Phase 1/2 study of ixazomib with cyclophosphamide and dexamethasone in newly diagnosed AL amyloidosis.
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ABSTRACT:
SUBMITTER: Rosenbaum CA
PROVIDER: S-EPMC9631711 | biostudies-literature | 2022 Sep
REPOSITORIES: biostudies-literature
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Phase 1/2 study of ixazomib with cyclophosphamide and dexamethasone in newly diagnosed AL amyloidosis.
Rosenbaum Cara A CA Özbek Umut U Sanchez Larysa L Lagdameo Jonathan J Abrahams Alex A Hassoun Hani H Lahoud Oscar O Niesvizky Ruben R Landau Heather J HJ Osman Keren K
Blood advances 20220901 18
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Project description:AimsThe purpose of this prospective, randomized study was to investigate the effectiveness and safety of the ixazomib+cyclophosphamide+dexamethasone (ICd) and ixazomib+dexamethasone (Id) regimens in newly diagnosed multiple myeloma (NDMM) who were elderly and frail and to compare the two regimens.MethodsPatients were randomly grouped into ICd and Id group. The primary end point was ORR, and patients who received at least two cycles were analyzed. The median follow-up was 13.5 months. After nine induction cycles, patients were instructed to take single ixazomib for maintenance.ResultsThe overall response rate in the ICd and Id groups was 78.9% and 70.6%, respectively, whereas the very good partial remission or better rate was 47.4% and 23.5%, respectively. For the ICd and Id groups, the response rate after 4 cycles was 76.5% and 57.1%, and the median duration to response was 2 and 4 months, respectively. Adverse events (AEs) included gastrointestinal intolerance, rash, fatigue, and thrombocytopenia, with severe AEs occurring in 21.1% and 23.5% patients in the ICd and Id groups, respectively, and the AEs were manageable. Both the QLQ-C30 and QLQ-MY20 scales indicated that ICd and Id regimens could help maintain and improve the quality of life(QoL).ConclusionsThe ICd and Id regimens might be effective and well-tolerated in elderly and frail patients with NDMM. In addition, a favorable outcome was observed that ICd might tend to cause faster and higher remission than Id regimen without increasing the risk of AEs. The long-term effectiveness and safety of the two regimens need further investigation.
| S-EPMC10067049 | biostudies-literature
Project description:Subcutaneous daratumumab plus bortezomib/cyclophosphamide/dexamethasone (VCd; D-VCd) improved outcomes versus VCd for patients with newly diagnosed immunoglobulin light-chain (AL) amyloidosis in the phase 3 ANDROMEDA study. We report a subgroup analysis of Asian patients (Japan; Korea; China) from ANDROMEDA. Among 388 randomized patients, 60 were Asian (D-VCd, n = 29; VCd, n = 31). At a median follow-up of 11.4 months, the overall hematologic complete response rate was higher for D-VCd versus VCd (58.6% vs. 9.7%; odds ratio, 13.2; 95% confidence interval [CI], 3.3-53.7; P < 0.0001). Six-month cardiac and renal response rates were higher with D-VCd versus VCd (cardiac, 46.7% vs. 4.8%; P = 0.0036; renal, 57.1% vs. 37.5%; P = 0.4684). Major organ deterioration progression-free survival (MOD-PFS) and major organ deterioration event-free survival (MOD-EFS) were improved with D-VCd versus VCd (MOD-PFS: hazard ratio [HR], 0.21; 95% CI, 0.06-0.75; P = 0.0079; MOD-EFS: HR, 0.16; 95% CI, 0.05-0.54; P = 0.0007). Twelve deaths occurred (D-VCd, n = 3; VCd, n = 9). Twenty-two patients had baseline serologies indicating prior hepatitis B virus (HBV) exposure; no patient experienced HBV reactivation. Although grade 3/4 cytopenia rates were higher than in the global safety population, the safety profile of D-VCd in Asian patients was generally consistent with the global study population, regardless of body weight. These results support D-VCd use in Asian patients with newly diagnosed AL amyloidosis. ClinicalTrials.gov Identifier: NCT03201965.
| S-EPMC9998577 | biostudies-literature
Project description:Bortezomib, a proteasome inhibitor (PI), has shown efficacy in the treatment of newly diagnosed and relapsed light chain (AL) amyloidosis, and is often used in combination with cyclophosphamide and dexamethasone. Ixazomib is the first oral PI to be approved in routine practice but has not yet been evaluated in the upfront treatment setting. Newly diagnosed AL amyloidosis patients with measurable disease and adequate organ function were enrolled. The primary objective was to determine the hematologic response rate of ixazomib in combination with cyclophosphamide and dexamethasone. Treatment was given for 12 cycles, followed by ixazomib maintenance until progression. Thirty-five patients were included; their median age was 67 years, and 69% were male. Major organ involvement included heart (66%) and kidneys (54%). A median of 4 induction cycles (range, 1-12) were administered. The overall hematologic response to induction was 63% and included complete response in 11.4% and very good partial response in 37.1% of patients. One patient was upstaged to complete response during maintenance. The most common reason for going off study was the institution of alternate therapy (61%). With a median follow-up of 29.7 months for the living patients, the 2-year progression-free survival and overall survival were 74% and 78%, respectively. The median time to alternate therapy was 7.5 months. Grade ≥3 hematologic and nonhematologic adverse events occurred in 23% and 49% of patients. Given ixazomib's favorable toxicity profile, which is an important advantage for the typically frail AL population, further evaluation of ixazomib in other combinations in the upfront setting is warranted. This trial was registered at www.clinicaltrials.gov as #NCT01864018.
| S-EPMC9631712 | biostudies-literature
Project description:In the first phase 3 study in relapsed/refractory AL amyloidosis (TOURMALINE-AL1 NCT01659658), 168 patients with relapsed/refractory AL amyloidosis after 1-2 prior lines were randomized to ixazomib (4 mg, days 1, 8, 15) plus dexamethasone (20 mg, days 1, 8, 15, 22; n = 85) or physician's choice (dexamethasone ± melphalan, cyclophosphamide, thalidomide, or lenalidomide; n = 83) in 28-day cycles until progression or toxicity. Primary endpoints were hematologic response rate and 2-year vital organ deterioration or mortality rate. Only the first primary endpoint was formally tested at this interim analysis. Best hematologic response rate was 53% with ixazomib-dexamethasone vs 51% with physician's choice (p = 0.76). Complete response rate was 26 vs 18% (p = 0.22). Median time to vital organ deterioration or mortality was 34.8 vs 26.1 months (hazard ratio 0.53; 95% CI, 0.32-0.87; p = 0.01). Median treatment duration was 11.7 vs 5.0 months. Adverse events of clinical importance included diarrhea (34 vs 30%), rash (33 vs 20%), cardiac arrhythmias (26 vs 15%), nausea (24 vs 14%). Despite not meeting the first primary endpoint, all time-to-event data favored ixazomib-dexamethasone. These results are clinically relevant to this relapsed/refractory patient population with no approved treatment options.
| S-EPMC8727292 | biostudies-literature
Project description:Immune-modulatory drugs are active in immunoglobulin light-chain amyloidosis and the addition of alkylating agents can potentiate their action. In this phase II prospective trial we used cyclophosphamide, lenalidomide and dexamethasone in the treatment of 21 patients who were refractory (n=13, 62%) or relapsed (n=8, 38%) after prior treatment including melphalan in all cases, bortezomib in 4 and thalidomide in 6. Median number of cycles administered was 4 (range 2-9 cycles). Severe adverse events were observed in 57% of patients, most common being neutropenia (29%). The hematologic response rate was 62%, with one complete response and 5 very good partial responses. Overall median survival was three years. The achievement of CR/VGPR was associated with a significant survival advantage. The combination of cyclophosphamide, lenalidomide and dexamethasone is an effective treatment for relapsed/refractory AL amyloidosis, and good quality hematologic response should be the aim of treatment in this setting. (clinicaltrials.gov identifier: NCT00607581).
| S-EPMC3659931 | biostudies-literature
Project description: Not available
| S-EPMC4916300 | biostudies-literature
Project description:Sixty-four transplant-eligible patients with newly diagnosed multiple myeloma (NDMM) received carfilzomib (days 1, 2, 8, 9, 15, 16), 300 mg/m(2) cyclophosphamide (days 1, 8, 15), 100 mg thalidomide (days 1-28) and 40 mg dexamethasone (days 1, 8, 15, 22) in 28-day cycles (CYKLONE regimen). Carfilzomib was dose-escalated to 15/20, 20/27, 20/36 and 20/45 mg/m(2) to determine the maximum tolerated dose (MTD), which was 20/36 mg/m(2) . Regardless of attribution, common Grade 3 or higher adverse events were lymphopenia (38%), neutropenia (23%) and anaemia (20%). All peripheral neuropathy (31%) was Grade 1 and considered most likely to be thalidomide-related. Common cardiac or pulmonary events of any grade in ≥5% of patients included dyspnoea (20%) and cough (6%). Overall (N = 64), 91% of patients achieved a best response of partial response or better across all cycles of treatment, including five patients with complete responses. At the MTD (n = 29), 59% of patients achieved a very good partial response or better after four cycles (primary end point). Stem cell collection was successful in all patients in whom it was attempted (n = 42). Progression-free survival and overall survival at 24 months was 76% and 96%, respectively (median follow-up of 17·5 months). CYKLONE appears highly efficacious in NDMM patients, with manageable toxicities.
| S-EPMC4521972 | biostudies-literature
Project description:BackgroundPatients with amyloid light chain amyloidosis and severe cardiac dysfunction have a poor prognosis. Treatment options that induce rapid and deep hematologic and organ responses, irrespective of cardiac involvement, are needed.ObjectivesThe aim of this study was to evaluate the impact of baseline cardiac stage on efficacy and safety outcomes in the phase 3 ANDROMEDA trial.MethodsRates of overall complete hematologic response and cardiac and renal response at 6 months and median major organ deterioration-progression-free survival and major organ deterioration-event-free survival were compared across cardiac stages (I, II, or IIIA) and treatments (daratumumab, bortezomib, cyclophosphamide, and dexamethasone [D-VCd] or bortezomib, cyclophosphamide, and dexamethasone [VCd]). Rates of adverse events (AEs) were summarized for patients with and without baseline cardiac involvement and by cardiac stage.ResultsMedian follow-up duration was 15.7 months. The proportions of stage I, II, and IIIA patients were 23.2%, 40.2%, and 36.6%. Across cardiac stages, hematologic and organ response rates were higher and major organ deterioration-progression-free survival and major organ deterioration-event-free survival were longer with D-VCd than VCd. AE rates were similar between treatments and by cardiac stage; serious AE rates were higher in patients with cardiac involvement and increased with increasing cardiac stage. The incidence of cardiac events was numerically greater with D-VCd vs VCd, but the rate of grade 3 or 4 events was similar. The exposure-adjusted incidence rate for cardiac events was lower with D-VCd than VCd (median exposure 13.4 and 5.3 months, respectively).ConclusionsThese findings demonstrate the efficacy of D-VCd over VCd in patients with newly diagnosed amyloid light chain amyloidosis across cardiac stages, thus supporting its use in patients with cardiac involvement. (NCT03201965).
| S-EPMC9700253 | biostudies-literature
Project description:The combination of lenalidomide and low-dose dexamethasone is an effective treatment for multiple myeloma (MM). Addition of alkylating agents to lenalidomide or thalidomide results in increased response rates and deeper responses. We designed this trial to study the combination of cyclophosphamide, lenalidomide, and dexamethasone (CRd) as initial therapy for MM. Fifty-three patients with previously untreated symptomatic MM was enrolled. Patients received 4-week treatment cycles consisting of lenalidomide (25 mg daily for 3 weeks), dexamethasone (40 mg weekly), and cyclophosphamide (300 mg/m(2) weekly for 3 weeks). A partial response or better was seen in 85% of patients including 47% with a very good partial response or better. The toxicities were manageable with over 80% of planned doses delivered; six patients went off study for toxicity. The median progression free survival (PFS) for the entire group was 28 months (95% CI: 22.7-32.6) and the overall survival (OS) at 2 years was 87% (95% CI: 78-96). Importantly, 14 patients with high-risk MM had similar PFS and OS as the standard-risk patients (n = 39). CRd is an effective and well-tolerated regimen for upfront therapy of MM with high response rates and excellent 2-year OS, and is suitable for long-term therapy.
| S-EPMC3901994 | 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