose of 50 mg/d p.o. once daily. Fifty patients completing at least one treatment cycle were evaluable for response. Complete, partial, and minor responses occurred in 16%, 66% and 8% of patients, respectively; overall response rate 90% (efficacy analysis). Median event-free survival was 12 months, with a median overall survival of 22 months. Adverse events (AE) of grades 3 or 4 occurring in at least 10% of patients comprised leucopenia, infection, herpes zoster, thrombocytopenia, neuropathy and fatigue. Bortezomib combined with DEX and CY is a highly effective treatment for relapsed MM at an acceptable rate of grade 3/4 AE. Antiviral prophylaxis appears to be mandatory. 相似文献
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A phase 1, open‐label,dose‐escalation study of pralatrexate in combination with bortezomib in patients with relapsed/refractory multiple myeloma
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Tamara J. Dunn Shira Dinner Elizabeth Price Steven E. Coutré Jason Gotlib Ying Hao Caroline Berube Bruno C. Medeiros Michaela Liedtke 《British journal of haematology》2016,173(2):253-259
Pralatrexate inhibits folic acid metabolism, and preclinical studies have shown that it is cytotoxic to multiple myeloma cells. This phase 1 study investigated the safety and efficacy of pralatrexate in combination with bortezomib in adults with relapsed or refractory multiple myeloma. A standard 3 + 3 design was used. Patients received intravenous pralatrexate at doses ranging from 10 to 30 mg/m2 and intravenous bortezomib at a dose of 1·3 mg/m2 on days 1, 8 and 15 of each 4‐week cycle. Eleven patients were enrolled and completed a median of two cycles. The maximum tolerated dose was 20 mg/m2. Two patients experienced dose‐limiting toxicity of mucositis. The most frequent non‐haematological toxicities were fatigue (55%) and mucositis (45%). There were three serious adverse events in three patients: rash, sepsis and hypotension. One patient (9%) had a very good partial response, 1 (9%) had a partial response, 1 (9%) had minimal response and two (18%) had progressive disease. The median duration of response was 4 months, the median time to next treatment was 3·4 months and the median time to progression was 4 months. Pralatrexate, in combination with bortezomib, was generally safe and demonstrated modest activity in relapsed or refractory multiple myeloma. Clinicaltrials.gov identifier: NCT01114282. 相似文献
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David S. Siegel Gary J. Schiller Kevin W. Song Richy Agajanian Keith Stockerl-Goldstein Hakan Kaya Michael Sebag Christy Samaras Ehsan Malek Giampaolo Talamo Christopher S. Seet Jorge Mouro William E. Pierceall Faiza Zafar Weiyuan Chung Shankar Srinivasan Amit Agarwal Nizar J. Bahlis 《British journal of haematology》2020,188(4):501-510
Patients with relapsed/refractory multiple myeloma (RRMM) for whom the benefits of lenalidomide have been exhausted in early treatment lines need effective therapies. In cohort A of the phase 2 MM-014 trial, we examined the safety and efficacy of pomalidomide plus low-dose dexamethasone immediately after lenalidomide-based treatment failure in patients with RRMM and two prior lines of therapy. Pomalidomide 4 mg was given on days 1 to 21 of 28-day cycles. Dexamethasone 40 mg (20 mg for patients aged >75 years) was given on days 1, 8, 15 and 22 of 28-day cycles. The primary endpoint was overall response rate (ORR), and secondary endpoints included progression-free survival (PFS), overall survival (OS) and safety. The intention-to-treat population comprised 56 patients; all received prior lenalidomide (87·5% lenalidomide refractory) and 39 (69·6%) received prior bortezomib. ORR was 32·1% (28·2% in the prior-bortezomib subgroup). Median PFS was 12·2 months (7·9 months in the prior-bortezomib subgroup). Median OS was 41·7 months (38·6 months in the prior-bortezomib subgroup). The most common grade 3/4 treatment-emergent adverse events were anaemia (25·0%), pneumonia (14·3%) and fatigue (14·3%). These findings support earlier sequencing of pomalidomide-based therapy in lenalidomide-pretreated patients with RRMM, including those who have become refractory to lenalidomide. Trial registration: www.ClinicalTrials.gov identifier NCT01946477. 相似文献
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Jakubowiak AJ Richardson PG Zimmerman T Alsina M Kaufman JL Kandarpa M Kraftson S Ross CW Harvey C Hideshima T Sportelli P Poradosu E Gardner L Giusti K Anderson KC 《British journal of haematology》2012,158(4):472-480
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. 相似文献
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OBJECTIVE: To conduct a systematic review of the efficacy of single-agent bortezomib vs. single-agent thalidomide in patients with relapsed/refractory multiple. METHODS: Publications in English from 1966 to June 2005 (MEDLINE, EMBASE, Cochrane library), publication reference lists, Janssen-Cilag data-on-file and abstracts from recent multiple myeloma conferences were reviewed. Prospective studies containing at least a single arm of either treatment group with n> or =30 were included. Studies adding dexamethasone for non-responders were excluded. Statistical pooling was performed for response rate and overallsurvival. RESULTS: One bortezomib study (n = 333, NEJM 2005, 352; 2487-98) and 15 thalidomide (n = 1007) studies met these criteria and were included. Patient baseline characteristics including age, gender, IgG : IgA, disease duration and beta-2 microglobulin were well matched except that 48% of bortezomib patients had received prior thalidomide. Response rate, defined as serum M-protein reduction > or =50%, was 53% for patients receiving bortezomib vs. 32% for thalidomide (P < 0.001, n = 10 studies). Response rate determined by European Group for Blood and Marrow Transplantation (EBMT) criteria was 41% for patients receiving bortezomib vs. 22% for thalidomide (P < 0.001, n = 4 studies). CONCLUSION: Bortezomib was associated with a significantly higher response rate and complete remission rate using both M-protein and EBMT criteria. 相似文献
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《British journal of haematology》2018,180(1):41-51
Marizomib (MRZ) is an irreversible, pan‐subunit proteasome inhibitor (PI) in clinical development for relapsed/refractory multiple myeloma (RRMM) and glioma. This study analysed MRZ, pomalidomide (POM) and low‐dose dexamethasone (Lo‐DEX) [PMD] in RRMM to evaluate safety and determine the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D). Intravenous MRZ (0·3–0·5 mg/m2) was administered over 2 h on days 1, 4, 8, 11; POM (3–4 mg) on days 1–21; and Lo‐DEX (5 or 10 mg) on days 1, 2, 4, 5, 8, 9, 11, 12, 15, 16, 22 and 23 of every 28‐day cycle. Thirty‐eight patients were enrolled that had received a median of 4 (range 1–10) prior lines of therapy; all patients received prior lenalidomide and bortezomib. No dose‐limiting toxicities (DLTs) were observed and 0·5 mg/m2 MRZ was determined to be the RP2D. The most common treatment‐related ≥Grade 3 adverse events were: neutropenia (11/38 patients: 29%), pneumonia (4/38 patients 11%), anaemia (4/38 patients; 11%) and thrombocytopenia (4/38 patients; 11%). The overall response rate and clinical benefit rate was 53% (19/36) and 64% (23/36), respectively. In conclusion, PMD was well tolerated and demonstrated promising activity in heavily pre‐treated, high‐risk RRMM patients. 相似文献
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Morris TC Kettle PJ Drake M Jones FC Hull DR Boyd K Morrison A Clarke P O'Reilly P Quinn J 《British journal of haematology》2008,143(3):349-354
A combination of clarithromycin, low dose of thalidomide and low dose dexamethasone was used in a phase II study to treat patients with relapsed and refractory myeloma. Thirty patients received clarithromycin 250 mg twice daily and thalidomide 50 mg at night on an ongoing basis with 4-d pulses of 10 mg dexamethasone given monthly. Eight patients had permitted escalation of thalidomide dosage up to 200 mg daily. The combination was well tolerated and could be given to elderly, infirm and severely cytopenic patients. Response rates were high, with 89% achieving at least 50% reduction in paraprotein and a 96% overall response rate. Although clarithromycin has only minimal anti-myeloma properties when used as a single agent, its combination with thalidomide and dexamethasone appears very effective, allowing these to be used in lower and more tolerable doses with good clinical effects. 相似文献
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《British journal of haematology》2017,178(5):756-763
Peripheral neuropathy (PN) is the most troublesome adverse event associated with the proteasome inhibitor bortezomib. Studies suggest an inflammatory aetiology for bortezomib‐induced PN (BiPN) and it has been hypothesized that reducing inflammation with concomitant dexamethasone may reduce BiPN incidence and/or severity. We retrospectively analysed PN rates from 32 studies (2697 patients with previously untreated multiple myeloma) incorporating bortezomib and differing dexamethasone schedules: partnered dosing (days of and after bortezomib), weekly dosing, and other dosing schedules (e.g. days 1–4, 8–11). Pooled overall PN rates were 45·5%, 63·9%, and 47·5%, respectively, with 5·3%, 11·0%, and 9·6% grade ≥3. Adjusting for potential confounders (age, gender, presence of thalidomide, bortezomib treatment duration), PN rates in patients on partnered dosing schedules appeared lower than in patients on weekly or other dosing schedules. Analyses conducted using patient‐level data suggest that cumulative dexamethasone dose, a potential confounding factor, is unlikely to have influenced the analyses. Findings were similar in a separate pooled analysis excluding data from regimens incorporating thalidomide, when pooled overall PN rates were 50·1%, 63·9%, and 48·3%, respectively, with 4·2%, 11·0%, and 8·6% grade ≥3. These findings suggest that partnered dexamethasone dosing may result in less severe BiPN compared with alternative dexamethasone dosing schedules. 相似文献