Reducing Gastrointestinal Toxicity Associated with Autologous Transplantation for Multiple Myeloma without Compromising Its Anti-Myeloma Effect

Abstract Early autologous hematopoietic stem cell transplantation (auto-HCT) is recommended for transplant-eligible patients (pts) with newly diagnosed multiple myeloma (MM). However, gastrointestinal toxicities, i.e., oral mucositis (OM), nausea and diarrhea, are the major limitation to the use of auto-HCT especially in the elderly population which constitute a significant proportion of MM pts, where the median age at diagnosis is 68 years. There is an unmet need for measures to minimize non-hematological toxicities without compromising melphalan anti-myeloma efficacy; this could lead to expansion of transplant eligibility to older pts. Amifostine, a FDA-approved cytoprotective agent to prevent OM for Head and Neck cancer, may reduce HDM-associated GI toxicity. We conducted a case-control study comparing auto-HCT with or without amifostine for MM pts. Methods pre-transplant amifostine has been incorporated to standard protocol for all MM patients underwent auto-HCT at University Hospitals Cleveland Medical Center (UH) for the last decade. One hundred and seven pts treated at UH who received amifostine, from January 2007 to July 2014, were compared to 114 matched-control pts treated at MD Anderson Cancer Center (MDACC) without use of this agent. The institutional review boards at both institutions approved the study. Amifostine 740 mg/m2 was administered as a bolus infusion at 24 hours and 15 minutes before HDM. All pts received ice chips peri-melphalan infusion. Survival outcomes were measured from the date of auto-HCT to the date of disease relapse or progression, Survival distribution was estimated using Kaplan-Meier methods. The effect of treatment on OS and PFS was estimated using a Cox model after controlling for the effects of age, gender, and number of prior therapies, time from diagnosis to transplant, Eastern Cooperative Oncology Group (ECOG) performance status and number of infused CD34+ cells. Results Pts' characteristics were similar in both groups.Median follow-up of surviving pts was 35 (range 2-100) months in both cohorts. Amifostine therapy was well tolerated without any serious adverse effects. There was no significant difference between all-grade OM, nausea or vomiting between the two cohorts. However, > grade II GI toxicities were significantly lower in the amifostine group as follows: OM: 27.1% vs 47.4% (P=0.002), diarrhea: 56.1% vs. 72.7% (P=0.006), nausea: 31.8% vs. 86.0% (P=0.0001) and vomiting: 18.7% vs. 52.6%, (P=0.0001) (Figure-1) (Table-1). Median time to platelet engraftment was similar between the two groups while neutrophil engraftment period was shorter with use of amifostine (10 vs. 11 days, P=0.011) (Table-2). Multivariable logistic regression showed that use of amifostine pre-transplant was associated with a significant decrease in OM, diarrhea, nausea and vomiting. Pts who received amifostine and melphalan developed grade ≥ II OM significantly less often than those given melphalan alone with odds ratio (OR) = 0.366 (95% CI: 0.196-0.685, P=0.001; Table 3). Female gender was associated with a significant increase in OM, nausea and vomiting. Female pts were more likely to develop grade ≥ II OM with OR of 1.967 (P=0.017). Similarly, an ECOG performance status (PS) of ≥ 2 was associated with a significant increase in OM and diarrhea. For every additional score of ECOG, the risk of having grade ≥ II OM increased 1.89 fold (p=0.015). Subgroup analysis of grade II and higher OM rates are shown in Table-4. Use of amifostine was associated with reduced grade II or higher GI toxicity after adjusting for the effects of age, gender, number of prior therapies, time from diagnosis to transplant, ECOG PS and infused CD34 cell dose. There was no detrimental effect of amifostine on progression-free or overall survival. Conclusions Our analysis indicates that the use of two amifostine doses of 740 mg/m2 before auto-HCT is safe and associated with significant reduction in grade II and higher GI toxicities without any deleterious effect on engraftment or anti-myeloma efficacy. Amifostine use could conceivably allow further melphalan dose-intensification for pts with resistant or high-risk disease. Also, pre-treatment with amifostine potentially could expand the utilization of auto-HCT for modestly frail MM pts that might not be considered eligible for this treatment modality. The protective effect of amifostine should be confirmed in randomized trial. Disclosures Malek: Celgene: Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees. Cooper: Novartis: Research Funding. Caimi: Abbvie: Equity Ownership; Incyte: Equity Ownership; Celgene: Speakers Bureau; Seattle Genetics: Equity Ownership. De Lima: Pfizer: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Research Funding.

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A Phase II Study of Modified Lenalidomide, Bortezomib, and Dexamethasone (RVD-lite) for Transplant-Ineligible Patients with Newly Diagnosed Multiple Myeloma

Blood ◽

10.1182/blood.v126.23.4217.4217 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4217-4217 ◽

Cited By ~ 5

Author(s):

Elizabeth K. O'Donnell ◽

Jacob P. Laubach ◽

Andrew J. Yee ◽

Carol A. Huff ◽

Frank G. Basile ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Research Funding ◽

Response Rate ◽

Performance Status ◽

Plasma Concentrations ◽

Newly Diagnosed ◽

Ecog Performance Status ◽

Advisory Committees ◽

Equity Ownership

Abstract Background: Multiple myeloma (MM) is primarily a disease of older adults with median age at diagnosis of 66 years. Although melphalan and prednisone-based regimens were traditionally the most accepted treatment options, recent use of lenalidomide and dexamethasone in this older, transplant-ineligible population as presented in the FIRST trial is the new standard of care in these patients (pts) (NEJM 2014). Here, we sought a regimen that incorporates optimal novel agents in transplant-ineligible, older pts that balances efficacy with toxicity. Building on our promising prior experience with RVD in predominantly younger pts (Blood 2010), our study evaluated a 3-drug regimen of modified RVD in the transplant-ineligible population. Methods: Modified RVD ("RVD-lite") was administered over a 35-day cycle. Lenalidomide 15 mg was given on days 1-21; bortezomib 1.3 mg/m2 once weekly subcutaneously (SC) on days 1, 8, 15, and 22; and dexamethasone 20 mg on days 1, 2, 8, 9, 15, 16, 22 and 23 for pts ≤75 yrs and days 1, 8, 15, 22 for pts older than 75 yrs. Intravenous (IV) bortezomib was used in cycle 1 for the first 10 pts for pharmacokinetic (PK) analysis. Eligibility requirements included ECOG performance status ≤ 2 and acceptable hepatic, renal and hematologic function. The primary objective was to evaluate the objective response rate (ORR) of modified RVD in transplant-ineligible pts. Secondary objectives included evaluation of the safety profile, progression free survival (PFS), overall survival, response rate with respect to cytogenetics, and the PK profile of IV and SC bortezomib. Exploratory analysis will determine minimal residual disease (MRD) status by deep sequencing and correlate with outcomes in patients who achieve a VGPR or better. Results: Fifty-three eligible pts have enrolled between 4/17/13 and 7/25/15, and of those, 50 received at least one dose of therapy. Median age at study entry was 72 years (range 65-91) with 29 women and 24 men. ECOG performance status of pts enrolled was 0 in 25 (47%), 1 in 20 (38%), and 2 in 8 (15 %) pts. The ISS stage was I in 21 (40%), II in 16 (30%), and III in 16 (30%) pts. Treatment-related toxicities were reported for 49 pts. Fatigue was the most commonly reported toxicity occurring in 31/49 (63%), and was mostly grade 1 or 2 and manageable (25/31). Peripheral neuropathy of any grade was reported in 21/49 (43%) pts including grade 1 (11, 22%), 2 (9, 18%), and 3 (1, 2%). Grade 3 or greater toxicities included hypophosphatemia in 15 (31%) and rash in 5 (10%) pts. PK data comparing IV and SC dosing showed no significant differences in plasma concentrations of bortezomib at 5 hours. In the SC route, high body mass index (BMI) patients tended to have low concentration at both the 5 and 30 minute measures but not at 5 hours. There was no correlation with BMI using the IV route. At the planned analysis after 4 cycles that now includes 40 pts, the investigator-reported ORR of PR or better was 90% (CR - 10, VGPR - 14, PR - 12, SD - 4). Five pts withdrew from the study after less than 4 cycles. Of those, one withdrew for worsening adrenal insufficiency, one for rash attributed to lenalidomide, one at the Investigator's discretion, and two for excessive travel distance. Five additional pts have been enrolled but have not completed 4 cycles. Of 48 evaluable patients, the median survival has not been reached. Median duration of follow-up is 17.2 months and the 1-year PFS is 95% (95% CI 0.888, 1) and 2-year PFS is 68% (95% CI 0.512, 0.908). Exploratory data on bone marrow samples on pts achieving VGPR or better have been collected and analysis for MRD is in process. Gene expression profiling was performed using MMprofiler (SkylineDx). High-risk signature will be correlated with pt outcomes. Conclusions: ModifiedRVD is a well-tolerated and highly effective regimen in the transplant-ineligible population. The ORR rate after 4 cycles suggests that this combination at modified doses and on a weekly schedule is very active. The side effect profile proved manageable and was well tolerated in an older population despite the variance of performance status at study entry. There were no significant differences in plasma concentrations of bortezomib observed between IV and SC dosing. The study is fully accrued and this analysis suggests that alternative dosing and schedule of RVD may both improve tolerability and enhance clinical benefit in newly diagnosed, transplant-ineligible MM pts. Disclosures O'Donnell: Millennium: Consultancy. Laubach:Novartis: Research Funding; Onyx: Research Funding; Celgene: Research Funding; Millennium: Research Funding. Schlossman:Millennium: Consultancy. Anderson:Millennium: Consultancy; BMS: Consultancy; Gilead: Consultancy; Oncopep: Equity Ownership; Acetylon: Equity Ownership; Celgene: Consultancy. Richardson:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gentium S.p.A.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Raje:AstraZeneca: Research Funding; Onyx: Consultancy; Millenium: Consultancy; Acetylon: Research Funding; Eli Lilly: Research Funding; Novartis: Consultancy; Celgene Corporation: Consultancy; Takeda: Consultancy; BMS: Consultancy; Amgen: Consultancy.

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Variation in Health-Related Quality of Life by ECOG Performance Status and Fatigue Among Patients with Chronic Lymphocytic Leukemia

Blood ◽

10.1182/blood.v118.21.4591.4591 ◽

2011 ◽

Vol 118 (21) ◽

pp. 4591-4591 ◽

Cited By ~ 1

Author(s):

Chris L. Pashos ◽

Christopher R Flowers ◽

Mark Weiss ◽

Nicole Lamanna ◽

Charles M Farber ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Performance Status ◽

Clinical Practices ◽

Employment Equity ◽

Ecog Performance Status ◽

Advisory Committees ◽

Equity Ownership ◽

Ecog Ps ◽

The Impact

Abstract Abstract 4591 Introduction: Clinicians and investigators appreciate the value of measuring HRQOL for monitoring CLL and the impact of treatments, and commonly use ECOG performance status (PS) and clinician-reported patient fatigue as surrogates for HRQOL in clinical practice. However, limited data exist on the relationships between PS, fatigue, and HRQOL in CLL patients (pts) undergoing treatment in clinical practices. We examined the associations between these measures and 3 psychometrically validated, patient-reported, HRQOL instruments: the Brief Fatigue Inventory (BFI), EQ-5D, and Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu). Methods: Data were collected as part of Connect CLL®, a prospective observational registry initiated in March 2010 involving US practices. Data on pt demographics and clinical characteristics were provided by clinicians. HRQOL was self-reported by pts at enrollment using the BFI, EQ-5D, and FACT-Leu. Mean BFI, EQ-5D and FACT-Leu scores were analyzed by ECOG PS and clinician-reported fatigue. Differences in HRQOL scores between sub-cohorts were assessed by ANOVA. Results: HRQOL data were reported by 604 pts enrolled from 10 academic, 148 community, and 3 government centers. Pts were predominantly male (62%) and white (90%); mean age was 70 (standard deviation 11) years. BFI data (scale: 0 [no fatigue] - 10 [worst fatigue]) indicated that on average pts report that global fatigue, fatigue severity and fatigue-related interference worsen by ECOG severity (Table 1) and are statistically associated with clinician-reported fatigue (Table 2). Mean EQ-5D overall HRQOL as measured by a Visual Analogue Scale (VAS) from 0 (worst) to 100 (best) worsens by ECOG severity and is significantly worse in pts with fatigue. Mean EQ-5D domain scores (scale: 1 [no problem], 2 [some problems], 3 [incapacity]) indicated that pain/discomfort, mobility and usual activities increase in severity as ECOG worsens and in pts with fatigue. FACT-Leu domains except social/family were statistically worse with worse ECOG PS and in pts with fatigue. Conclusions: Initial results from Connect CLL® indicate that HRQOL worsens with worsening ECOG PS, especially in physical / functioning domains, pain/discomfort, and mobility, and worsens across multiple domains among pts whose physicians reported fatigue. Future analyses should be conducted on how HRQOL, PS and fatigue may change over time with changes in CLL, and how they are influenced by therapies. These results may serve as 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.

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A Phase II Study of Modified Lenalidomide, Bortezomib, and Dexamethasone (RVD lite) for Transplant-Ineligible Patients with Newly Diagnosed Multiple Myeloma

Blood ◽

10.1182/blood.v124.21.3454.3454 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3454-3454 ◽

Cited By ~ 8

Author(s):

Elizabeth O'Donnell ◽

Jacob P. Laubach ◽

Andrew J Yee ◽

Carol Ann Huff ◽

Frank Basile ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Interim Analysis ◽

Research Funding ◽

Response Rate ◽

Performance Status ◽

Pharmacokinetic Analysis ◽

Newly Diagnosed ◽

Ecog Performance Status ◽

Advisory Committees

Abstract Background: Multiple myeloma (MM) is primarily a disease of older adults with a median age at diagnosis of 66 years. Despite significant improvements in patient outcomes, there is a lag in survival in older transplant-ineligible patients compared to their younger counterparts. Traditionally, melphalan and prednisone-based regimens were the most widely accepted treatment options in this older, transplant-ineligible population. More recently, the FIRST trial has explored the use of lenalidomide and dexamethasone in these patients. Here, we sought to incorporate optimal novel agent-containing regimens in transplant-ineligible, older patients that balance efficacy with toxicity. Building on our prior experience with RVD in predominantly younger patients, our study evaluated a 3-drug regimen of modified RVD in the transplant-ineligible population. Methods: Modified RVD (“RVD-lite”) was administered over a 35-day cycle. Lenalidomide was given as a single daily oral dose of 15 mg days 1-21; bortezomib 1.3 mg/m2 once weekly subcutaneously on days 1, 8, 15, and 22; and dexamethasone 20 mg on days 1, 2, 8, 9, 15, 16, 22 and 23 for patients ≤75 yrs and days 1, 8, 15, 22 for patients older than 75 yrs. Intravenous bortezomib was used only in cycle 1 for the first 10 patients for pharmacokinetic analysis. Eligibility requirements included ECOG performance status ≤ 2 and acceptable hepatic, renal and hematologic function. The primary objective was to evaluate the objective response rate (ORR) of modified RVD in transplant-ineligible patients. Secondary objectives included evaluation of the safety profile of modified RVD, progression free survival, overall survival, time to response, response duration, the response rate with respect to cytogenetics, and the pharmacokinetic profile of intravenous and subcutaneous bortezomib. Exploratory analysis will determine minimal residual disease (MRD) status by genotyping and correlate with outcomes in patients who achieve a VGPR or better. Results: Forty-one eligible patients have enrolled between 4/17/13 and 7/18/14, and of those 38 received at least one dose of therapy. Median age at study entry was 73 years (range 65-91) with 22 women and 16 men. ECOG performance status of patients enrolled was 0 in 19 (46.3%), 1 in 15 (36.6%), and 2 in 6 (14.6%) patients. The ISS stage was I in 15 (36.6%), II in 9 (22.0%), and III in 10 (24.4%) patients. Treatment-related toxicities were reported for 34 subjects. Fatigue was the most commonly reported toxicity occurring in 17/34 (50.0%), and of those 16/17 were grade 1 or 2 and manageable. Peripheral neuropathy of any grade was reported in 14/34 (41.2%) of patients including Grade 1 -7 (20.6%), 2 – 6 (17.6%), and 3 – 1 (2.9%). 12/34 (35.3%) reported edema of which 11/12 (91.7%) were grade 1. Grade 3 or greater toxicities included hypophosphatemia - 11 (32.3%), Rash - 4 (11.8%), and mood changes - 2 (5.9%). Pharmacokinetic data comparing intravenous and subcutaneous dosing of bortezomib has been completed and analysis is in process. At a planned interim analysis after 4 cycles that included 33 patients, the investigator-reported ORR of PR or better was 81.8% (CR -5, VGPR – 11, PR - 11, SD 3). Three patients withdrew from the study after less than 1 cycle. Of those, one withdrew for worsening adrenal insufficiency, one for rash attributed to lenalidomide, and one for an unrelated toxicity prompting withdrawal at the Investigator’s discretion. Five additional patients have enrolled but have not completed 4 cycles. Of those, responses thus far include 1 CR, 2 PRs, 1 SD, and 1 patient who has not completed one cycle at the time of this analysis. Exploratory data on bone marrow samples on patients achieving VGPR or better have been collected and analysis for MRD is in process. Conclusions: ModifiedRVD appears to be a well-tolerated and highly effective regimen in the transplant-ineligible population. The ORR rate after up to 4 cycles suggests that this combination at the modified doses and on a weekly schedule is very active. The side effect profile proved manageable and well-tolerated in an older population despite the variance of performance statuses at study entrance. Interim analysis of 38 patients suggests that alternative dosing and schedule of RVD may both improve tolerability and enhance clinical benefit in newly diagnosed, transplant-ineligible MM patients. Disclosures Laubach: Onyx, Novartis, Millenium, Celgene: Research Funding. Huff:Celgene, Millenium: Consultancy. Basile:Celgene: Speakers Bureau. Ghobrial:Millennium/Takeda: Membership on an entity's Board of Directors or advisory committees; Onyx: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Schlossman:Millennium: Consultancy. Munshi:Celgene, Onyx, Janssen, Sanofi-Aventi, Oncopep: Consultancy; Oncopep: Equity Ownership; Oncopep: Oncopep Patents & Royalties. Richardson:Celgene, Millenium, Johnson&Johnson: Membership on an entity's Board of Directors or advisory committees. Raje:Amgen, Novartis, Onyx, Celgene, Millenium: Consultancy; Eli Lilly, Acetylon: Research Funding.

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Progression-Free Survival Analysis of Denosumab Vs Zoledronic Acid in Intent to Transplant Multiple Myeloma Patients Based on Treatment Regimen and Baseline Characteristics

Blood ◽

10.1182/blood-2019-127290 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 606-606 ◽

Cited By ~ 7

Author(s):

Evangelos Terpos ◽

Ramón García-Sanz ◽

Kazuyuki Shimizu ◽

Wolfgang Willenbacher ◽

Anthony Glennane ◽

...

Keyword(s):

Multiple Myeloma ◽

Zoledronic Acid ◽

Board Of Directors ◽

Research Funding ◽

Performance Status ◽

Employment Equity ◽

Advisory Committees ◽

Treatment Regimens ◽

Equity Ownership ◽

Baseline Characteristics

Introduction: Denosumab is a monoclonal antibody targeting Receptor Activator of Nuclear Factor-Kappa B Ligand (RANKL) that has been shown to reduce skeletal related events associated with bone lesions in patients with multiple myeloma and solid tumors. Results from the full primary analysis of 1718 patients with newly diagnosed multiple myeloma in an international double blind, randomized, controlled phase 3 (20090482) study that assessed the efficacy of denosumab (Dmab) vs zoledronic acid (ZA) for preventing SREs met its primary end point of non-inferiority regarding time to first SRE. The analysis of the PFS exploratory endpoint showed a clinically meaningful 10.7 months median PFS benefit (HR, 0.82; 95% CI, 0.68-0.99; descriptive P= 0.036) of Dmab vs ZA. This benefit was most pronounced in patients who were stratified into the "intent to undergo Autologous Stem Cell Transplant (ASCT)" group at randomization. Thus, we present an in-depth analysis of relevant baseline characteristics, treatment regimens and PFS outcome in patients with intent to undergo transplant receiving Dmab and ZA. Methods: Adult patients with newly diagnosed multiple myeloma (NDMM) and stratified as "intent to undergo ASCT" at randomization were included in this analysis. Patients received subcutaneous denosumab (120 mg) plus intravenous placebo or intravenous zoledronic acid (4 mg) plus subcutaneous placebo in 4-week cycles. In this subgroup, the PFS outcome was examined. Baseline characteristics and treatment regimens were compared between treatment arms. Results: 54.1% of the 1718 enrolled patients were stratified into "intent to undergo ASCT" as part of their front-line therapy, and 61.8% of "intent to undergo ASCT" did receive an ASCT. In the "intent to undergo ASCT" group, 19.6% patients had disease progression in the Dmab arm compared to 28.0% in the ZA arm (HR 0.65 (0.49-0.85)) (Figure 1). No imbalance in terms of triplet therapy use between the two study arms (TABLE 1). 55.1% in Dmab vs 52.6% in ZA arm received Triplet Therapies which included Bortezomib, Cyclophosphamide, Dexamethasone (VCD), Bortezomib, Thalidomide, Dexamethasone (VTD), Cyclophosphamide, Thalidomide, Dexamethasone (CTD), or Bortezomib, Lenalidomide, Dexamethasone (VRD). The percentage of triplet therapies used in the "intent to undergo ASCT"patients was higher than in patients with no intent to undergo ASCT. Percentage of patients with ECOG performance status 2 was 19.4% in the Dmab group vs 18.6% in the ZA group. 26.2% of patients in the Dmab arm and 25% in the ZA arm had Multiple Myeloma ISS stage III upon diagnosis. Among intent to transplant patients there was no imbalance in terms of age, performance status, ISS stage, risk status, weight, bone marrow plasma cell % between the ZA and the Dmab arm Conclusion: Results from this post-hoc subgroup analysis suggest a more profound PFS benefit in the "intent to undergo ASCT" patient subgroup. Multiple myeloma treatment received in the intent to undergo transplant subjects was similar between the denosumab and zoledronic acid arms. No significant imbalance in demographics or baseline disease characteristics was observed between the two treatment arms. Disclosures Terpos: Janssen: Honoraria, Other: Travel expenses, Research Funding; Amgen: Honoraria, Research Funding; Takeda: Honoraria, Other: Travel expenses, Research Funding; Medison: Honoraria; Genesis: Honoraria, Other: Travel expenses, Research Funding; Celgene: Honoraria. Shimizu:Medical Biological Laboratory: Consultancy; Takeda: Speakers Bureau; Daiichi: Consultancy; Amgen: Consultancy; Fujimoto: Consultancy. Willenbacher:Abbvie: Consultancy, Honoraria; Sandoz: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; oncotyrol: Employment, Research Funding; Gilead Science: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; European Commission: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Tirol Program: Research Funding; Fujimoto: Consultancy, Honoraria; Myelom- und Lymphomselbsthilfe Österreich: Consultancy, Honoraria; Sanofi: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; IQVIA: Membership on an entity's Board of Directors or advisory committees. Glennane:amgen: Employment, Equity Ownership. Dai:Amgen: Employment, Equity Ownership. Pasteiner:Amgen: Employment, Equity Ownership. Raje:Amgen Inc.: Consultancy; Bristol-Myers Squibb: Consultancy; Celgene Corporation: Consultancy; Takeda: Consultancy; Janssen: Consultancy; Merck: Consultancy.

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CC-486 (Oral Azacitidine) Monotherapy in Patients with Acute Myeloid Leukemia (AML)

Blood ◽

10.1182/blood.v126.23.452.452 ◽

2015 ◽

Vol 126 (23) ◽

pp. 452-452 ◽

Cited By ~ 5

Author(s):

Michael R. Savona ◽

Steven D. Gore ◽

Kathryn S. Kolibaba ◽

Stacey M. Ukrainskyj ◽

Keshava Kumar ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Performance Status ◽

Leukemic Cells ◽

Employment Equity ◽

Ecog Performance Status ◽

Advisory Committees ◽

Dosing Regimens ◽

Equity Ownership ◽

Grade 3

Abstract Background: When administered subcutaneously (SC), the epigenetic modifier, azacitidine (AZA) is shown to improve overall survival in patients (pts) with AML compared with conventional care regimens (Fenaux, JCO, 2010; Dombret, Blood, 2015). CC-486, the oral formulation of AZA, is in clinical development for use in hematologic malignancies. An early dose-finding study of CC-486 administered on a 7-day schedule showed it to be safe and clinically active in pts with AML (Garcia-Manero, JCO, 2011; Gore, Blood, 2011). Extending CC-486 dosing for more than 7 days may increase AZA exposure to leukemic cells over the treatment (Tx) cycle to improve response. Objective: Evaluate the safety and efficacy of CC-486 administered in extended dosing schedules (14 days or 21 days per 28-day cycle) in pts with AML. Methods: Pts with AML from two phase I/II studies were sequentially assigned to receive CC-486 in 1 of 4 extended dosing regimens: 300mg QD x14 days (d)/28d (14-QD), 300mg QD x21d/28d (21-QD), 200mg BID x14d/28d (14-BID), or 200mg BID x21d/28d (21-BID). Hematologic responses (complete remission [CR], partial remission [PR], CR with incomplete hematologic recovery [CRi], marrow CR [mCR]), were assessed using IWG criteria for AML (Cheson, J Clin Oncol, 2003), and hematologic improvement (HI) and transfusion independence (TI) were assessed using IWG criteria for MDS (Cheson, Blood, 2006). Tx-emergent adverse events (TEAEs) were graded by NCI-CTCAE v3.1 or v4.0. Results: In all, 23 pts with AML participated in the studies: 14-QD n=4, 21-QD n=12, 14-BID n=4, 21-BID n=3. Median age was 68 years (range 44 - 93), 48% were male, 22% and 78% had ECOG performance status scores of 0-1 or 2, respectively, median % bone marrow blasts was 25%, and median baseline hematology counts were: Hgb 9.1 g/dL (7.4 - 11.7), platelets 33 x 109/L (3 - 435), and ANC 0.3 x 109/L (0 - 6.4). Median time from diagnosis was 1.1 month (range -0.2 - 82.1). Eleven pts (52%) had prior MDS and 13 pts (57%) had received prior Tx for MDS (n=5) or AML (n=8), including 5 pts (38%) who had received hypomethylating agents (HMAs). The median number of CC-486 Tx cycles for all pts was 4 (1 - 9) (Figure). Overall response (CR, PR, CRi, mCR, HI or TI) rate was 48% (11/23), with generally comparable responses and response rates across the 4 dosing regimens (Table 1). Responses were observed in 4 pts (50%) who were relapsed/refractory to prior AML Tx. Two pts (40%) who had received prior HMA Tx responded, 1 of whom attained CR. HI was achieved by 32% (7/22) of pts, and 20% (3/15) of RBC transfusion-dependent pts attained RBC TI. Six pts with prior MDS (55%) responded during Tx. One pt proceeded to transplant. Febrile neutropenia (30%) and anemia (22%) were the most common grade 3-4 TEAEs (Table 2). Incidences of grade 3-4 TEAEs were generally similar across the 4 CC-486 dosing regimens. Conclusions: CC-486 administered in extended 14- or 21-day per cycle schedules was well tolerated. One-half of these older pts with AML had a hematologic response, including pts who had prior MDS, or AML that failed or lost response to prior Tx. Interestingly, pts who previously received injectable HMA Tx had hematologic responses (including CR) with CC-486, likely due to the alternative methylation pattern obtained with prolonged oral administration (Laille, Plos One, in press). Ease of administration of CC-486 can facilitate long-term Tx for sustained disease modification, provide an additional option for failure of IV/SQ HMA therapy, and may improve outcomes in combination Tx regimens, which warrant investigation. Disclosures Savona: Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding. Gore:Celgene: Consultancy, Honoraria, Research Funding. Kolibaba:Janssen: Research Funding; Acerta: Research Funding; Amgen: Research Funding; Celgene: Research Funding; Gilead: Consultancy, Research Funding; Pharmacyclics: Research Funding; TG Therapeutics: Research Funding; Cell therapeutics: Research Funding; GSK: Research Funding; Novartis: Research Funding; Genentech, Inc.: Research Funding; Seattle Genetics: Research Funding. Ukrainskyj:Celgene Corporation: Employment, Equity Ownership. Kumar:Celgene Corporation: Employment, Equity Ownership. Dong:Celgene Corporation: Employment, Equity Ownership. Hetzer:Celgene Corporation: Employment, Equity Ownership. Skikne:Celgene Corporation: Employment, Equity Ownership.

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Incidence and Survival Impact of Self-Reported Symptom and Psychological Distress Among Patients with Multiple Myeloma

Blood ◽

10.1182/blood.v130.suppl_1.679.679 ◽

2017 ◽

Vol 130 (Suppl_1) ◽

pp. 679-679

Author(s):

Joshua R Richter ◽

Noa Biran ◽

Dhakshila Paramanathan ◽

Srikesh Arunajadai ◽

Victoria DeVincenzo ◽

...

Keyword(s):

Multiple Myeloma ◽

Chronic Disease ◽

Board Of Directors ◽

Research Funding ◽

Performance Status ◽

Survival Rates ◽

Employment Equity ◽

Advisory Committees ◽

Distress Score ◽

Equity Ownership

Abstract Background: Advances in the management of multiple myeloma (MM) have significantly extended survival and dramatically reduced painful skeletal-related events for most patients. As MM is evolving to a chronic disease increased attention towards symptom and psychological impact is required. We sought to determine the incidence of self-reported pain, depression, financial and family burden, and impairment of performance status in a cohort of patients with MM receiving outpatient therapy at a tertiary cancer center and to determine the correlation of total distress with survival. Methods: The Living with Cancer (LWC) patient reported outcome (PRO) instrument is a statistically validated tool (ASCO Palliative Care Symposium 2016) that evaluates distress from the point of view of the advanced cancer patient. The 7-item 5-level Likert survey measures 4 personhood domains (performance status, pain, burden [financial and family], depression). The questions are also weighted by the patient with regards to importance, yielding a total score range 0-112. In a pilot study of advanced cancer patients a score of >28 was associated with an increased likelihood of physicians' (blinded) opinion regarding need for end-of-life care discussions (J Palliative Med 2016). For individual survey items, a self-reported rating of 2-4 was considered to indicate patient concern. Results: 239 patients with MM completed the LWC PRO between Sept 2015 and Oct 2016. Patients were 57% male with a median age 67 years. 48% of patients were concerned that they could not do the things they wanted to do, with 33% reporting decreased performance status. Financial toxicity concerns were self-reported by 44%, with family burdens noted in 24%. Although depression was reported by only 15%, 41% reported lack of pleasure. Pain was self-reported as a concern by 36%. With a median follow up of 316 days since LWC completion, 13% of patients had died. A high total distress score (>28) was noted in 57 (24%) and associated with a decreased survival rate compared to the 182 (76%) patients with a low total distress score (p<0.05). The 6 month survival rates from the completion of the LWC survey for patients with high/low distress scores were 86% and 96% respectively, and 12 month survival rates were 76% and 87% respectively. Conclusions: Despite dramatic improvements in survival among patients with MM, symptom, financial, and psychosocial concerns continue to plague patients. As a chronic disease, additional attention to addressing these issues is required. Figure 1 Figure 1. Disclosures Richter: BMS: Speakers Bureau; Janssen: Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Biran: Celgene, Amgen: Consultancy, Speakers Bureau; Takeda: Speakers Bureau. Paramanathan: COTA: Employment. Arunajadai: COTA: Employment. DeVincenzo: COTA: Employment. Pe Benito: COTA: Employment. Gruman: COTA: Employment. Kaur: COTA: Employment. Hervey: COTA: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Schultz: COTA: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Paddock: COTA: Employment, Equity Ownership. Pecora: Caladrius Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; COTA: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Siegel: Celgene, Takeda, Amgen Inc, Novartis and BMS: Consultancy, Speakers Bureau; Merck: Consultancy. Goldberg: Ariad: Speakers Bureau; Pfizer: Honoraria; COTA: Employment, Equity Ownership; Novartis: Honoraria, Research Funding, Speakers Bureau; Bristol Myers Squibb: Research Funding, Speakers Bureau; Jazz: Speakers Bureau; Celgene: Speakers Bureau.

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

Blood ◽

10.1182/blood-2019-128467 ◽

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.

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

Blood ◽

10.1182/blood-2018-99-117871 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 804-804 ◽

Cited By ~ 7

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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The Characteristics, Treatment Patterns, and Outcomes of Older Adults with Multiple Myeloma

Blood ◽

10.1182/blood-2018-99-118660 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4463-4463

Author(s):

Mark A. Fiala ◽

Tanya M. Wildes ◽

Mark A. Schroeder ◽

Armin Ghobadi ◽

Keith E. Stockerl-Goldstein ◽

...

Keyword(s):

Older Adults ◽

Multiple Myeloma ◽

Board Of Directors ◽

Research Funding ◽

Performance Status ◽

Patient Characteristics ◽

Treatment Patterns ◽

Advisory Committees ◽

Improved Outcomes ◽

Immunomodulatory Drug

Abstract Background: Advances in the treatment for multiple myeloma (MM) have dramatically improved outcomes for younger patients. Older adults, particularly those 80 years of age or older at diagnosis, have seen more modest gains. MM incidence increases with age, and as more of the population is living later into life, the segment of the MM population over 80 will continue to grow. In this study, we sought to better understand the characteristics, treatment, and outcomes of older patients with MM. Methods: We identified all patients diagnosed with MM at age 80 or older in the Surveillance, Epidemiology, and End Results Program (SEER) database from 2007-2013 to determine incidence and outcomes. Subset analysis was then performed on patients included in the SEER-Medicare linked database who were enrolled in Medicare Parts A, B, and D to further explore patient characteristics and treatment patterns. Results: The incidence of MM increases over age, peaking after age 80. The annual incidence for those aged 65-69, 70-74, 75-79, 80-84 and 85+ was 24.4, 32.7, 39.5, 42.8 and 36.4 per 100,000, respectively. Based on 2010 US population estimates, approximately 4,500 new cases of MM were diagnosed annually 2007-2013 in patients age 80 or older. In that period, 8,093 cases, approximately 1,150 per year, were reported to SEER. The estimated median overall survival (OS) of these patients was 14 months (95% CI 13.2-14.8). The estimated relative 12 month survival was 58.9% (95% CI 57.4-60.4) compared to their peers without cancer. Of the 8,093 cases of MM reported to SEER during the study period, 2,385 were present in the SEER-Medicare linked dataset. Of these, 225 were identified as smoldering MM using a previously established algorithm (Fiala, et al, JCOCCI, 2018) and excluded leaving 2,160 for the analyses. The median age was 84 (range 80-100) and 55% were female. 81% were white, 13% black or African-American, and 6% another race. At disease presentation, 22% had claims indicating hypercalcemia, 61% renal failure or chronic kidney disease, 59% anemia, and 34% MM bone involvement. The estimated median OS was 13.4 months (95% CI 12.2-15.1). Only 52% of patients had claims indicating they received systemic MM treatment within 6 months post-diagnosis. Nearly all that did received novel agents; 38% received bortezomib-based treatment, 41% immunomodulatory drug (IMID)-based, and 14% both. The others received antineoplastic chemotherapies such as melphalan or cyclophosphamide. Interestingly, bortezomib utilization increased incrementally from 25% of patients treated in 2007 to 62% in 2013 while IMID utilization declined from 67% to 49%. The median OS of those receiving treatment was 21 months (95% CI 18.5-23.1) compared to 6.3 months (95% CI 5.3-7.3) for those who did not (p <0.0001). MM treatment was associated with a 26% decrease in hazard for death (aHR 0.74; 95% CI 0.67-0.82; p < 0.0001) independent of age, race, gender, poverty, comorbidities, and proxy measures of performance status. Outcomes improved for patients in more recent years; the hazard for death decreased by 3% (HR 0.97; 95% CI 0.94-0.99; p = 0.0096) each year 2007-2013. This can be attributed to increasing treatment rates. In 2007, only 41% of patients received treatment compared to 61% in 2013. After controlling for MM treatment, the year of diagnosis was no longer a significant predictor of survival. Conclusions: The outcomes of patients with MM over 80 years old are still relatively poor; nearly half of the patients do not receive systemic treatment and for those who do the median OS is just 21 months. The population over 80, when MM incidence peaks, is projected to triple over the next few decades. It is imperative that we improve our understanding of the needs of this vulnerable subgroup of patients of MM. Disclosures Schroeder: Amgen Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees. Vij:Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; 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; Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jansson: 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.

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A Phase I Study of Bendamustine Combined with Lenalidomide and Dexamethasone in Patients with Refractory or Relapsed Multiple Myeloma.

Blood ◽

10.1182/blood.v114.22.1856.1856 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1856-1856 ◽

Cited By ~ 1

Author(s):

Suzanne Lentzsch ◽

Amy O’Sullivan ◽

Silvana Lalo ◽

Carrie Kruppa ◽

Diane Gardner ◽

...

Keyword(s):

Multiple Myeloma ◽

Partial Response ◽

Board Of Directors ◽

Dose Level ◽

Research Funding ◽

Advisory Board ◽

Clinical Activity ◽

Advisory Committees ◽

Equity Ownership ◽

Grade 3

Abstract Abstract 1856 Poster Board I-882 Background: Lenalidomide is an analog of thalidomide that has shown significant clinical activity in patients with relapsed or refractory multiple myeloma (MM), both as a single agent and in combination with dexamethasone. Bendamustine is a bifunctional alkylating agent that is approved for the treatment of chronic lymphocytic leukemia and indolent non-Hodgkin's lymphoma that has progressed during or relapsed within 6 months following a rituximab-containing regimen. Bendamustine combined with lenalidomide may be an effective treatment option for MM patients, particularly those with preexisting or bortezomib-induced neuropathy. Our primary objective was to determine the maximum tolerated dose (MTD) and safety profile of bendamustine and lenalidomide when administered with dexamethasone for patients with relapsed or refractory MM. Methods: Patients aged ≥18 years with confirmed, measurable stage 2 or 3 MM that was refractory to or progressed after 1 or more prior therapies, including lenalidomide, received bendamustine by intravenous infusion on days 1 and 2, oral lenalidomide on days 1–21, and oral dexamethasone on days 1, 8, 15, and 22 of each 28-day cycle. Treatment was continued until a plateau of best response, as determined by the IBMTR/ABMTR, was reached. Study drug doses were escalated through 4 levels (Table), with 3–6 patients enrolled at each level depending on the rate of dose-limiting toxicity (DLT). After determining the MTD, up to an additional 12 patients will be enrolled in an MTD expansion arm to better evaluate toxicity and clinical activity. Secondary endpoints included preliminary efficacy, as evidenced by objective response, time to disease progression, and overall survival. Results: To date, 11 patients have been enrolled, with a median age of 63 years (range, 38–75 years). The MTD of bendamustine and lenalidomide has not been identified at this point; currently, patients are enrolling on dose level 3 with 100 mg/m2 bendamustine and 10 mg lenalidomide. Thus far, DLT included 1 grade 4 neutropenia at dose level 2. Nine of 11 patients are currently eligible for response assessment. A partial response was observed in 67% of patients, including 1 very good partial response and 5 partial responses (PR). Two patients experienced stable disease and 1 exhibited progressive disease. Grade 3/4 adverse events included grade 3 neutropenia, thrombocytopenia, anemia, hyperglycemia, and prolonged QTC, and 1 grade 4 neutropenia. Conclusions: Bendamustine, lenalidomide, and dexamethasone form a well-tolerated and highly active regimen even in heavily pretreated MM patients, with a PR rate of 67%. Additional updates on response and MTD will be available at the time of presentation. Disclosures: Lentzsch: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cephalon: Consultancy, Membership on an entity's Board of Directors or advisory committees. Off Label Use: Bendamustine is not FDA approved for the treatment of multiple myeloma in the USA. Burt:Millennium: Honoraria; Celgene: Honoraria. Mapara:Resolvyx: Consultancy, Research Funding; Genzyme: Membership on an entity's Board of Directors or advisory committees; Gentium: Equity Ownership; Celgene: Spouse is consultant , has received research funding, and participates on advisory board; Cephalon: Spouse has received funding for clinical trial and participates on advisory board. Redner:Biogen: Equity Ownership; Wyeth: Equity Ownership; Glaxo-Smith-Kline: Equity Ownership; Pfizer: Equity Ownership; Genzyme: Membership on an entity's Board of Directors or advisory committees. Roodman:Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy; Acceleron: Consultancy. Zonder:Amgen: Consultancy; Pfizer: Consultancy; Cephalon: Consultancy; Millennium: Consultancy, Speaking (CME only); no promotional talks.

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