Pomalidomide (POM) with Low-Dose Dexamethasone (LoDEX) in Patients with Relapsed and Refractory Multiple Myeloma (RRMM): Impact of Renal Function on Patient Outcomes

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4072-4072 ◽  
Author(s):  
David S. Siegel ◽  
Paul G. Richardson ◽  
Rachid Baz ◽  
Min Chen ◽  
Mohamed Zaki ◽  
...  
Keyword(s):  
Renal Function ◽  
Adverse Events ◽  
Safety Data ◽  
Parent Drug ◽  
Advisory Board ◽  
Investigational Drug ◽  
Employment Equity ◽  
Baseline Serum ◽  
Equity Ownership ◽  
Grade 3

Abstract Abstract 4072 Background: One of the most common end-organ damage in pts with MM is renal insufficiency (RI). Patients (pts) presenting with severe RI generally have a poor outcome. However, those pts who correct their renal function achieve outcomes comparable to those of pts with normal renal function (Chanan Khan, Clin Cancer Res 2012;18:2145-63). POM is extensively metabolized and renally eliminated, with <5% eliminated as the parent drug. POM is approximately 30% protein-bound. The characteristics of POM suggest that exposure to parent drug would not be substantively affected by the degree of renal function. MM-002 is a multicenter phase 1/2 study randomizing heavily-pretreated RRMM pts to receive POM alone or POM+LoDEX (Richardson PG, et al. Blood 2011;118:abs 634). In this post hoc analysis of pts who received POM+LoDEX, safety data are analyzed according to the degree of renal function to determine whether renal function alters the safety profile of POM therapy. Methods: Eligible pts with MM who had received ≥2 prior therapies were randomized to treatment with either POM+LoDEX (POM, 4 mg/day for days 1–21 of a 28-day cycle; LoDEX, 40 mg/week) or POM alone. Pts with baseline serum creatinine >3.0 mg/dL were excluded from the study. At progression, pts receiving POM alone could receive POM+LoDEX at investigator's discretion. Pts were retrospectively categorized into three groups based on calculated baseline creatinine clearance (CrCl) by the Cockcroft-Gault formula: CrCl >60 mL/min; CrCl 45–60 mL/min; CrCl <45 mL/min. Treatment-emergent adverse events (TEAEs) were defined as any AE occurring or worsening after first treatment with study medication and within 30 days after end of treatment. All pts received aspirin, 81 to 100 mg/day, or another form of thromboprophylaxis. Results: A total of 113 pts received POM+LoDEX; the median age of these pts was 64 years (range 34–88). Median number of prior therapies was 5 (range 2–13). The majority of pts were male (62/113, 54.9%) and had an ECOG status score of 0 (32/113, 28.3%), or 1 (68/113, 60.2%). Seventy pts had CrCl >60 mL/min, 14 had CrCl 45–60 mL/min, and 26 had CrCl <45 mL/min. Only 5 pts had CrCl ≤30. The average daily dose of POM (4 mg) and the relative dose intensity (0.9) were similar across the three renal groups. Median time to first POM dose reduction by renal group was 49.5 days (d), 71.0 d, and 32.5 d respectively; treatment duration was 5.5 months (mos), 5.0 mos, and 3.4 mos, in pts with CrCl >60 mL/min, CrCl 45–60 mL/min, and CrCl <45 mL/min, respectively. Grade 3/4 TEAEs occurring in ≥10% of pts are presented in the Table. Grade 3/4 neutropenia was observed in 40% of pts with CrCl >60 mL/min, 21% of pts with CrCl 45–60 mL/min, and 54% of pts with CrCl <45 mL/min. Grade 3/4 anemia and thrombocytopenia were observed in 19%, 21%, 35% and 20%, 14%, and 15%, respectively for pts with CrCl >60 mL/min, CrCl 45–60 mL/min, and CrCl <45 mL/min. Frequently observed non-hematological grade 3/4 AEs included pneumonia and fatigue which was observed in 24%, 21%, 19% and 14%, 29%, and 8% of pts, respectively for pts with CrCl >60 mL/min, CrCl 45–60 mL/min, and CrCl <45 mL/min. Conclusions: Adverse events observed with POM, given at 4 mg/day on days 1–21 of each 28-day cycle in combination with LoDEX, were generally comparable regardless to baseline renal function, however these data are confounded by low pt numbers. A prospective study (MM-008) investigating POM in MM pts with different degrees of renal impairment is ongoing. Disclosures: Siegel: Onyx: Advisory Board, Advisory Board Other, Honoraria, Speakers Bureau; Millennium Pharma: Advisory Board, Advisory Board Other, Honoraria, Speakers Bureau; Celgene: Advisory Board Other, Honoraria, Speakers Bureau; Merck: Advisory Board, Advisory Board Other, Honoraria, Speakers Bureau. Off Label Use: Pomalidomide is an investigational drug and is not approved for the treatment of patients with any condition. Richardson:Celgene, Millennium, Johnson & Johnson: Advisory Board Other. Baz:Celgene, Millennium, Bristol Myers Squibb, Novartis: Research Funding. Chen:Celgene: Employment, Equity Ownership. Zaki:Celgene: Employment, Equity Ownership. Anderson:Acetylon, Oncopep: Scientific Founder, Scientific Founder Other; Celgene, Millennium, BMS, Onyx: Membership on an entity's Board of Directors or advisory committees.

Pomalidomide (POM) with Low-Dose Dexamethasone (LoDEX) in Patients with Relapsed and Refractory Multiple Myeloma (RRMM): Outcomes Based on Prior Treatment Exposure

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4070-4070 ◽  
Author(s):  
Ravi Vij ◽  
Craig C. Hofmeister ◽  
Paul G. Richardson ◽  
Sundar Jagannath ◽  
David S. Siegel ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Low Dose ◽  
Advisory Board ◽  
Prior Exposure ◽  
Employment Equity ◽  
Advisory Committees ◽  
Duration Of Response ◽  
Equity Ownership ◽  
Grade 3

Abstract Abstract 4070 Background: There are currently limited effective treatment options for patients (pts) with RRMM with prior exposure to lenalidomide (LEN), bortezomib (BORT) and chemotherapy. In a multicenter, randomized phase 2 study, POM with or without LoDEX (n=221) was active in RRMM pts who had received ≥2 prior therapies, including LEN and BORT (Richardson PG, et al. Blood 2011;118:abs 634); activity was also observed in those with disease refractory to LEN, BORT, or both (Vij R, et al. J Clin Oncol 2012;30:abs 8016). Here we characterize outcomes in the POM+LoDEX group (n=113) according to the prior treatment exposure. Methods: Pts with RRMM who had received ≥2 prior therapies, including LEN and BORT, and had progressive disease (PD) within 60 days of their last treatment were randomized (1:1 ratio) to POM+LoDEX (POM, 4 mg/day for days 1–21 of a 28-day cycle; LoDex, 40 mg/week) or POM alone. At randomization, pts were stratified by age, prior number of treatments, and prior thalidomide exposure. At progression, pts receiving POM alone could receive POM+LoDEX at investigator's discretion. All pts received thromboprophylaxis (daily low-dose aspirin). The endpoints in this study were progression-free survival (PFS), response rates (using European Bone Marrow Transplantation [EBMT] criteria), duration of response, time to response, overall survival (OS), and safety. Response data according to prior therapy were assessed by investigator assessment. Results: All 113 pts assigned to POM+LoDEX had prior exposure to LEN (100%), BORT (100%), and steroids (100%). Most pts had also received prior alkylator therapy (93%), stem cell transplant (SCT) (73%), and thalidomide (THAL) (68%); 49% had received prior anthracyclines. Regimens immediately prior to study entry included BORT (50%), LEN (39%), cyclophosphamide (13%), THAL (8%), vorinostat (8%), carfilzomib (5%), and melphalan (5%). The median number of exposures to LEN and BORT in prior lines was once (range 1–4) and twice (range 1–6), respectively. The majority of pts (80%) had received >3 prior therapies. The overall response rate (ORR) was 48% and 30% in pts who had received ≤3 and >3 prior therapies, respectively. Of the pts who had ≤3 vs > 3 prior therapies, 9% vs 1% pts achieved complete response (CR), 39% vs 29% pts achieved partial response (PR), 9% vs 12% pts achieved minimal response (MR) and 44% vs 36 % pts achieved stable disease (SD), respectively. ORR was 34% and appeared similar regardless of prior exposure to alkylators (33%), anthracyclines (35%), SCT (35%), or THAL (35%). Median duration of response was also similar in pts who had received prior alkylators (8.4 mos), anthracyclines (10.1 mos), SCT (7.7 mos), and THAL (7.7 mos). Of the 69 pts who had a best response of SD or PD to their last prior antimyeloma therapy, 21 pts (12 SD and 9 PD) achieved a PR and 3 pts (1 SD and 2 PD) achieved a CR with POM+LoDEX treatment. Responding pts had longer time to progression (TTP; 11.1 mos) with POM+LoDex compared with the TTP (4.4 mos) observed with their last antimyeloma regimen prior to study. The most common grade 3–4 adverse events in the POM+LoDEX group were neutropenia (41%), anemia (22%), pneumonia (22%), thrombocytopenia (19%), and fatigue (14%). The incidence of at least 1 grade 3–4 adverse event was 100% in pts with ≤ 3 prior therapies, and 88% in pts with >3 therapies. Conclusions: The combination of POM+LoDEX has demonstrated an ORR of 34% in heavily pretreated pts with RRMM who have been previously exposed to LEN, BORT, steroids, and other treatments. Early treatment of POM+LoDEX (≤3 prior therapies) achieved better ORR (48%) compared with pts who received POM+LoDex later (>3 prior therapies; ORR, 30%). Disclosures: Vij: Onyx: Consultancy, Research Funding; Millennium Pharma: Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau. Off Label Use: Pomalidomide is an investigational drug and is not approved for the treatment of patients with any condition. Hofmeister:Celgene: Advisory Board Other, Honoraria. Richardson:Celgene, Millennium, Johnson & Johnson: Advisory Board Other. Jagannath:Onyx Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck Sharp & Dohme: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Siegel:Onyx: Advisory Board, Advisory Board Other, Honoraria, Speakers Bureau; Millennium Pharma: Advisory Board, Advisory Board Other, Honoraria, Speakers Bureau; Celgene: Advisory Board Other, Honoraria, Speakers Bureau; Merck: Advisory Board, Advisory Board Other, Honoraria, Speakers Bureau. Baz:Celgene, Millennium, Bristol Myers Squibb, Novartis: Research Funding. Chen:Celgene: Employment, Equity Ownership. Zaki:Celgene: Employment, Equity Ownership. Larkins:Celgene: Employment, Equity Ownership. Anderson:Acetylon, Oncopep: Scientific Founder, Scientific Founder Other; Celgene, Millennium, BMS, Onyx: Membership on an entity's Board of Directors or advisory committees.

Long-Term Safety, Efficacy, and Survival Findings From Comfort-II, a Phase 3 Study Comparing Ruxolitinib with Best Available Therapy (BAT) for the Treatment of Myelofibrosis (MF)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 801-801 ◽  
Author(s):  
Francisco Cervantes ◽  
Jean-Jacques Kiladjian ◽  
Dietger Niederwieser ◽  
Andres Sirulnik ◽  
Viktoriya Stalbovskaya ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Advisory Board ◽  
Extension Phase ◽  
Spleen Volume ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Grade 3

Abstract Abstract 801 Background: Ruxolitinib is a potent JAK1 & 2 inhibitor that has demonstrated superiority over traditional therapies for the treatment of MF. In the two phase 3 COMFORT studies, ruxolitinib demonstrated rapid and durable reductions in splenomegaly and improved MF-related symptoms and quality of life. COMFORT-II is a randomized, open-label study evaluating ruxolitinib versus BAT in patients (pts) with MF. The primary and key secondary endpoints were both met: the proportion of pts achieving a response (defined as a ≥ 35% reduction in spleen volume) at wk 48 (ruxolitinib, 28.5%; BAT, 0%; P < .0001) and 24 (31.9% and 0%; P < .0001), respectively. The present analyses update the efficacy and safety findings of COMFORT-II (median follow-up, 112 wk). Methods: In COMFORT-II, 219 pts with intermediate-2 or high-risk MF and splenomegaly were randomized (2:1) to receive ruxolitinib (15 or 20 mg bid, based on baseline platelet count [100-200 × 109/L or > 200 × 109/L, respectively]) or BAT. Efficacy results are based on an intention-to-treat analysis; a loss of spleen response was defined as a > 25% increase in spleen volume over on-study nadir that is no longer a ≥ 35% reduction from baseline. Overall survival was estimated using the Kaplan-Meier method. Results: The median follow-up was 112 wk (ruxolitinib, 113; BAT, 108), and the median duration of exposure 83.3 wk (ruxolitinib, 111.4 [randomized and extension phases]; BAT, 45.1 [randomized treatment only]). Because the core study has completed, all pts have either entered the extension phase or discontinued from the study. The primary reasons for discontinuation were adverse events (AEs; ruxolitinib, 11.6%; BAT, 6.8%), consent withdrawal (4.1% and 12.3%), and disease progression (2.7% and 5.5%). Overall, 72.6% of pts (106/146) in the ruxolitinib arm and 61.6% (45/73) in the BAT arm entered the extension phase to receive ruxolitinib, and 55.5% (81/146) of those originally randomized to ruxolitinib remained on treatment at the time of this analysis. The primary reasons for discontinuation from the extension phase were progressive disease (8.2%), AEs (2.1%), and other (4.1%). Overall, 70 pts (48.3%) treated with ruxolitinib achieved a ≥ 35% reduction from baseline in spleen volume at any time during the study, and 97.1% of pts (132/136) with postbaseline assessments experienced a clinical benefit with some degree of reduction in spleen volume. Spleen reductions of ≥ 35% were sustained with continued ruxolitinib therapy (median duration not yet reached); the probabilities of maintaining the spleen response at wk 48 and 84 are 75% (95% CI, 61%-84%) and 58% (95% CI, 35%-76%), respectively (Figure). Since the last report (median 61.1 wk), an additional 9 and 12 deaths were reported in the ruxolitinib and BAT arms, respectively, resulting in a total of 20 (14%) and 16 (22%) deaths overall. Although there was no inferential statistical testing at this unplanned analysis, pts randomized to ruxolitinib showed longer survival than those randomized to BAT (HR = 0.52; 95% CI, 0.27–1.00). As expected, given the mechanism of action of ruxolitinib as a JAK1 & 2 inhibitor, the most common new or worsened grade 3/4 hematologic abnormalities during randomized treatment were anemia (ruxolitinib, 40.4%; BAT, 23.3%), lymphopenia (22.6%; 31.5%), and thrombocytopenia (9.6%; 9.6%). In the ruxolitinib arm, mean hemoglobin levels decreased over the first 12 wk of treatment and then recovered to levels similar to BAT from wk 24 onward; there was no difference in the mean monthly red blood cell transfusion rate among the ruxolitinib and BAT groups (0.834 vs 0.956 units, respectively). Nonhematologic AEs were primarily grade 1/2. Including the extension phase, there were no new nonhematologic AEs in the ruxolitinib group that were not observed previously (in ≥ 10% of pts), and only 1 pt had a new grade 3/4 AE (epistaxis). Conclusion: In COMFORT-II, ruxolitinib provided rapid and durable reductions in splenomegaly; this analysis demonstrates that these reductions are sustained over 2 years of treatment in the majority of pts. Ruxolitinib-treated pts showed longer survival than those receiving BAT, consistent with the survival advantage observed in previous (Verstovsek et al. NEJM. 2012) and current analyses of COMFORT-I, as well as with the comparison of pts of the phase 1/2 study with matched historical controls (Verstovsek et al. Blood. 2012). Disclosures: Cervantes: Sanofi-Aventis: Advisory Board, Advisory Board Other; Celgene: Advisory Board, Advisory Board Other; Pfizer: Advisory Board, Advisory Board Other; Teva Pharmaceuticals: Advisory Board, Advisory Board Other; Bristol-Myers Squibb: Speakers Bureau; Novartis: AdvisoryBoard Other, Speakers Bureau. Kiladjian:Shire: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding. Niederwieser:Novartis: Speakers Bureau. Sirulnik:Novartis: Employment, Equity Ownership. Stalbovskaya:Novartis: Employment, Equity Ownership. McQuity:Novartis: Employment, Equity Ownership. Hunter:Incyte: Employment. Levy:Incyte: Employment, stock options Other. Passamonti:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Barbui:Novartis: Honoraria. Gisslinger:AOP Orphan Pharma AG: Consultancy, Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau. Vannucchi:Novartis: Membership on an entity's Board of Directors or advisory committees. Knoops:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Harrison:Shire: Honoraria, Research Funding; Sanofi: Honoraria; YM Bioscience: Consultancy, Honoraria; Novartis: Honoraria, Research Funding, Speakers Bureau.

Subcutaneous Omacetaxine (OM) Treatment of Chronic Phase (CP) Chronic Myeloid Leukemia (CML) Patients Following Multiple Tyrosine Kinase Inhibitor (TKI) Failure

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2290-2290 ◽  
Author(s):  
Jorge E. Cortes ◽  
Meir Wetzler ◽  
Jeff Lipton ◽  
Franck E Nicolini ◽  
Michele Baccarani ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Adverse Events ◽  
Median Duration ◽  
Bone Marrow Failure ◽  
Single Agent ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Employment Equity ◽  
Equity Ownership ◽  
Grade 3

Abstract Abstract 2290 Introduction: Multiple TKI failure is a growing problem in a subset of CML patients. Treatment with a third TKI after two have failed often yields poor results. New treatment options are needed for this patient population. OM is a first-in-class cetaxine with demonstrated activity as a single agent in CML. It inhibits the production of short-lived oncoproteins (such as Mcl-1) involved in cancer cell survival via a mechanism independent of Bcr-Abl binding. Several studies have suggested that OM has a favorable toxicity profile when given to patients with CML via the subcutaneous route. We explored OM efficacy and safety in a subset of patients who had received therapy with multiple prior approved TKI. Methods: We analyzed a subset of adult CML-CP patients who had received two or more TKI (imatinib, dasatinib, nilotinib), from a combined interim dataset of two prospective Phase 2 studies (CML-202, for patients with the T315I kinase domain mutation, and CML-203, for patients with failure to ≥2 TKI) utilizing OM in the treatment adult patients with all phases of CML who had failed TKI. TKI failure was defined as no complete hematologic response (CHR) by 12 weeks (wk), no cytogenetic response by 6 months (mo), no major cytogenetic response (MCyR) by 12 mo, loss of CHR or MCyR, or progressive leukocytosis. The focus of this analysis was to assess the CHR and MCyR response rates as well as the overall safety of OM in these patients. Adverse events presented are Grade 3/4 events that occurred in ≥ 5% of patients (regardless of causality). Results: A total of 73 of the 93 CML-CP patients from these two studies had received two or more TKI prior to OM treatment. Median time from initial CML diagnosis to first dose of OM was 74.4 months. Mutations of any kind were seen in 48% of the patients, whereas 29% had no identified mutation and 23% had no available data on mutation status. Sixty (82%) of these 73 patients achieved or maintained (twelve patients were in CHR at study entry) a CHR and 17 (23%) achieved a MCyR (9 complete and 8 partial). The median duration of MCyR was 4.4+ months (range 1.2–14.1+). Median overall survival for patients treated with OM after failure of 2 or more TKI has not yet been reached [95% Confidence Interval (CI) 22.9, NA months] (Figure 1). Eleven patients had a treatment—emergent adverse event leading to death, and two deaths were probably related to study drug. Median progression-free survival was 11.1 months (95% CI 6.5, 13.8 months). Median follow-up time was 7.5 months for all patients with twenty-five patients remaining on study at the time of this data cut. A total of 36 of the 93 CP patients from these two studies had been treated with three or more TKI; 27 (75.0%) achieved or maintained a CHR and 7 (19.4%) achieved a MCyR (4 complete and 3 partial) on OM treatment. The median duration of MCyR in this group was 4.0+ months (range 1.2–11.5+) at the time of data cut-off. The primary Grade 3/4 adverse events in patients who received OM after failure of 2 or more TKI were hematologic, including thrombocytopenia (64%), neutropenia (48%) and anemia (40%) most commonly, followed by febrile neutropenia (12%), bone marrow failure (12%), pancytopenia (7%) and febrile bone marrow aplasia (6%). These events were dosing schedule dependent. Clinical sequelae were uncommon and managed with transient treatment interruptions and dose adjustments. Grade 3/4 non-hematologic adverse events were infrequent, with only fatigue (6%) occurring ≥5% of patients. Conclusions: OM, through a mechanism of action independent of Bcr-Abl, may offer a clinically viable option for patients who have progressed on multiple TKI treatment. Disclosures: Off Label Use: The drug is currently in development and has an NDA submitted for use in TKI resistant CML. Cram: ChemGenex: Employment, Equity Ownership. Humphriss: ChemGenex: Employment, Equity Ownership. Benichou: ChemGenex: Consultancy, Equity Ownership. Craig: ChemGenex: Employment, Equity Ownership, Executive Management Level.

An Expanded Multicenter Phase I/II Study of CYT387, a JAK- 1/2 Inhibitor for the Treatment of Myelofibrosis,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3849-3849 ◽  
Author(s):  
Animesh Pardanani ◽  
Jason Gotlib ◽  
Vikas Gupta ◽  
Andrew W Roberts ◽  
Martha Wadleigh ◽  
...  
Keyword(s):  
Adverse Events ◽  
Board Of Directors ◽  
Multicenter Study ◽  
Employment Equity ◽  
Advisory Committees ◽  
Once Daily ◽  
Safety And Efficacy ◽  
Equity Ownership ◽  
Grade 3 ◽  
Study Sites

Abstract Abstract 3849 Background: CYT387 is a potent JAK-1/2 inhibitor. The maximum tolerated dose (MTD) and preliminary safety and efficacy of once daily dosing of CYT387 were determined in a single center Phase I/II study. Previously reported results from the first 60 subjects enrolled in this study determined a MTD of 300 mg QD and demonstrated improvements in splenomegaly and constitutional symptoms as well as in RBC transfusion requirements. The study was expanded into a multicenter study with planned accrual of 165 subjects at 6 study sites and a twice daily dosing arm was added. The preliminary safety and efficacy results from this expanded multicenter study will be presented. Methods: Subjects with high or intermediate-risk primary myelofibrosis (PMF) and post-polycythemia vera (post-PV) or post-essential thrombocythemia (ET) myelofibrosis were enrolled. In the core expansion study, oral CYT387 was administered either once daily at 150 mg or 300 mg or twice daily at 150 mg for 9 months. Patients who maintained at least stable disease were permitted to continue CYT387 treatment beyond 9 months in an extension phase of the study. Responses were assessed by International Working Group (IWG) Criteria. Results: At present, 163 subjects have been enrolled across the 6 study sites. The diagnoses of enrolled subjects include 64% PMF, 14% post-ET MF and 22% post-PV MF; 67% of the patients were JAK2V617F positive. Starting doses of CYT387 in the dose escalation, confirmation and expansion phases of the study are shown in Table 1. The median duration (range) of treatment was 6.6 months (0.25 to 20.4 months). Patient characteristics were as follows: median age 68 years, 58% male, 87% were spleen evaluable at baseline per IWG criteria (median spleen length was 18 cm by palpation). Sixty three percent (63%) of subjects were anemia evaluable at baseline per IWG criteria; 46% were transfusion dependent. Previous JAK inhibitor and IMiD therapy was reported for 11% and 8% of enrolled subjects, respectively. Reductions in spleen size, improvements in constitutional symptoms and the achievement of transfusion independence were observed in subjects in the expanded multicenter study. CYT387 was well tolerated. Based on currently available data, 73% of subjects reported treatment-related adverse events, with the majority reported as Grade 1. The most common Grade 3–4 treatment related adverse events included thrombocytopenia (16%), and hyperlipasemia (3%). New onset treatment-related Grade 3–4 anemia remains rare (<1%). Grade 1 toxicities included peripheral sensory neuropathy whose incidence and natural history is currently being studied. Twenty-five of 163 subjects (15%) have discontinued from the 9 month core study giving a retention rate of 85%. Conclusions: When examined in an expanded, multicenter study, CYT387 continues to show substantial clinical activity in myelofibrosis, with improvements in splenomegaly, constitutional symptoms and anemia. It appears to be well tolerated when administered in either a once or twice daily dosing regimen. CYT387 continues to demonstrate an ability to induce durable anemia responses in a subset of subjects. Detailed analyses of safety and efficacy will be available at the time of the meeting. Disclosures: Gupta: Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Smith:YM Biosciences: Employment, Equity Ownership. Bavisotto:YM Biosciences: Consultancy. Kowalski:YM Biosciences: Employment, Equity Ownership.

MM-008: A Phase 1 Trial Evaluating Pharmacokinetics and Tolerability Of Pomalidomide + Low-Dose Dexamethasone In Patients With Relapsed/Refractory Multiple Myeloma and Renal Impairment

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5393-5393 ◽  
Author(s):  
Jeffrey Matous ◽  
David S. Siegel ◽  
Hien K. Duong ◽  
Claudia Kasserra ◽  
Min Chen ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Renal Function ◽  
Adverse Events ◽  
Board Of Directors ◽  
Impaired Renal Function ◽  
Low Dose ◽  
Phase 1 ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership

Abstract Background Pomalidomide (POM) is indicated for patients (pts) with multiple myeloma who have received at least 2 prior therapies, including lenalidomide and bortezomib, and have demonstrated disease progression on or within 60 days of completion of the last therapy. Renal impairment (RI) is a common comorbidity in multiple myeloma (MM), occurring in > 40% of pts. POM is extensively metabolized, with < 5% eliminated renally as the parent drug. Thus, renal function may not substantively affect exposure of the active parent compound. POM + low-dose dexamethasone (LoDEX) has shown efficacy in pts with relapsed/refractory MM (RRMM) with moderate RI in phase 2 and phase 3 trials. However, pts with severe RI were excluded from these trials. MM-008 is an active multicenter, open-label, phase 1 study designed to prospectively assess the pharmacokinetics (PK) and safety of POM + LoDEX in pts with RRMM and normal or severely impaired renal function. Methods Pts with RRMM and ≥ 1 prior therapy were eligible for enrollment. Pts in Cohort A (creatinine clearance [CrCL] ≥ 60 mL/min) served as the control population and received POM 4 mg on days 1-21 of each 28-day cycle. Pts in Cohort B (CrCL < 30 mL/min but not requiring dialysis) followed a standard 3 + 3 dose-escalation design, receiving POM 2 mg on days 1-21 of each 28-day cycle and based on results, escalating to 4 mg. Dosing for Cohort C (CrCL < 30 mL/min and requiring dialysis) was informed by the results from Cohort B. All cohorts received dexamethasone 40 mg (20 mg for pts aged > 75 years) on days 1, 8, 15, and 22. Pts were not permitted to enroll in more than 1 cohort. Granulocyte colony-stimulating factor for management of neutropenia was not permitted in cycle 1, but could be started on day 1 of the next cycle at the physician’s discretion. Treatment was continued until disease progression or unacceptable toxicity. Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (V 4.0). PK samples were obtained pre- and post-POM dose on days 1, 2, and 3 (after single doses) and days 21, 22, and 23 (after multiple doses) of cycle 1 for cohorts A and B. PK data were dose-normalized for comparison across cohorts by dividing the measured exposure by the POM dose in milligrams. Results As of April 1, 2013, 11 pts have been treated (8 in Cohort A; 3 in Cohort B at 2 mg). At screening, median age (range) was 68 years (46-71 years) and 64 years (57-64 years) while median CrCL (range) was 85 mL/min (53.1- 114.8 mL/min) and 18.4 mL/min (12.5-25.7 mL/min) in cohorts A and B, respectively. The most common grade ≥ 3 adverse events were neutropenia (Cohort A: 4 pts; Cohort B: 1 pt), infections (Cohort A: 2 pts; Cohort B: 2 pts), and anemia (Cohort A: 2 pts; Cohort B: 1 pt). No dose-limiting toxicities in cycle 1 have been reported. Median duration of treatment and relative dose intensity were similar between cohorts A and B, 4.1 months (range, 1.8-5.1 months) vs 3.9 months (range, 1.8-8.5 months) and 1.0 (range, 0.5-1.1) and 1.1 (range, 1.0-1.1), respectively. Only 1 pt (Cohort A) discontinued treatment due to adverse events. Five pts remain on study (Cohort A: 3 pts; Cohort B: 2 pts). Initial PK analyses showed that mean dose-normalized AUC024 in Cohort B was approximately 20% lower than in Cohort A. Mean dose-normalized Cmax in Cohort B was approximately 30% lower than that in Cohort A after a single dose but comparable after multiple doses. Based on these results, additional pts in Cohort B and pts in Cohort C will receive POM 4 mg. Updated PK and adverse event data will be presented at the meeting. Conclusion MM-008 is an ongoing trial prospectively evaluating the PK and safety of POM + LoDEX in pts with severe RI. Preliminary data suggest that dose-normalized exposure in pts with RRMM with severe RI is similar to that in pts with normal to mildly impaired renal function. No dose-limiting toxicities have been reported, and early tolerability data are encouraging. Disclosures: Matous: Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Off Label Use: Approved in the US but not in Europe. Siegel:Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Duong:Celgene: Honoraria, Research Funding. Kasserra:Celgene: Employment, Equity Ownership. Chen:Celgene: Employment, Equity Ownership. Doerr:Celgene: Employment, Equity Ownership. Sternas:Celgene: Employment, Equity Ownership. Zaki:Celgene: Employment, Equity Ownership. Jacques:Celgene: Employment, Equity Ownership. Shah:Celgene: Consultancy, Research Funding.

Safety of Lenalidomide (LEN) 10mg in Non-Del(5q) Versus Del(5q) in the Treatment of Patients (Pts) with Lower-Risk Myelodysplastic Syndromes (MDS): Pooled Analysis of Treatment-Emergent Adverse Events (TEAEs)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2880-2880 ◽  
Author(s):  
Antonio Almeida ◽  
Valeria Santini ◽  
Stefanie Gröpper ◽  
Anna Jonasova ◽  
Norbert Vey ◽  
...  
Keyword(s):  
Adverse Events ◽  
Lower Risk ◽  
Research Funding ◽  
Pooled Analysis ◽  
Employment Equity ◽  
Pooled Data ◽  
Starting Dose ◽  
Equity Ownership ◽  
Grade 3

Abstract Introduction: Anemia represents the main therapeutic challenge in pts with lower-risk MDS (Fenaux P, Adès L. Blood. 2013;121:4280-6). Prospective studies evaluating LEN for the treatment of red blood cell transfusion-dependent pts showed significant clinical activity in both non-del(5q) and del(5q) International Prognostic Scoring System-defined lower-risk MDS (Raza A, et al. Blood. 2008;111:86-93; Santini V, et al. Blood. 2014;124:abstract 409; List A, et al. N Engl J Med. 2006;355:1456-65; Fenaux P, et al. Blood. 2011;118:3765-76). Hematologic adverse events (AEs) are common, but manageable, with LEN treatment (Giagounidis A, et al. Ann Hematol. 2008;87:345-52). However, there has been no direct comparison of safety profiles in non-del(5q) and del(5q) pts. This pooled analysis compared the incidence of AEs in LEN-treated lower-risk MDS pts with or without del(5q). Methods: This retrospective analysis of pooled data from 7 prospective clinical trials compared the incidence of AEs in LEN-treated lower-risk MDS pts with or without del(5q). The non-del(5q) group included 416 pts from 4 studies: MDS-005 (n = 160), MDS-002 (n = 215), MDS-001 (n = 24), and PK-002 (n = 17). The del(5q) group included 243 pts from 5 studies: MDS-003 (n = 148), MDS-004 (n = 69), MDS-007 (n = 11), MDS-001 (n = 8), and PK-002 (n = 7). A TEAE was defined as an AE that began or worsened in severity on or after the first dose of LEN through to 28 days after the last dose of LEN. Pts received the recommended starting dose of 10 mg LEN for ≥ 1 cycle; in study MDS-005, pts with impaired creatinine clearance (CrCl; ≥ 40 to < 60 mL/min) had a LEN 5 mg starting dose in order to achieve a similar area under the curve as pts with normal CrCl who were receiving LEN 10 mg. Results: Among the LEN-treated lower-risk MDS pts with or without del(5q) in this pooled analysis, the most commonly reported TEAEs (any grade) occurring in ≥ 5% of pts were hematologic: neutropenia [49.3% vs 73.7% for non-del(5q) vs del(5q), respectively], thrombocytopenia (37.3% vs 64.2%), and anemia (16.8% vs 20.2%). Overall, 84.6% of non-del(5q) pts and 96.3% of del(5q) pts experienced grade 3-4 hematologic TEAEs, including neutropenia [45.2% vs 72.0% for non-del(5q) and del(5q), respectively], thrombocytopenia (31.3% vs 52.7%), and anemia (11.8% vs 12.8%) (Table). Non-hematologic TEAEs were similar for both non-del(5q) and del(5q) pts, except deep-vein thrombosis (1.2% vs 4.9%, respectively) and hypertension (0.2% vs 3.7%). Acute myeloid leukemia was reported as a TEAE in 3 non-del(5q) and 9 del(5q) pts. Bleeding events (any grade) occurring concurrently with grade 3-4 thrombocytopenia were observed in 20.7% of non-del(5q) and 24.4% of del(5q) pts. Infection (any grade) occurring concurrently with grade 3-4 neutropenia was observed in 33.6% of non-del(5q) and 54.0% of del(5q) pts. Analysis of grade 3-4 hematologic TEAEs for pts receiving long-term (> 12 months) LEN treatment by time of onset (0 to 6, > 6 to 12, and > 12 to 18 months) showed that onset rates of grade 3-4 neutropenia during the first 6 months were higher versus rates at > 6 to 12 months for non-del(5q) (42.9% vs 19.5%, respectively) and del(5q) pts (65.4% vs 21.3%). Rates decreased similarly for thrombocytopenia in non-del(5q) (13.0% vs 5.2%) and del(5q) pts (40.4% vs 6.6%). At > 12 to 18 months, onset rates of neutropenia and thrombocytopenia for non-del(5q) pts were 15.6% and 9.1%, respectively; rates for del(5q) pts during this period were 23.5% and 4.4%. Grade 3-4 TEAEs resulted in discontinuation of LEN in 27.4% of non-del(5q) and 20.6% of del(5q) pts (Table); however, the criteria for discontinuation differed between studies. Conclusions: In this analysis of pooled data from 7 studies, the safety profiles of LEN-treated lower-risk MDS pts were similar between non-del(5q) and del(5q) pts. Neutropenia and thrombocytopenia were the most common TEAEs in both groups; however, the frequency of these TEAEs was lower in non-del(5q) pts. Among non-del(5q) and del(5q) pts receiving long-term treatment with LEN, onset rates of thrombocytopenia and neutropenia were lower at > 6 to 12 months versus the first 6 months of treatment. In summary, TEAEs in lower-risk MDS pts with or without del(5q) treated with LEN 10 mg for ≥ 1 cycle are predictable, well characterized, and clinically manageable. Disclosures Almeida: Shire: Speakers Bureau; Bristol Meyer Squibb: Speakers Bureau; Celgene: Consultancy; Novartis: Consultancy. Off Label Use: Lenalidomide used to treat MDS patients without del(5q). Santini:celgene, Janssen, Novartis, Onconova: Honoraria, Research Funding. Vey:Celgene: Honoraria; Roche: Honoraria; Janssen: Honoraria. Giagounidis:Celgene Corporation: Honoraria. Hellström-Lindberg:Celgene Corporation: Research Funding. Mufti:Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Skikne:Celgene Corporation: Employment, Equity Ownership. Hoenekopp:Celgene International: Employment, Equity Ownership. Séguy:Celgene International: Employment. Zhong:Celgene Corporation: Employment, Equity Ownership. Fenaux:CELGENE: Honoraria, Research Funding; NOVARTIS: Honoraria, Research Funding; AMGEN: Honoraria, Research Funding; JANSSEN: Honoraria, Research Funding.

scholarly journals Pomalidomide + Low-Dose Dexamethasone in Patients with Refractory or Relapsed and Refractory Multiple Myeloma and Renal Impairment: Analysis of Patients from the Phase 3b Stratus Trial (MM-010)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4755-4755 ◽  
Author(s):  
Katja Weisel ◽  
Meletios A. Dimopoulos ◽  
Michele Cavo ◽  
Enrique M. Ocio ◽  
Antonio Palumbo ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Renal Function ◽  
Adverse Events ◽  
Renal Impairment ◽  
Low Dose ◽  
Dose Intensity ◽  
High Dose ◽  
Employment Equity ◽  
Safety And Efficacy ◽  
Equity Ownership

Abstract Background: Treatment (Tx) with novel agents, including lenalidomide (LEN) and bortezomib (BORT), has extended survival of patients (pts) with multiple myeloma (MM); however, pts who have relapsed on or become refractory to Tx have significantly shortened overall survival (OS) and poorer outcomes (Kumar, Leukemia, 2012). Renal impairment (RI) occurs frequently, in approximately 20% to 40% of MM pts (Kastritis, Haematologica, 2007), and is a leading cause of death in this pt population (Korbet, J Am Soc Nephrol, 2006). In the phase 3 MM-003 trial, pomalidomide plus low-dose dexamethasone (POM + LoDEX) significantly extended progression-free survival (PFS) and OS vs. high-dose dexamethasone in pts in whom BORT and LEN Tx failed, including those with moderate RI (creatinine clearance [CrCl] < 60 mL/min; Weisel, Blood, 2013). STRATUS is a multicenter, single-arm, open-label, European, phase 3b trial to further evaluate safety and efficacy of POM + LoDEX in pts with refractory or relapsed and refractory MM (N = 456), including those with moderate RI. Methods: Pts must have had refractory or relapsed and refractory disease (progressive disease [PD] during or within 60 days of last line of Tx), at least 2 prior therapies, BORT and LEN failure after ≥ 2 cycles of each (alone or in combination), and adequate prior alkylator therapy as defined in study protocol. Pts must have been refractory to their last line of Tx; pts with CrCl < 45 mL/min were excluded. POM was administered 4 mg D1-21/28-day cycle and LoDEX 40 mg/day (20 mg for pts aged > 75 yrs) on D1, 8, 15, and 22 until PD or unacceptable toxicity. All pts received thromboprophylaxis with low-dose aspirin, low-molecular-weight heparin, or equivalent based on clinical recommendations. The primary endpoint was safety, and secondary endpoints included POM exposure, overall response rate (ORR; ≥ partial response), duration of response (DOR), PFS, and OS. For this analysis, pts were retrospectively grouped by baseline CrCl (< 60 mL/min vs. ≥ 60 mL/min). Results: A total of 456 pts have been enrolled, of whom 452 received POM + LoDEX and 165 (36%) had moderate RI (CrCl < 60 mL/min). After a median follow-up of 6.8 mos, the most frequently reported grade (Gr) 3-4 treatment-emergent adverse events (TEAEs) in pts with moderate RI vs. without moderate RI (CrCl ≥ 60 mL/min) were neutropenia (39% vs. 40%), anemia (33% vs. 24%), and thrombocytopenia (19% vs. 19%); the most common Gr 3-4 nonhematologic TEAEs were pneumonia (12% vs. 11%), fatigue (6% vs. 4%), and hypercalcemia (4% vs. 4%), respectively. Only 2% of pts in each respective renal subgroup discontinued POM due to Tx-related TEAEs. Gr 3-4 renal toxicities were similar in both subgroups: acute renal failure occurred in 3% of pts with moderate RI and 2% of pts without moderate RI; blood creatinine increased in 2% and 1% of pts, respectively. Overall, Gr 3-4 deep vein thrombosis (DVT), pulmonary embolism (PE), and peripheral neuropathy (PN) were infrequent independent of renal status (Table). Median relative POM dose intensity was similar between subgroups (0.95 in pts with moderate RI vs. 0.96 in pts without moderate RI). In pts with moderate RI vs. without moderate RI, ORR was 35% vs. 34%, median DOR was 5.8 mos vs. 6.5 mos, median PFS was 3.7 vs. 4.6 mos, and median OS was 9.3 vs. not reached, respectively (Table). The 1-yr OS was 33% for pts with moderate RI vs. 53% for pts without moderate RI. Conclusions: POM + LoDEX has acceptable safety and efficacy profiles comparable to those observed in the pivotal MM-003 trial. Tolerability was consistent across renal function subgroups, with few discontinuations due to adverse events. In addition, responses to POM + LoDEX were similar between pts, irrespective of renal function. POM is currently being prospectively evaluated in pts with severe RI in the MM-008 (US) and MM-013 (EU) trials. Table.With Moderate RICrCl < 60 mL/min (n = 162)Without Moderate RICrCl ≥ 60 mL/min(n = 290)Grade 3-4 TEAEs, %Neutropenia Anemia Thrombocytopenia Pneumonia39 33 19 1240 24 19 11Grade 3-4 EOI, %DVT/PE PN2 20 1Efficacy(n = 165)(n = 291)ORR (≥ PR), % (95% CI) Median DOR (95% CI), mos Median PFS (95% CI), mos Median OS (95% CI), mos35 (27.9-43.0) 5.8 (3.7-NE) 3.7 (2.9-5.2) 9.3 (6.3-11.5)34 (28.9-40.1) 6.5 (4.7-7.9) 4.6 (3.7-5.6) NR (10.9-NR) EOI, events of interest; NE, not estimable, NR, not reached. Disclosures Weisel: Celgene Corporation: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Onyx: Consultancy, Honoraria; BMS: Consultancy; Noxxon: Consultancy. Dimopoulos:Celgene: Consultancy, Honoraria. Cavo:Celgene: Consultancy, Honoraria, Speakers Bureau. Ocio:Celgene Corporation: Honoraria, Research Funding. Palumbo:Bristol-Myers Squibb: Consultancy, Honoraria; Genmab A/S: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria; Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria; Onyx Pharmaceuticals: Consultancy, Honoraria; Array BioPharma: Honoraria; Amgen: Consultancy, Honoraria; Sanofi: Honoraria. Delforge:Celgene Corp: Honoraria; Janssen: Honoraria. Oriol:Celgene Corporation: Consultancy. Goldschmidt:Celgene Corp: Consultancy, Honoraria, Speakers Bureau. Miller:Celgene Corporation: Employment, Equity Ownership. Peluso:Celgene: Employment. Sternas:Celgene Corp: Employment, Equity Ownership. Zaki:Celgene : Employment, Equity Ownership. Moreau:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Treatment Outcomes with Pomalidomide (POM) in Combination with Low-Dose Dexamethasone (LoDex) in Patients with Relapsed and Refractory Multiple Myeloma (RRMM) and Del(17p13) and/or t(4;14)(p16;q32) Cytogenetic Abnormalities Who Have Received Prior Therapy with Lenalidomide (LEN) and Bortezomib (BORT)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4053-4053 ◽  
Author(s):  
Paul G. Richardson ◽  
Andrzej Jakubowiak ◽  
Nizar J. Bahlis ◽  
David S. Siegel ◽  
Christine I. Chen ◽  
...  
Keyword(s):  
High Risk ◽  
Disease Progression ◽  
Risk Group ◽  
Advisory Board ◽  
Employment Equity ◽  
Cytogenetic Abnormalities ◽  
Duration Of Response ◽  
Equity Ownership ◽  
Grade 3 ◽  
Standard Risk

Abstract Abstract 4053 Background: Patients (pts) with MM who relapse and are refractory after therapy with bortezomib or immunomodulatory agents have overall survival (OS) and progression-free survival (PFS) of 9 mos and 5 mos, respectively (Kumar et al, Leukemia 2011). A number of cytogenetic abnormalities have also been associated with poor outcomes in MM, including t(4;14), and del(17p) (Avet-Loiseau et al, Blood 2007). In the multicenter, randomized, open-label MM-002 phase 1/2 study, the novel immunomodulatory agent POM, in combination with LoDEX, has demonstrated promising activity and favorable tolerability in pts with RRMM (Richardson PG, et al. Blood 2011;118:abs 634). Here we evaluated outcomes in pts participating in the study with high-risk cytogenetic profiles, with data as of 30 March 2012 presented. Methods: Eligible pts with MM who had received ≥2 prior therapies (including LEN and BORT) and had disease progression within 60 days of their last treatment were randomized to treatment with either POM+LoDEX (POM, 4 mg/day for days 1–21 of a 28-day cycle; LoDEX, 40 mg/week) or POM alone. At progression, patients receiving POM alone could receive POM+LoDEX at investigator's discretion. Thromboprophylaxis with daily low-dose aspirin was mandatory. The endpoints in this study were PFS, response rates (using European Bone Marrow Transplantation [EBMT] criteria), duration of response, time to response, OS, and safety. Efficacy outcomes and safety in pts with high-risk cytogenetics were compared with those of pts with standard-risk cytogenetics as well as with the overall population who received POM+LoDEX as part of an exploratory analysis. High-risk cytogenetics were defined based on modified criteria and included the presence of the following abnormalities: del(17p13) and/or t(4;14)(p16;q32), based on interphase FISH analysis from marrow aspirates collected at study entry. Results: The intention-to-treat population included 113 pts who were treated with POM+LoDex. At baseline, high-risk and standard-risk cytogenetic profiles were identified in 30 pts (27%) and 57 (50%) pts, respectively; 26 pts (23%) were inevaluable. Cytogenetic abnormalities included del(17p13) in 19 pts and t(4;14)(p16;q32) in 25 pts. Median follow-up time was 13.2 mos for the high-risk group and 17.7 mos for the standard-risk group. The median ORR (≥PR) for all pts was 34%; median ORR for high-risk pts was 23%, compared with 40% for standard-risk pts. The overall median duration of response (≥PR) was 8.3 mos for all pts, 4.9 mos for high-risk pts, and 10.1 mos for the standard-risk pts. The median PFS was 4.6 mos for all pts. The median PFS was 3.1 mos for pts with high-risk cytogenetics and 5.5 mos for pts with standard-risk cytogenetic profiles, respectively. Median OS for all pts was 16.5 mos and was 13.2 mos in the high-risk pts vs 21.7 mos in the standard-risk pts. The type and incidence of grade 3 or 4 adverse events (AEs) were similar in the high-risk pts (n=29) and those with standard-risk (n=57). The most common grade 3/4 AEs were neutropenia (48% vs 40%, respectively), thrombocytopenia (31% vs 16%), anemia (24% vs 25%), pneumonia (21% vs 28%), dyspnea (17% vs 11%), and fatigue (10% vs 18%). Febrile neutropenia developed in 2 pts (7%) with high-risk cytogenetics and in none with standard cytogenetics. There were no cases of grade 3/4 deep vein thrombosis in high-risk pts vs 2 pts (4%) in pts with standard-risk cytogenetics. There were no cases of grade 3/4 peripheral neuropathy in either group. Twenty-one (19%) of the POM+LoDex-treated subjects died during the study; 6 (21%) in the high-risk group (MM, n=3; disease progression, n=1; cardio-respiratory distress, n=1; not specified, n=1), and 10 (18%) in the standard-risk group (MM, n=4; disease progression, n=1; infection, n=3; cerebral/subarachnoid hemorrhage, n=2). Conclusions: POM+LoDex treatment appears to be effective in MM pts with high-risk cytogenetic profiles and advanced disease. Although this subgroup of pts has a shorter duration of response compared with RRMM pts without high-risk cytogenetic abnormalities, pts with high-risk demonstrated an ORR of 23%, which is comparable to that expected for the overall population treated in this study, and is therefore encouraging. Longer follow-up for PFS and OS is needed to better assess clinical benefit, with combination approaches (such as with bortezomib) in this high-risk population warranting further study. Disclosures: Richardson: Celgene, Millennium, Johnson & Johnson: Advisory Board Other. Off Label Use: Pomalidomide is an investigational drug and is not approved for the treatment of patients with any condition. Jakubowiak:Onyx: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Millennium: Honoraria, Speakers Bureau. Bahlis:Celgene: Honoraria; Johnson and Johnson: Honoraria, Research Funding. Siegel:Onyx: Advisory Board, Advisory Board Other, Honoraria, Speakers Bureau; Millennium Pharma: Advisory Board, Advisory Board Other, Honoraria, Speakers Bureau; Celgene: Advisory Board Other, Honoraria, Speakers Bureau; Merck: Advisory Board, Advisory Board Other, Honoraria, Speakers Bureau. Chen:Johnson & Johnson, Celgene, GlaxoSmithKline: Research Funding; Johnson & Johnson, Lundbeck, Celgene: Consultancy; Roche: Honoraria. Chen:Celgene: Employment, Equity Ownership. Zaki:Celgene: Employment, Equity Ownership. Larkins:Celgene Corporation: Employment, Equity Ownership. Anderson:Acetylon, Oncopep: Scientific Founder, Scientific Founder Other; Celgene, Millennium, BMS, Onyx: Membership on an entity's Board of Directors or advisory committees.

Pomalidomide (POM) with Low-Dose Dexamethasone (LoDex) in Patients (Pts) with Relapsed and Refractory Multiple Myeloma Who Have Received Prior Therapy with Lenalidomide (LEN) and Bortezomib (BORT): Updated Phase 2 Results and Age Subgroup Analysis

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 450-450 ◽  
Author(s):  
Sundar Jagannath ◽  
Craig C. Hofmeister ◽  
David S. Siegel ◽  
Ravi Vij ◽  
Sagar Lonial ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Low Dose ◽  
Dose Intensity ◽  
Advisory Board ◽  
Employment Equity ◽  
Advisory Committees ◽  
Duration Of Response ◽  
Equity Ownership ◽  
The Mean ◽  
Grade 3

Abstract Abstract 450 Background: New antimyeloma treatments that re-establish tumor response are required to improve survival for pts with advanced, treatment-refractory MM. The MM-002 phase 2 study evaluated the safety and efficacy of oral pomalidomide, in combination with low-dose dexamethasone (POM+LoDex), in pts with relapsed and refractory multiple myeloma (RRMM) who have who have received ≥2 prior therapies including LEN and BORT (Richardson PG, et al. Blood 2011;118:abs 634). Updated results from March 2012 for pts and the outcomes of subgroup analyses are presented. Methods: Eligible pts with MM who had received at least 2 prior therapies (including LEN and BORT) and had disease progression within 60 days of their last treatment were randomized (1:1 ratio) to either POM+LoDEX (POM, 4 mg/day for days 1–21 of a 28-day cycle; LoDex, 40 mg/week) or POM alone. At progression, pts receiving POM alone could receive POM+LoDEX at investigator's discretion. Pts aged over 75 years received LoDex, 20 mg/week. All pts received mandatory thromboprophylaxis (daily low-dose aspirin). Pts were stratified within each treatment group according to age. The key efficacy endpoints included the objective response rate using European Bone Marrow Transplantation (EBMT) criteria, duration of response, progression free survival (PFS) and overall survival (OS), and safety. This updated analysis focused on pts on the POM+LoDex arm. Results: The intention-to-treat efficacy analysis included 113 pts in the POM+LoDex group. The mean age of pts treated with POM+LoDex was 64 years (range, 34–88); 99 pts (88%) were aged ≤75 years. Response rates, median duration of response, and age subgroups are presented in the Table. Median PFS and OS were 4.6 months (mos) and 16.5 mos, respectively, in the POM+LoDex group overall. In the age subgroup analysis of pts treated with POM+LoDex, the median PFS was 4.7 mos in pts aged ≤65 years, and 3.7 mos in pts >65 years. Median OS was 19.7 mos in pts aged ≤65 years and 11.8 mos in pts >65 years. The most common grade 3 or 4 adverse events (AEs) occurring in >5% of pts were neutropenia (41%), anemia (22%), pneumonia (22%), thrombocytopenia (19%), fatigue (14%), dyspnea (13%), leukopenia (10%), back pain (10%), and urinary tract infection (9%). AEs led to at least one dose reduction in 26% of pts; neutropenia was associated with a dose reduction in 4% of pts. Overall, 78% of pts who developed grade 3 or 4 neutropenia used G-CSF during study treatment. There were no reports of grade 3 or 4 peripheral neuropathy (PN); grade 1 or 2 PN occurred in 7% of pts treated with POM+LoDex. Deep vein thrombosis (any grade) occurred in 2 pts (2%), both aged ≤65 years. Grade 3 or 4 neutropenia occurred in 46% of pts aged ≤65 years and in 35% of pts aged >65 years. Despite this, only 1 pt in each age group developed febrile neutropenia (2%). The mean relative dose intensity (dose intensity/planned dose intensity) was 0.9 in both pt groups of ≤65 years and > 65 years receiving POM+LoDex. Overall, 21 pts (19%) of the POM+LoDex group died during the study. The most common cause of death was progressive MM (52%; only in 14% of all cases was it due to disease progression); other causes of death (48%) included infections, cerebral/intracranial/subarachonoid hemorrhage, acute respiratory distress syndrome, and suicide in one pt with a history of severe depression. Conclusions: POM, 4 mg/day for days 1–21 of a 28-day cycle in combination with LoDex, is clinically effective and generally well tolerated in pts with RRMM who have received multiple prior treatments including LEN and BORT. POM+LoDex represents an important potential new treatment option for pts with advanced MM and appears active in both younger and older pts, with tolerability similar across different age groups. Phase 3 studies of POM+LoDEX in combination with other agents (e.g. bortezomib) are ongoing. Disclosures: Jagannath: Millennium Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck Sharp & Dohme: Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Off Label Use: Pomalidomide is an investigational drug and is not approved for the treatment of patients with any condition. Hofmeister:Celgene: Advisory Board Other, Honoraria. Siegel:Onyx: Advisory Board, Advisory Board Other, Honoraria, Speakers Bureau; Millennium Pharma: Advisory Board, Advisory Board Other, Honoraria, Speakers Bureau; Celgene: Advisory Board Other, Honoraria, Speakers Bureau; Merck: Advisory Board, Advisory Board Other, Honoraria, Speakers Bureau. Vij:Onyx: Consultancy, Research Funding; Millennium Pharma: Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau. Lonial:Millennium, Celgene, Novartis, BMS, Onyx, Merck; all < $10,000 per year and disclosed to my institution: Consultancy. Anderson:Acetylon, Oncopep: Scientific Founder, Scientific Founder Other; Celgene, Millennium, BMS, Onyx: Membership on an entity's Board of Directors or advisory committees. Chen:Celgene: Employment, Equity Ownership. Zaki:Celgene: Employment, Equity Ownership. Richardson:Celgene, Millennium, Johnson & Johnson: Advisory Board Other.

Population Pharmacokinetics and Exposure-Safety Of Lenalidomide In Patients With Multiple Myeloma, Myelodysplastic Syndromes and Mantle Cell Lymphoma

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3234-3234 ◽  
Author(s):  
Nianhang Chen ◽  
Ene Ette ◽  
Simon Zhou ◽  
Daniel Weiss ◽  
Maria Palmisano
Keyword(s):  
Renal Function ◽  
Body Weight ◽  
Hepatic Impairment ◽  
Cell Lymphoma ◽  
Employment Equity ◽  
Intrinsic Factors ◽  
Mantle Cell ◽  
Equity Ownership ◽  
Grade 3 ◽  
Mild Hepatic Impairment

Abstract Introduction Lenalidomide (LEN) has been approved for the treatment of multiple myeloma (MM: dose 25mg/day, in combination with dexamethasone), myelodysplastic syndromes (MDS: 10 mg/day), and mantle cell lymphoma (MCL: 25 mg/day). In patients with these 3 types of hematologic malignancies, grade 3/4 neutropenia and thrombocytopenia are the most common dose-limiting adverse events (AEs) associated with LEN treatment. Renal function has been used to guide the starting dose of LEN in these patients as renal excretion is the primary route for LEN clearance. However, questions remain whether other intrinsic factors (e.g., race, age, body weight, gender, mild hepatic impairment) should also be considered in determining LEN dose, and how hematologic AEs are related to LEN exposure. The aim of this study was to quantitatively assess the effect of various intrinsic factors on LEN clearance and to explore the exposure-response relationship for severe neutropenia and thrombocytopenia in patients with MM, MDS, and MCL. Methods Single- and multiple-dosing concentration data of LEN were pooled from 7 clinical studies yielding a total of 147 patients: 68 with MM, 25 with MDS, 24 with MCL, and 30 with renal impairment and without a malignant condition. In the entire analysis population, 39% of the patients had normal renal function (creatinine clearance [CrCl] ≥ 90 mL/min), 31% had mild renal impairment (RI) (CrCl = 60-89 mL/min, 26% had moderate to severe RI (CrCl = 15-59mL/min), and 4% of the patients were on hemodialysis. The LEN dose level studied was 5 mg [N = 6], 10 mg [N = 41], 25 mg [N = 80], or 50 mg [N = 20], respectively. Non-linear, mixed effects' modeling was used to develop a population pharmacokinetic (PK) model for LEN. Subsequently, Bayesian post-hoc population PK model parameters were used to generate LEN steady state area under the plasma concentration-time curve (AUC) and was analyzed via logistic regression to determine the probability of experiencing grade 3/4 neutropenia or thrombocytopenia during the treatment (N = 116). Results Plasma LEN concentrations were adequately described by a 2-compartment population PK model with first order absorption and elimination. LEN exhibited linear and time invariant PKs with moderate variability. The baseline CrCl was predictive of the apparent LEN clearance (CL/F). Inclusion of renal function (CrCl and hemodialysis) into the PK model explained 24% of the inter-individual variability in CL/F. The typical value of LEN CL/F at a CrCl level of 80 mL/min was 10.26 L/h, and each 10-mL/min decrease in CrCl resulted in approximately a 10% decrease in CL/F. Age (39-85 years), body weight (33-135 kg), gender, race (white [N=110]; Asian [N=27]; and other [N=10]), and mild hepatic impairment (total bilirubin > 1 to ≤ 1.5× upper level of normal [ULN] or alanine aspartate transaminase >ULN, N = 16) had no effect on LEN CL/F. All LEN PK parameters were comparable among MM, MDS, and MCL patients. Including all treatment cycles up to one year, and after adjusting for disease and baseline neutrophil or platelet counts, LEN AUC was a significant predictor of the probability experiencing Grade 3/4 thrombocytopenia (odds ratio [OR] = 3.337, 95%CI = 1.183 to 9.415) and it was also associated with an increased probability experiencing Grade 3/4 neutropenia (OR = 1.978, 95%CI = 0.999 to 3.917). However, these relationships were not apparent during the first treatment cycle. Conclusion Creatinine clearance is the only significant and clinically important predictor of LEN CL/F; race (White vs Asian), age, body weight, gender, and mild hepatic impairment had no effect. Also no difference in LEN disposition was observed between MM, MDS, and MCL patients. LEN AUC was a significant predictor of the probability of experiencing grade 3/4 thrombocytopenia and neutropenia. Disclosures: Chen: Celgene Corporation: Employment, Equity Ownership. Ette:Anoxis Corporation: Consultancy. Zhou:Celgene Corporation: Employment, Equity Ownership. Weiss:Celegene Corporation: Employment, Equity Ownership. Palmisano:Celgene Corporation: Employment, Equity Ownership.

Sign in / Sign up

Export Citation Format

Share Document