scholarly journals Selinexor Plus Pomalidomide and Low Dose Dexamethasone (SPd) in Patients with Relapsed or Refractory Multiple Myeloma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1993-1993
Author(s):  
Christine I Chen ◽  
Heather J. Sutherland ◽  
Rami Kotb ◽  
Michael Sebag ◽  
Darrell J. White ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Adverse Events ◽  
Board Of Directors ◽  
Nuclear Export ◽  
Research Funding ◽  
Low Dose ◽  
Published Data ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership

Abstract Introduction - The nuclear export protein exportin 1 (XPO1) is overexpressed in a wide variety of cancers including multiple myeloma (MM). Selinexor is a first-in-class Selective Inhibitor of Nuclear Export (SINE) compound that binds and inactivates XPO1. Selinexor forces nuclear retention and reactivation of cell cycle regulators such as p53, IkB, and Rb. Pomalidomide/dexamethasone (Pd) is approved in relapsed/refractory MM (RRMM)with an overall response rate (ORR) of 30% and progression-free survival (PFS) rate of <4 months in patients (pts) having received a prior proteasome inhibitor (PI) and IMiD. Strategies to improve the ORR and PFS are needed. In murine MM models, the combination of selinexor with IMiDs shows synergistic anti-MM activity and good tolerability. Methods- Pts with RRMM who received ≥ 2 prior therapies including lenalidomide (len) and a PI were enrolled. Selinexor was evaluated in 2 different dosing schedules of once-weekly (QW, 60 or 80 mg) or twice-weekly (BIW, 60 or 80 mg), with pomalidomide (pom)3 or 4 mg PO daily, and dexamethasone (dex) 20 mg BIW or 40 mg QW. The primary objectives were to determine the maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), safety, and preliminary efficacy of the combination of selinexor, pomalidomide, and low dose dex (SPd) in pts with RRMM. Results- As of July 20th2018, 34 pts (16 male / 18 female) have been enrolled. The median age is 61 years and patients received a median of 4 (range, 2 - 9) prior treatment regimens. Thirty-two patients were IMiD refractory (21 len, 11 pom/len). Six dose limiting toxicities (DLTs) were observed: G3 fatigue (60 mg BIW, pom 4 mg), G3 febrile neutropenia (FN) (60 mg BIW, pom 3 mg), G3 FN and G4 neutropenia (80 mg QW, pom 4), G3 thrombocytopenia (80 mg QW, pom 3 mg) and 4 missed doses in Cycle 1 due to symptomatic hyponatremia (80 mg BIW, pom 4 mg). Enrollment on selinexor 80 mg QW, pom 3 mg is ongoing. Common SPd treatment related adverse events included (all grades, grades 3/4): neutropenia (62%, 56%), thrombocytopenia (59%, 32%), anemia (53%, 29%), anorexia (56%, 0%), fatigue (50%, 9%), nausea (47%, 0% ). Thirty pts were evaluable for response, which is outlined in Table 1. Median PFS is 10.3 months with a median follow up of 9.4 months. Conclusions- Enrollment is ongoing to evaluate once weekly selinexor in combination with Pd , (SPd). This all-oral SPd combination has clinical activity with an ORR 55% in pom-naive pts with heavily pretreated MM compared to previously published data of 30% ORR for Pd alone. Similarly, the PFS on SPd is 10.3 months vs. <4 months for Pd alone. No unexpected adverse events were noted. Phase 1 dose escalation of the combination of SPd is ongoing to define the optimal RP2D. Disclosures Chen: Amgen: Honoraria. Sebag:Janssen Inc.: Membership on an entity's Board of Directors or advisory committees; Amgen Canada: Membership on an entity's Board of Directors or advisory committees; Takeda Canada: Membership on an entity's Board of Directors or advisory committees; Celgene Canada: Membership on an entity's Board of Directors or advisory committees. White:Amgen, Celgene, Janssen, Takeda: Honoraria. Bensinger:Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Speakers Bureau; celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; amgen: Speakers Bureau. Gasparetto:Bristol-Myers Squibb: Consultancy, Honoraria, Other: Travel; Janssen: Consultancy, Honoraria, Other: Travel; Takeda: Honoraria; Celgene: Consultancy, Honoraria, Other: Travel, Research Funding. Leblanc:Amgen Canada: Membership on an entity's Board of Directors or advisory committees; Janssen Inc.: Membership on an entity's Board of Directors or advisory committees; Celgene Canada: Membership on an entity's Board of Directors or advisory committees; Takeda Canada: Membership on an entity's Board of Directors or advisory committees. Venner:Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Amgen: Honoraria; Takeda: Honoraria. Schiller:Pharmacyclics: Research Funding; Celator/Jazz Pharmaceuticals: Research Funding. Lipe:Celgene: Consultancy. Shah:Karyopharm Therapeutics: Employment. Jeha:Karyopharm Therapeutics: Employment. Saint-Martin:Karyopharm Therapeutics: Employment. Kauffman:Karyopharm Therapeutics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Shacham:Karyopharm Therapeutics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Bahlis:Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding.

Selinexor Shows Synergy in Combination with Pomalidomide and Low Dose Dexamethasone in Patients with Relapsed / Refractory Multiple Myeloma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3330-3330 ◽  
Author(s):  
Christine Chen ◽  
Rami Kotb ◽  
Michael Sebag ◽  
Richard LeBlanc ◽  
Heather J. Sutherland ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Dose Level ◽  
Nuclear Export ◽  
Research Funding ◽  
Low Dose ◽  
Clinical Activity ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership

Abstract Introduction - The nuclear export protein exportin 1, (XPO1) is overexpressed in a wide variety of cancers including multiple myeloma (MM). Selinexor is a first-in-class Selective Inhibitor of Nuclear Export (SINE) compound that binds and inactivates XPO1. Selinexor forces nuclear retention and reactivation of tumor suppressor proteins (TSPs; NF-kB, p53 and FOXO) and reduction of many proto-oncogenes, including MDM2, MYC and Cyclin D. In murine MM models, the combination of selinexor with IMIDs shows synergistic anti-MM activity with good tolerability. Methods - This phase 1b/2 dose escalation study (NCT02343042) using the standard 3+3 design, is designed to determine the tolerability, maximum tolerated dose (MTD), recommended phase 2 dose (RP2D) and preliminary efficacy of selinexor in combination with pomalidomide and dexamethasone (SdP). Patients (pts) with relapsed/refractory MM who received ≥ 2 prior therapies including lenalidomide and a proteasome inhibitor (PI) were enrolled. Selinexor is dose escalated once-weekly (QW, starting at 80 mg) or twice-weekly (BIW, starting at 60 mg), pomalidomide 4 mg PO daily, days 1 -21 and dexamethasone (dex) 40 mg PO weekly in a 28 day cycle. Results - As of 25-Jul-2016, 11 pts (7 male / 4 female) have been enrolled. The median age is 58 years (range, 43 - 76), with a median of 5 (range, 2 - 9) prior treatment regimens. Eight pts had MM refractory to lenalidomide and 7 pts to bortezomib; including 5 pts with MM refractory to both. For the once-weekly selinexor cohort, the 80 mg dose level has been cleared and the 100 mg dose level is on going. For the twice-weekly cohort, the 60 mg dose level has been cleared and 80 mg dose level is on going. Common related grade 1/2 adverse events (AEs) include: nausea 7pts (64%), altered taste 5pts (45%), anorexia 3pts (27%), and diarrhea 3pts (27%). Grade 3/4 AEs include: neutropenia 8pts (73%), thrombocytopenia 4pts (36%), and leukopenia 3pts (27%). There was no febrile neutropenia or bleeding reported to date. No dose limiting toxicities have been observed and MTD has not been reached. Ten pts were evaluable for response including, 1 complete response (CR), 5 partial responses (PR), 3 minor responses (MR), and 1 stable disease (SD). The overall response rate (ORR) is 60% with a clinical benefit rate of 90% (ORR + MR). Responses are rapid in onset, with at least MR achieved by cycle 2 day 1. In lenalidomide and bortezomib refractory patients the ORR was 50%. One pt was deemed not evaluable due to non-compliance with study procedures. Eight pts are still on study, (range <1 - 7+ months) including 4 pts maintaining their response for > 3 months. Conclusions - The all oral combination of selinexor, pomalidomide and low dose dex (SdP) has significant clinical activity (ORR 60%) in pts with heavily pretreated MM. Responses are rapid in onset even with the lower dose cohorts tested thus far, CR can be achieved. No additive toxicities over monotherapy of either pomalidomide or selinexor have been observed. This novel treatment regimen therefore holds promise in addressing the urgent need to induce meaningful and durable responses in patients with IMiD and PI relapsed/refractory MM. Disclosures Chen: Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Takeda: Research Funding. Sebag:Celgene: Honoraria; Janssen: Honoraria; Novartis: Honoraria. Sutherland:Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. White:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Venner:Takeda: Honoraria; Celgene: Honoraria, Research Funding; J+J: Research Funding; Janssen: Honoraria; Amgen: Honoraria. Kouroukis:Karyopharm: Research Funding; Amgen: Research Funding; Janssen: Research Funding. McCurdy:Celgene: Honoraria. Lalancette:BMS: Honoraria; Celgene: Honoraria. Bensinger:Sanofi: Consultancy, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Acetylon: Research Funding; Bayer: Research Funding; Takeda: Honoraria, Research Funding. Lentzsch:Celgene: Consultancy, Honoraria; BMS: Consultancy. Kauffman:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Shacham:Karyopharm Therapeutics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Jeha:Karyopharm: Employment. Picklesimer:Karyopharm: Employment. Saint-Martin:Karyopharm: Employment. Choe-Juliak:Karyopharm Therapeutics: Employment. Bahlis:BMS: Honoraria; Janssen: Consultancy, Honoraria, Other: Travel Expenses, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Other: Travel Expenses, Research Funding, Speakers Bureau; Onyx: Consultancy, Honoraria; Amgen: Consultancy, Honoraria.

A Phase 1/2 Study of the Second Generation Selective Inhibitor of Nuclear Export (SINE) Compound, KPT-8602, in Patients with Relapsed Refractory Multiple Myeloma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4509-4509 ◽  
Author(s):  
R. Frank Cornell ◽  
Adriana C Rossi ◽  
Rachid Baz ◽  
Craig C Hofmeister ◽  
Chaim Shustik ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Board Of Directors ◽  
Nuclear Export ◽  
Research Funding ◽  
Low Dose ◽  
Phase 1 ◽  
Single Agent ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership

Abstract Introduction - Inhibition of Exportin 1 (XPO1) is a novel treatment approach for multiple myeloma (MM). XPO1 mediates the nuclear export of cell-cycle regulators and tumor suppressor proteins leading to their functional inactivation. In addition, XPO1 promotes the export and translation of the mRNA of key oncoproteins (e.g. c-MYC, BCL-2, Cyclin D). XPO1 overexpression occurs in solid and hematological malignancies, including MM and is essential for MM cell survival. Selinexor, the first oral SINE compound, has shown promising anti-MM activity in phase 1 studies but has been associated with gastrointestinal and constitutional toxicities including nausea, anorexia and fatigue. KPT-8602 is a second generation oral SINE compound with similar in vitro potency to selinexor, however, has substantially reduced brain penetration compared with selinexor, and demonstrated markedly improved tolerability with minimal anorexia and weight loss in preclinical toxicology studies. In murine models of MM, KPT-8602 can be dosed daily (QDx5) with minimal anorexia and weight loss. We have therefore initiated a phase 1/2 first-in-human clinical trial. Methods - This phase 1/2 clinical trial was designed to evaluate KPT-8602 as a single agent and in combination with low dose dexamethasone (dex) in patients (pts) with relapsed / refractory MM (RRMM). KPT-8602 is dosed orally (QDx5) for a 28-day cycle with a starting dose of 5 mg. Low dose dex (20 mg, twice weekly) is allowed after cycle 1 if at least a minimal response (MR) is not observed. The primary objective is to evaluate the safety and tolerability including dose-limiting toxicity (DLT), determine the maximum tolerated dose (MTD), the recommended Phase 2 dose (RP2D), and evidence for anti-MM activity for KPT-8602 single agent and in combination with dex. The pharmacokinetic (PK) and pharmacodynamic (PDn; XPO1 mRNA) profile of KPT-8602 will also be determined. PDn predictive biomarker analysis and ex vivo drug response assays are underway using tumor cells from bone marrow aspirates before treatment, during and at relapse. These analyses include cell death pathway assays by flow and nuclear/cytoplasmic localization of XPO1, NF-ƙB, IƙBα, IKKα, NRIF and p53 by imaging flow and IHC. Results - As of 01-Aug-2016, 6 pts 2 M/4 F, (median of 6 prior treatment regimens, median age of 71) with RRMM have been enrolled. Common related grade 1/2 adverse events (AEs) include thrombocytopenia (3 pts), nausea (2 pts) and diarrhea (2 pts). Grade 3 AEs include neutropenia (1 pt) and dehydration (1 pt). No grade 4 or 5 AEs have been reported. No DLTs have been observed and the MTD has not been reached. 5 pts were evaluable for responses (1 pt pending evaluation): 1 partial response, 1 minimal response, and 3 stable disease; no pts have progressed on therapy with the longest on for >5 months. The PK properties following oral administration showed that 5 mg of KPT-8602 was rapidly absorbed (mean tmax= 1 hr, mean Cmax= 30.6 ng/mL). The mean AUCinf was calculated to be 141 ng•hr/mL. After tmax, KPT-8602 declined at an estimated mean t½ of 4 hr. At the same dose level, XPO1 mRNA expression was the highest (~2.5 fold) at 8 hr post dose. Conclusions - Oral KPT-8602 is well tolerated in heavily pretreated pts with RRMM. Gastrointestinal and constitutional toxicities observed with twice weekly selinexor have not been observed with 5x/week KPT-8602, including in pts on study for >4 months. PK was predictable and in line with selinexor. These early results show encouraging disease control with pts remaining on therapy. Enrollment is on-going. Disclosures Rossi: Takeda: Speakers Bureau; Janssen: Speakers Bureau; Onyx: Research Funding, Speakers Bureau; Celgene: Consultancy, Speakers Bureau. Baz:Takeda/Millennium: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Signal Genetics: Research Funding; Bristol-Myers Squibb: Research Funding; Merck: Research Funding; Novartis: Research Funding. Hofmeister:Karyopharm Therapeutics: Research Funding; Arno Therapeutics, Inc.: Research Funding; Signal Genetics, Inc.: Membership on an entity's Board of Directors or advisory committees; Janssen: Pharmaceutical Companies of Johnson & Johnson: Research Funding; Incyte, Corp: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Takeda Pharmaceutical Company: Research Funding; Teva: Membership on an entity's Board of Directors or advisory committees. Shustik:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millenium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Richter:Amgen: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Jannsen: Speakers Bureau. Chen:Janssen: Honoraria, Research Funding; Takeda: Research Funding; Celgene: Honoraria, Research Funding. Vogl:Takeda: Consultancy, Research Funding; Celgene: Consultancy; GSK: Research Funding; Calithera: Research Funding; Teva: Consultancy; Karyopharm: Consultancy; Acetylon: Research Funding; Constellation: Research Funding. Shacham:Karyopharm Therapeutics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Baloglu:Karyopharm Therapeutics: Employment, Equity Ownership. Senapedis:Karyopharm Therapeutics: Employment, Equity Ownership. Ellis:Karyopharm Therapeutics: Employment, Equity Ownership. Friedlander:Karyopharm Therapeutics: Employment. Choe-Juliak:Karyopharm Therapeutics: Employment. Sullivan:Karyopharm Therapeutics: Research Funding. Kauffman:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

scholarly journals Pmd-107: Marizomib, Pomalidomide and Low Dose-Dexamethasone Combination Study in Relapsed/Refractory Multiple Myeloma (NCT02103335): Full Enrollment Results from a Phase-1 Multicenter, Open Label Study

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3326-3326 ◽  
Author(s):  
Andrew Spencer ◽  
Simon Harrison ◽  
Jacob P. Laubach ◽  
Jeffrey Zonder ◽  
Ashraf Z Badros ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Low Dose ◽  
Employment Equity ◽  
Advisory Committees ◽  
Refractory Multiple Myeloma ◽  
Heavily Pretreated ◽  
Equity Ownership

Abstract Marizomib (MRZ) is a novel, irreversible, pan subunit proteasome inhibitor (PI) with preclinical evidence demonstrating in vitro and in vivo activity in multiple myeloma (MM). This study was designed to evaluate the safety and antimyeloma activity of pomalidomide (POM), MRZ and low dose dexamethasone (Lo-DEX) (PMD) in patients with relapsed and refractory multiple myeloma (RRMM). Thirty-eight heavily pretreated patients with RRMM were enrolled [dose-escalation cohort (n=14); recommended Phase 2 dose (RP2D) cohort (n=24)]. IV MRZ (0.3 to 0.5 mg/m2) was administered on Days (D) 1, 4, 8, 11; POM (3 or 4 mg) on D1 through 21; and Lo-DEX (5 or 10 mg) on D1, 2, 4, 5, 8, 9, 11, 12, 15, 16, 22, 23 of every 28-D cycle. Patients received a median of 4 (range 1-9) prior lines of therapy; 100% received prior lenalidomide (LEN) and bortezomib (BTZ), 34% carfilzomib (CFZ), and 50% thalidomide. 53% of patients were refractory to both LEN and BTZ and 21% were refractory to LEN, BTZ, and CFZ. There were no dose limiting toxicities during the study. The most common study treatment related ≥Grade 3 adverse events (AEs) were neutropenia (11/38 pts: 29%), pneumonia (4/38 pts 11%), anemia (4/38 pts; 11%), thrombocytopenia (4/38 pts; 11%), and febrile neutropenia (2/38 pts; 5%), with two grade 4 AEs (neutropenia related to POM and viral infection related to DEX), and one grade 5 AE (cardio-respiratory arrest from a suspected PE related to POM). Overall, MRZ was well tolerated, did not add to the incidence or severity of POM/Lo-DEX AEs and the regimen may have fewer hematological and infectious AEs compared to that observed with POM/Lo-DEX. MRZ pharmacokinetic analysis revealed that it was rapidly cleared with a short T1/2 (6.2-11mins) and a large volume of distribution (41-86L) suggesting extensive tissue distribution. Pharmacodynamic analysis demonstrated rapid and robust inhibition of chymotrypsin-like activity in both packed whole blood (PWB) and peripheral blood mononuclear cells (PMBCs), reflecting the irreversible binding nature of MRZ. Evolving inhibition of trypsin-like and caspase-like proteasome activity was also observed in PWB and PBMC with continued dosing. The overall response rate (ORR) and clinical benefit rate (CBR) for the 36 response evaluable patients was 53% (19/36) and 64% (23/36), respectively (Table 1). Subpopulation analysis demonstrated an ORR of 50% (5/10) in high risk cytogenetic patients, 56% (10/18) in LEN/BTZ refractory patients, 71% (5/7) in LEN/BTZ/CFZ refractory patients and 80% (8/10) in CFZ refractory patients. These data compare favorably against POM/Lo-Dex with a near doubling of ORR in both the total patient population and the double refractory patients. Substantial activity in high-risk patients that are triple refractory and in patients that are refractory to CFZ in prior last regimen was observed. MRZ activity in RRMM patients exposed and/or refractory to multiple PIs is likely a consequence of its unique pan proteasome subunit inhibitory actions. In conclusion, MRZ in combination with POM and Lo-DEX was well tolerated and demonstrated promising activity in heavily pretreated, high-risk RRMM patients. Table 1 Table 1. Disclosures Harrison: Janssen-Cilag: Research Funding, Speakers Bureau; Celgene: Honoraria. Zonder:Prothena: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Pharmacyclics: Other: DSMC membership. Khot:Amgen: Honoraria; Janssen: Consultancy; Pfizer: Speakers Bureau. Anderson:C4 Therapeutics: Equity Ownership; Millennuim: Membership on an entity's Board of Directors or advisory committees; Oncoprep: Equity Ownership; C4 Therapeutics: Equity Ownership; Gilead: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Acetylon: Equity Ownership; Acetylon: Equity Ownership; Oncoprep: Equity Ownership; Millennuim: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees. MacLaren:Triphase Accelerator: Employment, Equity Ownership. Reich:Triphase Accelerator: Consultancy. Trikha:Encycle Therapeutics: Consultancy, Equity Ownership; Triphase Accelerator: Employment, Equity Ownership. Richardson:Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees.

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.

Analysis of Pomalidomide Plus Low-Dose Dexamethasone in Patients with Relapsed/Refractory Multiple Myeloma with Vs without Moderate Renal Impairment

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3031-3031 ◽  
Author(s):  
David S Siegel ◽  
Katja C. Weisel ◽  
Meletios A. Dimopoulos ◽  
Rachid Baz ◽  
Paul G. Richardson ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Research Funding ◽  
Low Dose ◽  
Pooled Analysis ◽  
Employment Equity ◽  
Advisory Committees ◽  
Safety And Efficacy ◽  
Equity Ownership ◽  
Support Research

Abstract Introduction: Renal impairment (RI) occurs in ≈ 20% to 40% of patients (pts) with multiple myeloma (MM; Kastritis et al, Haematologica, 2007) and is a major comorbidity with this disease (Korbet et al, J Am Soc Nephrol, 2006). Pts with MM who relapse on or become refractory to treatment (Tx) experience shortened overall survival (OS; Kumar et al, Leukemia, 2012). Pomalidomide + low-dose dexamethasone (POM + LoDEX) is approved for the Tx of relapsed/refractory MM (RRMM) in pts who have had Tx failure with lenalidomide and/or bortezomib. POM + LoDEX demonstrated safety and efficacy in pts with RRMM (MM-010; Dimopoulos et al, EHA 2015) as well as extended progression-free survival (PFS) and OS vs high-dose dexamethasone (MM-003; San Miguel et al, Lancet Oncol, 2013) or POM alone (MM-002; Richardson et al, Blood, 2014). Each trial included pts with moderate RI, and this pooled analysis examines the safety and efficacy of POM + LoDEX in pts with moderate RI. Patients and Methods: Pts from MM-002, MM-003, and MM-010 who had received POM + LoDEX were grouped by RI status (with moderate RI [creatinine clearance (CrCl) ≥ 30 to < 60 mL/min] and without RI [CrCl ≥ 60 mL/min]) and assessed for safety and efficacy. Results: Overall, from the 3 trials, data from 356 pts with moderate RI and 716 pts without RI were analyzed. Pts with moderate RI were slightly older (70 vs 63 yrs) and more commonly had International Staging System stage III disease (45.8% vs 25.4% in the 271 and 544 pts with available data). Median time from diagnosis was similar, 5.2 yrs (with moderate RI) vs 5.3 years (without RI); pts in both subgroups had a median of 5 prior Tx. The proportions of pts with moderate RI vs without RI who were refractory to LEN (95.5% vs 93.0%), BORT (82.0% vs 80.7%), and both LEN and BORT (78.4% vs 76.1%) were similar. The median Tx duration was slightly shorter for pts with moderate RI vs without RI (16.6 vs 20.4 weeks), but the median average daily dose (4.0 mg/day) and median relative dose intensity (0.9) were the same between renal subgroups. There were similar frequencies of discontinuations (7.4% vs 5.8%), dose reductions (22.7% vs 21.1%), and interruptions (63.1% vs 63.5%) due to adverse events (AEs) between subgroups of pts with moderate RI vs without RI. The most common grade 3/4 AEs for pts with moderate RI vs without RI were neutropenia (45.5% vs 48.3%), anemia (34.9% vs 27.5%), infections (31.3% vs 32.3%), and thrombocytopenia (21.3% vs 22.6%). The frequency of deep vein thrombosis/pulmonary embolism or peripheral neuropathy was ≤ 2% in both subgroups. The overall response rate (ORR) was 32.0% vs 33.0%, the median PFS was 18.1 weeks (95% CI, 15.6-20.9 weeks) vs 21.1 weeks (95% CI, 19.0-24.3 weeks), and median time to progression (TTP) was 20.3 weeks (95% CI, 17.3-24.1 weeks) vs 24.0 weeks (95% CI, 20.1-25.6 weeks) in pts with vs without moderate RI, respectively. Consistent with the poor prognosis associated with RI, median OS was shorter for pts with moderate RI (45.6 weeks [95% CI, 37.9-50.1 weeks]) vs those without RI (62.7 weeks [95% CI, 54.9-70.3 weeks]). Conclusions: In a pooled analysis of 3 trials of pts with RRMM treated with POM + LoDEX, ORR, PFS, TTP, and tolerability results appeared to be independent of the presence or absence of moderate RI. This analysis supports the use of POM + LoDEX as a standard of care in RRMM for pts with or without moderate RI. Disclosures Siegel: Celgene Corporation: Speakers Bureau; Amgen: Speakers Bureau; Takeda: Speakers Bureau; Merck: Speakers Bureau; Novartis: Speakers Bureau. Weisel:Amgen: Consultancy, Honoraria, Other: Travel Support; Celgene: Consultancy, Honoraria, Other: Travel Support, Research Funding; Janssen Pharmaceuticals: Consultancy, Honoraria, Other: Travel Support, Research Funding; Novartis: Other: Travel Support; Onyx: Consultancy, Honoraria; Noxxon: Consultancy; BMS: Consultancy, Honoraria, Other: Travel Support. Dimopoulos:Genesis: Honoraria; Novartis: Honoraria; Celgene: Honoraria; Onyx: Honoraria; Janssen: Honoraria; Amgen: Honoraria; Janssen-Cilag: Honoraria. Baz:Karyopharm: Research Funding; Millennium: Research Funding; Celgene Corporation: Research Funding; Sanofi: Research Funding. Richardson:Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Millennium Takeda: Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees. Delforge:Celgene Corporation: Honoraria; Janssen: Honoraria; Amgen: Honoraria; Novartis: Honoraria. Song:Celgene Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. San Miguel:Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees; Onyx: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; MSD: Membership on an entity's Board of Directors or advisory committees. Moreau:Millennium: 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; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: 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. Yu:Celgene Corporation: Employment, Equity Ownership. Hong:Celgene Corporation: Employment, Equity Ownership. Sternas:Celgene Corporation: Employment, Equity Ownership. Zaki:Celgene Corporation: Employment, Equity Ownership. Palumbo:Novartis, Sanofi Aventis: Honoraria; Celgene, Millennium Pharmaceuticals, Amgen, Bristol-Myers Squibb, Genmab, Janssen-Cilag, Onyx Pharmaceuticals: Consultancy, Honoraria.

scholarly journals Safety and Efficacy of the Combination of Selinexor, Lenalidomide and Dexamethasone (SRd) in Patients with Newly Diagnosed Multiple Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3165-3165 ◽  
Author(s):  
Darrell J White ◽  
Suzanne Lentzsch ◽  
Cristina Gasparetto ◽  
Nizar Bahlis ◽  
Christine I Chen ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Nuclear Export ◽  
Research Funding ◽  
Phase 2 ◽  
Newly Diagnosed ◽  
Efficacy And Safety ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership

Introduction: The nuclear export protein Exportin 1 (XPO1) is overexpressed in a wide variety of cancers including multiple myeloma. Selinexor is a novel, first-in-class selective inhibitor of nuclear export (SINE), which blocks XPO1, forcing the nuclear retention and activation of tumor suppressor proteins. Selinexor in combination with low dose dexamethasone (Sel-dex) was recently approved based on data from the STORM study, wherein Sel-dex induced an overall response rate (ORR) of 26.2% in patients with penta-exposed, triple-class refractory multiple myeloma. Lenalidomide in combination with dexamethasone has been approved for the treatment of relapsed/refractory multiple myeloma with an ORR of 60-76%. The STOMP study assessed the efficacy and safety of the all oral combination of selinexor, lenalidomide and dexamethasone (SRd) in patients with relapsed/refractory and newly diagnosed multiple myeloma. We previously reported the recommended phase 2 dose (RP2D) of once weekly selinexor 60 mg, lenalidomide 25 mg and dexamethasone achieved an ORR of 92% in patients with RRMM who were lenalidomide naive. Here we evaluated once weekly selinexor in combination with lenalidomide and dexamethasone in patients with newly diagnosed multiple myeloma. Methods: STOMP is a multicenter, open-label study with a dose escalation (phase 1) and expansion (phase 2) to assess the maximum tolerated dose, RP2D, efficacy and safety of SRd in patients with newly diagnosed multiple myeloma. Patients with newly diagnosed multiple myeloma were eligible if they had symptomatic myeloma per the International Myeloma Working Group (IMWG) guidelines with either hypercalcemia, renal failure, anemia, bone lesions (CRAB) criteria or myeloma defining events needing systemic therapy. Enrollment in this arm is ongoing. Results: As of July 01 2019, 8 patients (4 males and 4 females ) with newly diagnosed multiple myeloma were enrolled at the starting dose level of selinexor 60 mg on days 1, 8, 15, and 22; lenalidomide 25 mg daily 1-21and dexamethasone 40 mg weekly on a 28 day cycle. The median age was 74 years (range: 51-86 years). No dose limiting toxicities (DLT) were observed in 5 DLT evaluable patients, 3 patients were not DLT evaluable because 1 patient did not finish cycle 1 due to social reasons and 2 patients missed doses due to serious adverse events (SAEs) unrelated to study drugs.. Common treatment related hematologic AEs (Grades 1/2, ≥3) were neutropenia (0%, 75%), anemia (0%, 25%), and thrombocytopenia (0%, 25%). Common non-hematologic AEs were diarrhea (63%, 0%), nausea (50%, 0%), fatigue (0%, 38%) decreased weight (38%, 0%), constipation (25%, 0%), hypokalemia (25%, 0%), and hypomagnesemia (25%, 0%). Among 7 efficacy evaluable patients, 6 patients achieved a response (ORR of 86%) including 1 complete response, 1 very good partial responses, 4 partial responses (2 unconfirmed), and 1 patient achieved a minimal response. With a median follow-up of 6.1 months, median progression-free survival was not reached. Conclusions: The all oral combination of SRd has promising activity with 6 of 7 efficacy evaluable patients achieving an objective response in patients with newly diagnosed multiple myeloma and no new or unexpected safety signals. Disclosures White: Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria. Lentzsch:Bayer: Consultancy; Janssen: Consultancy; Takeda: Consultancy; BMS: Consultancy; Proclara: Consultancy; Abbvie: Consultancy; Clinical Care Options: Speakers Bureau; Sanofi: Consultancy, Research Funding; Multiple Myeloma Research Foundation: Honoraria; International Myeloma Foundation: Honoraria; Karyopharm: Research Funding; Columbia University: Patents & Royalties: 11-1F4mAb as anti-amyloid strategy; Caelum Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Gasparetto:Celgene: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; Janssen: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; BMS: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed . Bahlis:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Chen:Janssen: Honoraria, Research Funding; Amgen: Honoraria; Celgene: Honoraria, Research Funding. Lipe:Celgene: Consultancy; amgen: Research Funding; amgen: Consultancy. Schiller:Gilead: Research Funding; Incyte: Research Funding; J&J: Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; Karyopharm: Research Funding; Novartis: Research Funding; Sangamo Therapeutics: Research Funding; Pfizer Pharmaceuticals: Equity Ownership, Research Funding; Onconova: Research Funding; Agios: Research Funding, Speakers Bureau; Amgen: Other, Research Funding; Astellas: Research Funding; Biomed Valley Discoveries: Research Funding; Bristol Myer Squibb: Research Funding; Celgene: Research Funding, Speakers Bureau; Constellation Pharmaceutical: Research Funding; Daiichi Sankyo: Research Funding; Eli Lilly and Company: Research Funding; FujiFilm: Research Funding; Genzyme: Research Funding. Tuchman:Karyopharm: Honoraria; Prothena: Research Funding; Roche: Research Funding; Alnylam: Honoraria, Research Funding; Amgen: Research Funding; Sanofi: Research Funding; Merck: Research Funding; Celgene: Honoraria, Research Funding, Speakers Bureau. Kotb:Karyopharm: Equity Ownership; Janssen: Honoraria; Merck: Honoraria, Research Funding; Celgene: Honoraria; Amgen: Honoraria; Takeda: Honoraria. Leblanc:Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Sebag:Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees. Venner:Sanofi: Honoraria; Amgen: Honoraria, Research Funding; Janssen: Honoraria; J&J: Research Funding; Takeda: Honoraria; Celgene: Honoraria. Bensinger:Amgen, Celgene: Other: Personal Fees, Research Funding, Speakers Bureau; Takeda, Janssen: Speakers Bureau; Sanofi, Seattle Genetics, Merck, Karyopharm: Other: Grant. Sheehan:Karyopharm Therapeutics: Employment, Equity Ownership. Chai:Karyopharm Therapeutics: Employment, Equity Ownership. Kai:Karyopharm Therapeutics: Employment, Equity Ownership. Shah:Karyopharm Therapeutics: Employment, Equity Ownership. Shacham:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Kauffman:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Baljevic:Karyopharm: Other: Internal Review Committee participant; Cardinal Health Specialty Solutions: Consultancy; Takeda Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Safety and Efficacy in the Stratus (MM-010) Trial, a Single-Arm Phase 3b Study Evaluating Pomalidomide + Low-Dose Dexamethasone in Patients with Refractory or Relapsed and Refractory Multiple Myeloma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 80-80 ◽  
Author(s):  
Meletios A. Dimopoulos ◽  
Antonio Palumbo ◽  
Katja Weisel ◽  
Enrique M. Ocio ◽  
Michele Cavo ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Peripheral Neuropathy ◽  
Partial Response ◽  
Board Of Directors ◽  
Research Funding ◽  
Low Dose ◽  
Employment Equity ◽  
Advisory Committees ◽  
Safety And Efficacy ◽  
Equity Ownership

Abstract Background: Patients (pts) with multiple myeloma (MM) who have relapsed on or are refractory to treatment (Tx) with novel agents lenalidomide (LEN) and bortezomib (BORT) have few effective options for Tx and short overall survival (OS; Kumar, Leukemia, 2012). Pomalidomide (POM) is a distinct oral IMiDs® immunomodulatory agent with direct antimyeloma, stromal cell inhibitory, and immune modulatory effects (Quach, Leukemia 2010; Mark, Leuk Res, 2014). POM has been approved in the United States and the European Union for the Tx of pts with ≥ 2 prior Tx, including LEN and BORT, and progressive disease (PD) on Tx (EU, in combination with low-dose dexamethasone [LoDEX]) or within 60 days of completion of the last line of Tx (US). Results from the pivotal phase 3 MM-003 trial demonstrated that POM + LoDEX significantly extended progression-free survival (PFS) and OS vs high-dose dexamethasone in this pt population (San Miguel, Lancet Oncol, 2013). STRATUS is a multicenter, single-arm, open-label phase 3b trial with > 85 sites across Europe designed to further evaluate safety and efficacy of POM + LoDEX in a large pt population (N = 456 at data cutoff). Methods: Eligible pts had refractory or relapsed and refractory disease (PD during or within 60 days of last line of Tx), previous BORT and LEN Tx failure, and adequate prior alkylator therapy as defined in study protocol. Pts must have been refractory to their last prior line of Tx. Key exclusion criteria included absolute neutrophil count < 800/μL , platelet count < 75,000 or < 30,000/μL (for pts with < 50% or ≥ 50% of bone marrow nucleated cells as plasma cells, respectively), creatinine clearance < 45 mL/min, hemoglobin < 8 g/dL, and peripheral neuropathy ≥ grade (Gr) 2. POM was administered at 4 mg D1-21 of a 28-day cycle in combination with 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. The primary endpoint was safety, and key secondary endpoints included POM exposure, overall response rate (ORR; ≥ partial response), duration of response (DOR), PFS, OS, and cytogenetic analyses. STRATUS is registered with ClinicalTrials.gov (NCT01712789) and EudraCT (2012-001888-78). Results: As of March 17, 2014, 456 pts were enrolled and 452 had received POM + LoDEX; median age was 66 yrs (range, 37-88 yrs); median time since diagnosis was 4.9 yrs (range, 0.3-22.6 yrs). Pts were heavily pretreated with a median of 5 prior Tx (range, 2-18); 78% were refractory to BORT and LEN. Median follow-up was 6.8 mos with a median of 4 cycles received. Median PFS and OS were 4.3 mos and 10.9 mos, respectively (Figure 1). The ORR was 35%, with 6% of pts achieving ≥ very good partial response (VGPR); median DOR was 6.0 mos. Similar PFS (4.2 and 3.9 mos), OS (10.9 mos for each), and ORR (34% and 33%) were achieved in pts refractory to prior LEN (n = 427) or LEN and BORT (n = 356), respectively. In addition, PFS (4.3 and 3.9 mos), OS (11.5 mos and not estimable), and ORR (27% and 37%) were consistent in pts with LEN (N = 172) or BORT (N = 189) as last prior treatment, respectively. The most frequent Gr 3-4 treatment-emergent adverse events (TEAEs) were hematologic, including neutropenia (39%), anemia (27%), and thrombocytopenia (19%); Gr 3-4 non-hematological toxicities included pneumonia (11%), fatigue (5%), and hypercalcemia (4%). Gr 3-4 deep vein thrombosis was low (1%) with prophylaxis, and peripheral neuropathy was 1%. Dose reductions of either POM or LoDEX due to TEAEs were required in 28% of pts; discontinuations due to TEAEs were infrequent (9%). Conclusions: Results from STRATUS, the largest POM + LoDEX clinical trial thus far, were consistent with those observed in the pivotal MM-003 trial, and confirm that this regimen has an acceptable safety and efficacy profile and shows substantial improvements in PFS and OS benefits. Combination therapy with POM and LoDEX represents a new standard of therapy for pts with refractory or relapsed and refractory MM in whom LEN and BORT Tx failed. Disclosures Dimopoulos: Celgene: Consultancy, Honoraria. Palumbo:Array BioPharma: Honoraria; Onyx Pharmaceuticals: Consultancy, Honoraria; Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Genmab A/S: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Sanofi: Honoraria. Weisel:BMS: Consultancy; Onyx: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celgene Corporation: Consultancy, Honoraria; Noxxon: Consultancy. Ocio:Celgene Corporation: Honoraria, Research Funding. Cavo:Celgene Corporation: Consultancy, Honoraria, Speakers Bureau. Delforge:Celgene Corp: Honoraria; Janssen: Honoraria. Oriol:Celgene Corporation: Consultancy. Goldschmidt:Celgene Corporation: Consultancy, Research Funding, Speakers Bureau. Doyen:Celgene Corp: Membership on an entity's Board of Directors or advisory committees. Morgan:Celgene Corp: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Myeloma UK: Membership on an entity's Board of Directors or advisory committees; International Myeloma Foundation: Membership on an entity's Board of Directors or advisory committees; The Binding Site: Membership on an entity's Board of Directors or advisory committees; MMRF: Membership on an entity's Board of Directors or advisory committees. Simcock:Celgene Corporation: Employment. Miller:Celgene: Employment, Equity Ownership. Slaughter:Celgene: Employment. Peluso:Celgene: Employment. Sternas:Celgene Corp: Employment, Equity Ownership. Zaki:Celgene Corp: Employment, Equity Ownership. Moreau:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees.

scholarly journals Rapid and Robust Mobilization of CD34+ HSCs without G-CSF Following Administration of Mgta-145 Alone or in Combination with Plerixafor

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1961-1961
Author(s):  
John F. DiPersio ◽  
Jonathan Hoggatt ◽  
Steven Devine ◽  
Lukasz Biernat ◽  
Haley Howell ◽  
...  
Keyword(s):  
Single Dose ◽  
Adverse Events ◽  
Board Of Directors ◽  
Preliminary Data ◽  
Research Funding ◽  
Fold Change ◽  
Employment Equity ◽  
Advisory Committees ◽  
Cd34 Cells ◽  
Equity Ownership

Background Granulocyte colony-stimulating factor (G-CSF) is the standard of care for mobilization of hematopoietic stem cells (HSCs). G-CSF requires 4-7 days of injections and often multiple aphereses to acquire sufficient CD34+ cells for transplant. The number of CD34+ HSCs mobilized can be variable and patients who fail to mobilize enough CD34+ cells are treated with the combination of G-CSF plus plerixafor. G-CSF use is associated with bone pain, nausea, headaches, fatigue, rare episodes of splenic rupture, and is contraindicated for patients with autoimmune and sickle cell disease. MGTA-145 (GroβT) is a CXCR2 agonist. MGTA-145, in combination with plerixafor, a CXCR4 inhibitor, has the potential to rapidly and reliably mobilize robust numbers of HSCs with a single dose and same-day apheresis for transplant that is free from G-CSF. MGTA-145 plus plerixafor work synergistically to rapidly mobilize HSCs in both mice and non-human primates (Hoggatt, Cell 2018; Goncalves, Blood 2018). Based on these data, Magenta initiated a Phase 1 dose-escalating study to evaluate the safety, PK and PD of MGTA-145 as a single agent and in combination with plerixafor. Methods This study consists of four parts. In Part A, healthy volunteers were dosed with MGTA-145 (0.0075 - 0.3 mg/kg) or placebo. In Part B, MGTA-145 dose levels from Part A were selected for use in combination with a clinically approved dose of plerixafor. In Part C, a single dose MGTA-145 plus plerixafor will be administered on day 1 and day 2. In Part D, MGTA-145 plus plerixafor will be administered followed by apheresis. Results MGTA-145 monotherapy was well tolerated in all subjects dosed (Table 1) with no significant adverse events. Some subjects experienced mild (Grade 1) transient lower back pain that dissipated within minutes. In the ongoing study, the combination of MGTA-145 with plerixafor was well tolerated, with some donors experiencing Grade 1 and 2 gastrointestinal adverse events commonly observed with plerixafor alone. Pharmacokinetic (PK) exposure and maximum plasma concentrations increased dose proportionally and were not affected by plerixafor (Fig 1A). Monotherapy of MGTA-145 resulted in an immediate increase in neutrophils (Fig 1B) and release of plasma MMP-9 (Fig 1C). Neutrophil mobilization plateaued within 1-hour post MGTA-145 at doses greater than 0.03 mg/kg. This plateau was followed by a rebound of neutrophil mobilization which correlated with re-expression of CXCR2 and presence of MGTA-145 at pharmacologically active levels. Markers of neutrophil activation were relatively unchanged (<2-fold vs baseline). A rapid and statistically significant increase in CD34+ cells occurred @ 0.03 and 0.075 mg/kg of MGTA-145 (p < 0.01) relative to placebo with peak mobilization (Fig 1D) 30 minutes post MGTA-145 (7-fold above baseline @ 0.03 mg/kg). To date, the combination of MGTA-145 plus plerixafor mobilized >20/µl CD34s in 92% (11/12) subjects compared to 50% (2/4) subjects receiving plerixafor alone. Preliminary data show that there was a significant increase in fold change relative to baseline in CD34+ cells (27x vs 13x) and phenotypic CD34+CD90+CD45RA- HSCs (38x vs 22x) mobilized by MGTA-145 with plerixafor. Mobilized CD34+ cells were detectable at 15 minutes with peak mobilization shifted 2 - 4 hours earlier for the combination vs plerixafor alone (4 - 6h vs 8 - 12h). Detailed results of single dose administration of MGTA-145 and plerixafor given on one day as well as also on two sequential days will be presented along with fully characterized graft analysis post apheresis from subjects given MGTA-145 and plerixafor. Conclusions MGTA-145 is safe and well tolerated, as a monotherapy and in combination with plerixafor and induced rapid and robust mobilization of significant numbers of HSCs with a single dose in all subjects to date. Kinetics of CD34+ cell mobilization for the combination was immediate (4x increase vs no change for plerixafor alone @ 15 min) suggesting the mechanism of action of MGTA-145 plus plerixafor is different from plerixafor alone. Preliminary data demonstrate that MGTA-145 when combined with plerixafor results in a significant increase in CD34+ fold change relative to plerixafor alone. Magenta Therapeutics intends to develop MGTA-145 as a first line mobilization product for blood cancers, autoimmune and genetic diseases and plans a Phase 2 study in multiple myeloma and non-Hodgkin lymphoma in 2020. Disclosures DiPersio: Magenta Therapeutics: Equity Ownership; NeoImmune Tech: Research Funding; Cellworks Group, Inc.: Membership on an entity's Board of Directors or advisory committees; Karyopharm Therapeutics: Consultancy; Incyte: Consultancy, Research Funding; RiverVest Venture Partners Arch Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; WUGEN: Equity Ownership, Patents & Royalties, Research Funding; Macrogenics: Research Funding, Speakers Bureau; Bioline Rx: Research Funding, Speakers Bureau; Celgene: Consultancy; Amphivena Therapeutics: Consultancy, Research Funding. Hoggatt:Magenta Therapeutics: Consultancy, Equity Ownership, Research Funding. Devine:Kiadis Pharma: Other: Protocol development (via institution); Bristol Myers: Other: Grant for monitoring support & travel support; Magenta Therapeutics: Other: Travel support for advisory board; My employer (National Marrow Donor Program) has equity interest in Magenta. Biernat:Medpace, Inc.: Employment. Howell:Magenta Therapeutics: Employment, Equity Ownership. Schmelmer:Magenta Therapeutics: Employment, Equity Ownership. Neale:Magenta Therapeutics: Employment, Equity Ownership. Boitano:Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties. Cooke:Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties. Goncalves:Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties. Raffel:Magenta Therapeutics: Employment, Equity Ownership. Falahee:Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties. Morrow:Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties. Davis:Magenta Therapeutics: Employment, Equity Ownership.

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.

Targeted MEK Inhibition in Patients with Previously Treated Multiple Myeloma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4775-4775 ◽  
Author(s):  
Christoph Heuck ◽  
Yogesh Jethava ◽  
Rashid Z Khan ◽  
Scott Miller ◽  
Alan Mitchell ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Research Funding ◽  
Mapk Pathway ◽  
Objective Response ◽  
Genomic Profiling ◽  
Employment Equity ◽  
Advisory Committees ◽  
Comprehensive Genomic Profiling ◽  
Equity Ownership

Abstract Background: Diagnostic and therapeutic advances have significantly improved the outcomes for multiple myeloma (MM) patients. However, pts who are refractory to or relapse after therapy with immune modulatory drugs and proteasome inhibitors remain a therapeutic challenge. Comprehensive genomic profiling via clinical next generation sequencing (NGS)-based assays studies of MM cases have revealed multiple targetable mutations that were previously unexploited in MM. Methods: Between June 2013 and May 2014 we performed genomic profiling of 351 patients who had progressed after initial therapy to assist physicians in therapy planning. Comprehensive genomic profiling was performed using the FoundationOne¨ or FoundationOne Heme¨ assays. FoundationOne assays 374 cancer-related and 24 frequently rearranged genes via DNA-seq, and FoundationOneHeme assays 405 cancer-related and 31 frequently rearranged genes via DNA-seq as well as 265 frequently rearranged genes by RNA-seq. All samples were sequenced in a CLIA-certified CAP-accredited laboratory to an average depth >500x . Patients with activating alterations of KRAS, NRAS or BRAF were considered for therapy with the targeted agent trametinib (TMTB) as were patients who had a gene expression signature suggesting activation of the MAPK pathway. Retrospective review of this case series was approved by the UAMS institutional review board. Results: We identified 63 patients who underwent treatment with Trametinib. 60 were treated based on activating mutations of KRAS, NRAS or BRAF and 3 were treated based on a GEP signature. The median age was 65 and patients had a median of 5 lines of prior therapy (range 1-20). 38 of 63 patients had prior treatment with Total Therapy. 43 underwent salvage with chemotherapy prior to initiation of TMTB, 15 had salvage transplants, 33 patients were exposed to novel agents (Pomalidomide, Carfilzomib) and 33 had Metronomic therapy before TMTB. 25% of patients were ISS stage 3 and 37% had GEP70 defined high risk. 13 had PET defined extra medullary disease (EMD). 41 patients were administered TMTB monotherapy and 22 received TMTB treatment in combination with other agents. In general the treatment was well tolerated. 10 patients discontinued therapy because of toxicities, 29 discontinued because of disease progression or death. None of the deaths were attributed to TMTB, Best treatment responses were SD in 30, PR in 8, VGPR in 2 and CR in 3 of the 63 pts. For 25 patients with evaluable PET data, treatment resulted in complete resolution of FDG avid lesions in 9 patients and a better than 50% reduction in 15 (Figure 1). We will present updated data on clinical responses as well as toxicities. Conclusions: Treatment with targeted therapy guided by prospective comprehensive genomic profiling across all classes of genomic alterations in this heavily pretreated population of MM patients resulted in an unexpectedly high objective response rate. Observation of CR with TMTB monotherapy further supports continued investigation of this individualized approach to MM management. Disclosures Van Laar: Signal Genetics: Employment, Equity Ownership. Ali:Foundation Medicine, Inc.: Employment, Equity Ownership. Miller:Foundation Medicine, Inc: Employment. Zangari:Norvartis: Membership on an entity's Board of Directors or advisory committees; Onyx: Research Funding; Millennium: Research Funding. van Rhee:Millenium: Speakers Bureau; Sanofi: Speakers Bureau; Celgene: Speakers Bureau; Janssen: Speakers Bureau. Morgan:Celgene Corp: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Myeloma UK: Membership on an entity's Board of Directors or advisory committees; International Myeloma Foundation: Membership on an entity's Board of Directors or advisory committees; The Binding Site: Membership on an entity's Board of Directors or advisory committees; MMRF: Membership on an entity's Board of Directors or advisory committees.

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