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 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.

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.

Evaluation of Ofatumumab, a Novel Human CD20 Monoclonal Antibody, as Single Agent Therapy in Rituximab-Refractory Follicular Lymphoma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 935-935 ◽  
Author(s):  
Anton Hagenbeek ◽  
Luis Fayad ◽  
Vincent Delwail ◽  
Jean Francois Rossi ◽  
Eric Jacobsen ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Research Funding ◽  
Response Rate ◽  
Single Agent ◽  
Advisory Board ◽  
Employment Equity ◽  
Duration Of Response ◽  
Heavily Pretreated ◽  
Equity Ownership ◽  
Grade 3

Abstract Abstract 935 Introduction: Patients with follicular lymphoma (FL) who are refractory to rituximab-based therapy have a need for new non-cytotoxic treatment options. Ofatumumab targets a unique small-loop epitope on CD20 and elicits rapid and efficient in vitro cell lysis via complement-dependent cytotoxicity, even in rituximab-resistant B cells that express high levels of complement inhibitory proteins. Ofatumumab as single agent showed activity in relapsed/refractory FL, including in some patients previously exposed to rituximab (Hagenbeek et al, Blood 2008). Here we report preliminary results from an international, single-arm trial assessing ofatumumab monotherapy in patients with rituximab-refractory FL. Methods: Eligible patients (aged ≥18 years), with Grade 1 or 2 CD20+ FL considered refractory to rituximab alone or in combination with chemotherapy, were enrolled between Sept 2006 and Sept 2008 (N=116). Refractoriness to rituximab (at least 4 doses) was defined as failure to achieve at least a partial response, disease progression during rituximab treatment, or disease progression following a response within 6 months of last treatment with rituximab-containing regimens. Patients received 8 weekly infusions of ofatumumab (Dose 1, 300 mg; Doses 2–8, 500 or 1000 mg); glucocorticoid premedication was required before infusions 1 and 2, and acetaminophen and antihistamine were administered before every infusion. The primary endpoint was objective response (International Working Group criteria) in the 1000 mg dose group over 6 months from the start of treatment, as assessed by an Independent Endpoint Review Committee. Secondary endpoints included duration of response, progression-free survival (PFS) and adverse events (AEs). Results: Table 1 summarizes the baseline characteristics; 90% of patients received all 8 ofatumumab doses. The median follow-up time on the study was 4.7 months overall and 5.5 months for the 1000 mg group. The overall response rate (ORR) in the 1000 mg group was 10% (95% CI: 4, 17%), including 1 complete response. Stable disease was observed in 50% of patients. In the 1000 mg group, the median duration of response was 6.0 months (95% CI: 2.8, upper limit not estimable) and median PFS was 6.0 months (95% CI: 4.9, 9.1). The ORR in the total population was 11% (95% CI: 5, 17%). Among patients who were refractory to prior rituximab monotherapy (n=27), the ORR was 22% (95% CI: 7, 38%). The ORR among patients who were refractory to rituximab maintenance therapy (n=44) and rituximab combined with chemotherapy (n=45) was 9% (95% CI: 1, 18%) and 7% (95% CI: 0, 14%), respectively. During treatment and up to 30 days following the last dose, the most common AEs (>10% of patients) included rash (15%), urticaria (14%), fatigue (14%), pruritis (13%), nausea (12%), pyrexia (11%) and cough (11%); grade 3–4 infusion-related reactions occurred in only 3 patients (all grade 3 events), none of which were considered serious events; grade 3–4 hematologic AEs included neutropenia in 5% of patients, anemia in 3% and thrombocytopenia in 1%; grade 3 infections (sepsis, febrile neutropenia) occurred in 2 patients. Conclusions: The majority of patients with rituximab-refractory FL in this study were heavily pretreated, were also refractory to chemotherapy and had high-risk FLIPI scores. Although response rates were low with single-agent ofatumumab in patients refractory to rituximab-chemotherapy, a higher response rate was observed in patients who were refractory to rituximab monotherapy, indicating activity despite being refractory to single-agent rituximab. Ofatumumab was well tolerated in this heavily-pretreated population. Infusion reactions were manageable and no unexpected toxicities were observed. Further investigations with ofatumumab are warranted, including in combination with other therapies in patients with FL. Disclosures: Hagenbeek: Roche, Bayer Schering Pharma, Genmab: Advisory roles. Off Label Use: Ofatumumab is an investigational anti-CD20 monoclonal antibody, currently under development for the treatment of B-cell malignancies (chronic lymphocytic leukemia, diffuse large B-cell lymphoma, Waldenstroms macroglobulinemia and follicular lymphoma) as well as autoimmune diseases (rheumatoid arthritis and multiple sclerosis).. Fayad:GlaxoSmithKline, Genmab: Research Funding. Rossi:GlaxoSmithKline: Investigator on trial funded by GSK. Kuliczkowski:GlaxoSmithKline: Investigator on trial funded by GSK. Link:Genentech: Advisory Board, Research Funding; Genmab, GlaxoSmithKline: Research Funding. Radford:GlaxoSmithKline: Equity Ownership. Hellmann:Novartis, BMS: Consultancy, Honoraria. Gupta:GlaxoSmithKline: Employment. Arning:GlaxoSmithKline: Employment, Equity Ownership. Begtrup:Genmab: Employment, Equity Ownership. Schultz:Genmab: Employment. Bang:Genmab: Employment. Russell:Genmab: Employment, Equity Ownership. Czuczman:GlaxoSmithKline: Advisory Board, Honoraria, Research Funding; Genmab: Advisory Board, Research Funding.

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.

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.

scholarly journals Mature Follow up from a Phase 2 Study of PI3K-Delta Inhibitor Idelalisib in Patients with Double (Rituximab and Alkylating agent)-Refractory Indolent B-Cell Non-Hodgkin Lymphoma (iNHL)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1708-1708 ◽  
Author(s):  
Ajay K. Gopal ◽  
Brad S. Kahl ◽  
Sven de Vos ◽  
Nina D. Wagner-Johnston ◽  
Stephen J. Schuster ◽  
...  
Keyword(s):  
B Cell ◽  
Research Funding ◽  
Employment Equity ◽  
Non Hodgkin Lymphoma ◽  
Duration Of Response ◽  
Equity Ownership ◽  
Grade 3 ◽  
Systemic Therapies

Abstract Introduction: Rituximab-alkylator combinations are the standard therapies for patients (pts) with iNHL, however, refractory disease nearly uniformly develops. Once iNHL becomes “double-refractory” to both rituximab + alkylating agents, there are limited options to induce durable remissions. PI3K-delta signaling is critical for activation, proliferation and survival of B cells, and is hyperactive in many B-cell malignancies. Idelalisib, a selective oral inhibitor of PI3Kd, demonstrated considerable clinical activity in double-refractory iNHL (Gopal NEJM 2014). FDA granted accelerated approval for Idelalisib (Zydelig®) in patients who have received at least two prior systemic therapies with relapsed FL or SLL. Based on these encouraging initial results, we now describe long-term follow up, safety, and remission durations of this double-refractory iNHL population treated with idelalisib. Methods: Eligible iNHL pts included those with measurable disease refractory to both rituximab and an alkylating agent. Refractory was defined as lack of response to, or progression of lymphoma within 6 months of completion of index therapy, confirmed by imaging. Idelalisib 150 mg PO BID was administered continuously until disease progression or intolerance. Responses were evaluated by an independent review committee, using standard criteria (Cheson, 2007, and Owen 2013). The new data cutoff date for this analysis was June 2014, 20 months after the last patient enrolled. Results: Enrolled pts (N = 125) had a median age of 64 years and included follicular lymphoma (FL) n=72 (58%), small lymphocytic lymphoma (SLL) n=28 (22%), marginal zone lymphoma (MZL) n=15 (12%) and lymphoplasmacytic lymphoma (LPL)/Waldenstrom's macroglobulinemia (WM) n=10 (8%). The median number of prior therapies was 4 [range 2-12], including bendamustine/rituximab (BR) (n=60) and rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP) (n=56) and autologous transplant (n=14). 81 pts (65%) had prior bendamustine, of which 61/81 (75%) were refractory. 112 pts (90%) were refractory to their last regimen, and 99 pts (79%) were refractory to ≥2 regimens. 38 pts (30%) had elevated LDH, and 33 pts (26%) had bulky disease >7 cm. The median time to progression from last prior therapy was 3.9 months. With a median exposure of 11.1 months (range 0.7 to 35.4), the overall response rate (ORR) is 56% (95% CI = 46.8-64.9) with 70 responders, comprising 12 CRs (9.6%), 58 PRs (46.4%). The median time to response was 1.9 months (time of first evaluation) and time to CR was 4.5 months. There were 43 pts with stable disease (SD) (34.4%). 90% of pts experienced some decrease in tumor burden. ORR for iNHL subtypes is: FL (54%), SLL (61%), MZL (47%), and LPL/WM (70%). CR rate for iNHL subtypes is: FL (14%), SLL (4%), MZL (7%), and LPL/WM (0%). Among responders, median DOR is 13.9 (0.03-31.3) months. DOR for iNHL subtypes in months (Figure 1) is: FL 11.8, SLL 13.9, MZL 18.4, and LPL/WM (not yet reached). Median PFS for all pts is 11.0 months, in comparison to a median PFS of the last prior regimen of 3.9 months (p<.0001). The median PFS for individual subtypes in months was: FL 11.0, SLL11.1, MZL 6.6, and LPL/WM 22.2. The median overall survival of all patients was 30.8 months. The adverse events include (total%/≥ grade 3%) diarrhea/colitis (50/18), fatigue (30/2), nausea (31/2), cough (32/0), pyrexia (30/2), dyspnea (18/5), rash (14/2), pneumonia (14/11), and pneumonitis (4/3). Based on central laboratory measurements, Grade ≥3 ALT/AST elevations occurred in 18 pts (14%). Drug was temporarily held in these pts, and 11/15 pts (73%) were re-treated without recurrence of ALT/AST elevation. Overall, 30 pts (24%) have discontinued therapy due to adverse events. Conclusions: The prolonged administration of idelalisib was well tolerated, had an acceptable safety profile, and was highly effective in inducing and maintaining remissions in double-refractory iNHL population with an ORR of 56%, PFS of 11 months, and DOR of 13.9 months. The response rate and long term duration of responses in the small number of subjects with LPL/WM is very promising, and will be evaluated in larger trials of this disease. The observed disease control compared to prior regimens suggests the potential for prolonged clinical benefit in this challenging patient population with unmet medical need. Figure 1: Duration of Response by Disease Group. Figure 1:. Duration of Response by Disease Group. Disclosures Gopal: Gilead Sciences: Research Funding. Off Label Use: Zydelig is a kinase inhibitor indicated for the treatment of patients with: 1) Relapsed chronic lymphocytic leukemia (CLL), in combination with rituximab, in patients for whom rituximab alone would be considered appropriate therapy due to other co-morbidities; 2) Relapsed follicular B-cell non-Hodgkin lymphoma (FL) in patients who have received at least two prior systemic therapies; and 3) Relapsed small lymphocytic lymphoma (SLL) in patients who have received at least two prior systemic therapies.. Kahl:Gilead Sciences: Research Funding. de Vos:Gilead Sciences: Research Funding. Wagner-Johnston:Gilead Sciences: Research Funding. Schuster:Gilead Sciences: Research Funding. Jurczak:Gilead Sciences: Research Funding. Flinn:Gilead Sciences: Research Funding. Flowers:Gilead Sciences: Research Funding. Martin:Gilead Sciences: Research Funding. Viardot:Gilead Sciences: Research Funding. Blum:Gilead Sciences: Research Funding. Goy:Gilead Sciences: Research Funding. Davies:Gilead Sciences: Research Funding. Zinzani:Gilead Sciences: Research Funding. Dreyling:Gilead Sciences: Research Funding. Holes:Gilead Sciences: Employment, Equity Ownership. Sorensen:Gilead Sciences: Employment, Equity Ownership. Godfrey:Gilead Sciences: Employment, Equity Ownership. Salles:Gilead Sciences: Research Funding.

scholarly journals Comparison of 2 Doses of Intravenous (IV) Temsirolimus (Temsr) in Patients with Relapsed/Refractory Mantle Cell Lymphoma (MCL)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1775-1775
Author(s):  
Wojciech Jurczak ◽  
Sundra Ramanathan ◽  
Pratyush Giri ◽  
Francesco Di Raimondo ◽  
Heidi Mocikova ◽  
...  
Keyword(s):  
Mantle Cell Lymphoma ◽  
Disease Progression ◽  
Safety Profile ◽  
Dose Regimen ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Employment Equity ◽  
Mantle Cell ◽  
Equity Ownership ◽  
Grade 3

Abstract Introduction: Temsr (Torisel®) administered at 175 mg IV once weekly for first 3 weeks, followed by 75mg IV once weekly (Temsr 175/75 mg) is approved in the European Union for the treatment of adult patients with relapsed and/or refractory MCL based on an overall positive benefit-risk relationship demonstrated for this treatment regimen in the pivotal phase III study (Hess et al. J Clin Oncol. 2009;27:3822-9). This ongoing phase 4, multicenter, randomized, open-label study was conducted to explore whether similar efficacy can be achieved for the treatment of patients with relapsed/refractory MCL with a Temsr regimen that is expected to yield fewer side effects than the Temsr 175/75 mg dose regimen, by skipping the first 3 doses of Temsr 175 (Clinicatrials.gov: NCT01180049). Methods: In this study, previously treated (2-7 lines of prior therapy) patients with relapsed/refractory mantle cell lymphoma were stratified by the histologic subtype (blastoid vs. non blastoid vs unknown histology) and randomized (1:1) to receive Temsr 175/75 mg, or 75mg IV once weekly (Temsr 75 mg). Treatment continued until disease progression, provided that patients were tolerating treatment and achieving clinical benefit. The primary endpoint was progression-free survival (PFS) based on independent assessment. Secondary endpoints included objective response rate (ORR), overall survival (OS) and safety with a particular focus on bleeding- and infection-related adverse events (AEs). Results: Of the 90 patients (77.8% males; 93.3% white, mean age 66.6 years) randomized, 47 were treated with Temsr 175/75 mg, 42 were treated with Temsr 75 mg, and 1 patient was randomized but not treated. At the cutoff date for analysis (November 12, 2015), 39 (83.0%) patients in Temsr 175/75 mg arm and 41 (95.3%) patients in Temsr 75 mg arm discontinued treatment with the primary reason being objective disease progression (53.8% in Temsr 175/75 mg and 56.1% in Temsr 75 mg). Median duration of treatment was comparable in the Temsr 175/75 mg arm and Temsr 75 mg arm (3.2 vs. 3.1 months). Median PFS (80% CI) was 4.3 (3.3-6.4) months in Temsr 175/75 mg arm versus 4.5 (2.7-4.9) months in Temsr 75 mg arm (hazard ratio [HR] 0.731; 80% CI 0.520-1.027). ORR (80% CI) was 27.7% (19.1%-37.7%) in Temsr 175/75 mg arm versus 20.9% (13.0%-31.0%) in Temsr 75 mg arm. Median OS (80% CI) was 18.7 (7.5-48.2) months in Temsr 175/75 mg arm versus 11.0 (6.3-16.2) months in Temsr 75 mg arm (HR 0.681, 80% CI 0.472-0.982). Median duration of response was comparable in both treatment arms (9.0 vs. 8.7 months in Temsr 175/75 mg and Temsr 75 mg arms, respectively). Overall, the safety profile was comparable in both treatment arms, although the number of patients with serious AEs, dose reduction and deaths was lower in the 175/75mg arm compared with 75 mg arm (57.4%, 48.9% and 48.9% vs. 73.8%, 64.3% and 65.1%, respectively), and the number of treatment discontinuations due to AEs was higher in the Temsr 175/75mg arm compared with 75mg arm (19.1% vs. 14.3%). Common (>10%) grade ≥3, all-causality, treatment-emergent AEs in the Temsr 175/75 mg arm and Temsr 75 mg arm, respectively, were thrombocytopenia (46.8% vs. 38.1%), neutropenia (25.5% vs. 21.4%), and pneumonia (10.6% vs. 19.0%). Treatment-emergent bleeding-related grade ≥2 AEs in the Temsr 175/75 mg arm and Temsr 75 mg arm, respectively, included epistaxis (10.6% vs. 2.4%) and ecchymosis (2.1% vs. 0). Only 1 grade 3 AE of epistaxis which was not related to Temsr was reported in the Temsr 175/75 arm, and no grade 3 events were reported in Temsr 75 arm. Pneumonia was the most commonly occurring treatment-emergent infection-related grade ≥2 AEs 12.8% in Temsr 175/75 mg arm and 19.0% in Temsr 75 mg arm. Of the 51 deaths reported during the study, none were treatment-related and most were due to disease progression. Conclusions: Overall, PFS, ORR and OS favored the Temsr 175/75 arm, although no formal statistical conclusions were made as the study was not powered for differences. The safety profile in both study arms was comparable, but there was a lower incidence of serious AEs, dose reductions and deaths in the 175/75 mg arm. Temsr 175/75 mg remains the preferred dose regimen for patients with relapsed/refractory MCL. Disclosures Jurczak: Sandoz - Novartis, Morphosys, Roche: Speakers Bureau; Acerta, Novartis, Pfizer, Celgene, Gillead, Janssen, Celtrion, Bayer, Morphosys, Takeda, Servier, Teva, and Roche: Research Funding; Morphosys: Consultancy. Clancy:Pfizer Inc: Consultancy. Lechuga:Pfizer Inc: Employment, Equity Ownership. Casey:Pfizer Inc: Employment, Equity Ownership. Boni:Pfizer Inc: Employment, Equity Ownership. Hess:Roche, CTI, Pfizer, Celgene: Research Funding; Janssen: Honoraria; Roche: Honoraria; Celgene: Honoraria; Novartis: Honoraria; Pfizer: Honoraria.

Overall Safety and Treatment Duration in Lenalidomide (LEN)-, Thalidomide (THAL)-, and Bortezomib (BORT)-Treated Patients (Pts) within the European Post-Approval Safety Study (EU PASS) of Relapsed/Refractory Multiple Myeloma (RRMM)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4068-4068
Author(s):  
Barbara Gamberi ◽  
Charalampia Kyriakou ◽  
John Ashcroft ◽  
Miguel T. Hernandez ◽  
Jo Caers ◽  
...  
Keyword(s):  
Clinical Practice ◽  
Disease Progression ◽  
Treatment Duration ◽  
Treatment Discontinuation ◽  
Study Entry ◽  
Current Clinical Practice ◽  
Employment Equity ◽  
Equity Ownership ◽  
Grade 3

Abstract Abstract 4068 Background: The efficacy and tolerability of LEN in pts with RRMM has been demonstrated in 2 large, randomized, phase 3 studies (MM-009/010). BORT and THAL have also been shown to be effective for RRMM treatment. While many studies have described the safety of antimyeloma drugs in the clinical trial setting, few have addressed the issue of tolerability in current clinical practice. Aims: In this study, we compared the incidence of adverse events (AEs) of special interest, such as neutropenia, thrombocytopenia, venous thromboembolism (VTE), peripheral neuropathy (PN) and second primary malignancies (SPM) in pts treated with LEN versus other antimyeloma therapies for RRMM in current clinical practice. Additionally, duration of treatment was assessed in the context of therapy received just prior to study entry. Methods: In this post-approval, observational, non-interventional, EU PASS study, pts with RRMM were enrolled into either the LEN cohort (LEN-based therapy) or the background cohort (all non-LEN based therapies) at the investigators' discretion. Thromboprophylaxis was per local standard practice. AEs were graded according to NCI-CTCAE v3.0. Assessments for SPM were to be conducted up to 36 months (mos) after treatment discontinuation. Results: As of May 2012, overall median follow-up was 5.7 mos (range 0.02–39.8), (6.4 mos LEN, 5.7 mos THAL, 4.9 mos BORT). There were 3107 pts across 268 institutions in 17 European countries enrolled: 2141 received LEN, 751 received BORT, 110 received THAL, and 105 received other therapies or had incomplete information on the treatment arm. 127 pts from the background cohort crossed over following the physician's decision to initiate LEN treatment as a subsequent therapy. Median age was 70 years (range, 25–95) and 54% were male. Most pts (65%) had good performance status (ECOG score 0–1); 17% had an ECOG score of 2–4. Median overall number of prior therapies was 2 (range, 0–6) and this was consistent across the cohorts: 53% had 2 prior therapies and 21% had ≥3. Baseline characteristics were similar between groups. Overall, 1397 (45.0%) had a grade 3–4 AE. Grade 3–4 neutropenia occurred in 14%, 4%, and 5% of pts in the LEN, BORT, and THAL groups, respectively. Grade 3–4 thrombocytopenia developed in 8%, 9%, and 3% of pts, respectively. In the LEN group, only 7% of pts (1% grade 3–4) reported PN (4% newly occurring) while receiving LEN (despite 36% of pts presenting with PN at baseline) compared with 28% (5% grade 3–4) with BORT (22% PN at baseline) and 16% (2% grade 3–4) with THAL (19% PN at baseline). Grade 3–4 VTE developed in 2.7% of pts in the LEN group, 0.7% in the BORT group, and 1.8% in the THAL group. Overall treatment discontinuation rates (including disease progression) were 70%, 85%, and 86% in the LEN, BORT, and THAL groups, respectively, with nearly identical discontinuation rates due to AEs (17%) in each group, and disease progression rates of 15–20%. SPM incidence was ≤1% overall and invasive SPM incidence rate per 100 patient-years (95% CI) was 1.4 (0.94 –2.09) at a median follow-up of 10 mos and was comparable across the cohorts. Incidence of death during the study was comparable with all treatments (LEN 6%, BORT 4%, and THAL 5%); the incidence of treatment-related AEs leading to death was 1.4%, 1.2% and 0.9%, respectively. The median treatment duration was 4.6 mos in the overall population; 5.4 mos in pts treated with LEN, 3.7 mos in pts treated with BORT, and 4.6 mos in pts treated with THAL. At a 5.7 mos median follow-up, 19.9%, 2.0%, and 14.5% of pts in the LEN, BORT, and THAL arms had a treatment duration of >12 mos; and 2.2%, 0.3%, and 0.9% had a treatment duration of >24 mos, respectively. In an analysis of study treatment by last therapy prior to study entry, patients receiving THAL or BORT followed by LEN had a median on-study treatment duration of 5.7 mos and 5.2 mos, respectively, independent of the line of treatment. In comparison, pts receiving THAL or BORT followed by BORT had lower median study treatment duration of 3.7 mos and 3.8 mos, respectively. Conclusions: Results of this non-interventional, observational study show that AEs were similar with all treatments except for higher rates of neutropenia and lower rates of PN with LEN, compared with BORT or THAL. Despite the current short overall follow-up, treatment duration within the LEN, BORT, or THAL groups appears to be unaffected by prior treatment received but was longer for LEN when compared with BORT or THAL. Disclosures: Küenburg: Celgene Corporation: Employment, Equity Ownership. Rosettani:Celgene Corporation: Employment, Equity Ownership. Ryder-Smith:Celgene Corporation: Employment, Equity Ownership.

Cytogenetic Progression in Patients with Multiple Myeloma As Assessed By Serial Bone Marrow Biopsy Is Associated with Worse Outcome

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4209-4209
Author(s):  
Catherine Randall Paschal ◽  
Jens C Eickhoff ◽  
Aric C Hall ◽  
Jennifer Laffin ◽  
Natalie Scott Callander ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Overall Survival ◽  
High Risk ◽  
Risk Group ◽  
Clonal Evolution ◽  
Intermediate Risk ◽  
Disease Course ◽  
Cytogenetic Abnormalities ◽  
Standard Risk

Abstract Background:Multiple Myeloma (MM) is a hematologic malignancy characterized by the proliferation of clonal, mutated plasma cells, which ultimately leads to multi-organ damage and in most cases death. Despite improved treatments, clinical heterogeneity remains, with some patients succumbing to disease within 1-2 years. Certain cytogenetic and FISH abnormalities at diagnosis confer a higher likelihood of poor outcomes (Mikhael et al., 2013). Still, the utility of repeated cytogenetic assessment over the course of disease is unknown. Methods: We performed a retrospective review to identify MM patients with cytogenetics (CG) performed at diagnosis who had two or more bone marrow (BM) examinations performed during follow up over a five year period at UW Carbone Cancer Center. We reviewed the pathology and CG results from each BM sample. CG data was categorized into risk groups using the mSMART stratification criteria: High risk - deletion 17p13, t(14;16), t(14;20); intermediate risk - t(4;14), hypodiploid, deletion 13, gain of 1q21; standard risk - hyperdiploidy and all other abnormalities, and normal CG. CG progression over disease course was categorized based on stability or change in CG risk group. We measured survival from date of diagnosis to death or last follow up. Results: 130 patients with CG at diagnosis were identified over the five year period of the study. These patients had 365 follow-up bone marrow (BM) aspirates, 341 with repeat CG study. Initial cytogenetics were as follows: 90 (69%) of 130 patients had normal CG at diagnosis, 13 (10%) standard risk CG, 16 (13%) intermediate risk CG, and 11 (8%) high risk CG. Serial CG studies showed both development of new CG abnormalities in patients with previously normal studies, and clonal evolution with CG abnormal patients acquiring additional abnormalities on repeat testing. 24 (27%) of 90 patients with normal CG at diagnosis developed abnormal CG during disease course: 12 had intermediate risk CG and 9 high risk CG, the latter all due to p53 deletion. Clonal evolution and drift among initially CG abnormal patients were also common. Of the 34 patients with abnormal CG results on diagnosis and subsequent bone marrow samples, clonal evolution was identified in 19 patients (56%) and 4 (12%) patients developed new CG abnormalities unrelated to the prior clone, while 11 (32%) showed stable CG. Despite this high rate of change, only two patients with abnormal CG at diagnosis moved from a lower to a higher cytogenetic risk group. When we correlated CG at diagnosis with survival, we found that patients with high risk CG at diagnosis appeared to have shorter median overall survival at 3.8 yrs (range 1-12 yrs) compared with 7.4 yrs (range 2-12 yrs) for intermediate risk, 8.5 yrs (range 2-9 yrs) for standard risk, and 8.2 yrs (range 1-12 yrs) for normal CG. Comparison among all four groups was not statistically significant however, possibly due to the small proportion of high risk CG patients. When we examined the effect of acquiring CG abnormalities, we found that development of abnormal CG in patients with normal CG at diagnosis was associated with shorter median OS (4.0 yrs) compared to either persistent normal CG (11.3 yrs) or any CG abnormality at diagnosis (7.4 yrs), overall comparison p = 0.0048. Conclusion: Our longitudinal study of 130 unselected patients with MM revealed a cohort who showed cytogenetic progression. In patients with normal CG at diagnosis, the presence of cytogenetic abnormalities in follow-up BM specimens was associated with inferior overall survival. This finding indicates that serial testing may facilitate the detection of a higher risk patient cohort. Further analysis is underway to identify clinical parameters that underlie a higher risk of clonal evolution or development of new cytogenetic abnormalities. The results of our study will help elucidate the optimal prognostic utility of cytogenetic analysis in patient care. Disclosures No relevant conflicts of interest to declare.

scholarly journals Open-Label, Phase 2 Study of Blinatumomab after First-Line Rituximab-Chemotherapy in Adults with Newly Diagnosed, High-Risk Diffuse Large B-Cell Lymphoma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4077-4077 ◽  
Author(s):  
Deborah A. Katz ◽  
Michael P. Chu ◽  
Kevin A. David ◽  
Catherine Thieblemont ◽  
Nicholas J. Morley ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Metabolic Response ◽  
B Cell Lymphoma ◽  
Newly Diagnosed ◽  
First Line ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Grade 3

Background: Rituximab combined with chemotherapy (R-chemotherapy) is the standard of care first-line treatment for diffuse large B-cell lymphoma (DLBCL). Despite success with R-chemotherapy, 30% to 50% of patients with high-risk DLBCL will relapse, and outcomes are poor among patients who relapse within one year of diagnosis. Given the challenge of successful salvage, novel first-line therapies are needed. Blinatumomab, a bispecific T-cell engager (BiTE®) antibody construct that directs cytotoxic T cells to lyse CD19-expressing B cells, has shown efficacy as salvage therapy in patients with relapsed or refractory DLBCL. This open-label, multicenter, phase 2 study (ClinicalTrials.gov, NCT03023878) assessed the efficacy and safety of blinatumomab after first-line R-chemotherapy for patients with newly diagnosed, high-risk DLBCL. Methods: Patients (≥18 y) had proven high-risk DLBCL (International Prognostic Index [IPI] 3−5 and double/triple hit or double MYC/BCL2 expressor) and Eastern Cooperative Oncology group performance status ≤2. To be eligible for blinatumomab, patients were required to achieve complete metabolic response (CMR), partial metabolic response (PMR), or stable metabolic response by PET/CT after a run-in period with 6 cycles of R-chemotherapy (R-CHOP, R-DA-EPOCH, or R-CHOEP). Blinatumomab was given by continuous intravenous infusion in a single 84-day cycle 1 (9 μg/day for 7 days, 28 μg/day for 7 days, and 112 μg/day for 42 days, followed by a 28-day treatment-free interval) and an optional 28-day cycle 2 (9 μg/day for 7 days, 28 μg/day for 7 days, and 112 μg/day for 14 days) for patients without progressive metabolic disease (PMD). The primary endpoint was the incidence and severity of adverse events (AEs). Additional endpoints were objective response rate (ORR [CMR + PMR]) per Lugano criteria, minimal residual disease (MRD) by plasma cell−free circulating tumor DNA, overall survival (OS), and pharmacokinetics (PK). Results: Of 47 patients enrolled, 17 (36%) discontinued R-chemotherapy run-in (protocol criteria, n=6; patient request, n=5; disease progression, n=3; ineligibility, n=1; AE, n=1; death, n=1) and 30 (64%) completed the run-in (2 did not proceed to blinatumomab). Of 28 patients who received blinatumomab, 26 (93%) had high or high-intermediate IPI; 8 (29%) were double/triple hit and 10 (36%) were double protein expressors (Table). In total, 26 (93%) patients completed cycle 1; ten of 11 (91%) patients completed optional cycle 2. Blinatumomab PK were consistent with those in previous studies. After the R-chemotherapy run-in before starting blinatumomab, 24 patients had objective metabolic responses and 4 had no metabolic response (NMR). After blinatumomab treatment, the ORR (within 12 weeks of starting blinatumomab) was 89% (25/28 patients; 95% CI, 72−98; Table). The 4 patients with NMR before blinatumomab had objective responses after blinatumomab treatment. Three patients with objective responses before blinatumomab relapsed after blinatumomab. Twenty-six (93%) patients were still alive with a median follow-up time of 8.6 months; 2 died (disease progression; n=1; infection not related to treatment, n=1). Nine of 13 (69%) patients during the R-chemotherapy run-in were MRD positive, all of whom converted to MRD negative after treatment with blinatumomab. After treatment with blinatumomab, 17 of 18 (94%) patients were MRD negative; the MRD positive patient had PMD. During blinatumomab treatment, 11 (39%) patients had grade ≥3 AEs, and 5 (18%) had grade ≥4 AEs. Two (7%) patients discontinued treatment due to AEs (grade 3 neurotoxicity; grade 4 neutropenia). Consistent with previous blinatumomab reports, neurologic events (NEs) were reported in 17 (61%) patients, including 3 (11%) with grade 3 NEs and 1 (4%) with NEs leading to treatment discontinuation. No patients had grade ≥3 cytokine release syndrome. Other grade ≥3 events of interest included neutropenia and febrile neutropenia (n=4; 14%) and infection (n=3; 11%). Conclusions: In patients with newly diagnosed, high-risk DLBCL, blinatumomab monotherapy after first-line R-chemotherapy led to an 89% ORR, and safety was consistent with that in earlier studies in DLBCL. Thus, blinatumomab is a potential treatment option for patients with newly diagnosed disease. Disclosures Katz: Stemline: Speakers Bureau; Dova: Consultancy. Chu:Celgene: Honoraria; Teva: Consultancy; AstraZeneca: Honoraria; Amgen Inc.: Honoraria; Gilead: Honoraria. Thieblemont:Roche: Honoraria, Research Funding; Gilead: Honoraria; Novartis: Honoraria; Kyte: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Cellectis: Membership on an entity's Board of Directors or advisory committees. Morley:Amgen: Membership on an entity's Board of Directors or advisory committees, Other: speaker fees, conference support ; TAKEDA: Other: conference support ; Janssen Pharmaceuticals: Other: speaker fees; ROCHE: Membership on an entity's Board of Directors or advisory committees, Other: conference support; ABBVIE: Other: speaker fees. Chen:Amgen Inc.: Employment, Equity Ownership. Kalabus:Amgen Inc.: Employment, Equity Ownership. Morris:Amgen: Employment, Equity Ownership. Anderson:Amgen Inc.: Employment, Equity Ownership. Avilion:Amgen Inc.: Employment, Equity Ownership. González-Barca:Takeda: Honoraria; Kiowa: Consultancy; Celtrion: Consultancy; Janssen: Consultancy, Honoraria; Celgene: Consultancy; Roche: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria.

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