A Phase II Study of Pomalidomide, Daily Low Dose Oral Cyclophosphamide, and Dexamethasone in Relapsed/Refractory Multiple Myeloma
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PROVIDER: PRJNA576896 | ENA |
REPOSITORIES: ENA
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Project description:High-througput transcriptome analysis by RNA-seq of multiple myeloma tumor samples (CD138+ cells) in subjects treated with pomalidomide, daily low dose oral cyclophosphamide and dexamethasone in the context of a phase II clinical trial. Samples were collected at baseline as a correlative study to determine whether gene expression profiles could distinguish patients with (un)favorable response to treatment.
2019-10-11 | GSE138717 | GEO
Project description:Treatment options for patients with heavily pretreated relapsed and/or refractory multiple myeloma remain limited. We evaluated a novel therapeutic regimen consisting of carfilzomib, pomalidomide, and dexamethasone (CPD) in an open-label, multicenter, phase 1, dose-escalation study. Patients who relapsed after prior therapy or were refractory to the most recently received therapy were eligible. All patients were refractory to prior lenalidomide. Patients received carfilzomib IV on days 1, 2, 8, 9, 15, and 16 (starting dose of 20/27 mg/m(2)), pomalidomide once daily on days 1 to 21 (4 mg as the initial dose level), and dexamethasone (40 mg oral or IV) on days 1, 8, 15, and 22 of 28-day cycles. The primary objective was to evaluate the safety and determine the maximum tolerated dose (MTD) of the regimen. A total of 32 patients were enrolled. The MTD of the regimen was dose level 1 (carfilzomib 20/27 mg/m(2), pomalidomide 4 mg, dexamethasone 40 mg). Hematologic adverse events (AEs) occurred in ?60% of all patients, including 11 patients with grade ?3 anemia. Dyspnea was limited to grade 1/2 in 10 patients. Peripheral neuropathy was uncommon and limited to grade 1/2. Eight patients had dose reductions during therapy, and 7 patients discontinued treatment due to AEs. Two deaths were noted on study due to pneumonia and pulmonary embolism (n = 1 each). The combination of CPD is well-tolerated and highly active in patients with relapsed/refractory multiple myeloma. This trial was registered at www.clinicaltrials.gov as #NCT01464034.
| S-EPMC4643003 | biostudies-literature
Project description:Pomalidomide is a third generation immunomodulatory drug which in combination with dexamethasone, has been shown to be active in relapsed/refractory multiple myeloma. However, the data in Asian patients remain limited. We conducted a prospective phase two clinical trial in major cancer centers in Singapore, South Korea, Taiwan, Japan and Hong Kong to assess the efficacy and safety of pomalidomide and dexamethasone combination (PomDex)?+/-?cyclophosphamide in Asian patients with relapsed/refractory multiple myeloma who failed lenalidomide and bortezomib. Patients were treated with pomalidomide (4?mg daily for 21 days every 4 weeks) and dexamethasone (40?mg weekly). If there is less than a minimal response after three cycles of PomDex, cyclophosphamide 300?mg/m2 can be added (PomCyDex). A total of 136 patients were enrolled. The median PFS was 9 and 10.8 months for the PomDex and PomCyDex group, respectively. The median OS was 16.3 months. This regimen appears to be active across age groups and prior lines of treatment. This combination was overall well tolerated with grade 3 and 4 adverse events of mainly cytopenias. PomDex is highly active and well-tolerated in Asian patients. The addition of cyclophosphamide can improve the response and outcomes further in patients with suboptimal response to PomDex.
| S-EPMC6783445 | biostudies-literature
Project description:Patients with multiple myeloma who have relapsed after or become refractory to lenalidomide in early treatment lines represent a clinically important population in need of effective therapies. The safety and efficacy of pomalidomide, low-dose dexamethasone, and daratumumab was evaluated in lenalidomide-pretreated patients with relapsed or refractory multiple myeloma (RRMM) after one to two prior treatment lines in the phase 2 MM-014 study. Patients received pomalidomide 4?mg daily from days 1-21 and dexamethasone 40?mg weekly (28-day cycles). Daratumumab 16?mg/kg was administered per label. Primary endpoint was overall response rate (ORR); secondary endpoints included progression-free survival (PFS) and safety. Per protocol, all patients (N?=?112) had received lenalidomide in their most recent prior regimen (75.0% lenalidomide refractory). ORR was 77.7% (76.2% in lenalidomide-refractory patients); median follow-up was 17.2 months. Median PFS was not reached (1-year PFS rate 75.1%). The most common hematologic grade 3/4 treatment-emergent adverse event was neutropenia (62.5%). Grade 3/4 infections were reported in 31.3% of patients, including 13.4% with grade 3/4 pneumonia. These results demonstrate the safety and efficacy of pomalidomide-based therapy as early as second line in patients with RRMM, even immediately after lenalidomide failure, indicating that switching from the immunomodulatory agent class is not necessary.
| S-EPMC7685974 | biostudies-literature
Project description:Daratumumab plus pomalidomide and dexamethasone (pom-dex) was evaluated in patients with relapsed/refractory multiple myeloma with ≥2 prior lines of therapy who were refractory to their last treatment. Patients received daratumumab 16 mg/kg at the recommended dosing schedule, pomalidomide 4 mg daily for 21 days of each 28-day cycle, and dexamethasone 40 mg weekly. Safety was the primary end point. Overall response rate (ORR) and minimal residual disease (MRD) by next-generation sequencing were secondary end points. Patients (N = 103) received a median (range) of 4 (1-13) prior therapies; 76% received ≥3 prior therapies. The safety profile of daratumumab plus pom-dex was similar to that of pom-dex alone, with the exception of daratumumab-specific infusion-related reactions (50%) and a higher incidence of neutropenia, although without an increase in infection rate. Common grade ≥3 adverse events were neutropenia (78%), anemia (28%), and leukopenia (24%). ORR was 60% and was generally consistent across subgroups (58% in double-refractory patients). Among patients with a complete response or better, 29% were MRD negative at a threshold of 10-5 Among the 62 responders, median duration of response was not estimable (NE; 95% confidence interval [CI], 13.6-NE). At a median follow-up of 13.1 months, the median progression-free survival was 8.8 (95% CI, 4.6-15.4) months and median overall survival was 17.5 (95% CI, 13.3-NE) months. The estimated 12-month survival rate was 66% (95% CI, 55.6-74.8). Aside from increased neutropenia, the safety profile of daratumumab plus pom-dex was consistent with that of the individual therapies. Deep, durable responses were observed in heavily treated patients. The study was registered at www.clinicaltrials.gov as #NCT01998971.
| S-EPMC5570682 | biostudies-literature
Project description:This phase 1/2 trial evaluated the maximum tolerated doses, safety, and efficacy of pomalidomide, bortezomib, and dexamethasone (PVD) combination in patients with relapsed lenalidomide-refractory multiple myeloma (MM). In phase 1, dose level 1 consisted of pomalidomide (4 mg by mouth on days 1 to 21), IV or subcutaneous bortezomib (1.0 mg/m2 on days 1, 8, 15, and 22), and dexamethasone (40 mg by mouth on days 1, 8, 15, and 22) given every 28 days. Bortezomib was increased to 1.3 mg/m2 for dose level 2 and adopted in the phase 2 expansion cohort. We describe the results of 50 patients. Objective response rate was 86% (95% confidence interval [CI], 73-94) among all evaluable patients (stringent complete response, 12%; complete response, 10%; very good partial response, 28%; and partial response, 36%) and 100% among high-risk patients. Within a median follow-up of 42 months, 20% remain progression free, 66% are alive, and 4% remain on treatment. Median progression-free survival was 13.7 months (95% CI, 9.6-17.7). The most common toxicities were neutropenia (96%), leukopenia (84%), thrombocytopenia (82%), anemia (74%), and fatigue (72%); however, the majority of these were grade 1 or 2. The most common grade ≥3 toxicities included neutropenia (70%), leukopenia (36%), and lymphopenia (20%). Deep vein thrombosis occurred in 5 patients. In conclusion, PVD is a highly effective combination in lenalidomide-refractory MM patients. Weekly administration of bortezomib enhanced tolerability and convenience. Toxicities are manageable, mostly consisting of mild cytopenias with no significant neuropathy. This trial was registered at www.clinicaltrials.gov as #NCT01212952.
| S-EPMC5606008 | biostudies-literature
Project description: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.
| S-EPMC7027539 | biostudies-literature
Project description:The addition of clarithromycin enhances the efficacy of lenalidomide plus dexamethasone in treatment-naive multiple myeloma (MM). We conducted a phase 2 trial to evaluate the safety and efficacy of clarithromycin, pomalidomide, and dexamethasone (ClaPd) in relapsed or refractory multiple myeloma (RRMM) with prior lenalidomide exposure. One hundred twenty patients with a median of 5 prior lines of therapy received clarithromycin 500 mg orally twice daily, pomalidomide 4 mg orally on days 1 to 21, and dexamethasone 40 mg orally on days 1, 8, 15, and 22 of a 28-day cycle. The overall response rate (ORR) was 60% with 23% achieving at least a very good partial response. There was no statistical difference in response rates for patients who were refractory to lenalidomide (ORR, 58%), bortezomib (ORR, 55%), or both lenalidomide and bortezomib (ORR, 54%). Median progression-free survival (PFS) for the cohort was 7.7 months and median overall survival (OS) was 19.2 months. A history of dual-refractoriness to lenalidomide and bortezomib did not significantly impact either PFS or OS. The most common toxicities were neutropenia (83%), lymphopenia (74%), and thrombocytopenia (71%). The most common grade ?3 toxicities included neutropenia (58%), thrombocytopenia (31%), and anemia (28%). ClaPd is an effective combination in RRMM with response and survival outcomes that are independent of lenalidomide- or bortezomib-refractory status. Toxicities are manageable with low rates of nonhematologic or high-grade events. ClaPd is a convenient, all-oral option in RRMM with comparable efficacy to other highly active, 3-drug, pomalidomide-based combinations. This trial was registered at www.clinicaltrials.gov as #NCT01159574.
| S-EPMC6391672 | biostudies-literature
Project description:In the phase 3 OPTIMISMM trial, pomalidomide, bortezomib and dexamethasone (PVd) significantly improved the progression-free survival (PFS) and the overall response rate (ORR) vs bortezomib and dexamethasone (Vd) in patients with relapsed or refractory multiple myeloma. All patients were previously treated with lenalidomide (70% refractory to lenalidomide) and had received one to three prior regimens. Here we report the first efficacy and safety analysis of PVd vs Vd in Japanese patients with relapsed or refractory multiple myeloma. Seventeen patients enrolled in the OPTIMISMM trial in Japan. With a median follow-up of 14.8 months, the median PFS was 17.6 months with PVd (n = 12) vs 4.4 months with Vd (n = 5), and the ORR was 100% vs 60.0%, respectively. The safety profile was as expected for PVd. Toxicities were managed with dose reductions and interruptions, and no patients discontinued PVd due to treatment-emergent adverse events. These results are consistent with those in the overall OPTIMISMM patient population and confirm the clinical benefit of PVd in Japanese patients.
| S-EPMC7293071 | biostudies-literature
Project description:This phase 1b dose-escalation study evaluated isatuximab plus pomalidomide/dexamethasone in patients with relapsed/refractory multiple myeloma (RRMM). Patients who had received ≥2 prior MM therapies, including lenalidomide and a proteasome inhibitor (PI), were enrolled and received isatuximab at 5, 10, or 20 mg/kg (weekly for 4 weeks, followed by every 2 weeks), pomalidomide 4 mg (days 1-21), and dexamethasone 40 mg (weekly) in 28-day cycles until progression/intolerable toxicity. The primary objective was to determine the safety and recommended dose of isatuximab with this combination. Secondary objectives included evaluation of pharmacokinetics, immunogenicity, and efficacy. Forty-five patients received isatuximab (5 [n = 8], 10 [n = 31], or 20 [n = 6] mg/kg). Patients received a median of 3 (range, 1-10) prior lines; most were refractory to their last regimen (91%), with 82% lenalidomide-refractory and 84% PI-refractory. Median treatment duration was 9.6 months; 19 patients (42%) remain on treatment. Most common adverse events included fatigue (62%), and upper respiratory tract infection (42%), infusion reactions (42%), and dyspnea (40%). The most common grade ≥3 treatment-emergent adverse event was pneumonia, which occurred in 8 patients (17.8%). Hematologic laboratory abnormalities were common (lymphopenia, leukopenia, anemia, 98% each; neutropenia, 93%; and thrombocytopenia, 84%). Overall response rate was 62%; median duration of response was 18.7 months; median progression-free survival was 17.6 months. These results demonstrate potential meaningful clinical activity and a manageable safety profile of isatuximab plus pomalidomide/dexamethasone in heavily pretreated patients with RRMM. The 10 mg/kg weekly/every 2 weeks isatuximab dose was selected for future studies. This trial was registered at www.clinicaltrials.gov as #NCT02283775.
| S-EPMC6659612 | biostudies-literature