Expert panel consensus statement on the optimal use of pomalidomide in relapsed and refractory multiple myeloma.
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ABSTRACT:
SUBMITTER: Dimopoulos MA
PROVIDER: S-EPMC4131249 | biostudies-other | 2014 Aug
REPOSITORIES: biostudies-other
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Project description:Many studies have documented racial, socioeconomic, geographic, and other disparities for United States (US) patients with multiple myeloma pertaining to diagnosis and frontline management. In contrast, very little is known about disparities in the management of relapsed/refractory multiple myeloma (RRMM) despite a plethora of novel treatment options. In this review, we discuss the manifestations of disparities in RRMM and strategies to mitigate their impact. Immunomodulatory drugs can create disparities on many axes, for example inappropriately low dosing due to Duffy-null status as well as time toxicity and financial toxicity from logistical hurdles for socioeconomically vulnerable patients. Access to myeloma expertise at high-volume centers is a critical consideration given the disconnect between how drugs like carfilzomib and dexamethasone are prescribed in trials versus optimized in real-world practice to lower toxicities. Disparities in chimeric antigen receptor T-cell therapy and bispecific antibody therapy span across racial, ethnic, and socioeconomic lines in large part due to their limited availability outside of high-volume centers. Another insidious source of disparities is supportive care in RRMM, ranging from inadequate pain control in Black patients to limited primary care provider access in rural settings. We discuss the rationales and evidence base for several solutions aimed at mitigating these disparities: for example, (1) bidirectional co-management with community-based oncologists, (2) screening for risk factors based on social determinants of health, (3) strategies to build patient trust with regard to clinical trials, and (4) longitudinal access to a primary care provider. As the treatment landscape for RRMM continues to expand, these types of efforts by the field will help ensure that this landscape is equally accessible and traversable for all US patients.
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Project description:This study sought to understand how the programmed death ligand 1 (PD-L1) inhibitor durvalumab and the immunomodulatory agent pomalidomide regulate immune cell activation and function in patients with relapsed/refractory (RR) multiple myeloma (MM). Immunologic changes in peripheral blood and bone marrow of patients treated with durvalumab as monotherapy or in combination with pomalidomide with/without dexamethasone were characterized by assessing subsets of immune cells and gene signatures to understand the immunomodulatory effect of the treatment. Soluble PD-L1 levels were elevated at screening in patients with RRMM but did not correlate with response to durvalumab combination therapy. Immune cell subsets were increased in peripheral blood during treatment with durvalumab and pomalidomide, and combination therapy induced significant gene expression changes in the MM tumor microenvironment versus durvalumab alone. Estimation of cell populations based on RNA sequencing data revealed increased monocytes, neutrophils, and natural killer cells with the combination therapy, but not with durvalumab alone. Additionally, multiplex immunofluorescence of bone marrow demonstrated that immune populations were different in responders versus nonresponders to durvalumab plus pomalidomide with dexamethasone therapy. Overall, durvalumab effectively blocked soluble PD-L1; however, durvalumab monotherapy was not associated with immunologic changes, which were observed with combination therapy.
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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.
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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.
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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.
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Project description:In this work, we aim to further analyze the effect of pomalidomide for relapsed and/or refractory multiple myeloma (RRMM). A systematic literature search of PubMed, MEDLINE and EMBASE was conducted on September 20, 2016. Pooled effect size (ES) with corresponding 95% confidence intervals (CIs) were calculated using random-effects model. STATA software (version 12.0; Stata Corporation; College Station, TX, USA) was employed to do all statistical analyses. A total of 8 studies were included for analysis. The combined results demonstrated that the pooled proportion of overall response rate (ORR) was 0.35 (95% CI 0.27 to 0.43, P=0.000), and the pooled proportion of complete response rate (CRR) was 0.02 (95% CI 0.01 to 0.03, P=0.541). Pomalidomide was generally well tolerated by patients reported in the studies. Further studies would be required to conduct more prospective randomized controlled trials (RCTs) with larger samples to assess the proper place of pomalidomide as single agent or combined with other agents for RRMM.
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Project description:Pomalidomide is a potent immunomodulatory agent that is currently a standard of care backbone for the treatment of multiple myeloma (MM) patients in the relapsed/refractory setting after exposure to lenalidomide and a proteasome inhibitor. The present review addresses current knowledge regarding the clinical use of pomalidomide in relapsed myeloma patients. Pomalidomide has direct myeloma cell tumoricidal effects by activating proteasomal degradation of Ikaros and Aiolos transcription factors and also indirect effects by modulation of immune responses, interaction with bone marrow stromal cells, and inhibition of angiogenesis. It is approved by regulatory authorities as doublet combination with dexamethasone but four more triplets are also approved for this setting. Many ongoing trials are evaluating the pomalidomide-dexamethasone backbone with newer anti-myeloma class agents or in quadruplet combinations. Pomalidomide-dexamethasone is currently one of the powerful tools available for use in the relapsed/refractory MM setting. Insights into the synergistic immunomodulatory effects of pomalidomide and other anti-myeloma agents and the mechanisms that overcome clonal resistance will potentially allow targeted use of triplet combinations at each relapse.
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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.
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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.
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