Response-adapted intensification with cyclophosphamide, bortezomib, and dexamethasone versus no intensification in patients with newly diagnosed multiple myeloma (Myeloma XI): a multicentre, open-label, randomised, phase 3 trial.
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ABSTRACT:
SUBMITTER: Jackson GH
PROVIDER: S-EPMC7043012 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:This United States community study evaluated the combination of daratumumab, bortezomib, cyclophosphamide and dexamethasone (D-VCd) in newly diagnosed multiple myeloma (NDMM) and relapsed multiple myeloma (RMM). Patients received 4-8 induction cycles of bortezomib 1·5 mg/m2 , cyclophosphamide 300 mg/m2 and dexamethasone 40 mg weekly. Intravenous daratumumab 16 mg/kg was administered as approved except for a split-first dose in Cycle 1. Eligible patients underwent autologous stem cell transplantation. All patients received ≤12 daratumumab maintenance doses monthly. Eighty-six NDMM and 14 RMM patients received ≥1 treatment dose. In NDMM patients, very good partial response or better (≥VGPR) and overall response rates after 4 induction cycles were 44% (primary endpoint) and 79%, respectively, and 56% and 81% at end of induction. The 12-month progression-free survival (PFS) rate was 87%. Efficacy was also observed in RMM patients. Fatigue (59%) and neutropenia (13%) were the most frequent treatment-emergent adverse event (TEAE) and grade 3/4 TEAE, respectively. Infusion reactions occurred in 54% of patients, primarily during the first dose, and were mild (2% grade 3). The first 2 daratumumab infusions were 4·5 and 3·8 h (median). Overall, D-VCd was well tolerated, split-first daratumumab dosing was feasible, the ≥VGPR rate after 4 cycles was 44% and the 1-year PFS rate was 87%.
| S-EPMC6593455 | biostudies-literature
Project description:A clinical trial was initiated to evaluate the recommended dose of cyclophosphamide in combination with bortezomib and dexamethasone as induction treatment before stem cell transplantation for younger patients with newly diagnosed multiple myeloma (MM). Thirty patients were treated with three 21-day cycles of bortezomib 1.3 mg/m(2) on days 1, 4, 8, and 11 plus dexamethasone 40 mg on the day of bortezomib injection and the day after plus cyclophosphamide at 900, 1,200, or 1,500 mg/m(2) on day 1. The maximum tolerated dose of cyclophosphamide was defined as 900 mg/m(2). At this dose level, 92% of patients achieved at least a partial response. The overall response rate [complete response (CR) plus partial response (PR)] across all dose levels was 77%, with a 10% CR rate. No patient experienced progressive disease. The most frequent adverse events were hematological and gastrointestinal toxicities as well as neuropathy. The results suggest that bortezomib in combination with cyclophosphamide at 900 mg/m(2) and dexamethasone is an effective induction treatment for patients with newly diagnosed MM that warrants further investigation.
| S-EPMC2745621 | biostudies-literature
Project description: Not available
| S-EPMC4916300 | biostudies-literature
Project description:BackgroundThe treatment of multiple myeloma (MM) has evolved significantly in the past decade, and new drug combinations have improved the response rates and prolonged survival. Studies comparing different induction chemotherapy regimens have shown that triple combinations have better results than double combinations. However, comparisons among different triple combinations are rare in the literature.MethodsWe retrospectively compared two triple combinations comprising bortezomib, cyclophosphamide and dexamethasone (VCD) versus thalidomide, cyclophosphamide and dexamethasone (CTD), and aimed at identifying which of the two combinations would yield better response rates following four induction cycles prior to hematopoietic cell transplantation in patients with untreated multiple myeloma.ResultsWe retrospectively reviewed the medical records of 311 patients from 24 different centers.The VCD regimen was used as induction therapy by 117 (37.6%) patients, whereas 194 (62.4%) patients received the CTD regimen. After four cycles of induction on an intention-to-treat basis, 54% of the patients in the VCD group achieved at least very good partial response versus 42.8% in the CTD group (p=0.05). We observed no difference in neuropathy or thrombotic events rates among the two regimens.ConclusionOur results corroborate the superiority of the triple combination regimes containing bortezomib over the triple combination with thalidomide as pre ASCT induction therapy in MM.
| S-EPMC7248497 | biostudies-literature
Project description:This phase 1 study (Clinicaltrials.gov: NCT00507442) was conducted to determine the maximum tolerated dose (MTD) of cyclophosphamide in combination with bortezomib, dexamethasone and lenalidomide (VDCR) and to assess the safety and efficacy of this combination in untreated multiple myeloma patients. Cohorts of three to six patients received a cyclophosphamide dosage of 100, 200, 300, 400 or 500 mg/m(2) (on days 1 and 8) plus bortezomib 1.3 mg/m(2) (on days 1, 4, 8 and 11), dexamethasone 40 mg (on days 1, 8 and 15) and lenalidomide 15 mg (on days 1-14), for eight 21-day induction cycles, followed by four 42-day maintenance cycles (bortezomib 1.3 mg/m(2), on days 1, 8, 15 and 22). The MTD was the cyclophosphamide dose below which more than one of six patients experienced a dose-limiting toxicity (DLT). Twenty-five patients were treated. Two DLTs were seen, of grade 4 febrile neutropenia (cyclophosphamide 400 mg/m(2)) and grade 4 herpes zoster despite anti-viral prophylaxis (cyclophosphamide 500 mg/m(2)). No cumulative hematological toxicity or thromboembolic episodes were reported. The overall response rate was 96%, including 20% stringent complete response (CR), 40% CR/near-complete response and 68% >or=very good partial response. VDCR is well tolerated and highly active in this population. No MTD was reached; the recommended phase 2 cyclophosphamide dose in VDCR is 500 mg/m(2), which was the highest dose tested.
| S-EPMC2957585 | biostudies-literature
Project description:We conducted a phase 1/2 trial evaluating the combination of cyclophosphamide, bortezomib, pegylated liposomal doxorubicin, and dexamethasone (CVDD) for newly diagnosed multiple myeloma (MM). The primary objective of the phase 1 was to evaluate the safety and tolerability of maximum planned dose (MPD) and the phase 2 was to assess the overall response rate. Patients received 6-8 cycles of CVDD at four dose levels. There were no dose-limiting toxicities. The MPD was cyclophosphamide 750 mg/m(2) IV on day 1, bortezomib 1.3 mg/m(2) IV on days 1, 4, 8, 11, pegylated liposomal doxorubicin 30 mg/m(2) IV on day 4, and dexamethasone 20 mg orally on the day of and after bortezomib (21-d cycle). Forty-nine patients were treated at the MPD of which 22% had high-risk myeloma. The most common grade ≥3 toxicities included myelosuppression, infection, and fatigue. Overall response and complete response rates were 91% and 26% in standard-risk, and 100% and 58% in high-risk cohort, respectively. After a median follow-up of 34 months, the median progression-free survival was 31.3 months. The 2-yr overall survival was 91.1% in the standard-risk and 88.9% in the high-risk cohort, respectively. CVDD regimen was well tolerated and was highly active in newly diagnosed MM.
| S-EPMC4508238 | biostudies-literature
Project description: Not available
| S-EPMC9894356 | biostudies-literature
Project description:This phase 1/2 study is the first prospective evaluation of lenalidomide-bortezomib-dexamethasone in front-line myeloma. Patients (N = 66) received 3-week cycles (n = 8) of bortezomib 1.0 or 1.3 mg/m(2) (days 1, 4, 8, 11), lenalidomide 15 to 25 mg (days 1-14), and dexamethasone 40 or 20 mg (days 1, 2, 4, 5, 8, 9, 11, 12). Responding patients proceeded to maintenance or transplantation. Phase 2 dosing was determined to be bortezomib 1.3 mg/m(2), lenalidomide 25 mg, and dexamethasone 20 mg. Most common toxicities included sensory neuropathy (80%) and fatigue (64%), with only 27%/2% and 32%/3% grade 2/3, respectively. In addition, 32% reported neuropathic pain (11%/3%, grade 2/3). Grade 3/4 hematologic toxicities included lymphopenia (14%), neutropenia (9%), and thrombocytopenia (6%). Thrombosis was rare (6% overall), and no treatment-related mortality was observed. Rate of partial response was 100% in both the phase 2 population and overall, with 74% and 67% each achieving very good partial response or better. Twenty-eight patients (42%) proceeded to undergo transplantation. With median follow-up of 21 months, estimated 18-month progression-free and overall survival for the combination treatment with/without transplantation were 75% and 97%, respectively. Lenalidomide-bortezomib-dexamethasone demonstrates favorable tolerability and is highly effective in the treatment of newly diagnosed myeloma. This study is registered at http://clinicaltrials.gov as NCT00378105.
| S-EPMC3324254 | biostudies-literature
Project description:PurposeThe combination of lenalidomide, bortezomib, and dexamethasone (RVD) is a highly effective and convenient induction regimen for both transplantation-eligible and -ineligible patients with myeloma. Here, we present the largest cohort of patients consecutively treated with RVD induction therapy followed by risk-adapted maintenance therapy with the longest follow-up and important information on long-term outcomes.Patients and methodsWe describe 1,000 consecutive patients with newly diagnosed myeloma treated with RVD induction therapy from January 2007 until August 2016. Demographic and clinical characteristics and outcomes data were obtained from our institutional review board-approved myeloma database. Responses and progression were evaluated per International Myeloma Working Group Uniform Response Criteria.ResultsThe overall response rate was 97.1% after induction therapy and 98.5% after transplantation, with 89.9% of patients achieving a very good partial response (VGPR) or better and 33.3% achieving stringent complete response after transplantation at a median follow-up time of 67 months. The estimated median progression-free survival time was 65 months (95% CI, 58.7 to 71.3 months) for the entire cohort, 40.3 months (95% CI, 33.5 to 47 months) for high-risk patients, and 76.5 months (95% CI, 66.9 to 86.2 months) for standard-risk patients. The median overall survival (OS) time for the entire cohort was 126.6 months (95% CI, 113.3 to 139.8 months). The median OS for high-risk patients was 78.2 months (95% CI, 62.2 to 94.2 months), whereas it has not been reached for standard-risk patients. Five-year OS rates for high-risk and standard-risk patients were 57% and 81%, respectively, and the 10-year OS rates were 29% and 58%, respectively.ConclusionRVD is an induction regimen that delivers high response rates (VGPR or better) in close to 90% of patients after transplantation, and risk-adapted maintenance can deliver unprecedented long-term outcomes. This study includes the largest cohort of patients treated with RVD reported to date with long follow-up and demonstrates the ability of 3-drug induction regimens in patients with newly diagnosed multiple myeloma to result in a substantial survival benefit.
| S-EPMC7587409 | biostudies-literature
Project description:BackgroundCarfilzomib is a second-generation irreversible proteasome inhibitor that is efficacious in the treatment of myeloma and carries less risk of peripheral neuropathy than first-generation proteasome inhibitors, making it more amenable to combination therapy.Methods and findingsThe Myeloma XI+ trial recruited patients from 88 sites across the UK between 5 December 2013 and 20 April 2016. Patients with newly diagnosed multiple myeloma eligible for transplantation were randomly assigned to receive the combination carfilzomib, lenalidomide, dexamethasone, and cyclophosphamide (KRdc) or a triplet of lenalidomide, dexamethasone, and cyclophosphamide (Rdc) or thalidomide, dexamethasone, and cyclophosphamide (Tdc). All patients were planned to receive an autologous stem cell transplantation (ASCT) prior to a randomisation between lenalidomide maintenance and observation. Eligible patients were aged over 18 years and had symptomatic myeloma. The co-primary endpoints for the study were progression-free survival (PFS) and overall survival (OS) for KRdc versus the Tdc/Rdc control group by intention to treat. PFS, response, and safety outcomes are reported following a planned interim analysis. The trial is registered (ISRCTN49407852) and has completed recruitment. In total, 1,056 patients (median age 61 years, range 33 to 75, 39.1% female) underwent induction randomisation to KRdc (n = 526) or control (Tdc/Rdc, n = 530). After a median follow-up of 34.5 months, KRdc was associated with a significantly longer PFS than the triplet control group (hazard ratio 0.63, 95% CI 0.51-0.76). The median PFS for patients receiving KRdc is not yet estimable, versus 36.2 months for the triplet control group (p < 0.001). Improved PFS was consistent across subgroups of patients including those with genetically high-risk disease. At the end of induction, the percentage of patients achieving at least a very good partial response was 82.3% in the KRdc group versus 58.9% in the control group (odds ratio 4.35, 95% CI 3.19-5.94, p < 0.001). Minimal residual disease negativity (cutoff 4 × 10-5 bone marrow leucocytes) was achieved in 55% of patients tested in the KRdc group at the end of induction, increasing to 75% of those tested after ASCT. The most common adverse events were haematological, with a low incidence of cardiac events. The trial continues to follow up patients to the co-primary endpoint of OS and for planned long-term follow-up analysis. Limitations of the study include a lack of blinding to treatment regimen and that the triplet control regimen did not include a proteasome inhibitor for all patients, which would be considered a current standard of care in many parts of the world.ConclusionsThe KRdc combination was well tolerated and was associated with both an increased percentage of patients achieving at least a very good partial response and a significant PFS benefit compared to immunomodulatory-agent-based triplet therapy.Trial registrationClinicalTrials.gov ISRCTN49407852.
| S-EPMC7799846 | biostudies-literature