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.

Variation in Health-Related Quality of Life (HRQOL) Among Multiple Myeloma Patients by Insurance Coverage

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3150-3150 ◽  
Author(s):  
Chris L. Pashos ◽  
Brian GM Durie ◽  
Robert Rifkin ◽  
Howard Terebelo ◽  
Cristina Gasparetto ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Insurance Coverage ◽  
Insurance Status ◽  
Employment Equity ◽  
Advisory Committees ◽  
The Us ◽  
Related Quality ◽  
Health Related ◽  
Equity Ownership

Abstract Abstract 3150 Introduction. Affordability of health care in the United States (US), and the impact of patient insurance coverage on it have been shown to be associated with the delivery and timeliness of access to care. With increasing costs of novel therapies in hematology and oncology, this concern has been raised in hematologic cancers. This analysis evaluates whether the health-related quality of life (HRQOL) of patients with active, symptomatic multiple myeloma (MM) patients in the US varies by their insurance coverage as they initiate treatment. Methods. Baseline data were collected in Connect MM®, a prospective observational registry initiated in September 2009 involving centers in the US. Data on patient demographics and clinical characteristics were provided by clinicians. HRQOL was reported by patients in the clinic at enrollment, within two months of diagnosis. Patients completed 3 psychometrically validated instruments: the Brief Pain Inventory (BPI), EQ-5D, and Functional Assessment of Cancer Therapy-Multiple Myeloma (FACT-MM). Standard analyses were conducted of each instrument given clinical characteristics at that time. Patients were characterized as to the main source of their insurance coverage: Medicare, Medicaid or Commercial. The Medicare cohort included those with supplemental commercial coverage, and the Medicaid cohort included those with dual Medicare-Medicaid coverage. Reported mean BPI, EQ-5D and FACT-MM scores were analyzed by patient insurance coverage. Statistical significance of score differences among sub-cohorts was ascertained by ANOVA using SAS 9.1. Results. HRQOL data and insurance status were reported by 863 patients, enrolled from 189 centers. Patients were predominantly male (57%) and white (82%) with mean age at 67.0 (standard deviation [SD] 11.3) yrs. HRQOL scores by insurance status are presented: Overall FACT-MM results indicate that Medicaid insurance status is associated with greater decrement in baseline HRQOL compared to the other groups. Statistically significant differences are noted in the FACT-G general cancer HRQOL score, and its physical, social/family and emotional component scores. BPI data (on a scale of 0 [no pain] to 10 [worst pain] indicate that average pain may be worse among Medicaid patients compared to either Medicare or commercially insured patients. There are no statistically significant differences on EQ-5D scores (on a scale of 1 [no problem] to 2 [some problems] to 3 [incapacity] between cohorts based on insurance status. Conclusions. Initial results from the Connect MM® Registry indicate that HRQOL at baseline prior to initiation of treatment is worse among Medicaid patients compared to those with either Medicare or commercial coverage. This should be investigated to determine whether Medicaid patients are accessing care later in disease progression than others covered by Medicare or commercial insurance. Furthermore, future analyses should be conducted of patients by insurance coverage to determine whether status may be associated with access to medical care, subsequent clinical outcomes, and HRQOL over time. Results reported here should serve as a baseline reference. Disclosures: Pashos: Celgene: Membership on an entity's Board of Directors or advisory committees. Durie:Celgene: Membership on an entity's Board of Directors or advisory committees. Rifkin:Celgene: Membership on an entity's Board of Directors or advisory committees. Terebelo:Celgene: Membership on an entity's Board of Directors or advisory committees. Gasparetto:Celgene: Membership on an entity's Board of Directors or advisory committees. Mehta:Celgene: Membership on an entity's Board of Directors or advisory committees. Toomey:Celgene: Membership on an entity's Board of Directors or advisory committees. Abonour:Celgene: Membership on an entity's Board of Directors or advisory committees. Fonseca:Celgene: Membership on an entity's Board of Directors or advisory committees. Narang:Celgene: Membership on an entity's Board of Directors or advisory committees. Shah:Celgene: Membership on an entity's Board of Directors or advisory committees. Swern:Celgene Corporation: Employment, Equity Ownership. Sullivan:Celgene: Employment, Equity Ownership. Street:Celgene: Employment, Equity Ownership. Khan:Celgene: Employment, Equity Ownership.

Association of Race with Health-Related Quality of Life (HRQOL) Among Multiple Myeloma Patients

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 5070-5070 ◽  
Author(s):  
Chris L. Pashos ◽  
Brian GM Durie ◽  
Robert Rifkin ◽  
Howard Terebelo ◽  
Cristina Gasparetto ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Employment Equity ◽  
Advisory Committees ◽  
Patient Race ◽  
The Us ◽  
Related Quality ◽  
Health Related ◽  
Equity Ownership

Abstract Abstract 5070 Introduction. Studies in the United States (US) have identified variation in incidence and survival of multiple myeloma (MM) patients of different races, and noted that MM is the most common hematologic cancer among African Americans. This analysis was conducted to evaluate whether the health-related quality of life (HRQOL) of patients in the US as they initiate treatment with active, symptomatic MM varies by race. Methods. Data were collected in Connect MM®, a prospective observational registry begun in September 2009 involving centers in the US. Data on patient demographics and clinical characteristics were provided by clinicians. HRQOL was reported by patients in the clinic at enrollment, within two months of diagnosis. Patients completed 3 psychometrically validated instruments: the Brief Pain Inventory (BPI), EQ-5D, and Functional Assessment of Cancer Therapy-Multiple Myeloma (FACT-MM). Standard analyses were conducted of each instrument. Reported mean BPI, EQ-5D and FACT-MM scores were analyzed by patient race. Statistical significance of score differences was ascertained by ANOVA using SAS 9.1 in two ways: (1) among three different racial categories (White, Black and Other), and (2) between Blacks and non-Blacks. Hispanic/Latino patients and Asian patients comprise most of the Other cohort. Results. HRQOL data at baseline were reported by 916 pts, enrolled from 189 centers. Of these patients, 82% were White, 12% were Black, and 5% were of another race (Other). Among evaluable patients, the different race groups did not differ statistically by ECOG status or multiple myeloma stage (measured by either the International Staging System or the Durie and Salmon system). The three racial groups differed by age, with the mean (SD) age of Blacks (63 (11)) and Others (63 (13)) being less than that of Whites (68 (11), p<0.0001). Gender was trending, but not statistically significantly different, between races, with males comprising 58% of Whites, 52% of Blacks, and 46% of Others (p=0.1803). HRQOL scores by race are presented here: Overall FACT-MM results indicate that baseline HRQOL does not vary between races, as the main summary scores do not differ statistically, although the FACT-MM Total scores of Blacks and Whites are trending higher than those of Others. Only the emotional and social/family domain scores of the FACT-MM vary statistically, as Blacks show a worse mean score in the social/family domain and a better score in the emotional domain. BPI data (on a scale of 0 [no pain] to 10 [worst pain] do not show a statistically significant difference between races, and the same is true of the five EQ-5D domains (measured on a scale of 1 [no problem] to 2 [some problems] to 3 [incapacity]. Conclusions. Initial results from the Connect MM® Registry indicate that HRQOL at baseline prior to initiation of treatment does not vary by patient race. As such, these results may serve as a baseline reference for future analyses. In particular, as patients proceed through therapy, analyses should be conducted of patients by race, among other factors, to determine whether it may be associated with subsequent clinical outcomes and HRQOL over time. Disclosures: Pashos: Celgene: Membership on an entity's Board of Directors or advisory committees. Durie:Celgene: Membership on an entity's Board of Directors or advisory committees. Rifkin:Celgene: Membership on an entity's Board of Directors or advisory committees. Terebelo:Celgene: Membership on an entity's Board of Directors or advisory committees. Gasparetto:Celgene: Membership on an entity's Board of Directors or advisory committees. Mehta:Celgene: Membership on an entity's Board of Directors or advisory committees. Toomey:Celgene: Membership on an entity's Board of Directors or advisory committees. Abonour:Celgene: Membership on an entity's Board of Directors or advisory committees. Fonseca:Celgene: Membership on an entity's Board of Directors or advisory committees. Narang:Celgene: Membership on an entity's Board of Directors or advisory committees. Shah:Celgene: Membership on an entity's Board of Directors or advisory committees. Swern:Celgene Corporation: Employment, Equity Ownership. Sullivan:Celgene: Employment, Equity Ownership. Street:Celgene: Employment, Equity Ownership. Khan:Celgene: Employment, Equity Ownership.

Variation in Health-Related Quality of Life by Age Among Patients with Chronic Lymphocytic Leukemia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2085-2085
Author(s):  
Chris L. Pashos ◽  
Christopher R Flowers ◽  
Mark Weiss ◽  
Nicole Lamanna ◽  
Charles M Farber ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Age Groups ◽  
Lymphocytic Leukemia ◽  
Age Group ◽  
Employment Equity ◽  
Advisory Committees ◽  
Related Quality ◽  
Health Related ◽  
Equity Ownership

Abstract Abstract 2085 Introduction. Although advanced patient age is commonly used as a factor in selecting therapy for patients with chronic lymphocytic leukemia (CLL), based on presumed associations with functional status, limited data exist regarding the relationships between age and physical, emotional, social, and functional well being. We examined the relationships between age and these domains of health-related quality of life (HRQOL) for CLL patients treated in US community practices. Methods. Baseline data were collected as part of Connect CLL®, a prospective observational registry initiated in March 2010 involving centers in the US. Data on patient demographics and clinical characteristics were provided by clinicians. HRQOL was self-reported by patients in the clinic at enrollment. Patients completed 3 psychometrically validated instruments: the Brief Fatigue Inventory (BFI), EQ-5D, and Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu). Standard analyses were conducted of each instrument given clinical characteristics at that time. Reported mean BFI, EQ-5D and FACT-Leu scores were analyzed by age group (<65, 65–74, >74). Statistical significance of score differences among sub-cohorts was ascertained by ANOVA using SAS 9.1. Results. Baseline HRQOL data were reported by 604 patients, enrolled from 161 centers. Patients were predominantly male (62%) and white (90%) with mean age at 69.9 (standard deviation [SD] 11.2) yrs. HRQOL scores by age group are presented: There were no significant differences between the age groups in fatigue as measured by the BFI, or differences in overall HRQOL as measured by the EQ-5D Visual Analogue Scale (VAS) or the FACT-G. Anxiety/depression and self care are EQ-5D domains that also did not vary by age. Although mobility was most impaired in the oldest age group compared to the two younger groups, usual activities and pain/discomfort were worse in both the younger and older cohorts compared to those 65–74 years of age. FACT-Leu results indicated that the social/family domain scores did not vary by age, but that physical, emotional, and functional domains did vary statistically with the oldest typically doing better than the 65–74 year olds, but not necessarily better than those <65. Conclusions. Initial results from the Connect CLL® Registry indicate that HRQOL does not worsen monotonically with older age. In this cohort, both the youngest and oldest age groups had worse HRQOL in certain domains, presenting an inverted v-shaped relationship. Future analyses should be conducted on: (1) how HRQOL may be affected over time with changes in disease; and, (2) how HRQOL may be influenced by alternative therapies. Results reported here should serve as a useful baseline reference. Disclosures: Pashos: Celgene: Membership on an entity's Board of Directors or advisory committees. Flowers:Genentech/Roche (unpaid): Consultancy; Celgene: Consultancy; Millennium/Takeda: Research Funding; Wyeth: Research Funding; Novartis: Research Funding. Weiss:Celgene: Membership on an entity's Board of Directors or advisory committees. Lamanna:Celgene: Membership on an entity's Board of Directors or advisory committees. Farber:Celgene: Membership on an entity's Board of Directors or advisory committees. Kipps:Igenica: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Research Funding; Abbot Industries: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; GSK: Research Funding; Gilead Sciences: Consultancy, Research Funding; Amgen: Research Funding. Lerner:Celgene: Membership on an entity's Board of Directors or advisory committees. Kay:Celgene: Membership on an entity's Board of Directors or advisory committees. Sharman:Celgene: Membership on an entity's Board of Directors or advisory committees. Grinblatt:Celgene: Membership on an entity's Board of Directors or advisory committees. Flinn:Celgene: Membership on an entity's Board of Directors or advisory committees. Kozloff:Celgene: Membership on an entity's Board of Directors or advisory committees. Swern:Celgene Corporation: Employment, Equity Ownership. Kahn:Celgene Corporation: Employment, Equity Ownership. Street:Celgene: Employment, Equity Ownership. Sullivan:Celgene: Employment, Equity Ownership. Keating:Celgene: 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.

Continued Treatment Duration, Drug dosing  and Health-Related Quality Of Life (HRQoL) Of Patients With Relapsed/Refractory Multiple Myeloma (RRMM) Receiving 2nd and 3rd Line Treatments: Results From a European Multicentre Study

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5368-5368
Author(s):  
Maria Teresa Petrucci ◽  
Xavier Leleu ◽  
Charalampia Kyriakou ◽  
Isabelle Vande Broek ◽  
Philip T Murphy ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Multiple Myeloma ◽  
Final Visit ◽  
Employment Equity ◽  
Advisory Committees ◽  
Multicenter Observational Study ◽  
Related Quality ◽  
Health Related ◽  
Equity Ownership

Abstract Introduction The use of novel therapeutic agents has significantly improved both progression-free and overall survival in multiple myeloma (MM) patients. In this context, evaluating health-related quality of life (HRQoL) gains in importance. The objective of this analysis is to explore patients’ HRQoL associated with 2nd and 3rdline treatments for Relapsed/Refractory MM (RRMM) and to compare HRQoL in those patients that completed 6 months of treatment vs. patients who discontinued from the study earlier. Methods A multicenter observational study is being conducted in 34 sites in Italy, Germany, France, UK, Ireland and Belgium in RRMM patients starting 2nd or 3rd line bortezomib- or lenalidomide-based treatment. HRQoL and symptoms of patients are assessed at baseline, month 3, and month 6 or discontinuation visit using two EORTC questionnaires: 1) Quality-of-Life Core Questionnaire (QLQ-C30) including 15 domains (Global Health Status/QoL, Physical, Role, Emotional, Cognitive and  Social Functioning; Fatigue, Nausea and Vomiting, Pain, Dyspnea, Insomnia, Appetite Loss, Constipation, Diarrhea and Financial Difficulties); 2) and QLQ-Multiple Myeloma (QLQ-MY20) including four domains (Disease Symptoms, Side Effects of Treatment, Body Image and Future Perspective). All EORTC scores range 0-100. Higher HRQoL scores indicate better HRQoL, higher symptom scores indicate worse symptoms. Descriptive statistics and paired t-tests were used in this interim analysis to evaluate changes in scores from baseline. Results As of June 2013, 206 patients (mean age: 69; 51% male) were enrolled in the study and included in this interim analysis. The average time since diagnosis was 3.4 years, with 90% of patients starting 2nd line and 10% starting 3rdline treatment. Overall, EORTC questionnaires were completed by 197, 130, 84 and 34 patients at baseline, month 3, month 6 and discontinuation, respectively. A total of 84 patients received bortezomib and 117 received lenalidomide. Out of 84 bortezomib patients, 54 had already completed their final visit, split about evenly between month 6 (29 patients) and early discontinuation (25 patients, 46%). Out of 117 lenalidomide patients, 64 had completed their final visit assessment, 55 with continued treatment until month 6 and nine patients discontinuing earlier (14%). A substantial and often clinically meaningful decline in HRQoL (Minimal Important Difference, MID > 6, based on 1 standard error measurement, SEM, as calculated from study patients’ baseline QoL), was observed within the patient group discontinuing treatment (see Table 1). The average dosage of lenalidomide treatment was 17.0 mg/day. Bortezomib patients received vial injections at an average of 1.2 mg/m2/day, close to the pre-specified starting dose of 1.3 mg/m2/day. Bortezomib patients who discontinued early had an average number of 3.2 vials per cycle (closer to bi-weekly dosing) and continuers up to month 6 an average of 2.3 vials per cycle, closer to weekly dosing. Conclusions First results of this multicenter observational study show a strong association between treatment discontinuation and HRQoL in RRMM. While HRQoL is maintained in patients who pursue treatment, early treatment discontinuation is significantly associated with worsened HRQoL. Higher discontinuation rates were observed amongst bortezomib treated patients as compared to lenalidomide treated patients.  A direct comparison by treatment group will be performed when final data is available. Disclosures: Petrucci: Celgene: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria. Leleu:Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Onyx: Consultancy, Honoraria; Leopharma: Consultancy, Honoraria; Millennium : Honoraria; Amgen: Honoraria; Novartis: Honoraria. Lewis:Celgene GmbH : Employment, Equity Ownership. Bacon:Celgene International : Employment, Equity Ownership. Arnould:Celgene: Consultancy. Welslau:Celgene: Membership on an entity’s Board of Directors or advisory committees; Janssen: Membership on an entity’s Board of Directors or advisory committees.

scholarly journals A Phase I Trial of Janus Kinase (JAK) Inhibition with INCB039110 in Acute Graft-Versus-Host Disease (aGVHD)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 390-390 ◽  
Author(s):  
Mark A. Schroeder ◽  
H. Jean Khoury ◽  
Madan Jagasia ◽  
Haris Ali ◽  
Gary J. Schiller ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Janus Kinase ◽  
Cell Transplant ◽  
Employment Equity ◽  
Advisory Committees ◽  
Daily Dose ◽  
Equity Ownership ◽  
Grade 3 ◽  
Steroid Refractory

Abstract Background: Corticosteroids are considered standard first-line systemic therapy for patients with aGVHD, but this approach is effective in only approximately half of all cases. For patients who progress or do not respond to corticosteroids, no specific agent has been identified as standard, and regimens are typically selected based on investigator experience and patient co-morbidities. In preclinical models, JAK inhibition has been shown to impair production of cytokines as well as the differentiation and trafficking of T cells implicated in the pathogenesis of aGVHD. Retrospective studies have suggested that JAK1/JAK2 inhibition with ruxolitinib treatment provides clinical benefit in patients with steroid-refractory GVHD (Zeiser et al, Leukemia 2015;29:2062-2068). Herein, we report preliminary safety results from a prospective randomized, parallel-cohort, open-label phase 1 trial evaluating the potent and selective JAK 1 inhibitor INCB039110 in patients with aGVHD. Methods: Male or female patients 18 years or older who underwent their first allo-hematopoietic stem cell transplant (HSCT) from any donor source and developed grades IIB-IVD aGVHD were eligible for the study. Patients were randomized 1:1 to either a 200 or 300 mg oral daily dose of INCB039110 in combination with corticosteroids, and were stratified based on prior treatment status (treatment-naive [TN] versus steroid-refractory [SR]). The primary endpoint of the study was safety and tolerability; secondary endpoints included overall response rate at Days 14, 28, 56, and 100, non-relapse mortality, and pharmacokinetic (PK) evaluations. Patients were assessed through Day 28 for dose-limiting toxicities (DLTs) and response. A Bayesian approach was used for continuous monitoring of DLTs from Days 1-28. Treatment continued until GVHD progression, unacceptable toxicity, or withdrawal from the study. Acute GVHD was graded according to MN-CIBMTR criteria; adverse events (AEs) were graded according to NCICTCAE v 4.03. Results: Between January and June 2016, 31 patients (TN, n=14; SR, n= 17) were randomized. As of July 25, 2016, data were available from 30 patients who received an oral daily dose of 200 mg (n=14) or 300 mg (n=16) INCB039110 in combination with 2 mg/kg methylprednisolone (or equivalent dose of prednisone). The median durations of treatment were 60.8 days and 56.5 days for patients receiving a daily dose of 200 mg and 300 mg INCB039110, respectively. One DLT of Grade 3 thrombocytopenia was reported. The most frequently reported AEs included thrombocytopenia/platelet count decrease (26.7%), diarrhea (23.3%), peripheral edema (20%), fatigue (16.7%), and hyperglycemia (16.7%). Grade 3 or 4 AEs occurred in 77% of patients and with similar frequency across dose groups and included cytomegalovirus infections (n=3), gastrointestinal hemorrhage (n=3), and sepsis (n=3). Five patients had AEs leading to a fatal outcome, including multi-organ failure (n=2), sepsis (n=1), disease progression (n=1), and bibasilar atelectasis, cardiopulmonary arrest, and respiratory distress (n=1); none of the fatal events was attributed to INCB039110. Efficacy and PK evaluations are ongoing and will be updated at the time of presentation. Conclusion: The oral, selective JAK1 inhibitor INCB039110 can be given safely to steroid-naive or steroid-refractory aGVHD patients. The safety profile was generally consistent in both dose groups. Biomarker evaluation, PK, and cellular phenotyping studies are ongoing. The recommended phase 2 dose will be selected and reported based on PK studies and final safety data. Disclosures Schroeder: Incyte Corporation: Honoraria, Research Funding. Khoury:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding. Jagasia:Incyte Corporation: Research Funding; Therakos: Research Funding; Janssen: Research Funding. Ali:Incyte Corporation: Research Funding. Schiller:Incyte Corporation: Research Funding. Arbushites:Incyte Corporation: Employment, Equity Ownership. Delaite:Incyte Corporation: Employment, Equity Ownership. Yan:Incyte Corporation: Employment, Equity Ownership. Rhein:Incyte Corporation: Employment, Equity Ownership. Perales:Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Chen:Incyte Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding. DiPersio:Incyte Corporation: Research Funding.

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.

Carfilzomib, Lenalidomide, and Dexamethasone In Newly Diagnosed Multiple Myeloma: Initial Results of Phase I/II MMRC Trial

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 862-862 ◽  
Author(s):  
Andrzej J Jakubowiak ◽  
Dominik Dytfeld ◽  
Sundar Jagannath ◽  
David H. Vesole ◽  
Tara B. Anderson ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Board Of Directors ◽  
Newly Diagnosed ◽  
Employment Equity ◽  
Advisory Committees ◽  
Level 3 ◽  
Equity Ownership ◽  
Level 1 ◽  
Level 2

Abstract Abstract 862 Background: Carfilzomib (Cfz) is a novel, irreversible proteasome inhibitor that has demonstrated promising single-agent activity and favorable toxicity profile, including very low rates of peripheral neuropathy and neutropenia in relapsed/refractory multiple myeloma (MM). Combining Cfz with Lenalidomide (Revlimid®, Len), and Dexamethasone (Dex) into CRd shows an additive anti-MM effect in preclinical studies and lack of overlapping toxicity allowing for the use of these agents at full doses and for extended duration of time in relapsed/refractory MM (Niesvizky et al, ASH, 2009). This Phase I/II study was designed to determine the maximum tolerated dose (MTD) of CRd and to assess safety and evaluate efficacy of this combination in newly diagnosed MM. Methods: In Phase I, dose escalation follows the TITE-CRM algorithm, with Cfz as the only escalating agent starting at 20 mg/m2 (level 1), maximal planned dose 27 mg/m2 (level 2), and 15 mg/m2, if needed (level -1), given IV on days 1, 2, 8, 9, 15, 16 in 28-day cycles. Len is used at 25 mg PO (days 1–21), and Dex at 40/20 mg PO weekly (cycles 1–4/5-8) for all dose levels. Based on toxicity assessment, the study was amended to add dose level 3 with Cfz at 36 mg/m2 and the number of pts in the Phase I was increased to 35. A total of 36 pts are planned to be treated at the MTD in Phase I/II. Pts who achieve ≥ PR can proceed to stem cell collection (SCC) and autologous stem cell transplant (ASCT) after ≥ 4 cycles, although per protocol design, ASCT candidates are offered to continue CRd treatment after SCC. After completion of 8 cycles, pts receive 28-day maintenance cycles with Cfz (days 1, 2 15, 16), Len days 1–21, and Dex weekly at the doses tolerated at the end of 8 cycles. Responses are assessed by IMWG criteria with the addition of nCR. Results: The study has enrolled 24 pts to date, 4 pts at level 1 (Cfz 20), 14 at level 2 (Cfz 27) and at 6 at level 3 (Cfz 36). Toxicity data are available for 21 pts, of which 19 have completed at least the first cycle required for DLT assessment; 2 pts were removed during the first cycle for events unrelated to study therapy (1 at level 1 and 1 at level 2), and 3 are currently within their first cycle of treatment. There was a single DLT event at dose level 2 (non-febrile neutropenia requiring dose reduction of Len per protocol) and the MTD has not been reached. Hematologic toxicities were reversible and included Grade (G) 3/4 neutropenia in 3 pts, G3/4 thrombocytopenia in 3, and G3 anemia in 2. There have been additional G3 non-hematologic AEs including 1 case of DVT while on ASA prophylaxis, 1 fatigue, 1 mood alteration, and 5 glucose elevations; the last 2 AEs were related to Dex. There was no emergence of peripheral neuropathy (PN), even after prolonged treatment, except in 2 pts who developed G1 sensory PN. Twenty-three pts continue on treatment, most (20 pts) without need for any dose modifications. After a median of 4 (range 1–8) months of treatment, preliminary response rates by IMWG in 19 evaluable pts who completed at least 1 cycle are: 100% ≥ PR, 63% ≥ VGPR, 37% CR/nCR, including 3 pts with sCR. Responses were rapid with 17 of 19 pts achieving PR after 1 cycle and improving responses with continuing therapy in all pts. To date, 7 pts proceeded to SCC using growth factors only, with a median 6.3 × 106 CD34+ cells/kg collected (range 4.1–8.2), after a median of 4 cycles of CRd (range 4–8); all resumed CRd treatment after SCC. After a median of 4 months of follow-up, none of evaluable pts progressed and all are alive. Conclusion: CRd is well tolerated and highly active in newly diagnosed MM with ≥ PR of 100%, including 63% ≥VGPR and 37% CR/nCR. Accrual is ongoing, with updated toxicity and efficacy data to be presented at the meeting. The results of this study represent the first report of treatment of frontline myeloma with Cfz to date, and provide additional support to recently initiated Phase 3 trial of CRd vs. Rd in relapsed MM. Disclosures: Jakubowiak: Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Exelixis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Centocor OrthoBiotech: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Off Label Use: Lenalidomide for newly diagnosed multiple myeloma. Jagannath:Millennium: Honoraria; OrthoBiotech (Canada): Honoraria; Celgene: Honoraria; Merck: Honoraria; Onyx Pharmaceuticals: Honoraria; Proteolix, Inc: Honoraria; Imedex: Speakers Bureau; Medicom World Wide: Speakers Bureau; Optum Health Education: Speakers Bureau; PER Group: Speakers Bureau. Vesole:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Anderson:Millennium: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau. Stockerl-Goldstein:Celgene: Speakers Bureau; Millennium: Speakers Bureau. Barrickman:Celgene: Employment, Equity Ownership. Kauffman:Onyx Pharmaceuticals: Employment, Equity Ownership. Vij:Proteolix: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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.

Targeted MEK Inhibition in Patients with Previously Treated Multiple Myeloma

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

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

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