scholarly journals Interval Progression Serves As a Predictor of Adverse Outcomes in Patients with Multiple Myeloma

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3940-3940
Author(s):  
Alicia Bao ◽  
Qiuhong Zhao ◽  
Nidhi Sharma ◽  
Naresh Bumma ◽  
Srinivas Devarakonda ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Maintenance Therapy ◽  
Disease Progression ◽  
Board Of Directors ◽  
Induction Therapy ◽  
Regression Models ◽  
Competing Risk ◽  
Cell Transplant ◽  
Advisory Committees ◽  
Increased Risk

Abstract Background: Multiple myeloma (MM) remains an incurable disease, but deep, lasting remission can be achieved with induction therapy and autologous stem cell transplant (ASCT). The current ASCT treatment timeline includes a gap between the end of induction and the day of ASCT to permit correct mobilization and collection of stem cells. During this interval, some patients experience increases in their MM markers. We specifically evaluated if patients with interval progression (IP) have different outcomes post-ASCT compared to patients without IP. Methods: We completed a retrospective analysis of 482 patients who underwent ASCT at The Ohio State University Wexner Medical Center between 2011 and 2016. MM labs, including protein electrophoresis with immunofixation and free light chains, were obtained at day of diagnosis, end of induction, and day of ASCT. A 20% increase in the index protein between the end of induction and the day of ASCT was defined as IP. The primary outcomes evaluated were time-to-progression (TTP), progression-free survival (PFS), and overall survival (OS). TTP was defined as time from ASCT to disease progression, treating death without progression as a competing risk. PFS was defined as the time from ASCT until either disease progression or death, while OS was defined as the time from ASCT until death or last follow-up. Poisson regression models with robust variance were used to evaluate the associations between patients' characteristics and IP, while competing risk regression models were used for TTP analysis, and Cox regression models for OS and PFS analysis. Results: 482 patients who underwent ASCT for MM between 2011 and 2016 were studied. The patient population was primarily male (n = 296, 61.4%), Caucasian (n = 420, 87.1%), and had IgG disease (n = 269, 55.8%). MM stage at diagnosis was equally represented. Cytogenetic analysis showed 108 (22.4%) patients with 1q21 amplification, 60 (12.4%) patients with t(11;14) translocation, 33 (6.8%) patients with t(4;14) translocation, and 40 (8.3%) patients with 17p deletion. More than 80% of patients underwent maintenance therapy following ASCT. One hundred and fifty-six (32.3%) patients were defined as having IP. Patients in the IP group were significant more likely to have LC disease (p = 0.0018), but no other patient characteristics varied significantly between the two groups. LC disease (relative risk (RR adj) = 2.12, 95% CI 1.37-3.30, p = 0.001) and deletion 17p (RR adj = 1.62, 95% CI 1.08-2.42, p = 0.02) were associated with increased risk of IP on multivariate analysis (MVA). Five-year PFS rates were 47.2% and 36.8% in the non-IP and IP groups, respectively. Five-year cumulative progression rates were 49.0% in the non-IP group and 57.8% in the IP group. Five-year OS rates were 76.8% in the non-IP group and 69.6% in the IP group. On univariate analysis (UVA), IP correlated with inferior outcomes in both TTP (hazard ratio (HR) = 1.39, p = 0.01) and OS (HR = 1.39, p = 0.04). In agreement with previous literature, other factors independently correlated with inferior TTP and OS outcomes, including MM stage, cytogenetics (amp1q, t(4;14), and del(17p)), and absence of maintenance therapy post-ASCT. On MVA, IP was no longer significantly associated with a shorter TTP (HR = 1.16, p = 0.35), but approached statistical significance in conferring inferior OS (HR = 1.40, p = 0.07). Notably, once deletion 17p was removed from the MVA, the presence of IP once again conferred significantly lower OS (HR = 1.45, 95% CI 1.01-2.07, p = 0.04), suggesting that deletion 17p, which is a significant risk factor for both IP and OS, may mediate the effect of IP. Combined, all data suggest that uncontrolled disease prior to ASCT trends towards worse long-term outcomes. Conclusion: In this study, we report the first data regarding patients who experienced rapid disease progression in the interval between induction therapy and ASCT. These patients have inferior TTP, PFS, and OS, likely due to the presence of LC disease or deletion 17p. IP may provide a valuable predictor of robustness of response to ASCT and prompt the need for additional induction cycles or alternative regimens. This is especially relevant for patients with deletion 17p. Indeed, these data support a prospective study of concepts to improve outcomes for patients with IP prior to ASCT. Disclosures Bumma: Amgen: Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Phase III Intergroup Study of Lenalidomide Versus Placebo Maintenance Therapy Following Single Autologous Hematopoietic Stem Cell Transplantation (AHSCT) for Multiple Myeloma: CALGB 100104

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 37-37 ◽  
Author(s):  
Philip L. McCarthy ◽  
Kouros Owzar ◽  
Kenneth C. Anderson ◽  
Craig C. Hofmeister ◽  
David Duane Hurd ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Maintenance Therapy ◽  
Disease Progression ◽  
Board Of Directors ◽  
Stable Disease ◽  
Interim Analysis ◽  
Research Funding ◽  
Phase Iii ◽  
Cell Transplant ◽  
Advisory Committees

Abstract Abstract 37 The primary objective of CALGB 100104 was to determine if maintenance lenalidomide would prolong time to progression (TTP) after single AHSCT for multiple myeloma. Eligibility included: Stage I-III multiple myeloma, ≤ 1 year from diagnosis, ≥ 2 months of induction with stable disease or better and age < 70 years. AHSCT regimen was melphalan 200 mg/m2. Patients (pts) with stable disease or better were randomized double-blinded at day 100–110 post-AHSCT to lenalidomide or placebo, after stratification by diagnostic β2-microglobulin (β2M) level and prior thalidomide or lenalidomide therapy. Starting dose was 10 mg/day, escalated to 15 mg/day after 3 months and continued until disease progression. Drug was stopped and dose reduced according to the development of toxicity. Drug was held for ≥ Gr 3 toxicity, restarted at resolution to ≤ Gr 2 and de-escalated by 5 mg or maintained as tolerated at 15, 10, 5 mg daily or 5 mg daily for 21 of 28 days per month. All pts required some form of anticoagulation including aspirin, warfarin or heparin compounds. There was no consolidation therapy. Results: 568 pts were enrolled before AHSCT (04/15/05-07/03/09) from 47 centers. Of 108 pts (19%) not randomized, reasons were: progressive disease/no response 16%, adverse events (AEs) 5%, died during therapy 2%, refusal 26 %, other disease 1%, other therapy 4 %, other reasons 33%, unknown 14%. Pt characteristics in the lenalidomide arm and placebo arm respectively were: median age (range) 58 (29-70) and 57 (39-70); male gender 48% and 52%; β2M >2.5 mg/L, 28% and 27%. For 554 pts with complete data, induction regimens were thalidomide based (27%), lenalidomide based (22%), bortezomib based (20%), bortezomib and thalidomide based (12%), bortezomib and lenalidomide based (9%), dexamethasone based (4%), lenalidomide and thalidomide (3%), lenalidomide, thalidomide and bortezomib (1%), other (1%) and missing (1%); hence 74% of pts received either lenalidomide or thalidomide prior to enrollment. The primary endpoint of the study, TTP was met in a planned protocol interim analysis in the 3rd quarter of 2009 and the study results were released on 12/17/09. This updated 3rd interim analysis for TTP includes further events up until 12/17/09 after which study pts were un-blinded. This interim analysis is based on 460 randomized pts with approximately 33% of the required number of events (progression or death before progression) observed. The median follow-up is 17.5 months from ASHCT. The number of events among 231 pts randomized to lenalidomide was 44 compared to 91 among 229 pts randomized to placebo. The one-sided unadjusted P-value was <0.0001. Pts receiving lenalidomide experienced a 61% reduction in the risk of disease progression or death when compared to pts receiving placebo. The estimated hazard ratio was 0.39 (95% CI,0.27-0.56 p < 0.0001). The preliminary estimated median TTP is 42.3 months for the lenalidomide arm and the estimated median TTP is 21.8 months for the placebo arm. Deaths in the lenalidomide and placebo arms were 19 and 28 respectively (p=0.13) and as of this analysis, there is no difference between these two arms. Significant improvements in TTP were observed in the lenalidomide maintenance arm regardless of β2M level or prior thalidomide or lenalidomide induction therapy. For 389 reported pts, the post-randomization, hematologic AEs were Gr 3 (32%), Gr 4 (13%) and Gr 5 (0) for the lenalidomide arm and Gr 3 (6%) Gr 4 (4%) and Gr 5 (0) for placebo (p=0.0001). The non-hematologic AEs were Gr 3 (30%), Gr 4 (3%) and Gr 5 (1%) for the lenalidomide arm and Gr 3 (19%), Gr 4 (3%), and Gr 5 (2%) for placebo (p=0.0048). Comparing lenalidomide versus placebo post-randomization pooled Gr 3–5 AEs, there were significantly more episodes of thrombocytopenia (11% versus 3%, p=0.01), neutropenia (44% vs 8%, p<0.0001) anemia (5% vs 1%, p=0.0082) and all infections (16% vs 3%, p<0.0001) with lenalidomide. There were no significant differences in incidence of fatigue, neuropathy, rash and thromboembolism. A minority of patients discontinued therapy due to AEs (12%, 28 of 231 on lenalidomide vs 2%, 5 of 229 on placebo) and for other reasons (13%, 29 of 231 on lenalidomide vs 6%, 14 of 231 on placebo). Conclusions: Long term administration of lenalidomide is feasible. When compared to placebo controls, lenalidomide initiated at day 100–110 post-AHSCT in multiple myeloma patients significantly delays TTP. Disclosures: McCarthy: Celgene: Honoraria, Research Funding. Off Label Use: Lenalidomide maintenance therapy for myeloma following autologous hematopoietic cell transplant. Anderson:Millenium: Consultancy, Honoraria; Celgene: Consultancy; Novartis: Consultancy; Onyx: Consultancy; Merck: Consultancy; Bristol Myers Squibb: Consultancy; Acetylon: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Hurd:Celgene: Research Funding. Giralt:Celgene: Honoraria, Speakers Bureau; Millenium: Honoraria, Speakers Bureau. Stadtmauer:Celgene: Speakers Bureau. Richardson:Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees. Vij:Celgene: Honoraria, Speakers Bureau. Callander:Millenium: Research Funding. Maziarz:Millenium: Speakers Bureau; Genzyme: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Landau:Millenium: Membership on an entity's Board of Directors or advisory committees. Martin:Celgene: Speakers Bureau; Millenium: Speakers Bureau; Novartis: Speakers Bureau. Qazilbash:Celgene: Speakers Bureau. Shea:Millenium: Consultancy, Research Funding.

Characteristics Of Multiple Myeloma Patients With 6-Year Or Longer Progression-Free Survival After a Single Autologous Transplant

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3366-3366 ◽  
Author(s):  
Kehinde U.A. Adekola ◽  
Qaiser Bashir ◽  
Nina Shah ◽  
Sai Ravi Pingali ◽  
Simrit Parmar ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Induction Therapy ◽  
Progression Free Survival ◽  
High Dose ◽  
Cell Transplant ◽  
Advisory Committees ◽  
Free Survival ◽  
Autologous Transplant ◽  
Preparative Regimen

Background High dose chemotherapy followed by an autologous stem cell transplant (auto-HCT) is considered standard of care in patients with newly diagnosed multiple myeloma (MM). In a recent randomized trial, median progression free survival (PFS) after auto-HCT, with or without maintenance therapy was 46 and 27 months, respectively (McCarthy P et al. NEJM 2012). However, about 15% of patients are reported to have much longer PFS (Pineda-Roman M et al. Cancer 2008). Here we tried to identify the factors that may predict a long PFS after auto-HCT. Methods We performed a retrospective chart review of patients who received an auto-HCT for MM between January 2000 and March 2007. A total of 1135 patients underwent an auto-HCT during this period, and 194 patients (17%) had a minimum PFS of 72 months or longer after a single auto-HCT. The primary objective was to determine the variables associated with a long PFS and overall survival (OS). Results Patient characteristics and outcomes are shown in the attached Table. The median age at auto-HCT was 56 years, and the median time from diagnosis to auto-HCT was 7.5 months. Twenty-three (13%) patients had ≥ 10% plasma cells in the bone marrow at auto-HCT and only 9 patients (4.8%) had high-risk cytogenetic abnormalities. One-hundred and fifty (77%) patients received induction therapy containing either an immunomodulatory (IMiD) agent or a proteasome inhibitor (PI). At the time of the auto-HSCT, only 13 (6.7%) patients were in CR and 38 (19.6%) were CR or VGPR after induction therapy (Table). One-hundred and sixty three (84%) patients received mephalan alone as conditioning regimen. Eighty-one (42%) patients received post auto-HCT maintenance. Eighty (41%) patients achieved a CR, while 104 (54%) achieved CR + VGPR after auto-HCT. Six patients (3.1%) developed a second primary malignancy post- autologous transplant. After a median follow-up of 95.4 months, median PFS was 97.3 months and median OS has not been reached. The 10-year PFS and OS were 41% and 73% respectively. Use of melphalan alone as preparative regimen was associated with a longer PFS and OS (p=0.004 and 0.004, respectively). Achievement of CR after auto-HCT was associated with a longer PFS only (p=0.001), and the use of IMiD or a PI as induction was associated with a longer OS (p=0.01). Conclusion Approximately 17% patients achieved a median PFS of 6 years or longer after a single auto-HCT. The long PFS in this cohort may be associated with younger age, low incidence of HR cytogenetics, use of an IMiD or PI as induction therapy, relatively low disease burden at auto-HCT, transplant from the year 2000 onwards, achievement of CR in >40% and the use of melphalan alone as preparative regimen. Disclosures: Shah: Celgene: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Qazilbash:Celgene: Membership on an entity’s Board of Directors or advisory committees.

Venetoclax Monotherapy for Relapsed/Refractory Multiple Myeloma: Safety and Efficacy Results from a Phase I Study

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 488-488 ◽  
Author(s):  
Shaji Kumar ◽  
Ravi Vij ◽  
Jonathan L. Kaufman ◽  
Joseph Mikhael ◽  
Thierry Facon ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Disease Progression ◽  
Board Of Directors ◽  
Dose Escalation ◽  
Research Funding ◽  
Objective Response ◽  
White Blood Cells ◽  
Cell Transplant ◽  
Weekly Dose ◽  
Advisory Committees

Abstract Background: Venetoclax (VEN) is a potent, selective, orally available small-molecule BCL-2 inhibitor that induces cell death in multiple myeloma (MM) cell lines and primary samples, particularly those with t(11;14), which mostly have a favorable high BCL-2, low BCL-XL, and low MCL-1 profile. Methods: In this Phase 1, open-label study, patients (pts) with relapsed/refractory (R/R) MM received VEN monotherapy. Objectives of the study were to assess safety, pharmacokinetics, maximum tolerated dose, recommended phase 2 dose, and efficacy (objective response rate [ORR], time to progression [TTP], and duration of response [DoR]) of VEN. After a 2-week lead in period with weekly dose escalation, VEN was given daily at final doses of 300, 600, 900, or 1200mg in dose escalation cohorts and 1200mg in the safety expansion. Pts who progressed during VEN monotherapy could receive VEN plus dexamethasone and continue in the study. Results: As of 01July2016, 66 pts were enrolled in the study (30 in dose escalation cohorts and 36 in safety expansion). Median age was 63 years and 39 (62%) pts were ISS stage II/III. The median number of prior therapies was 5 (range: 1-15), and 62 (94%) pts had received bortezomib (46 [70%] refractory), 62 (94%) received lenalidomide (51 [77%] refractory), and 50 (76%) had prior autologous stem cell transplant. Thirty (46%) pts had t(11;14) MM. Median time on VEN monotherapy for all pts was 2.5 months (.2-23); 17 (26%) elected to receive VEN and dexamethasone combination after disease progression for a median of 1.4 months (.1-11). Fifty-one (77%) pts discontinued the study for the following primary reasons: 39 related to disease progression, 5 due to AEs/toxicity, 2 withdrew consent, 1 was lost to follow up, and 4 for other reasons not specified. Common adverse events (AEs) in ≥20% of pts were nausea (48%), diarrhea (36%), neutropenia (32%), thrombocytopenia (32%), fatigue (27%), anemia (23%), back pain (21%), and vomiting (21%). Grade 3/4 AEs in ≥10% of pts were thrombocytopenia (26%), neutropenia (20%), lymphopenia (15%), anemia (14%), and decreased white blood cells (12%). Serious AEs in ≥2 pts were pneumonia (n=5), sepsis (3), pain, pyrexia, cough, and hypotension (2 each). Two pts experienced dose-limiting toxicities at 600mg of abdominal pain and nausea. Eight deaths were reported: 6 due to disease progression, 1 due to lung disorder, and 1 due to brain hemorrhage following injury; neither were considered by the investigator as related to VEN. Steady state VEN exposures were approximately dose proportional at all doses but 900mg. As of 20July2016, ORR for all pts on VEN monotherapy was 21% (14/66) and 10 (15%) achieved very good partial response (VGPR) or better (2 stringent complete response [sCR], 2 CR, 6 VGPR) (Figure); median DoR and TTP was 9.7 and 2.6 months, respectively. Most objective responses (12/14 [86%]) were reported in the subset of pts with t(11;14) MM. In this group, ORR was 40% (12/30) and 27% (8/30) achieved a response of ≥VGPR; median DoR for pts with t(11;14) was 9.7 months (95% CI: 6.3, -). Pts who achieved at least minimal response in the t(11;14) group (14/30) had a median of 4 prior therapies and were mostly refractory to bortezomib, lenalidomide, or double refractory (71% [10/14] each). For two pts with response in the non-t(11;14)/undetermined group, 1 had a translocation of chromosome 14 with an unidentified partner, and the other had no cytogenetics data available. DoR was 9.5 and 7.2 months in these pts and both are still ongoing. Median TTP for pts with or without/undetermined t(11;14) was 6.6 and 1.9 months, respectively. The median best percent change in primary M protein for pts with t(11;14) (n=23) was -53% vs +11% in the non-t(11;14)/undetermined group (n=23). Additional biomarker subgroup analyses (n=32) showed that efficacy was primarily observed in pts with myeloma cells expressing a favorable BCL-2 family expression profile (high BCL-2, low BCL-XL, low MCL-1) by immunohistochemistry, which was significantly enriched in the t(11;14) population. Indeed, although high BCL-2 expression was observed in a majority of bone marrow core biopsy samples (88%), the t(11;14) subgroup was enriched (81% vs 25%) for tumors expressing high BCL-2, low BCL-XL, and low MCL-1. Conclusions: VEN monotherapy has an acceptable safety profile and clear anti-myeloma activity in pts with R/R MM, primarily with t(11;14) having a high BCL-2, low BCL-XL and low MCL-1 expression levels. Figure Figure. Disclosures Kumar: Janssen: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Noxxon Pharma: Consultancy, Research Funding; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx: Consultancy, Research Funding; Glycomimetics: Consultancy; AbbVie: Research Funding; Array BioPharma: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Kesios: Consultancy; BMS: Consultancy. Kaufman:Novartis: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Pharmacyclics: Consultancy; Incyte: Consultancy. Mikhael:Abbvie: Research Funding; Celgene: Research Funding; Onyx: Research Funding; Sanofi: Research Funding. Facon:Amgen: Consultancy, Speakers Bureau; Novartis: Consultancy; Bristol: Consultancy; Millenium/Takeda: Consultancy; Janssen: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Karyopharm: Consultancy. Benboubker:Takeda: 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; 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. Moreau:Celgene: Honoraria; Janssen: Honoraria; Takeda: Honoraria; Novartis: Honoraria; Amgen: Honoraria. Alzate:AbbVie: Employment. Ross:AbbVie: Employment, Equity Ownership. Dunbar:AbbVie Inc.: Employment, Other: may own stock. Xu:AbbVie: Employment. Agarwal:AbbVie: Employment. Leverson:AbbVie: Employment, Other: Shareholder in AbbVie. Maciag:AbbVie: Employment. Verdugo:AbbVie: Employment, Other: may own stock. Touzeau:AbbVie: Research Funding.

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 Supermobilizers with High CD34 + Cell Collection for Autologous Transplant and Impact on Survival Outcomes in Multiple Myeloma

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1837-1837
Author(s):  
Eyal Lebel ◽  
Katherine Lajkosz ◽  
Esther Masih-Khan ◽  
Donna E. Reece ◽  
Suzanne Trudel ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Maintenance Therapy ◽  
Board Of Directors ◽  
Induction Therapy ◽  
Research Funding ◽  
Survival Outcomes ◽  
Advisory Committees ◽  
Cd34 Cells

Abstract Introduction: Autologous stem cell transplantation (ASCT) is standard therapy for selected patients with newly diagnosed multiple myeloma (MM). Studies in MM and lymphoma have suggested that ability to mobilize and collect a higher yield of CD34 + cells predicts for improved survival outcomes, perhaps reflecting better bone marrow reserve (Bolwell 2007, Raschle 2011). We aimed to validate this hypothesis by correlating high CD34 + cell collection ("supermobilizers") and survival outcomes in a large myeloma cohort with long follow-up. Methods: We retrospectively reviewed MM patients (pts) who underwent ASCT at our centre 2000-2010, correlating number of CD34 + cells collected with post-transplant progression-free survival (PFS) and overall survival (OS). Stem cells were mobilized using cyclophosphamide 2.5 g/m 2 IV (day 1), G-CSF 10 ug/kg/day SC (starting on day 4), and leukapheresis (day 11), targeting 4x10 6/kg but accepting a minimum of 2x10 6/kg to support a single transplant. Using a cut-off used in previous studies, pts were categorized as "supermobilizers" if ≥8x10 6/kg CD34+ cells were collected. Results: 621 pts were analyzed. Most pts (422/605; 70%) received high dose dexamethasone (HDD) alone or in combination with vincristine and adriamycin (VAD) for pre-transplant induction therapy (pre-dating the novel agent era) with only 18% (110/605) receiving more contemporary bortezomib-based induction (mostly cyclophosphamide, bortezomib and dexamethasone; CyBORD). The median number of CD34 + cells collected for all pts was 13.9x10 6/kg (range 2.1-61.8). The median CD34 + cells re-infused was 6.2x10 6/kg (range 2.1-25), as some cells were reserved for 2 nd ASCT, but median CD34+ cells collected correlated with CD34 + cells infused (Pearson coefficient 0.81, p&lt;0.001). At a median follow-up of 74 months (m), we were surprised to report an inferior PFS of 24.1m for the supermobilizers collecting ≥8x10 6/kg vs 33.7m for the &lt;8 group (p=0.038, Figure 1a), without differences in OS (p=0.612, Figure 1b). No further discrimination in PFS was observed when using a more extreme supermobilizer cut-off of 15x10 6/kg. To further understand the counterintuitive result of shorter PFS with higher mobilization capacity, we explored the continuous relationship between CD34 + cells and PFS, identifying another optimal cut-off of 4.5x10 6/kg. Pts collecting in the mid-range (4.5-8; n=129) achieved the best PFS of 34.5m, significantly improved over 24.1m in the ≥8 group (n=478) and 11.4m in the small group at the extreme lower collection range (n=14; ≤4.5x10 6/kg)(Figure 1c). A similar pattern was seen with OS (Figure 1d). Clinical and laboratory parameters that may impact both collection capacity and survival, such as age, ISS, and kidney dysfunction, were investigated as confounders but were similar between collection groups and did not predict for PFS in multivariable analyses. Treatment variables, however, differed between groups: the lower collection groups more often received bortezomib-based induction (29%, 31% and 14% in the ≤4.5, 4.5-8 and ≥8 groups, respectively, p&lt;0.001) resulting in deeper responses pre-transplant (VGPR 50% in the ≥8 group vs 43% in the 4.5-8 group, p=0.024) (Table 1). Use of maintenance therapy post-ASCT also differed (50%, 40% and 28% in the ≤4.5, 4.5-8 and ≥8 groups, respectively, p=0.006). Discussion: In this large cohort of 621 MM patients, we report that "supermobilizers" who collected ≥8 x 10 6 CD34 + cells/kg exhibit inferior PFS from transplant than those with less robust mobilization. We suspected that this unexpected observation was due to confounding variables, and identified differences in treatment, primarily greater use of bortezomib-based induction and post-transplant maintenance therapy in the lower collection group. This group was able to achieve deeper responses (≥VGPR) even before transplant than the supermobilizer group, leading to improved PFS. Although bortezomib is routinely used as induction therapy pre-transplant currently and is not felt to be stem cell toxic, it may impair mobilization to a lesser degree, leading not to abject failure of collection but lowered capacity to achieve "supermobilizer" status. Although more research is needed to validate this hypothesis, we can at minimum conclude that high stem cell collection does not appear to predict for a long-term survival advantage. Figure 1 Figure 1. Disclosures Reece: Millennium: Research Funding; Sanofi: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Research Funding; GSK: Honoraria; BMS: Honoraria, Research Funding. Trudel: Amgen: Honoraria, Research Funding; BMS/Celgene: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Genentech: Research Funding; Sanofi: Honoraria; Pfizer: Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Roche: Consultancy. Prica: Astra-Zeneca: Honoraria; Kite Gilead: Honoraria. Chen: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astrazeneca: Membership on an entity's Board of Directors or advisory committees; Beigene: Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy.

scholarly journals Health-Related Quality of Life of Patients with Newly Diagnosed Multiple Myeloma Receiving Any or Lenalidomide Maintenance after Autologous Stem Cell Transplant in the Connect® MM Disease Registry

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 537-537 ◽  
Author(s):  
Rafat Abonour ◽  
Brian G.M. Durie ◽  
Sundar Jagannath ◽  
Jatin J. Shah ◽  
Mohit Narang ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Maintenance Therapy ◽  
Board Of Directors ◽  
Autologous Stem Cell Transplant ◽  
Cell Transplant ◽  
Employment Equity ◽  
Advisory Committees ◽  
Related Quality ◽  
Health Related ◽  
Equity Ownership

Abstract Introduction: Phase 3 trials demonstrated maintenance therapy after autologous stem cell transplant (ASCT) extended time to progression, progression-free survival, and in some cases overall survival for patients (pts) with multiple myeloma (MM) (Sonneveld, 2012; McCarthy, 2012; Attal, 2012; Palumbo, 2014; Attal, 2016). Maintenance treatment until progression has the potential to adversely impact health-related quality of life (HRQoL). Few HRQoL analyses have been published in MM, especially with regard to maintenance therapy after ASCT. Connect® MM is the first and largest multicenter, US-based, prospective observational cohort study designed to characterize treatment patterns and outcomes for pts with newly diagnosed MM (NDMM). This analysis evaluated HRQoL of pts who received Any maintenance therapy, lenalidomide (LEN) only, or No maintenance post-ASCT. Methods: Pts ≥ 18 years with NDMM within 60 days of diagnosis were eligible for enrollment in the registry. For this analysis, pts who completed induction therapy and first-line ASCT who may or may not have gone on to receive maintenance (yes/no) were included. Pts were evaluated in 3 groups: Any maintenance (including LEN-only), LEN-only maintenance, and No maintenance. Pt-reported HRQoL data were collected at protocol-defined quarterly visits. The primary HRQoL measure analyzed was the EQ-5D Index score. Secondary measures included the Functional Assessment of Cancer Therapy-Multiple Myeloma (FACT-MM) total score and the Brief Pain Inventory (BPI). HRQoL assessments were analyzed at study entry (study baseline); after induction therapy but prior to ASCT (analytic baseline); and quarterly from 100 days post-ASCT until the end of maintenance (maintenance groups) or until progressive disease, discontinuation, or death (all groups) (analytic period). SAS Proc Mixed with a random effects unstructured covariance matrix was used to estimate mixed regression models to test the null hypothesis of no HRQoL difference between pts receiving Any or LEN-only maintenance vs No maintenance. A quadratic growth model was used with time as a continuous variable (given that ASCT can occur at any fractional quarterly period post-enrollment and having a starting at 100 days post-ASCT), adjusted for potential confounders. Results: Between September 2009 and December 2011, Connect® MM enrolled 1493 pts in Cohort 1 from community (82%) and academic (17%) centers. Of the 540 pts who received ASCT, 238 met the analysis criteria for Any maintenance, 167 for LEN-only, and 138 for No maintenance. Median age (range) was 60 years (24-78); 61% were male, and 85% were white. The majority were Eastern Cooperative Oncology Group performance status 0/1 (64%) and International Staging System stage I/II (56%). A higher proportion of pts in the Any and LEN-only maintenance groups received triplet therapy as induction vs the No maintenance group (64%, 66%, and 51%, respectively). Median duration (range) of maintenance in the Any and LEN-only maintenance groups was 23.0 months (0.8-50.4) and 24.4 months (0.6-50.4), respectively. During the analytic period, the EQ-5D questionnaire completion rate across the 3 comparison groups was similar and decreased at a similar rate over time. The median number (range) of EQ-5D forms completed per patient was 4.5 (1.0-16.0), 5.0 (1.0-15) and 5.0 (1.0-16.0) for Any, LEN-only, and No maintenance groups, respectively. The mean baseline HRQoL scores for each measure were similar across the 3 groups, with ranges of EQ-5D (0.75-0.76), FACT-MM Total (114.8-119.7), and BPI (3.87-4.06). There were no significant differences in estimated mean post-ASCT scores when comparing Any or LEN-only with the No maintenance group for the EQ-5D Overall Index, the FACT-MM Total Score, or the BPI (Table and Figure). Conclusions: NDMM pts in the Connect® MM registry receiving Any or LEN-only maintenance therapy vs No maintenance after ASCT demonstrated generally similar HRQoL scores for the EQ-5D Index, FACT-MM, and BPI. These results suggest that there is no difference in HRQoL for those who received maintenance compared with those who did not despite the risks associated with continued active therapy. Save Disclosures Abonour: Celgene: Membership on an entity's Board of Directors or advisory committees. Jagannath:Bristol-Myers Squibb: Consultancy; Celgene: Consultancy; Merck: Consultancy. Terebelo:Celgene: Membership on an entity's Board of Directors or advisory committees. Gasparetto:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy; Bristol-Myers Squibb: Honoraria; Onyx: Honoraria; Janssen: Honoraria. Toomey:Celgene: Consultancy. Hardin:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees. Kitali:Celgene: Employment, Equity Ownership. Gibson:Celgene: Employment, Equity Ownership; Sanofi: Other: Spouse employment . Srinivasan:Celgene: Employment; Individual Patent: Patents & Royalties: US7,495,673B1 Used for MM-Connect Treatment Patterns Abstract.. Swern:Celgene: Employment, Equity Ownership. Rifkin:Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen/ONYX: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Favorable Long-Term Outcomes after Daratumumab Discontinuation in AL Amyloidosis Patients Achieving Deep Responses

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1884-1884 ◽  
Author(s):  
Alfred Chung ◽  
Gregory P. Kaufman ◽  
Surbhi Sidana ◽  
David Iberri ◽  
Erik Eckhert ◽  
...  
Keyword(s):  
Disease Progression ◽  
Board Of Directors ◽  
Median Duration ◽  
Research Funding ◽  
Control Group ◽  
Al Amyloidosis ◽  
Cell Transplant ◽  
Advisory Committees ◽  
Free Interval ◽  
Significant Difference

Daratumumab (DARA) is a CD38-targeted antibody FDA-approved for the treatment of multiple myeloma (MM) and its efficacy has recently been demonstrated in the treatment of AL amyloidosis. DARA is conventionally given indefinitely until evidence of disease progression or intolerance for the treatment of MM. In AL amyloidosis, the optimal duration of therapy is not known, and patients may be treated indefinitely on maintenance, extrapolating from MM data. However, the plasma cell burden observed in AL amyloidosis is often lower than in MM, and thus certain patients achieving deep responses may have durable responses with time-limited treatment. Outcomes for patients who are observed after DARA discontinuation are not known. We report the outcomes of patients at our institution who received time-limited DARA. A retrospective analysis of AL amyloidosis patients treated at Stanford University from 2016 to 2019 with DARA monotherapy and dexamethasone for at least 2 months was performed, and patients who subsequently had DARA discontinued for reasons other than disease progression or lack of response were selected for the study. Hematologic responses were assessed by consensus guidelines. Duration on and off therapy were explored, along with time-to-next treatment or death (TTNT), defined as the time from DARA initiation to restarting/switching therapy or death. An exploratory analysis comparing TTNT between the study population and a control cohort who achieved hematologic CR and were maintained on DARA was conducted with the Kaplan-Meier method and log-rank testing. 67 patients received at least 2 months of DARA monotherapy and dexamethasone; among these, 15 patients discontinued therapy for reasons other than disease progression and were included. Median age was 66 years old and median lines of prior therapies was 4 (range: 1 - 6). Baseline difference between involved and uninvolved free light chains (dFLC) prior to DARA initiation was 2.6 mg/dL (range: 0 - 16.8 mg/dL). 10 of 15 patients had cardiac involvement with median NT-proBNP of 1982 pg/mL and 9 of 15 patients had renal involvement with median 24-hour proteinuria of 6.2 g and eGFR of 32 mL/min/1.73m2 at DARA initiation. Median duration from starting to stopping DARA was 7.8 months (range: 2 - 21 months). Median duration from achieving best hematologic response to stopping DARA was 3 months (range: 0 - 17 months). Reasons for discontinuation included: patient preference (5), fatigue/body aches (4), infection (2), other active medical comorbidities (3), and lack of perceived further benefit (1). At DARA discontinuation, median dFLC was 0.1 mg/dL (range: 0 - 2.2 mg/dL) and there were 12 hematologic CR, 1 VGPR, 1 PR, and 1 not assessable for response. Outcomes for all 15 patients are shown in Figure 1. The median treatment-free interval was 17.5 months (range: 5 - 34 months); estimated 2-year TTNT-free survival was 83% (95% CI: 61 - 100%). All 14 evaluable patients eventually achieved CR. 3 patients restarted DARA for rising dFLC, and all 3 patients demonstrated response to retreatment (2 achieving CR and 1 near PR with ongoing follow-up). There were 2 deaths. One patient with severe baseline cardiac amyloidosis developed sudden rise in dFLC after treatment-free interval of 21 months; although he rapidly achieved hematologic CR on retreatment, he died of heart failure within 2 months of restarting DARA. The other patient developed therapy-related AML while off therapy and underwent allogenic stem cell transplant but died of leukemia (censored for AL amyloidosis outcomes at transplant). There was no significant difference in the TTNT between the study group and a control group of 16 patients who achieved CR and were on continuous maintenance (Figure 2; p=0.807). AL amyloidosis patients achieving deep responses with DARA can have favorable outcomes after treatment discontinuation, including a long treatment-free interval. Although our sample size is small, the outcomes of these patients appeared comparable to those achieving CR on continuous DARA maintenance, and patients were able to regain responses when retreatment was necessary. These results suggest that DARA may be safely discontinued in patents achieving deep hematologic responses, which has significant implications for quality of life and financial burden of treatment. Future studies evaluating time-limited versus continuous DARA maintenance after achievement of deep responses are warranted. Disclosures Kaufman: Janssen: Other: travel/lodging, Research Funding. Liedtke:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; IQVIA/Jazz: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech/Roche: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celator: Research Funding; Caelum: Membership on an entity's Board of Directors or advisory committees; BlueBirdBio: Research Funding; Amgen/Onyx: Consultancy, Honoraria, Research Funding; Agios: Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Daratumumab for treatment of AL amyloidosis

scholarly journals VTE Rates and Safety Analysis of Newly Diagnosed Multiple Myeloma Patients Receiving Carfilzomib-Lenalidomide-Dexamethasone (KRD) with or without Rivaroxaban Prophylaxis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1835-1835 ◽  
Author(s):  
Katrina M Piedra ◽  
Hani Hassoun ◽  
Larry W. Buie ◽  
Sean M. Devlin ◽  
Jessica Flynn ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Venous Thromboembolism ◽  
Board Of Directors ◽  
Research Funding ◽  
High Dose ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Cancer Trial ◽  
Oncology Research ◽  
Increased Risk

Introduction Immunomodulatory agents (IMiD's) are associated with an increased risk of venous thromboembolism (VTE), particularly when combined with high dose steroids. Studies evaluating the use of lenalidomide-bortezomib-dexamethasone (RVD) and carfilzomib-lenalidomide-dexamethasone (KRD) in the frontline setting for multiple myeloma (MM) have reported a 6% and 24% incidence of thrombosis, respectively, despite primary thrombotic prophylaxis with aspirin (ASA) (Richardson, et al. Blood. 2010; Korde, et al. JAMA Oncol 2015). Recent data, including the Hokusai VTE Cancer Trial, have suggested that safety and efficacy of direct oral anticoagulants (DOACs) are preserved in the setting of treatment of solid malignancy-associated thrombosis (Raskob, et al. N Engl J Med. 2018; Mantha, et al. J Thromb Thrombolysis. 2017). Despite this data, there is limited experience and use of DOACs in prevention of thromboses in the setting of hematologic malignancies, specifically MM. After careful review of literature, since early 2018, we changed our clinical practice and routinely placed newly diagnosed MM (NDMM) patients receiving KRD at Memorial Sloan Kettering Cancer Center (MSKCC) on concomitant rivaroxaban 10 mg once daily, regardless of VTE risk stratification. In the following abstract, we present VTE rates and safety data for newly diagnosed MM patients receiving RVD with ASA vs. KRD with ASA vs. KRD with rivaroxaban prophylaxis. Methods This was an IRB-approved, single-center, retrospective chart review study. All untreated patients with newly diagnosed MM, receiving at least one cycle of RVD or KRD between January 2015 and October 2018 were included. The period of observation included the time between the first day of therapy until 90 days after completion of induction therapy. Patients were identified by querying the pharmacy database for carfilzomib or bortezomib administration and outpatient medication review of thromboprophylaxis with rivaroxaban or ASA. VTE diagnoses were confirmed by ICD-10 codes and appropriate imaging studies (computed tomography and ultrasound). Descriptive statistics were performed. Results During the observation period, 241 patients were identified to have received RVD or KRD in the frontline (99 RVD with ASA; 97 KRD with ASA; 45 KRD with rivaroxaban). Baseline characteristics were well distributed among the three arms, with a median age of 60 (30-94) in the RVD ASA arm, 62 (33-77) in the KRD ASA arm, and 60 (24-79) in the KRD rivaroxaban arm. Patients had International Staging System (ISS) stage 3 disease in 13% (N=13), 9.3% (N=9), and 11% (N=5) of the RVD ASA, KRD ASA, and KRD rivaroxaban arms, respectively. Median weekly doses of dexamethasone were higher in both KRD arms, 40 mg (20-40) vs. 20 mg (10-40) in the RVD ASA arm. The average initial doses of lenalidomide were 22 mg in the RVD ASA arm compared to 25 mg in both the KRD ASA and KRD rivaroxaban arms. After querying the pharmacy database, no patients were identified to have a history or concomitant use of erythropoietin stimulating agent (ESA) use. Treatment-related VTE's occurred in 4 patients (4.0%) in the RVD ASA arm, 16 patients (16.5%) in the KRD ASA arm, and in 1 patient (2.2%) in the KRD rivaroxaban arm. Average time to VTE was 6.15 months (Range 5.42, 9.73) after treatment initiation in the RVD ASA group, while it was 2.61 months (Range 0.43, 5.06) in the KRD ASA group and 1.35 months in the KRD rivaroxaban group. Minor, grade 1 bleeding events per the Common Terminology Criteria for Adverse Events (CTCAE) were identified in 1 (1.1%) patient in the RVD ASA arm, 5 (5.2%) patients in the KRD ASA arm, and 1 (2.2%) patient in the KRD rivaroxaban arm. Conclusion More efficacious MM combination therapies have been found to increase the risk of VTE when using ASA prophylaxis, indicating better thromboprophylaxis is needed. We found patients receiving ASA prophylaxis with KRD were more likely to experience a VTE and these events occurred earlier compared to patients receiving ASA prophylaxis with RVD. Importantly, the rate of VTE was reduced to the same level as ASA prophylaxis with RVD when low-dose rivaroxaban 10 mg daily was used with KRD, and without necessarily increasing bleeding risk. Our retrospective data support the development of prospective clinical trials further investigating DOAC use in thromboprophylaxis for NDMM patients receiving carfilzomib-based treatments. Figure Disclosures Hassoun: Novartis: Consultancy; Janssen: Research Funding; Celgene: Research Funding. Lesokhin:BMS: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Janssen: Research Funding; GenMab: Consultancy, Honoraria; Serametrix Inc.: Patents & Royalties; Genentech: Research Funding; Juno: Consultancy, Honoraria. Mailankody:Juno: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Takeda Oncology: Research Funding; CME activity by Physician Education Resource: Honoraria. Smith:Celgene: Consultancy, Patents & Royalties, Research Funding; Fate Therapeutics and Precision Biosciences: Consultancy. Landgren:Theradex: Other: IDMC; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees; Karyopharm: 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; Merck: Other: IDMC; Sanofi: Membership on an entity's Board of Directors or advisory committees; Adaptive: 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, Research Funding. OffLabel Disclosure: Off-label use of rivaroxaban for outpatient prophylaxis of venous thromboembolism (VTE) will be explicitly disclosed to the audience.

scholarly journals Results of a Phase I Study of Pnk-007, Allogeneic, Off the Shelf NK Cell, Post Autologous Transplant in Multiple Myeloma (NCT02955550)

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4451-4451
Author(s):  
Sarah A. Holstein ◽  
Sarah Cooley ◽  
Parameswaran Hari ◽  
Sundar Jagannath ◽  
Catherine R Balint ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Maintenance Therapy ◽  
Board Of Directors ◽  
Research Funding ◽  
Phase I Study ◽  
Nk Cell ◽  
Single Infusion ◽  
Advisory Committees ◽  
Cd34 Cells ◽  
Equity Ownership

Background: PNK-007 is an allogeneic, off the shelf cell therapy product enriched for CD56+/CD3- NK cells expanded from placental CD34+ cells. PNK-007 cells exhibit cytotoxicity against various cancer cell types, including multiple myeloma (MM), and secrete cytokines during co-culture with cancer cells. This is a Phase I study of single infusion PNK-007 after autologous stem cell transplant (ASCT) in MM. Methods: Placental CD34+ cells were cultivated in the presence of cytokines for 35 days to generate PNK-007 under cGMP standards followed by release testing. HLA matching and KIR mismatching were not used. Four treatment arms were evaluated on patients (pts) following ASCT: 10 million (M) cells/kg Day (D) 14 with or without recombinant human IL-2 (rhIL-2), 30M cells/kg D14 with rhIL-2, or 30M cells/kg D7 with rhIL-2. rhIL-2 was administered subcutaneously at 6M units every other day for up to 6 doses to facilitate PNK-007 expansion. Pts received variable pre-ASCT induction therapy. Maintenance therapy was permitted after the Day 90-100 visit (D90). Subjects were followed for up to 1-year. Results: 15 pts who received PNK-007 (12 of whom received rhIL-2) were followed on this study. Pts aged 44-69 yrs included 12 newly diagnosed (ND)MM and 3 relapsed/refractory (RR)MM. The 3 RRMM pts had received 1, 2 or 5 prior lines of therapy, with 2 pts having previous ASCT. All pts had been exposed to immunomodulatory drug (IMiDs) and proteasome inhibitors (PIs). No serious adverse events (AEs) were attributable to PNK-007 and no dose-limiting toxicity, GvHD, graft failure or graft rejection were observed. 12/15 pts started maintenance therapy following the transplant while participating in this study, at the physician's discretion. Based on physician assessed responses by International Myeloma Working Group pre-ASCT, of the NDMM pts 10/12 achieved VGPR or better (1 CR and 9 VGPR), 1/12 achieved PR and 1/12 was not assessed during pre-ASCT induction. By D90 10/12 pts achieved VGPR or better (5 CR or sCR and 5 VGPR), 1/12 maintained PR and 1/12 stable disease. At 1-year 9/11 achieved VGPR or better (4 CR or sCR and 5 VGPR), 2/11 were not assessed and 1 was removed from the study prior to 1 year due to failure to respond to ASCT. Of the RRMM pts 2/3 achieved PR and 1/3 was not assessed during pre-ASCT induction, by D90 2/3 achieved VGPR and the pt that had not been assessed pre-ASCT achieved PR. At 1-year, 1 pt maintained VGPR, 1 pt was not assessed and 1 pt did not continue to the 1-year visit. Using a validated Euro-flow minimal residual disease (MRD) assay of bone marrow aspirate (BMA) samples, of the NDMM pts 4/12 were MRD negative (MRD-) pre-ASCT; by D90 9/12 were MRD-. At 1-year 6/12 were MRD-, 2/12 had insufficient BMA to perform testing, 2/12 refused BMA procedure, 1/12 did not convert to MRD-, and 1 was removed from the study prior to 1-year due to failure to respond to ASCT. Of the RRMM pts 0/3 were MRD- pre-ASCT with 1/3 having insufficient BMA to perform testing; by D90 1/3 were MRD-. At 1-year 1/3 was MRD-, 1/3 did not convert to MRD- and 1 pt did not continue to the 1-year visit. PNK-007 infusion did not interfere with immune reconstitution kinetics. Platelet, neutrophil, and absolute lymphocyte counts recovered by day 28 post-ASCT in 12/15 patients. All pts' sera tested negative for the presence of anti-HLA antibodies at all timepoints indicating the absence of humoral immunity and alloantibodies to PNK-007. Conclusion: PNK-007 is the first fully allogeneic, off the shelf CD34+ derived NK cell product in MM clinical trials. A single infusion of PNK-007 up to 30M cells/kg with and without rhIL-2 was well tolerated in the post-ASCT setting. We established the feasibility of infusing PNK-007 as early as 7 days post-ASCT without negative impact on blood count recovery or successful engraftment. BMA MRD- status was observed in 7/9 MRD evaluable pts at 1-year post ASCT. These clinical data are encouraging and warrant further evaluation. Disclosures Holstein: Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; Takeda: Membership on an entity's Board of Directors or advisory committees; Sorrento: Consultancy; GSK: Consultancy; Genentech: Membership on an entity's Board of Directors or advisory committees. Cooley:Fate Therapeutics, Inc: Employment, Equity Ownership. Hari:Cell Vault: Equity Ownership; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Research Funding; Janssen: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Amgen: Research Funding; Spectrum: Consultancy, Research Funding; Sanofi: Honoraria, Research Funding; AbbVie: Consultancy, Honoraria. Jagannath:BMS: Consultancy; Merck: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Medicom: Speakers Bureau; Multiple Myeloma Research Foundation: Speakers Bureau. Balint:Celgene: Equity Ownership; Celularity, Inc: Employment. Van Der Touw:Celularity, Inc: Employment. Zhang:Celularity Inc: Employment. Hariri:Celularity Inc: Employment. Vij:Bristol-Myers Squibb: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Genentech: Honoraria; Janssen: Honoraria; Karyopharm: Honoraria; Sanofi: Honoraria; Takeda: Honoraria, Research Funding.

scholarly journals Phase II Trial of the Combination of Ixazomib, Lenalidomide, and Dexamethasone in High-Risk Smoldering Multiple Myeloma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 804-804 ◽  
Author(s):  
Mark Bustoros ◽  
Chia-jen Liu ◽  
Kaitlen Reyes ◽  
Kalvis Hornburg ◽  
Kathleen Guimond ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
High Risk ◽  
Disease Progression ◽  
Board Of Directors ◽  
Rna Sequencing ◽  
Research Funding ◽  
Response Rate ◽  
Advisory Committees ◽  
Equity Ownership

Abstract Background. This study aimed to determine the progression-free survival and response rate using early therapeutic intervention in patients with high-risk smoldering multiple myeloma (SMM) using the combination of ixazomib, lenalidomide, and dexamethasone. Methods. Patients enrolled on study met eligibility for high-risk SMM based on the newly defined criteria proposed by Rajkumar et al., Blood 2014. The treatment plan was designed to be administered on an outpatient basis where patients receive 9 cycles of induction therapy of ixazomib (4mg) at days 1, 8, and 15, in combination with lenalidomide (25mg) at days 1-21 and Dexamethasone at days 1, 8, 15, and 22. This induction phase is followed by ixazomib (4mg) and lenalidomide (15mg) maintenance for another 15 cycles. A treatment cycle is defined as 28 consecutive days, and therapy is administered for a total of 24 cycles total. Bone marrow samples from all patients were obtained before starting therapy for baseline assessment, whole exome sequencing (WES), and RNA sequencing of plasma and bone marrow microenvironment cells. Moreover, blood samples were obtained at screening and before each cycle to isolate cell-free DNA (cfDNA) and circulating tumor cells (CTCs). Stem cell collection is planned for all eligible patients. Results. In total, 26 of the planned 56 patients were enrolled in this study from February 2017 to April 2018. The median age of the patients enrolled was 63 years (range, 41 to 73) with 12 males (46.2%). Interphase fluorescence in situ hybridization (iFISH) was successful in 18 patients. High-risk cytogenetics (defined as the presence of t(4;14), 17p deletion, and 1q gain) were found in 11 patients (61.1%). The median number of cycles completed was 8 cycles (3-15). The most common toxicities were fatigue (69.6%), followed by rash (56.5%), and neutropenia (56.5%). The most common grade 3 adverse events were hypophosphatemia (13%), leukopenia (13%), and neutropenia (8.7%). One patient had grade 4 neutropenia during treatment. Additionally, grade 4 hyperglycemia occurred in another patient. As of this abstract date, the overall response rate (partial response or better) in participants who had at least 3 cycles of treatment was 89% (23/26), with 5 Complete Responses (CR, 19.2%), 9 very good partial responses (VGPR, 34.6%), 9 partial responses (34.6%), and 3 Minimal Responses (MR, 11.5%). None of the patients have shown progression to overt MM to date. Correlative studies including WES of plasma cells and single-cell RNA sequencing of the bone microenvironment cells are ongoing to identify the genomic and transcriptomic predictors for the differential response to therapy as well as for disease evolution. Furthermore, we are analyzing the cfDNA and CTCs of the patients at different time points to investigate their use in monitoring minimal residual disease and disease progression. Conclusion. The combination of ixazomib, lenalidomide, and dexamethasone is an effective and well-tolerated intervention in high-risk smoldering myeloma. The high response rate, convenient schedule with minimal toxicity observed to date are promising in this patient population at high risk of progression to symptomatic disease. Further studies and longer follow up for disease progression are warranted. Disclosures Bustoros: Dava Oncology: Honoraria. Munshi:OncoPep: Other: Board of director. Anderson:C4 Therapeutics: Equity Ownership; Celgene: Consultancy; Bristol Myers Squibb: Consultancy; Takeda Millennium: Consultancy; Gilead: Membership on an entity's Board of Directors or advisory committees; Oncopep: Equity Ownership. Richardson:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: 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; BMS: Research Funding; Janssen: 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. Ghobrial:Celgene: Consultancy; Takeda: Consultancy; Janssen: Consultancy; BMS: Consultancy.

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