Phase II Study Of The Combination Of MLN 9708 With Lenalidomide As Maintenance Therapy Post Autologous Stem Cell Transplant In Patients With Multiple Myeloma

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1983-1983 ◽  
Author(s):  
Jatin J. Shah ◽  
Veera Baladandayuthapani ◽  
Donna M. Weber ◽  
Sheeba K. Thomas ◽  
Raymond Alexanian ◽  
...  
Keyword(s):  
Maintenance Therapy ◽  
Board Of Directors ◽  
Research Funding ◽  
Stem Cell Transplant ◽  
Phase Ii Study ◽  
Autologous Stem Cell Transplant ◽  
Cell Transplant ◽  
Newly Diagnosed ◽  
Time To Progression ◽  
Advisory Committees

Abstract Background The role of lenalidomide for maintenance after myeloblative therapy and autologous stem cell transplant (ASCT) has been established based on the CALBG 100104 and IFM 2005-02 experience. Continuous low dose lenalidomide demonstrated a significant benefit in progression free survival (PFS), time to progression (TTP) in both trials and the CALBG trial also demonstrated a benefit in early overall survival. The benefit in PFS with lenalidomide is preserved in patients with high risk cytogenetics and in complete remission after ASCT. Proteaseome inhibitors (PI) have been studied after ASCT in a hybrid consolidation/maintenance model with a predefined course of bortezomib-based therapy, which was well tolerated and led to a significant improvement in response rates and in PFS. However long term proteasome inhibitor maintenance therapy has been limited by the route of administration. The combination of PIs and immunomodulatory agents (IMiDs) have a strong preclinical rationale, and their activity has been confirmed with high response rates in various combinations in both newly diagnosed and relapsed/refractory myeloma. MLN9708, an oral PI, may be more convenient as an oral therapy to be studied in the maintenance setting. Here we report preliminary data from a pilot study of the combination of MLN9708 and lenalidomide as maintenance therapy post ASCT. Methods This is a single arm phase II study with the primary objective to establish the safety and efficacy (PFS) of MLN 9708 (Ixazomib) and lenalidomide in the maintenance setting post ASCT. The secondary objectives were to evaluate the incidence of secondary primary malignancy, the best response rate (sCR/nCR/VGPR/PR), time to progression and time to next therapy. Patients must have undergone ASCT with melphalan as a preparative regimen within 12 months of initiation of induction for newly diagnosed myeloma. Patients started maintenance therapy 60-180 days post ASCT. Treatment consisted of 28 day cycles of oral MLN9708 4 mg on days 1, 8, 15, and oral lenalidomide 10 mg daily on days 1-28 with a dose increase to 15 mg after 3 months if tolerating well. Adverse events (AEs) were graded by NCI-CTCAE v4. Response was assessed by the modified International Uniform Response Criteria. Results A total of 16 patients have been enrolled with a median age of 60 years (range 51-74); 12/16 patients were male. 6 patients had ISS stage 1, 2 patients had stage II, 5 patients had stage III, and 3 had an unknown stage. 14 of the patients remain on trial, 2 patients have discontinued maintenance therapy. 1 patient with high risk disease, including del17p, del 13 discontinued due to rapidly progressive disease during cycle 2; 1 patient discontineud due to hospitalization for bilateral pneumonia. 3 patients had a treatment related SAE including 2 patients with PNA, 1 pt with G2 dehydration requiring hospitalization. 5 patients required a dose reduction in MLN9708 or lenalidomide due to G3/4 thrombocytopenia (n=2); dose delays for thrombocytopenia/neutropenia (n=3); one patient also had concurrent grade 3 rash. Hematologic toxicity included 3/16 patients with G3/4 thrombocytopenia, 9/16 with G1/2 thrombocytopenia, 5/16 patients with G3 neutropenia and 6/16 patients with G1/2 neutropenia. G3/4 drug-related non-hematologic AEs occurring in >1/16 of patients were limited to 2 patients with G3 creatinine elevation (in the setting of hospitalization for pneumonia). Additional non-hematologic G1/2 events included 9/16 patients with nausea, 5/16 with diarrhea, 9/16 with constipation, 4/16 with emesis, 6/16 patients with G1 rash; 1 pt with worsening of baseline G1 neuropathy. Conclusions The combination of MLN9708 and lenalidomide as maintenance therapy post ASCT for NDMM is a well-tolerated combination. 14/16 patients remain on study with only 1 patient discontinuing due to toxicity (pneumonia). The preliminary experience demonstrates the combination is safe, feasible and well tolerated with minimal toxicity and no unexpected toxicity. Disclosures: Shah: Celgene: Consultancy, Research Funding; Array: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Millenium: Consultancy, Research Funding; Onyx: Consultancy, Research Funding. Off Label Use: This abstract describes bortezomib + rituximab as 1st line induction therapy for patients with Waldenstrom macroglobulinemia. Thomas:Millenium: Research Funding; Novartis: Research Funding; Celgene: Research Funding; Immunomedics: Research Funding; Pharmacyclics: Membership on an entity’s Board of Directors or advisory committees; Onyx: Membership on an entity’s Board of Directors or advisory committees. Wang:Onyx: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Millennium: Research Funding; Pharmacyclics: Research Funding; Janssen: Research Funding; Novartis: Research Funding. Qazilbash:Otsuka Pharmaceuticals: Research Funding. Orlowski:Bristol-Myers Squibb: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Millennium: The Takeda Oncology Company: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Onyx: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Resverlogix: Research Funding; Array Biopharma: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Merck: Membership on an entity’s Board of Directors or advisory committees.

scholarly journals The Effect of Maintenance Therapy Following Salvage Autologous Stem Cell Transplant in Multiple Myeloma Patients

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3439-3439
Author(s):  
Brandon B. Wang ◽  
Mark A. Fiala ◽  
Mark A. Schroeder ◽  
Tanya Wildes ◽  
Armin Ghobadi ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Maintenance Therapy ◽  
Board Of Directors ◽  
Research Funding ◽  
Stem Cell Transplant ◽  
Autologous Stem Cell Transplant ◽  
Cell Transplant ◽  
Advisory Committees ◽  
The Impact

Abstract Background: In the current era, autologous stem cell transplant (ASCT) remains an effective form of treatment for patients diagnosed with multiple myeloma (MM), but it is not curative and a relapse is inevitable. A second, or salvage, ASCT provides better outcomes than conventional chemotherapy but it is infrequently used. Maintenance therapy after initial ASCT has been adopted as the standard in the US; however, there is limited data on the effects of maintenance therapy following salvage ASCT and the benefits are still unclear. Methods: We performed retrospective chart review of all patients with MM who received a second, salvage ASCT at time of first relapse at Washington University in St. Louis from 2008 to 2016. We identified two cohorts of patients, those who received maintenance therapy following salvage ASCT and those who did not. Patients who received maintenance therapy post-initial ASCT were excluded as the objective of this study was to determine the impact of maintenance post-salvage ASCT and maintenance post-initial ASCT may confound the results. Results: Sixty-five patients (who underwent second/salvage ASCT) were identified. Three were excluded from the analysis-two had treatment-related mortality following salvage ASCT and one received maintenance other than a proteasome inhibitor (PI) or an immunomodulatory drug (IMID). The maintenance cohort consisted of 31 patients, with 68% (n = 21) males and 32% (n = 10) females; the median age at salvage ASCT was 61 years (range 38-73). The no-maintenance cohort consisted of 31 patients as well with 45% (n = 14) males and 55% (n = 17) females. Their median age at salvage ASCT was 62 years (range 44-74). The characteristics of the two cohorts are summarized in Table 1. Most patients received PIs and/or IMIDs as part of their induction regimens prior to initial ASCT. All received melphalan conditioning. The response to treatment was similar between the two cohorts, with respective CR rates of 68% (n = 21) and 77% (n = 24) and median progression-free survival (PFS) of 46 months compared to 33 months. Following relapse, 16% (n = 5) of patients in the no-maintenance cohort proceeded directly to salvage ASCT without re-induction. All other patients received re-induction, mostly with PIs and/or IMIDs, with a median of 4 cycles for the maintenance cohort and 2 cycles for the no-maintenance cohort. For conditioning prior to salvage ASCT, 4 patients received Velcade-BEAM conditioning as part of a prospective trial at our site (NCT01653418); 3 from the maintenance cohort and 1 from the no-maintenance cohort. The rest received melphalan conditioning. Both cohorts had a CR rate of 52% (n = 16) post-salvage ASCT. Maintenance therapy after salvage ASCT consisted of lenalidomide (74%, n = 23), bortezomib (23%, n = 7), or pomalidomide (3%, n = 1). Three of the patients on bortezomib were originally started on lenalidomide but were switched due to intolerance. At time of data collection, the median follow-up was 49 months (range 9-105) for the maintenance cohort and 61 months (range 19-113) for the no-maintenance cohort. 45% (n = 14) of patients in the maintenance cohort and 90% (n = 28) of the no-maintenance cohort had relapsed. In the maintenance cohort, PFS following salvage ASCT was similar to what was observed following initial ASCT. The median estimated PFS post-salvage ASCT was 53 months (95% CI 42-64) compared to 46 months post initial ASCT (p = 0.144). Conversely, in the no-maintenance cohort PFS following salvage was only about 60% that of initial ASCT (21 months [95% CI 18-24]; compared to 33 months; p = 0.002). Conclusion: These results suggest that maintenance following salvage ASCT is associated with improved outcomes. Although patients who received maintenance post-initial ASCT were excluded, the benefits of maintenance post-salvage ASCT may extend to them as well. Ongoing prospective clinical trials will further clarify these benefits. Disclosures Schroeder: Amgen Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees. Wildes:Janssen: Research Funding. Vij:Jazz Pharmaceuticals: 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, Research Funding; Jansson: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharma: 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; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

scholarly journals Elotuzumab As Post-Autologous Stem Cell Transplant Consolidation in Patients with High-Risk Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3141-3141 ◽  
Author(s):  
Nikhita Gadi ◽  
Linda Schmidt ◽  
Jaeil Ahn ◽  
Tianmin Wu ◽  
Scott D. Rowley ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Stem Cell Transplant ◽  
Autologous Stem Cell Transplant ◽  
Cell Transplant ◽  
Advisory Committees ◽  
Ultra High Risk ◽  
Equity Ownership ◽  
Baseline Characteristics

Introduction: Patients (pts) with high-risk multiple myeloma (HRMM) experience early disease progression post autologous stem cell transplant (ASCT). The median progression free survival (PFS) for HRMM pts undergoing ASCT with lenalidomide (len) maintenance ranges between 27 and 42 months in high risk pts and 22 months in ultra-high risk, defined by two or more adverse cytogenetic abnormalities such as: gain(1q), t(4;14), t(14;16),t(14;20), or del(17p)( Chakraborty et al, Leukemia,2018 and Jackson et al, Lancet, 2018). Elotuzumab, a humanized IgG kappa monoclonal antibody against SLAM-F7 (CS-1), is approved in combination with len and dexamethasone (ERd) in pts with relapsed MM (Dimopoulus et al, BJH, 2017). It directly activates natural killer (NK) cells and mediates myeloma cell death by antibody-dependent cell mediated cytoxicity. We hypothesized that administration of ERd as post-ASCT consolidation will enhance an immune-competent phenotype, by restoring NK cells and effector T-cell populations at a time of maximal disease de-bulking, and will ultimately improve outcomes among pts with HRMM. Methods: Thirty-one HRMM patients who achieved stable disease or better were treated beginning at 30-90 days post ASCT with ERd (29/31 pts) or elotuzumab/pomalidomide )/dex (EPd) (2/31 pts) between September 2016 and February 2019. With institutional review board approval, electronic medical records were reviewed for baseline characteristics, treatment history, adverse events (AE) while on therapy as defined by common terminology criteria for adverse events (CTCAE), and survival outcomes. Treatment with ERd or EPd was administered for 4 consecutive 28-day cycles per standard dosing regimens with a tapering or discontinuation of corticosteroids per investigator discretion with cycles 3 and 4. HRMM was defined by any of the following: ISS or Revised-ISS stage 3, CD-138 selected FISH with del 17p, 1q21 gain, t(4;14), t(14;16), and t(14;20), cytogenetics with 13q del or complex karyotype, and/or high-risk gene expression profile score. Ultra-HR pts were defined by having both del 13q and 1q21 gain by FISH based on recent unpublished COMPASS data. Minimal residual disease (MRD) was evaluated upon achievement of very good partial remission or complete remission using 10-color multiparametric flow cytometry. PFS was measured using the log-rank test. Response criteria was defined per International Myeloma Working Group criteria. Results: Baseline characteristics of all 31 patients are shown in Table 1. Thirty-four percent were ISS-3, 71% (22/31 pts) had high-risk FISH, of which 19% were ultra-high risk (6/22 pts). Seven pts (22.6%) underwent tandem-ASCT pre-consolidation. Of the 8 pts who had GEP testing, 2 (25%) were high risk. Best response to treatment by cycle is depicted in Table 2. Consolidative ERd/EPd deepened response compared to post-ASCT with 71.4% vs 19.4% achieving stringent complete remission (sCR). Post-consolidation, 19.3% vs 12.9%, pre-consolidation, achieved MRD negativity. With a median follow-up of 24.8 months, median PFS was 31.4 months (Figure 1). There was no significant association between median PFS and variables such as tandem ASCT and ultra-HR using multivariate cox regression. Although all pts experienced at least one AE while on therapy, only 1 patient (3.22%) experienced a grade 3 AE. Hematologic AEs included: anemia (48%), neutropenia (45%), and thrombocytopenia (52%), while the most common non-hematologic AEs included: fatigue (32%), malaise (23%), and back pain (19%). One patient experienced a serious AE (SAE) which was PCP pneumonia requiring hospitalization, resulting in early discontinuation from therapy. There was no treatment-related mortality. Conclusion: ERd or EPd as 4 months of fixed duration consolidation therapy post-ASCT resulted in a median PFS of 31.4 months amongst pts with HRMM, similar to or perhaps surpassing historical reports of HRMM pts receiving lenalidomide maintenance until progression. This therapy may offer comparable, if not superior, outcomes while having the advantage of allowing for significant time without therapy and perhaps improving quality of life and financial toxicity. This study is limited due to its retrospective nature. Larger prospective studies evaluating fixed duration ERd/EPd in HRMM patients post ASCT should be conducted. Disclosures Rowley: Allergan: Equity Ownership; Fate Therapeutics: Consultancy. Goldberg:COTA: Equity Ownership; Bristol-Myers Squibb: Consultancy; Cancer Outcomes Tracking and Analysis (COTA) Inc.: Equity Ownership. Siegel:Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb Company: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Biran:Bristol Meyers Squibb: Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Merck: Research Funding.

scholarly journals Prognostic Impact of CD3 Count in Apheresis Collection in Multiple Myeloma Patients Undergoing Autologous Stem Cell Transplant

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3774-3774
Author(s):  
Marcella Kaddoura ◽  
Morie A. Gertz ◽  
David Dingli ◽  
Francis K. Buadi ◽  
Martha Q. Lacy ◽  
...  
Keyword(s):  
Stem Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Stem Cell Transplant ◽  
Autologous Stem Cell Transplant ◽  
Prognostic Impact ◽  
Cell Transplant ◽  
Immune Competence ◽  
Advisory Committees ◽  
Stem Cell Collection

Abstract Background: The use of immunotherapeutic agents in multiple myeloma (MM) has shown improvements in clinical outcomes, emphasizing the role the host immune system plays in disease control. In recognition of this relationship, efforts aimed at identifying biomarkers of immune surveillance in MM have identified prognostic value in the peripheral absolute lymphocyte (ALC) and absolute monocyte (AMC) counts at various stages of disease and following autologous stem cell transplant (ASCT), with lower ALC and AMC serving as a surrogate for immune dysregulation and correlating with inferior progression free (PFS) and overall survival (OS). With ASCT remaining the standard of care in the treatment of MM, we sought to examine whether CD3 content of the apheresis product during stem cell collection could be used as a biomarker for immune competence and whether it influences outcomes. Methods: A retrospective study was conducted on 1086 MM patients who underwent stem cell (CD34) collection with available CD3 data and subsequent ASCT at our institution. We recorded the total absolute CD3 and CD34 cell count upon completion of mobilization, with a higher CD3 count serving as a surrogate for immune competence. In addition to investigating the absolute CD3 count, we calculated the CD3/CD34 ratio given variation in the CD34 goals. Patients were dichotomized based on whether their absolute CD3 and CD3/CD34 ratio values were above or below medians. A Kaplan-Meier model was used to compare median PFS and OS between groups. A cox proportional hazards model was used to determine its prognostic impact, adjusting for ISS stage 3, high risk FISH, achievement of CR near day 100, and maintenance therapy received post-ASCT. Results: The median length of follow-up from date of ASCT for the entire cohort (N=1086) was 34.1 months (range: 0.26-157 months) and the median time from stem cell collection to ASCT was 9 days (range: 3-3143 days). The most common mobilizing regimen was Neupogen and plerixafor (N=425, 39%) and 694 (64%) patients received ASCT in the first line setting. The median absolute total CD3 count was 4.3 x 10^6/kg (range: 0.1-21.9) with 542 patients above and 544 patients at or below the median. The median absolute total CD34 count was 8.53 x 10^6/kg (range: 0.2-37.0) and median CD3/CD34 ratio was 0.50 (range: 0.01-15), with 536 patients above and 550 patients at or below the median ratio. The median PFS among patients with a CD3 count > 4.25 x 10^6/kg was 23.1 vs. 16.9 months among patients with CD3 count ≤ 4.25 x 10^6/kg (p<0.0001) and median OS was 65.3 months vs. 41.6 months (p<0.0001), respectively. A similar trend was observed when dividing patients based on CD3/CD34 ratio, with median PFS of 22.4 vs. 17.5 months (p=.0003) and median OS of 61.5 vs. 45.7 months (p=.0001), both favoring the cohort with a CD3/CD34 ratio > 0.5 (Figure 1). The prognostic value among patients with a CD3/CD34 ratio > 0.5 was retained after adjusting for ISS stage III, high risk FISH features, and use of maintenance therapy as follows: PFS HR: 0.73 (95% CI: 0.62-0.86; p=0.0002); OS 0.71 (95% CI: 0.59-0.88; p=0.001). Conclusions: Our study demonstrates that patients who have higher CD3 content in their apheresis product have better PFS and OS following ASCT. These findings reveal a possible role for using absolute CD3 and CD3/CD34 ratios in the apheresis product as a surrogate marker for immune competence and in predicting clinical outcomes. Figure 1 Figure 1. Disclosures Gertz: Akcea Therapeutics, Alnylam Pharmaceuticals Inc, Prothena: Consultancy; Akcea Therapeutics, Ambry Genetics, Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Karyopharm Therapeutics, Pfizer Inc (to Institution), Sanofi Genzyme: Honoraria; Aurora Biopharma: Other: Stock option; AbbVie Inc, Celgene Corporation: Other: Data Safetly & Monitoring; Ionis Pharmaceuticals: Other: Advisory Board. Dingli: GSK: Consultancy; Sanofi: Consultancy; Janssen: Consultancy; Alexion: Consultancy; Apellis: Consultancy; Novartis: Research Funding. Dispenzieri: Takeda: Research Funding; Pfizer: Research Funding; Alnylam: Research Funding; Oncopeptides: Consultancy; Sorrento Therapeutics: Consultancy; Janssen: Consultancy, Research Funding. Kapoor: Sanofi: Research Funding; Takeda: Research Funding; Ichnos Sciences: Research Funding; Glaxo SmithKline: Research Funding; Regeneron Pharmaceuticals: Research Funding; AbbVie: Research Funding; Karyopharm: Research Funding; Karyopharm: Consultancy; Cellectar: Consultancy; BeiGene: Consultancy; Pharmacyclics: Consultancy; Sanofi: Consultancy; Amgen: Research Funding. Kumar: Novartis: Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Antengene: Consultancy, Honoraria; Tenebio: Research Funding; Amgen: Consultancy, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bluebird Bio: Consultancy; BMS: Consultancy, Research Funding; Oncopeptides: Consultancy; Carsgen: Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche-Genentech: Consultancy, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Beigene: Consultancy; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding.

scholarly journals Outcomes after Autologous Stem Cell Transplant in Patients with Relapsed Multiple Myeloma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 11-12
Author(s):  
Christopher Lemieux ◽  
Juliana Craig ◽  
David Iberri ◽  
Sally Arai ◽  
Laura J. Johnston ◽  
...  
Keyword(s):  
Stem Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Stem Cell Transplant ◽  
Autologous Stem Cell Transplant ◽  
Cell Transplant ◽  
Private Company ◽  
Advisory Committees ◽  
First Relapse ◽  
Support Research

Introduction: Given similar overall survival (OS) seen in patients receiving delayed vs. early autologous stem cell transplant (ASCT) in multiple myeloma (MM), some patients are electing to proceed with transplant at relapse instead of with upfront therapy. However, there is limited data in the era of novel therapies on expected disease control and outcomes in MM when ASCT is done for relapsed disease. The objective of this single-center retrospective study was to evaluate the outcomes of ASCT in patients with relapsed MM. Methods: Between January 1, 2010, and November 31, 2019, 168 consecutive patients with relapsed MM received ASCT at our center and constitute the study cohort. Progression free survival (PFS) was estimated from start of therapy at relapse until progression or death. PFS-PRIOR represents PFS of the immediate prior line of therapy before current relapse for which ASCT was pursued. OS was estimated from start of therapy at relapse and also from diagnosis until death. Results: Of the 168 patients, the majority underwent transplant in first relapse (69%, n=116) and the majority had not received a prior transplant (80%, n=135). Baseline and treatment characteristics of the cohort are shown in Table 1. High-risk cytogenetics were seen in 27% and ISS stage III disease in 15%. Median PFS-PRIOR was 20 months (range 2-228). The induction regimen used before ASCT included a doublet in 32%, a triplet in 56%, a quadruplet in 1.5% and a chemotherapy-based regimen in 9% of patients. Stem cell collection was done after relapse in 72% of the cohort. Conditioning regimen included melphalan 200 mg/m2 in 90% patients, including melphalan 200 mg/m2+BCNU in 55%. Median time to neutrophil and platelet engraftment was 11 and 16 days, respectively. Response after ASCT was very good partial response or better in 82% (n=124) of patients. Maintenance therapy was given in 35% (n=56) of patients after ASCT, with 73% patients receiving IMiD maintenance and a median duration of maintenance of 7 months (range 1-41). Survival: Median follow-up of this cohort was 61 months. Median PFS from start of treatment was 28 months. Median OS from start of treatment was 69 months and from diagnosis was 118 months. Two patients (1%) died within the first 3 months of complications related to transplant. As expected, patients who received ASCT at first relapse had a longer PFS of 33 months compared to 22 months when the transplant was done at second or later relapse, p=0.003 (Fig. 1A). OS from treatment start in patients undergoing transplant at first relapse was 82 months and those undergoing ASCT at second or later relapse was 45 months, p=0.004 (Fig. 1B). However, there was no difference in OS from diagnosis in these two groups (118 vs 134 months, p=0.97). Subgroup analysis was done in patients undergoing transplant at first relapse. Patients who had a PFS-PRIOR of ≥36 months had OS of 91 months compared to 62 months for those who experienced a shorter PFS-PRIOR, p=0.03. PFS in the subgroup of patients without prior ASCT undergoing transplant in first relapse (N=96) was 30 months. Multivariate Cox proportional hazards analysis was done for PFS and OS incorporating the following covariates: high risk cytogenetics, Karnofsky performance status (KPS), relapse number, PFS-PRIOR ≥36 months, response at ASCT, and use of maintenance. ASCT in first relapse was associated with better PFS with a hazard ratio (HR) of 0.63 (95% CI 0.42-0.94, p=0.03) and OS (HR 0.59, 95% CI 0.35-0.99, p=0.04). Achieving a PFS-PRIOR of ≥36 months was associated with improved PFS (HR 0.62, 95% CI 0.39-0.99, p=0.04) and OS (HR 0.41, 95% CI 0.21-0.82, p=0.01). Better KPS was also associated with longer PFS (HR 0.61, 95% CI 0.41-0.91, p=0.01) and OS (HR 0.52, 95% CI 0.31-0.86, p=0.01). Progressive disease at transplant was, as expected, associated with worse PFS (HR 3.28, 95% CI 1.89-5.70, p<0.001) and OS (HR 2.70, 95% CI 1.39-5.22, p=0.003). Conclusions: This study provides comprehensive data on expected outcomes and prognostic factors amongst patients with MM undergoing ASCT at relapse, with median PFS and OS being 28 and 69 months in a cohort where only a third of patients received maintenance therapy. Disease response at transplant, PFS-PRIOR and KPS were prognostic for survival. These data can serve as a guide when counseling patients undergoing ASCT for relapsed MM and also serve as benchmark in designing clinical trials of transplant and comparative novel therapies for relapsed MM. Disclosures Muffly: Amgen: Consultancy; Adaptive: Research Funding; Servier: Research Funding. Shiraz:Kite, a Gilead Company: Research Funding; ORCA BioSystems: Research Funding. Liedtke:Adaptive: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Caelum: Membership on an entity's Board of Directors or advisory committees. Rezvani:Pharmacyclics: Research Funding. Meyer:Orca Bio: Research Funding. Shizuru:Jasper Therapeutics, Inc: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees. Negrin:Biosource: Current equity holder in private company; Magenta Therapeutics: Consultancy, Current equity holder in publicly-traded company; BioEclipse Therapeutics: Current equity holder in private company; UpToDate: Honoraria; KUUR Therapeutics: Consultancy; Amgen: Consultancy. Miklos:Pharmacyclics: Consultancy, Other: Travel support, Patents & Royalties, Research Funding; Novartis: Consultancy, Other: Travel support, Research Funding; Allogene Therapeutics Inc.: Research Funding; Juno-Celgene-Bristol-Myers Squibb: Consultancy, Other: Travel support, Research Funding; Kite-Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Janssen: Consultancy, Other: Travel support; Miltenyi Biotec: Research Funding; Adaptive Biotech: Consultancy, Other: Travel support, Research Funding. Sidana:Janssen: Consultancy.

scholarly journals Safety and Clinical Activity of Atezolizumab (Anti-PDL1) in Combination with Obinutuzumab in Patients with Relapsed or Refractory Non-Hodgkin Lymphoma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5104-5104 ◽  
Author(s):  
Brian G. Till ◽  
Steven I. Park ◽  
Leslie L. Popplewell ◽  
Andre Goy ◽  
Elicia Penuel ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Stem Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Stem Cell Transplant ◽  
Autologous Stem Cell Transplant ◽  
Clinical Activity ◽  
Cell Transplant ◽  
Advisory Committees ◽  
Grade 3

Abstract Introduction: Despite modern chemo-immunotherapy regimens, the outcomes for patients with relapsed or refractory diffuse-large B-cell lymphoma (DLBCL) or follicular lymphoma (FL) remain poor, and more effective therapies are sorely needed. Immune checkpoint inhibitors (anti-PDL1 or anti-PD-1) represent a novel class of therapeutics with great promise. Atezolizumab (MPDL3280A) is a fully humanized IgG1 monoclonal antibody that blocks the interaction between PD-L1 and its receptors PD-1 and B7.1, thereby preventing inhibition of T-cell activity. Clinical activity of atezolizumab has been seen in multiple tumor types, including NHL as monotherapy. Increased PD-L1 expression has been reported in DLBCL and FL on tumor cells, stromal cells and tumor-infiltrating immune cellsand may represent a mechanism of tumor escape from immune surveillance. Obinutuzumab is a next generation anti-CD20 monoclonal antibody with enhanced ADCC activity. The combination of atezolizumab and obinutuzumab has the potential to activate both innate and adaptive immunity to enhance anti-tumor responses in lymphoma. Methods: This multi-center, open-label, Phase Ib (NCT02220842) study is evaluating atezolizumab in combination with obinutuzumab in patients with relapsed or refractory DLBCL or FL. Primary endpoints were safety and tolerability, with secondary endpoints of PK and clinical activity. Key eligibility criteria included measurable disease and treatment with ≥ 1 prior chemo-immunotherapy regimen. Previous autologous stem cell transplant was allowed, but not allogeneic stem cell transplant. During cycle 1, patients received obinutuzumab alone on days 1 (100 mg), 2 (900 mg), 8 and 15 (1000 mg). From cycles 2-8, atezolizumab (1200 mg) and obinutuzumab (1000 mg) were administered on day 1 every 3 weeks. This was followed by atezolizumab consolidation (1200 mg q3 weeks) for an additional 6 months. ORR was assessed by IWG NHL criteria (Cheson et al, J Clin Oncol 2007). Pre-treatment biopsies and on-treatment samples are being collected to determine PD-L1 expression and other biomarkers of response and resistance. Results: As of July 28, 2015, all 6 patients (2 male, 4 female) evaluable for safety have completed at least 4 cycles of therapy. Median age was 68.5 years (range, 58-81 years). Three patients had FL, and 3 patients had DLBCL. The median number of prior therapies was 4 (range, 2-6). All patients have received at least one prior rituximab-containing chemo-immunotherapy regimen. One patient with DLBCL had received a prior autologous stem cell transplant, as well as CD19 CAR T-cell therapy. The median disease burden at baseline was 2717.4 mm2 (range, 990-7247 mm2). The median duration of therapy was 118 days (range, 64-212 days). One dose-limiting toxicity (Grade 3 thrombocytopenia) was observed. Three patients experienced 1 treatment-emergent Grade 3 AE each (thrombocytopenia, ileus, intestinal obstruction). No Grade ≥ 3 infusion-related reactions, Grade 4 or 5 AEs, treatment related deaths or discontinuations due to study treatment have been seen. Responses for 5 patients who have completed the first disease assessment time point are available. Preliminary efficacy evaluation (CT scan) after 4 cycles (3 months) of therapy are as follows: 2 PRs (up to 68.6% reduction; 1 pt with DLBCL and 1 pt with FL), 2 SDs and 1 PD. Three of 4 patients, experiencing SD or better have ongoing clinical benefit. Expansion cohorts in FL and DLBCL are currently enrolling, and updated safety and efficacy data will be presented. Biomarker data will also be discussed. Conclusions: Preliminary results indicate that the combination of atezolizumab and obinutuzumab appears well tolerated with early evidence of activity in patients with heavily pretreated relapsed or refractory DLBCL and FL. Disclosures Till: Roche-Genentech: Research Funding. Park:TEVA: Research Funding; Seattle Genetics: Research Funding; Jannsenn: Other: Travel. Goy:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics/JNJ: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Acerta: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Penuel:Genentech, Inc.: Employment. Venstrom:Genentech: Employment. Liu:Genentech: Employment. Fingerle-Rowson:F.Hoffmann-LaRoche: Employment. Byon:Genentech: Employment. Woodard:Genentech: Employment.

Once a Week Bortezomib with Dexamethasone Is Effective with Limited Toxicity in Newly Diagnosed Multiple Myeloma Patients with Older Age and Co-Morbidities,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3964-3964
Author(s):  
Nikhil C. Munshi ◽  
Saem Lee ◽  
Suman Kambhampati ◽  
Michal Rose ◽  
Abid Mohiuddin ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Older Patients ◽  
Research Funding ◽  
Autologous Stem Cell Transplant ◽  
Cell Transplant ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Respiratory Problems ◽  
Grade 3

Abstract Abstract 3964 Background: Bortezomib in combination with dexamethsone is administered twice a week for 2 weeks with excellent therapeutic outcome. However, in a proportion of patients it is associated with toxicities such as neuropathy and twice a week regimen is inconvenient especially in older patients. To improve convenience and compliance, we have investigated the efficacy and safety of a weekly bortezomib regimen. Methods: We conducted a phase II multi-center single-arm study in participating Veterans Hospitals (VA) nationwide evaluating bortezomib administered at 1.6 mg/m2 IV weekly for 4 weeks with 1 week off with dexamethasone 40mg PO on the day of and day after bortezomib for upto 6 cycles in newly diagnosed multiple myeloma patients not considered for autologous stem cell transplant. The objective is to evaluate overall response rate (ORR) and toxicity of this regimen. Results: We have enrolled all planned 50 patients (median age-71; range 50–89) at 12 VA Hospitals. Patients had significant co-morbidities including 86% with cardiovascular problems, 67% with diabetes and/or hyperlipidemia, 54% with renal dysfunction, 37% with respiratory problems, and 18% with history of cancer. All patients were on at least 5 daily medications. Of the 50 patients enrolled, 42 patients have received at least 1 cycle of therapy and were evaluable for toxicity and efficacy. With a median of 4 cycles administered, this regimen was very well tolerated. Ten patients experienced neuropathy: 6 patients experienced grade 1, two patients developed grade 2 neuropathy, while two patients who had grade 1 neuropathy at diagnosis increased to grade 2 neuropathy with pain, and the other patient increased to grade 3 neuropathy with pain, with an overall Grade 3 neuropathy rate of 2.4%.Dexamethasone dose was reduced in 30% while bortezomib dose was reduced in 10% of the patients. Additionally, grade ≥1 asthenia was observed in 52%, constipation in 38%, diarrhea in 34%, anemia in 64%, vomiting/nausea in 26%, and thrombocytopenia in 54%. Four patients have died of co-morbidities which were considered unrelated or probably unrelated to the treatment with bortezomib. Of the patients who received at least 1 cycle of therapy, 62% patients achieved ≥PR; 12% CR/nCR and an additional 14% achieved VGPR. Including MR in the analysis, ORR was observed in 90% of the evaluable patients. On intent to treat analysis including all 50 patients, ORR was observed in 76% patients and ≥ PR in 52% patients. Conclusions: Once a week bortezomib with dexamethasone regimen is effective and well tolerated even in older patients with significant co-morbidities and should be considered as an important option in multiple myeloma. Disclosures: Munshi: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Onyx: Membership on an entity's Board of Directors or advisory committees. Yellapragada:Celgene: Research Funding; BMS: Research Funding. Roodman:Amgen: Consultancy; Millennium: Consultancy.

scholarly journals Long Term Outcome of Lenalidomide-Dexamethasone (Rd) Vs Melphalan-Lenalidomide-Prednisone (MPR) Vs Cyclophosphamide-Prednisone-Lenalidomide (CPR) As Induction Followed By Lenalidomide-Prednisone (RP) Vs Lenalidomide (R) As Maintenance in a Community-Based Newly Diagnosed Myeloma Population: Updated Analysis of EMN01 Phase III Study

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. 901-901
Author(s):  
Sara Bringhen ◽  
Massimo Offidani ◽  
Pellegrino Musto ◽  
Anna Marina Liberati ◽  
Giulia Benevolo ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Phase Iii ◽  
Cell Transplant ◽  
Newly Diagnosed ◽  
Community Based ◽  
Advisory Committees ◽  
Risk Of Death ◽  
Grade 3 ◽  
To Receive

Abstract Introduction : Rd and MPR showed to be effective combinations in elderly newly diagnosed multiple myeloma (NDMM) patients (pts). Cyclophosphamide is a less toxic alkylating alternative agent. EMN01 is the first trial to formally compare these three different Lenalidomide-based combinations. Maintenance with Lenalidomide has been recently approved in patients eligible for autologous stem cell transplant (ASCT). Few data are available about the best combination as maintenance in patients not eligible for ASCT. Methods : 662 pts with NDMM were randomized to receive 9 28-day cycles of Rd (lenalidomide 25 mg/day for 21 days; dexamethasone 40 mg on days 1,8,15 and 22 in pts 65-75 years old and 20 mg in those >75 years), MPR (lenalidomide 10 mg/day for 21 days; melphalan orally 0.18 mg/Kg for 4 days in pts 65-75 years old and 0.13 mg/Kg in >75 years pts; prednisone 1.5 mg/Kg for 4 days) or CPR (lenalidomide 25 mg/day for 21 days; cyclophosphamide orally 50 mg/day for 21 days in pts 65-75 years old and 50 mg every other day in >75 years pts; prednisone 25 mg every other day). After induction, pts were randomized to receive maintenance with lenalidomide alone (R; 10 mg/day for 21 days) or with prednisone (RP; R, 10 mg/day for 21 days and P, 25 mg every other day), until disease progression. Results : Pts characteristics were well balanced in all groups; 217 pts in Rd, 217 in MPR and 220 in CPR arms could be evaluated. After a median follow-up of 63.7 months, median PFS was 23.2 months in MPR, 18.9 months in CPR and 18.6 months in Rd (MPR vs CPR p=0.02; MPR vs Rd p=0.08). Median overall survival (OS) was 79.9 months in MPR, 69.4 months in CPR and 68.1 months in Rd (MPR vs CPR p=0.98; MPR vs Rd p=0.64). The most common grade ≥3 adverse event (AEs) was neutropenia: 64% in MPR, 29% in CPR and 25% in Rd pts (p<0.0001). Grade ≥3 non hematologic AEs were similar among arms. At the end of induction, 402 pts were eligible for maintenance, 198 in the RP and 204 in the R groups. PFS from start of maintenance was 22.2 months in the RP group and 17.6 in the R group, with 20% reduced the risk of death/progression for pts receiving RP maintenance (HR 0.81, p=0.07; Figure 1). A subgroup analysis was performed to determine the consistency of RP vs R treatment effect in different subgroups using interaction terms between treatment and cytogenetic abnormalities, ISS, age, sex, induction treatment and response before maintenance (Figure 1). No difference in OS was observed (HR 1.02, p=0.93) but the OS analysis was limited by the low number of events. Median duration of maintenance was 23.0 months in RP pts and 20.5 months in R pts, 14% and 13% of pts discontinued due to AEs, in RP and R groups, respectively. Conclusion : This phase III trial compared 2 different Lenalidomide-containing induction regimens and 2 different Lenalidomide-containing maintenance regimens in an elderly community-based NDMM population. MPR prolonged PFS by approximately 5 months, yet the higher incidence of hematologic toxicity should be carefully considered. The addition of low-dose prednisone to standard lenalidomide maintenance reduced the risk of death/progression by 20%, with a good safety profile. Updated results will be presented at the meeting. Disclosures Bringhen: Mundipharma: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Celgene: Honoraria; Bristol Myers Squibb: Honoraria; Karyipharm: Membership on an entity's Board of Directors or advisory committees. Offidani: celgene: 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. Musto: Celgene: Honoraria; Janssen: Honoraria. Gaidano: Gilead: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Roche: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. De Sabbata: Celgene: Membership on an entity's Board of Directors or advisory committees. Palumbo: Sanofi: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Binding Site: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding; Genmab A/S: Consultancy, Honoraria, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Employment, Equity Ownership, Honoraria, Research Funding. Hájek: Amgen, Takeda, BMS, Celgene, Novartis, Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Honoraria; Pharma MAR: Consultancy, Honoraria. Boccadoro: Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; AbbVie: Honoraria; Mundipharma: Research Funding; Sanofi: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding.

A Phase III Study to Determine the Efficacy and Safety of Lenalidomide in Combination with Melphalan and Prednisone (MPR) in Elderly Patients with Newly Diagnosed Multiple Myeloma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 613-613 ◽  
Author(s):  
Antonio Palumbo ◽  
Meletios A. Dimopoulos ◽  
Michel Delforge ◽  
Martin Kropff ◽  
Robin Foa ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Maintenance Therapy ◽  
Board Of Directors ◽  
Primary Endpoint ◽  
Interim Analysis ◽  
Newly Diagnosed ◽  
Efficacy And Safety ◽  
Time To Progression ◽  
First Line ◽  
Advisory Committees

Abstract Abstract 613 Background: Lenalidomide (Revlimid®) is an oral immunomodulatory agent with clinical efficacy in patients with multiple myeloma (MM). In patients with relapsed/refractory MM, lenalidomide plus dexamethasone improved time to progression (TTP) and overall survival (OS) in comparison with dexamethasone alone. In newly diagnosed MM patients, the current study compares the efficacy and safety of melphalan, prednisone and lenalidomide (MPR) with that of MP alone. Methods: Key inclusion criteria were: ≥65 years of age, newly diagnosed and symptomatic MM. 459 patients were randomly assigned to receive MPR followed by lenalidomide maintenance therapy or MPR followed by placebo maintenance therapy or MP followed by placebo maintenance therapy (Figure 1). The study induction and maintenance phases were followed by an open label lenalidomide extension and a follow-up phase. All patients received aspirin 100 mg/day as thrombo-prophylaxis. The primary endpoint of the study is progression free survival (PFS). The secondary endpoints are OS, time-to-progression, response rate, time to response, response duration, time-to-next anti-myeloma therapy, safety, quality of life and exploratory assessment of cytogenetic abnormalities. Primary comparison is based on the intent-to-treat population comparing PFS between MPR followed by lenalidomide with MP followed by placebo; secondary comparisons are between MPR followed by lenalidomide and MPR followed by placebo, and between MPR followed by placebo and MP followed by placebo. Results: The first patient was enrolled in February 2007. A pre-planned interim analysis to evaluate the efficacy and safety was performed at 50% information. An independent central adjudication committee determined the assessment and timing of progressive disease prior to the interim analysis. At the interim analysis, it was determined by the Data Monitoring Committee (DMC) that the study had crossed the O'Brien Fleming superiority boundary for the primary endpoint, demonstrating a highly statistically significant improvement in PFS for patients treated with MPR compared with MP as first-line treatment for MM patients. The topline results will be availabel at the time of the meeting. Conclusions: MPR is an effective and safe regimen for front-line use in MM. PFS was significantly improved in patients who received MPR followed by lenalidomide maintenance compared with those who received MP followed by placebo maintenance. MPR followed by lenalidomide maintenance is a new therapeutic option and can be considered a new standard for patients older than 65 years old. Disclosures: Palumbo: Celgene: 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; Pharmion: Honoraria, Membership on an entity's Board of Directors or advisory committees. Off Label Use: Lenalidomide is not approved for first line use in multiple myeloma. Dimopoulos:Celgene: Honoraria. Delforge:Janssen-Cilag: Consultancy, Honoraria; Celgene: Honoraria, Speakers Bureau. Kropff:Ortho Biotech: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau. Foa:Celgene: Membership on an entity's Board of Directors or advisory committees. Yu:Celgene: Employment. Herbein:Celgene: Employment. Mei:Celgene: Employment. Jacques:Celgene: Employment. Catalano:Celgene: Research Funding.

Phase 1 Study of the Novel Kinesin Spindle Protein Inhibitor ARRY-520 + Carfilzomib in Patients with Relapsed and/or Refractory Multiple Myeloma

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4082-4082 ◽  
Author(s):  
Jatin J. Shah ◽  
Donna M. Weber ◽  
Sheeba K. Thomas ◽  
Raymond Alexanian ◽  
Michael Wang ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Dose Escalation ◽  
Research Funding ◽  
Single Agent ◽  
Autologous Stem Cell Transplant ◽  
Hematologic Toxicity ◽  
Cell Transplant ◽  
Advisory Committees ◽  
Kinesin Spindle Protein

Abstract Abstract 4082 Background: ARRY-520, a novel kinesin spindle protein (KSP) inhibitor, has been studied as a single agent and in combination with dexamethasone, and demonstrated promising clinical activity in patients with bortezomib- and lenalidomide-refractory multiple myeloma (MM). Carfilzomib, a novel irreversible proteasome inhibitor (PI), has also demonstrated single agent activity in relapsed and refractory MM, and recently received regulatory approval for this indication. Preclinical data support the presence of synergy with the combination of a PI and a KSP inhibitor via the latter's ability to down-regulate Mcl-1, supporting our hypothesis that the combination of carfilzomib and ARRY-520 (Car-ARRY) would be highly active in relapsed and/or refractory myeloma. We therefore aimed to combine these two agents for the first time, and here report the initial findings from the phase I dose-escalation in patients with relapsed and/or refractory MM. Methods: The primary objective was to determine the maximum tolerated dose (MTD) and the safety/tolerability of the Car-ARRY combination. Secondary objectives were to determine efficacy as measured by the overall response rate, time to progression, progression free survival and time to next therapy. Patients had to have myeloma that was relapsed and/or refractory, be ineligible for autologous stem cell transplant, bortezomib refractory/intolerant, and prior lenalidomide exposure. ARRY-520 was administered intravenously over 1 hour on days 1, 2, 15 and 16, while carfilzomib was administered intravenously over 30 minutes on days 1, 2, 8, 9, 15 and 16 on a 28 day cycle. All patients received growth factor support with filgrastim. Dose-escalation used a standard 3+3 schema proceeded based on dose-limiting toxicities (DLTs) during cycle 1, with planned escalation of the dose of ARRY-520. Dose level 1 was ARRY-520 0.75 mg/m2, and carfilzomib was dosed at 20 mg/m2 for cycle 1 on days 1 and 2 and all subsequent dose were at 27 mg/m2. Adverse events (AEs) were graded by NCI-CTCAE v4, while responses were assessed by the modified International Uniform Response Criteria. Results: To date, 8 patients have been enrolled in the ongoing dose escalation phase. The median age was 66 (range 47–80), 6/8 were males, and the median number of prior therapies was 4 (range 2–10). 7/8 patients had undergone prior autologous stem cell transplant, and all patients were bortezomib refractory or intolerant. In the first cohort, 3 patients were enrolled and no dole limiting toxicity (DLT) was observed. During the second cohort, ARRY-520 was escalated to 1 mg/m2 with carfilzomib at 20/27 mg/m2, and among the first 3 patients, one patient suffered a DLT in the form of an admission for influenza pneumonia with non-neutropenic fever. Expansion of cohort 2 is currently underway. Among the 6 patients who completed the first cycle of therapy, 5 remain on study. In the first cohort, one patient remains on study with 6 cycles and achieved a near complete remission, 1 patient achieved stable disease, and 1 patient suffered disease progression after first cycle. In the second cohort, all three patients who completed the first cycle have stable disease and remain on trial. In the first 6 toxicity-evaluable patients who have completed one cycle, grade (G) 3 events included one each of pneumonia, diarrhea, and hyperglycemia. There was limited hematologic toxicity with 4/6 patients with G1/2 thrombocytopenia, 3/6 patients with G1/2 anemia, and 1/6 patient with G1/2 neutropenia. Additional G1/2 non-hematologic toxicity included 3/6 patients with diarrhea, 3/6 patients with dyspnea, 3/6 patients with transient elevations in creatinine and 3/6 patients with aspartate aminotransferase elevations. An MTD has not been established and enrollment is ongoing in cohort 2 with carfilzomib at 20/27mg/m2 and ARRY-520 at 1.0 mg/m2. Conclusions: The combination of ARRY-520 and carfilzomib is well tolerated with limited hematologic toxicity and a manageable side effect profile. Notably, in this patient population, with patients who have bortezomib refractory/intolerant myeloma, the combination has demonstrated early signals of activity. Updated safety and efficacy data for all patients will be presented at the meeting. Disclosures: Shah: Onyx: Honoraria, Research Funding, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Array BioPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Research Funding, Speakers Bureau. Off Label Use: This presentation will include information about Arry-520 which is not yet approved for use in patients with multiple myeloma. Wang:Pharmacyclic: Research Funding; onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Hilder:Array BioPharma: Employment. Orlowski:onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; array biopharma: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Practice Patterns of Re-Initiation of Therapy at Time of Relapse or Progression Post- Autologous Stem Cell Transplant (ASCT) Among Patients with AL Amyloidosis

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3444-3444 ◽  
Author(s):  
Yi L. Hwa ◽  
Rahma Warsame ◽  
Morie A. Gertz ◽  
Francis K Buadi ◽  
Martha Q. Lacy ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Practice Patterns ◽  
Autologous Stem Cell Transplant ◽  
Al Amyloidosis ◽  
Cell Transplant ◽  
Second Line ◽  
Second Line Therapy ◽  
Advisory Committees ◽  
Line Therapy

Abstract Background: Among patients with immunoglobulin light chain (AL) amyloidosis, there is little consensus on when reinstitution of chemotherapy should occur (Milani and Dispenzieri, International Society of Amyloidosis 2016). AL amyloidosis patients who are treated with high dose chemotherapy followed by autologous stem cell transplant (ASCT) are a relatively low-risk and homogenous population, making them an ideal group to study practice patterns. Methods: We conducted a retrospective study to evaluate the patterns of relapse or progression and the timing of re-initiation of therapy among 146 patients who were initially treated with ASCT at Mayo Clinic between 1996 and 2009 and who received second-line therapy between 7/9/1997 and 4/12/2012. Results: The median time from ASCT to second-line therapy was 23.6 months and the median follow up post ASCT was 57.5 months. The indications for second-line treatment were: 1) both hematologic and organ progression 24.7% (36 patients); 2) organ progression only 41.1% (60); 3) hematologic relapse only 34.2% (50). The median dFLC at the time of starting second-line therapy was 10.5 mg/dL (1.6 - 59.5 mg/dL), which was 44.9% (13.8-167.2%) of dFLC level at diagnosis. Increase in proteinuria by > 50% from nadir (that was also at least 1g/24 hours, i.e. renal progression) was present in 35.8%. Increase in NT proBNP by >30% from nadir and minimum of 300 pg/mL was present in 48.9% of patients. The respective 4 years overall survival rates from the time of ASCT were 87.8%, 63.9%, and 56.7% (p=0.0016) for patients who had hematologic relapse, organ progression only and both organ and hematologic progression. Comparisons of laboratory markers at diagnosis, nadir of post ASCT and initiation of second-line therapy are listed in the table. Conclusions: Our study investigated the patterns of relapse / progression following upfront ASCT. This provides some insights on practice patterns of when physicians re-initiate therapy. Table Table. Disclosures Gertz: NCI Frederick: Honoraria; Celgene: Honoraria; Med Learning Group: Honoraria, Speakers Bureau; Research to Practice: Honoraria, Speakers Bureau; Novartis: Research Funding; Prothena Therapeutics: Research Funding; GSK: Honoraria; Sandoz Inc: Honoraria; Ionis: Research Funding; Alnylam Pharmaceuticals: Research Funding; Annexon Biosciences: Research Funding. Kumar:Millennium: Consultancy, Research Funding; Array BioPharma: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Noxxon Pharma: Consultancy, Research Funding; AbbVie: Research Funding; Glycomimetics: Consultancy; Janssen: Consultancy, Research Funding; BMS: Consultancy; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx: Consultancy, Research Funding; Kesios: Consultancy. Kapoor:Celgene: Research Funding; Amgen: Research Funding; Takeda: Research Funding. Dispenzieri:Prothena: Membership on an entity's Board of Directors or advisory committees; Alnylam: Research Funding; Celgene: Research Funding; Jannsen: Research Funding; pfizer: Research Funding; GSK: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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