Could Patients with Multiple Myeloma (MM) Derive Additional Benefit from Their Treatments? Real-World Evidence for Carfilzomib Dosing Intensity on Survival and Treatment Progression

Abstract Introduction: Carfilzomib (K) was first approved in 2012 for the treatment of relapsed/refractory multiple myeloma (RRMM) at a dose of 27 mg/m2 twice weekly (27 BIW). The K dose has since been optimized; carfilzomib plus dexamethasone (Kd) is approved for patients with RRMM at a recommended K dose of 56 mg/m2 twice weekly (56 BIW) since 2016. Recently, the A.R.R.O.W trial showed that Kd 70mg/m2 once weekly (70 QW) significantly improved progression free survival compared to Kd 27 BIW. Considering the study time-period, however, patients are still treated with 27 BIW in the real-world leaving them possibly under-treated. The Kd 27 BIW, corresponds to a cumulative weekly dose (CWD) of K <120mg, while both Kd 56 BIW and Kd 70 QW (optimized dose-56 BIW/70 QW) correspond to a CWD of K >120mg. Therefore, in order to understand the relationship between dose and outcomes we examined the impact of K-dosing (CWD >120mg [optimized dose-56 BIW/70 QW] vs. CWD ≤120 mg [27 BIW]) on time to next treatment (TTNT) and overall survival (OS) among patients treated with Kd regimen. Methods: IQVIA's Oncology Electronic Medical Records database was used to identify patients ≥18 years of age, with a diagnosis of MM between 1/1/2010 and 10/31/2017, receiving Kd regimen in any line of therapy, with ≥ 3 doses of K on or after their K-index date (first administration of K in the Kd regimen, between 1/1/2013 and 10/31/2017). Patients were required to have ≥ 3 doses of K in order to establish continuity and for calculating CWD. CWD was calculated as the cumulative sum of weekly dose of K received by the patient divided by the number of weeks with Kd administration. The first two K doses were excluded from the calculation of CWD as these represent the loading dose. OS and TTNT were compared between patients receiving optimized dose-56 BIW/70 QW vs. 27 BIW. OS was evaluated among the subset of patients with a recorded deceased or alive status and measured from the K-index date until death due to any cause or the end of the study period, where they were censored. TTNT was defined as the time from initiation of the Kd regimen until the start of a subsequent regimen that did not contain Kd (treatment progression). Additionally, a landmark analysis at 12 months from initiation of Kd regimen was conducted to measure the proportion of patients alive and the proportion of patients with treatment progression. Kaplan-Meier analysis was used to estimate OS and TTNT and the log-rank test was used to compare the groups. Adjusted hazard ratios for OS and TTNT were evaluated using Cox models. Results : A total of 1,469 eligible MM patients with ≥3 Kd administrations were identified, of which 129 (8.8%; mean age: 63.5, SD: 9.8) received optimized dose-56 BIW/70 QW and 1,340 (91.2%; mean age: 67.0, SD: 10.4) received 27 BIW. The median follow-up time was slightly over a year for patients in both cohorts. The median K dose was 147.0 mg among patients in optimized dose-56 BIW/70 QW group and 88.1 mg among patients in 27 BIW group. Median OS was not estimable (NE), however, OS for the optimized dose-56 BIW/70 QW group (n=78) was significantly longer than that of the 27 BIW group (n=771; p=0.002) (Fig. 1). The proportion of patients in optimized dose-56 BIW/70 QW group alive at 12 months was 90.3% compared to 79.7% for patients in 27 BIW group respectively. Covariate-adjusted cox model showed that patients in optimized dose-56 BIW/70 QW group had a 64% lower risk of death than patients in 27 BIW group (adjusted HR: 0.364; 95% CI: 0.178-0.745; p = 0.0057, Table 1). TTNT was significantly longer for patients in optimized dose-56 BIW/70 QW group compared to patients in 27 BIW group (p=0.023; median TTNT: 17.5 [95% CI: 14.8-NE] and 13.2, [95% CI: 12.4-14.4], respectively) (Fig. 2). Covariate-adjusted cox model showed that patients in optimized dose-56 BIW/70 QW group had a 33% lower risk of treatment progression than patients in 27 BIW group (adjusted HR: 0.669; 95% CI: 0.483-0.927; p=0.0155, Table 1). Conclusion: Among patients treated with Kd regimen, a smaller proportion were prescribed K at optimized dose-56 BIW/70 QW. Patients receiving the optimized dose-56 BIW/70 QW had significantly improved OS and TTNT compared to those receiving 27 BIW. Our findings suggest that these patient-relevant outcomes may be improved in a vast majority of RRMM patients currently under-treated with carfilzomib by optimizing the dose, taking into consideration patients' comorbidities and ability to tolerate therapy. Disclosures Medhekar: Amgen: Employment, Equity Ownership. Hines:Amgen: Consultancy. Panjabi:Amgen: Employment, Equity Ownership. Welliver:Amgen: Employment, Equity Ownership. Wang:Amgen: Consultancy. Wade:Amgen: Consultancy.

Download Full-text

Treatment Sequencing Patterns in Medicare-Enrolled Patients with Multiple Myeloma

Blood ◽

10.1182/blood.v128.22.2120.2120 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2120-2120 ◽

Cited By ~ 1

Author(s):

Shuling Li ◽

Tanya Natwick ◽

Akeem Yusuf ◽

Irena Sarah Vidito ◽

Khalid Mezzi ◽

...

Keyword(s):

Multiple Myeloma ◽

Index Date ◽

Employment Equity ◽

Drug Regimens ◽

Medicare Patients ◽

Equity Ownership ◽

Treatment Sequencing ◽

Line Of Therapy ◽

The Impact ◽

Treatment Sequences

Abstract Introduction: Over the last decade, several novel therapies have been approved for multiple myeloma (MM) leading to significant improvement in the prognosis of MM patients. MM patients are often treated with multiple lines of therapy as relapse occurs. With the numerous options of therapeutic agents and novel combinations of regimens, the treatment for MM has become more complicated. However, little is known regarding the treatment sequencing patterns for Medicare patients with MM. In this study, we described the use of drug regimens by lines of therapy and characterized treatment sequences in Medicare patients with MM. Methods: Using a validated algorithm (Princic et al. Blood 2015;126:4521), we identified adult MM patients (≥ 18 years old) in 2008-2011 from the Centers for Medicare & Medicaid Services 100% Hematologic Cancer file (2007-2012) who began first-line (1L) treatment. Patients who advanced to second-line (2L), third-line (3L), and fourth-line (4L) were identified if a 90 day gap in all treatments was observed or when a drug was added to a regimen >90 days after the line index date. Drug regimens were based on National Comprehensive Cancer Network MM treatment guidelines and were identified using National Drug Code and Healthcare Common Procedure Coding System codes. Patients were included in the study if they received monotherapy, doublets, or triplets at 1L. The study period was from the 1L initiation date to the earliest of death, disenrollment from Medicare Parts A, B, and D coverage, receipt of treatments other than the above-mentioned drug regimens, or December, 31, 2012. We described the distribution of type of drug regimens by lines of therapy, overall and by age defined at MM index date, and characterized treatment sequencing patterns for patients who advanced to 2L, 3L, and 4L by type of drug regimens in the prior line of therapy, respectively. Results: In total, 12563 MM patients initiated 1L therapy. Of these, 9% were aged 18-64 years (enrolled in Medicare due to disabilities), 42% aged 65-74 years, and 49% aged ≥ 75 years. Most patients were white (78%) and more than half were female (53%). We identified 5647 (45%), 2243 (18%), and 773 (6%) patients who advanced to 2L, 3L, and 4L, respectively. Overall, doublets were the most common 1L regimen (62%), followed by monotherapy (21%) and triplets (17%). Most common treatments for monotherapy in 1L were dexamethasone (52%), lenalidomide (21%), and bortezomib (17%). The pattern was similar among patients who advanced to a 2L, 3L, or 4L, respectively, though more triplets were used at advanced lines. For 1L therapy, only 12% of patients aged ≥ 75 years received triplets, in contrast to >20% of triplet use in 3L and 4L respectively (Table). Of patients who received monotherapy in 1L and advanced to 2L, 37% continued monotherapy and 63% switched to more dense regimens (doublets, 53%; triplets 10%). Of patients who received doublets in 1L and advanced to 2L, 58% continued doublets, 22% switched to triplets, and 20% to monotherapy. Of patients who received triplets in 1L and advanced to 2L, 26% continued triplets and 74% switched to less dense regimens (doublets, 47%; monotherapy, 27%). Treatment sequencing patterns were similar for patients who advanced to 3L and 4L with monotherapy or doublets in prior lines, while the proportion of patients who repeated triplets increased to about 32% in 3L and 37% in 4L (Figure). Conclusions: Among Medicare patients with MM, doublets were the most frequently used regimens across all lines of therapy, while triplets were used in more advanced lines. Patients on monotherapy or doublets were more likely to retain their treatment pattern when they advance to the next line of therapy, while those on triplet regimen were more likely to switch to a less dense regimen when they advance to their next line of therapy. Fewer patients of older age (75+ years) were prescribed triplet therapies, however triplet use in this patient group increases in more advanced lines. These results provide a baseline description of treatment patterns from which we will be able to benchmark the impact of the recent introduction of novel agents and their use in elderly MM patients. Further studies assessing the comparative effectiveness and benefit-risk of treatment sequences are warranted. Figure Figure. Disclosures Yusuf: Amgen Inc.: Employment, Equity Ownership. Vidito:Amgen Inc.: Employment, Equity Ownership. Mezzi:Amgen Inc.: Employment, Equity Ownership. Werther:Amgen Inc.: Employment, Equity Ownership.

Download Full-text

Health Care Utilization and Costs Among Patients with Chronic Myeloid Leukemia Using Tyrosine Kinase Inhibitors

Blood ◽

10.1182/blood-2018-99-113809 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3537-3537

Author(s):

Joanna C Huang ◽

Sudeep Karve ◽

Sanchita Porwal ◽

Kushan Thakkar ◽

Thomas Marshall ◽

...

Keyword(s):

Tyrosine Kinase ◽

Emergency Room ◽

Tyrosine Kinase Inhibitors ◽

Health Plan ◽

Real World ◽

Index Date ◽

Kinase Inhibitors ◽

Employment Equity ◽

The Us ◽

Equity Ownership

Abstract INTRODUCTION: Tyrosine kinase inhibitors (TKIs) remain mainstay in the management of patients with CML. Several TKIs have been approved over the last two decades. Even though efficacy and safety remain as the primary drivers in treatment selection, in recent years importance has been placed on treatment affordability and economic burden associated with the long-term cancer treatments such as TKIs. However, current literature lacks real-world data on healthcare utilization (HCU) and costs among patients with CML using TKIs, which this study aims to address. METHODS: Retrospective cohort study was conducted using MarketScan Commercial, and Supplemental Medicare databases (2012-2016). Data includes medical and pharmacy utilization and costs for over 90 million individuals enrolled in employer-sponsored health-plans in the US. Data includes information on but not limited to medical diagnosis, procedures, drugs dispensed, date of service, health plan enrollment. Study involves adult patients (≥18 years) with ≥2 medical claims with a diagnosis of CML (ICD-9-CM: 205.10 - 205.12; ICD-10: C92.10-C92.12) and with a prescription claim for TKI. The date of first-TKI claim defined the index date. Patients were required to have continuous health plan enrollment ≥6 months before (defined as baseline period) and ≥6 months after index date. Selected patients were further classified into 5 sub-groups based on the index TKI observed (prescribed) post CML diagnosis (imatinib, dasatinib, nilotinib, bosutinib, ponatinib). Among the selected patients, all-cause HCU and costs were assessed from index date until end of database or end of enrollment, whichever occurred earlier. HCU and associated costs were assessed overall and by care settings including inpatient, emergency room, physician office, outpatient hospital, outpatient pharmacy, nursing facility and ancillary care. In addition, baseline (6 month) utilization and costs were assessed. Monthly and annual resource utilization and costs were reported for the overall CML cohort (across all TKI users) and by index TKI sub-groups. All costs were reported from a payer perspective (i.e., costs reimbursed by health plan) and adjusted to 2017 US dollars using the US consumer price index (medical component). All analyses were descriptive in nature. RESULTS: The study cohort included 2,213 CML patients. Distribution for the index TKI treatment was as follows: 41% imatinib, 36% dasatinib, 21% and 1% each for bosutinib and ponatinib. Mean age (standard deviation [SD]) of the cohort was 55 (15) years which was similar for individual TKI sub-groups. Majority of patients were males (55%) and 56% were enrolled in a preferred provider organization plan. The mean follow-up duration post-TKI initiation was 607 (442) days. The average baseline monthly all-cause costs were $4,365 with inpatient and pharmacy costs accounting for over 3/4th of the total costs (Figure 1). Post-TKI initiation the average monthly costs were twice ($9,288) compared with the baseline costs ($4,365) and the increase was primarily attributable to higher outpatient pharmacy costs ($6,619, accounted for 71% of total costs) (Figure 2). Monthly costs across other care settings (inpatient, outpatient, emergency room) were similar for the baseline and post-TKI initiation. On average patients had 1.4 office visits, 2.5 prescriptions and 0.7 hospital outpatient visits per month at baseline, which increased by 23%, 38% and 49%, respectively post TKI-initiation. During the 1st year post TKI-initiation, 17% patients in the overall CML cohort had at least 1 inpatient admission and this was consistent across individual TKI-sub-groups (except ponatinib, 50%). CONCLUSIONS: Findings on TKI utilization and costs in employer-sponsored health-plan database indicate that average costs and utilization were similar across the TKI sub-groups with pharmacy costs accounting for 71% of the total post TKI initiation costs. Overall, this study helps address the literature gap by providing recent real-world treatment care-setting specific utilization and costs among TKI uses and these data can be of value to several healthcare stakeholders including physicians, managed care plans and researchers in supporting clinical and formulary decisions and also serve as inputs for economic models. Finally, the sample sizes for ponatinib and bosutinb were small and results for these TKIs should be interpreted with caution. Disclosures Huang: ZS Associates: Employment; Novo Nordisk Inc: Equity Ownership; AstraZeneca: Research Funding. Karve:AbbVie: Employment, Equity Ownership. Porwal:ZS Associates: Employment. Thakkar:ZS Associates: Employment. Marshall:AbbVie: Employment, Equity Ownership. Rosenberg:AbbVie: Employment, Equity Ownership.

Download Full-text

Prognostic Molecular Stratification in Relapsed/Refractory Multiple Myeloma - Results of the Pomalidomide Mukseven (NCT02406222) Biomarker Trial

Blood ◽

10.1182/blood-2019-123640 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4327-4327

Author(s):

James Croft ◽

Andrew Hall ◽

Amy L Sherborne ◽

Katrina Walker ◽

Sidra Ellis ◽

...

Keyword(s):

Multiple Myeloma ◽

Flow Cytometry ◽

T Cell ◽

High Risk ◽

Real World ◽

Research Funding ◽

Unmet Need ◽

Employment Equity ◽

Equity Ownership

Background Treatment of relapsed/refractory multiple myeloma (RRMM) remains challenging as durable remissions are achieved in patient sub-groups only. Identifying patients that are likely to benefit prior to or early after starting relapse treatments remains an unmet need. MUKseven is a trial specifically designed to investigate and validate biomarkers for treatment optimization in a 'real-world' RRMM population. Design In the randomized multi-center phase 2 MUKseven trial, RRMM patients (≥2 prior lines of therapy, exposed to proteasome inhibitor and lenalidomide) were randomized 1:1 to cyclophosphamide (500 mg po d1, 8, 15), pomalidomide (4 mg days 1-21) and dexamethasone (40 mg; if ≥75 years 20 mg; d1, 8, 15, 21) (CPomD) or PomD and treated until progression. All patients were asked to undergo bone marrow (BM) and peripheral blood (PB) bio-sampling at baseline, cycle 1 day 14 (C1D14, on-treatment) and relapse. For biomarker discovery and validation, IGH translocations were profiled by qRT-PCR, copy number aberrations by digital MLPA (probemix D006; MRC Holland), GEP by U133plus2.0 array (Affymetrix), PD protein markers by IHC and PB T-cell subsets by flow cytometry for all patients with sufficient material. Primary endpoint was PFS, secondary endpoints included response, OS, safety/toxicity and biomarker validation. Original planned sample size was 250 patients but due to a change in UK standard of care during recruitment with pomalidomide becoming available, a decision was made to stop recruitment early. Results In total, 102 RRMM patients were randomized 1:1 between March 2016 and February 2018. Trial entry criteria were designed to include a real-world RRMM population, permitting transfusions and growth factor support. Median age at randomization was 69 years (range 42-88), 28% of patients had received ≥5 prior lines of therapy (median: 3). Median follow-up for this analysis was 13.4 months (95% CI: 12.0-17.5). 16 patients remained on trial at time of analysis (median number of cycles: 19.5; range 8-28). More patients achieved ≥PR with CPomD compared to PomD: 70.6% (95% CI: 56.2-82.5%) vs. 47.1% (CI: 32.9-61.5%) (P=0.006). Median PFS was 6.9 months (CI: 5.7-10.4) for CPomD vs. 4.6 months (CI: 3.5-7.4) for PomD, which was not significantly different as per pre-defined criteria. Follow-up for OS is ongoing and will be presented at the conference. High-risk genetic aberrations were found at following frequencies: t(4;14): 6%, t(14;16)/t(14;20): 2%, gain(1q): 45%, del(17p): 13%. Non-high risk lesions were present as follows: t(11;14): 22%, hyperdiploidy: 44%. Complete information on all high-risk genetic markers was available for 71/102 patients, of whom 12.7% had double-hit high-risk (≥2 adverse lesions), 46.5% single-hit high-risk (1 adverse lesion) and 40.8% no risk markers, as per our recent meta-analysis in NDMM (Shah V, et al., Leukemia 2018). Median PFS was significantly shorter for double-hit: 3.4 months (CI: 1.0-4.9) vs. single-hit: 5.8 months (CI: 3.7-9.0) or no hit: 14.1 months (CI: 6.9-17.3) (P=0.005) (Figure 1A). GEP was available for 48 patients and the EMC92 high-risk signature, present in 19% of tumors, was associated with significantly shorter PFS: 3.4 months (CI: 2.0-5.7) vs. 7.4 (CI: 3.9-15.1) for EMC92 standard risk (P=0.037). Pharmacodynamic (PD) profiling of cereblon and CRL4CRBN ubiquitination targets (including Aiolos, ZFP91) in BM clots collected at baseline and C1D14 is currently ongoing. Preliminary results for the first 10 patients demonstrate differential change of nuclear Aiolos (Figure 1C), with a major decrease in Aiolos H-scores in 7/10 patients from baseline to C1D14 and reconstitution at relapse. T-cell PB sub-sets were profiled at baseline and C1D14 by flow cytometry. Specific sub-sets increased with therapy from baseline to C1D14, e.g. activated (HLA-DR+) CD4+ T-cells, as reported at last ASH. CD4+ T-cell % at baseline was associated with shorter PFS in these analyses in a multi-variable Cox regression model (P=0.005). PD and T-cell biomarker results will be updated and integrated with molecular tumor characteristics and outcome. Discussion Our results demonstrate that molecular markers validated for NDMM predict treatment outcomes in RRMM, opening the potential for stratified delivery of novel treatment approaches for patients with a particularly high unmet need. Additional immunologic and PD biomarkers are currently being explored. Disclosures Croft: Celgene: Other: Travel expenses. Hall:Celgene, Amgen, Janssen, Karyopharm: Other: Research funding to Institution. Walker:Janssen, Celgene: Other: Research funding to Institution. Pawlyn:Amgen, Janssen, Celgene, Takeda: Other: Travel expenses; Amgen, Celgene, Janssen, Oncopeptides: Honoraria; Amgen, Celgene, Takeda: Consultancy. Flanagan:Amgen, Celgene, Janssen, Karyopharm: Other: Research funding to Institution. Garg:Janssen, Takeda, Novartis: Other: Travel expenses; Novartis, Janssen: Research Funding; Janssen: Honoraria. Couto:Celgene Corporation: Employment, Equity Ownership, Patents & Royalties. Wang:Celgene Corporation: Employment, Equity Ownership. Boyd:Novartis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Pierceall:Celgene: Employment. Thakurta:Celgene: Employment, Equity Ownership. Cook:Celgene, Janssen-Cilag, Takeda: Honoraria, Research Funding; Janssen, Takeda, Sanofi, Karyopharm, Celgene: Consultancy, Honoraria, Speakers Bureau; Amgen, Bristol-Myers Squib, GlycoMimetics, Seattle Genetics, Sanofi: Honoraria. Brown:Amgen, Celgene, Janssen, Karyopharm: Other: Research funding to Institution. Kaiser:Takeda, Janssen, Celgene, Amgen: Honoraria, Other: Travel Expenses; Celgene, Janssen: Research Funding; Abbvie, Celgene, Takeda, Janssen, Amgen, Abbvie, Karyopharm: Consultancy.

Download Full-text

Carfilzomib Dosing Patterns and Survival in Patients with Relapsed and Refractory Multiple Myeloma: An Analysis from US Community Oncology Practices

Blood ◽

10.1182/blood.v126.23.2084.2084 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2084-2084

Author(s):

Robert M. Rifkin ◽

Eileen Fonseca ◽

Yaozhu J. Chen ◽

Patricia S. Fox ◽

James E. Browning ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Employment Equity ◽

Advisory Committees ◽

Risk Of Death ◽

Community Oncology ◽

Social Security Death Index ◽

Equity Ownership ◽

The Impact ◽

Dosing Patterns

Abstract Introduction While novel agents have improved survival over the last decade, multiple myeloma (MM) remains incurable. Carfilzomib (CFZ), a second-generation proteasome inhibitor, was approved in July 2012 by the US Food and Drug Administration and had a label change in July 2015. During this study's data period, the label recommended Cycle 1 dose at 20 mg/m2/day and if tolerated increase Cycle 2 dose and subsequent cycles doses to 27 mg/m2/day. The purpose of this study is to assess baseline characteristics, CFZ dosing patterns and survival among MM patients in a US community oncology setting. Methods A retrospective study of MM patients from US Oncology Network practices that fully implemented McKesson Specialty Health's iKnowMed (iKM) oncology-specific electronic health records database was conducted on patients whose first treatment of CFZ (index) occurred between Jul-2012 and Nov-2014. Patients were eligible if they had a documented initial MM diagnosis date and had their first CFZ cycle documented in the database. Additionally, patients were required, before Dec-2014, to have either another visit to the practice post-index or a record of death and not have participated in interventional clinical trials during the previous 6 years. Data on eligible patients were collected up to March 2015. The death event was defined by the Social Security Death Index, supplemented by iKM; patients without the event were censored at the date of last observed visit. To adjust for clinical practice variations, a 10% variability was allowed for the recommended daily dose levels of 20 mg/m2 and 27 mg/m2. A subgroup was defined for patients with a 2nd cycle: "escalators" if they received 20 mg/m2/day doses throughout Cycle 1 and increased to 27 mg/m2/day on the first dose of Cycle 2; "non-escalators" if they received only 20 mg/m2 doses throughout Cycle 1 and did not increase to 27 mg/m2 on the first dose of Cycle 2; receiving any dose not equal to 20 or 27 mg/m2 were classified into "other". Survival after index was estimated using the Kaplan-Meier method with 95% confidence intervals (CI). A multivariable Cox proportional hazards (PH) model was conducted to evaluate the impact of escalation on survival accounting for selected baseline demographic and clinical characteristics. Results The cohort of 718 CFZ patients were identified with a median (interquartile range [IQR]) age of 68 (61-75) years at index, 57% (n=409) were male, and 12% (n=87) were Black and 77% (n=551) were Caucasian. At initial MM diagnosis, 19%, 27% and 42% were ISS Stage I, II, and III, respectively. Median (IQR) time from MM diagnosis to index was 3.6 (1.9-5.8) years. At index, 66% of patients had an ECOG performance status of 0-1, 21% of 2, and 2% of 3+; 54% (n=369) had moderate to severe renal impairment (eGFR<60 mL/min per 1.73 m2). Ninety percent (n=644) of patients started CFZ at 20 mg/m2, 4% (n=27) at 27 mg/m2 and 4% (n=25) at 15 mg/m2. Patients had a median (IQR) of 4 (2-7) cycles of CFZ and 45% (n=321) escalated to ≥27 mg/m2. Among these 321 patients, median (IQR) time to first escalation was 30 (28-56) days with 60% escalating in Cycle 2. The subgroup defined in "Methods" included 605 patients: 148 (24%) escalators, 342 (57%) non-escalators, and 115 (19%) other. Median (95% CI) duration from index to death was 21 (17.5-23.2) months. Unadjusted overall survival (OS) was significantly lower among non-escalators compared to escalators (log-rank p=0.024) [Figure 1]. Survival rates (95% CI) for non-escalators and escalators were 68% (62-74%) and 75% (66-82%) at year 1 and 42% (33-50%) and 61% (49-71%) at year 2, respectively. Within the multivariable Cox model, escalators showed a 33% significantly lower risk of death compared to non-escalators (HR=0.67, p=0.03) while also accounting for race, sex, age group, renal function per EGFR, and MM chain type. Other significant variables in this model were: EGFR < 15 and 15-29 vs 30-59 ml/min per 1.73m2 (HR=2.79, p<0.01; HR=1.64, p=0.04, respectively) and lambda vs kappa light chain (HR=1.55, p=0.03). Conclusions These results indicate escalation of CFZ at first dose of Cycle 2 is associated with better survival than dosing at 20 mg/m2 in Cycle 1 but not escalating at the start of Cycle 2. More research is needed to assess factors that impact physician decision-making on dose escalation to better inform physicians to improve the quality of multiple myeloma care. Disclosures Rifkin: Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Onyx Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Fonseca:McKesson Specialty Health, which received funding to conduct this research: Employment, Equity Ownership. Chen:Onyx Pharmaceuticals: Employment. Fox:McKesson Specialty Health, which received funding to conduct this research: Employment. Browning:Onyx Pharmaceuticals, An Amgen Subsidiary: Employment. Cong:Onyx Pharmaceuticals: Employment, Equity Ownership.

Download Full-text

Cardiac Events in Real-World Multiple Myeloma Patients Treated with Carfilzomib: A Retrospective Claims Database Analysis

Blood ◽

10.1182/blood.v128.22.3319.3319 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3319-3319 ◽

Cited By ~ 3

Author(s):

Ajai Chari ◽

Sanjay K. Aggarwal ◽

Khalid Mezzi ◽

Kenneth Wang ◽

Christopher Kim ◽

...

Keyword(s):

Real World ◽

Research Funding ◽

Cardiac Event ◽

Index Date ◽

Hospitalized Patients ◽

Cardiac Events ◽

Employment Equity ◽

Claims Database ◽

History Of ◽

Equity Ownership

Abstract Introduction: Multiple myeloma (MM) is a hematologic cancer that mostly affects elderly patients who are at increased risk for development of cardiac-related comorbidities due to age-, disease-, and treatment-related factors. In real world data, approximately 25-30% of MM patients are hospitalized for a cardiac event after MM diagnosis (Kistler et al. American Society Hematology 2012 Annual Meeting, poster 2916). The proteasome inhibitor, carfilzomib, is approved for treatment of patients with relapsed or refractory MM. In carfilzomib clinical trials, grade 3 or higher cardiac failure was reported for ~4% of patients (Stewart et al. NEJM 2015;372:142-52, Dimopoulos et al. Lancet Oncol 2016;17:27-38). In this retrospective analysis, we sought to evaluate the incidence rate (IR) of cardiac events in MM patients treated with carfilzomib in a real-world setting in the US and to describe differences in baseline characteristics between carfilzomib-treated MM patients who do and do not have cardiac events. Methods: Newly-diagnosed MM patients with symptomatic disease were identified in the Truven MarketScan claims database from 1/1/05 to 6/30/15 using an algorithm validated for ascertainment of MM patients in claims data (Princic et al. Blood 2015;126:4521). All carfilzomib-treated patients were included in the analysis. The first dose of carfilzomib was the index date. The baseline period was 12 months prior to the MM diagnosis date to the index date. Cardiac events (hypertension, heart failure, ischemic heart disease, arrhythmias and conduction disorders, and cardiomyopathy) were identified during baseline by inpatient (IP) or outpatient (OP) claims and after index date by primary diagnosis on IP claims (hospitalized events). Logistic regression was used to estimate baseline covariates associated with any cardiac event. Due to sample size constraints, multivariate regression was not performed. The incidence rate (IR) per 1000 patient-years (PYRs) and associated 95% confidence interval (CI) of hospitalized cardiac events during carfilzomib treatment which included 30 days after the last carfilzomib dose were calculated among patients without a history of the corresponding hospitalized event during the baseline period. Results: The cohort included 498 MM patients treated with carfilzomib; 108 (22%) patients had ≥1 cardiac event identified by both IP and OP claims and 24 (5%) had ≥1 hospitalized cardiac event. Of the 24 hospitalized patients, 14 were hospitalized during carfilzomib treatment (median days to onset = 104) and 8 were hospitalized after carfilzomib treatment (>30 days post dosing; median days to onset = 284). The median age (range) of the 24 patients with hospitalized cardiac events and those with no hospitalized cardiac claims (n=474) was 62 (37, 79) and 61 (36, 96) years, respectively (Table). Baseline medical history of any cardiac event was evident for 92% of hospitalized patients and 84% of non-hospitalized patients. Among hospitalized patients, 25% were over 75 years as compared with 13% of non-hospitalized patients. In univariate analysis, patients with baseline amyloidosis, hypertensive chronic kidney disease, and chronic kidney disease had higher odds of having a hospitalized cardiac event. No significant differences were seen in the proportion of patients with or without a hospitalized cardiac event when evaluated by line of therapy or by carfilzomib treatment regimen (monotherapy or combination). Among patients aged 75+ years, 8.7% were hospitalized, while 2.5% and 4.9% of 65-74 and 18-64 year old patients were hospitalized, respectively (Table). IR per 1000 PYRs [95% CI] among the 14 carfilzomib-treated MM patients hospitalized for any cardiac event during the carfilzomib treatment period was 89.7 (49.0; 150.5) - see Figure for IRs of specific cardiac events. Conclusions: Among carfilzomib-treated patients in a US claims database, hospitalization for a cardiac event was uncommon (~5%) and does not exceed what has been observed in MM patients. Patients at highest risk for cardiac hospitalizations had a history of amyloidosis or chronic renal failure. Additional analyses in much larger populations are needed to better understand risk factors for these events. Disclosures Chari: Array Biopharma: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Amgen Inc.: Honoraria, Research Funding; Novartis: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Pharmacyclics: Research Funding; Janssen: Consultancy, Research Funding. Aggarwal:Amgen: Employment, Equity Ownership. Mezzi:Amgen Inc.: Employment, Equity Ownership. Wang:Amgen Inc.: Employment, Equity Ownership. Kim:Amgen Inc.: Employment, Equity Ownership. Zhu:Amgen Inc.: Consultancy. Braunlin:Amgen Inc.: Employment, Equity Ownership. Werther:Amgen Inc.: Employment, Equity Ownership. Mikhael:Abbvie: Research Funding; Celgene: Research Funding; Sanofi: Research Funding; Onyx: Research Funding.

Download Full-text

Safety and Efficacy of Venetoclax (ABT-199/GDC-0199) Monotherapy for Relapsed/Refractory Multiple Myeloma: Phase 1 Preliminary Results

Blood ◽

10.1182/blood.v126.23.4219.4219 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4219-4219 ◽

Cited By ~ 10

Author(s):

Shaji K. Kumar ◽

Ravi Vij ◽

Jonathan L. Kaufman ◽

Joseph R. Mikhael ◽

Thierry Facon ◽

...

Keyword(s):

Multiple Myeloma ◽

Abdominal Pain ◽

Research Funding ◽

Phase 1 ◽

Cell Transplant ◽

Brain Hemorrhage ◽

Employment Equity ◽

Equity Ownership ◽

Upper Abdominal ◽

The Impact

Abstract Background: The anti-apoptotic protein BCL-2 has been implicated in mediating the survival of multiple myeloma (MM) cells. Venetoclax is a potent, selective, orally bioavailable small-molecule BCL-2 inhibitor. Venetoclax induces cell death in MM cell lines in vitro and primary MM samples ex vivo. Certain genetic subtypes of MM cells are particularly sensitive to venetoclax, including t(11;14) cells, which express a high ratio of BCL2 to MCL1 (venetoclax resistance factor). The current Phase 1 study evaluates safety, efficacy, and pharmacokinetics (PK) in patients (pts) with relapsed/refractory MM. Methods: Primary objectives are to evaluate safety, PK, and recommended phase two dose; other objectives include assessing preliminary efficacy and the impact of chromosomal abnormalities. In dose-escalation (DE) cohorts, venetoclax was given orally daily at 300, 600, 900, or 1200 mg after a 2-week dose ramp-up (3+3 design). Patients in the safety expansion (SE) cohort received 1200 mg daily after ramp-up. All patients were monitored for tumor lysis syndrome (TLS). Results: As of June 17, 2015, 37 patients were enrolled in the study: 30 from DE cohorts and 7 from the SE. Median (range) age was 66 years; 19 (51%) were female. Fourteen were ISS stage I, 13 stage II, 8 stage III, 2 unknown. The median (range) number of prior lines of therapy was 6 (1-19). Thirty-two had prior bortezomib (20 refractory), 35 lenalidomide (18 refractory), and 26 had prior stem cell transplant. Fourteen patients had t(11;14), 4 had t(4;14), 5 had del 17p, and 17 had del 13q. Adverse events (AEs) in ≥20% of patients were nausea (49%), diarrhea (38%), vomiting (30%), anemia (27%), fatigue (24%). Grade 3/4 AEs (≥10%): thrombocytopenia (22%), anemia (19%), neutropenia (11 %). Serious AEs (≥2 patients): pyrexia (n=3), cough, malignant neoplasm progression, and sepsis (2 each); 2 (upper abdominal pain and anemia) were possibly related to venetoclax. Thirty (81%) patients have discontinued venetoclax: 24 due to PD, 3 for AEs (worsening shortness of breath, hypokalemia, and nausea), 2 withdrew consent, 1 due to death (brain hemorrhage following injury). Four deaths occurred (2 due to PD, 1 due to brain hemorrhage, 1 due to pneumopathy). Two of the 6 patients in the 600 mg cohort experienced DLTs of upper abdominal pain and nausea with abdominal pain. No patients met the criteria for laboratory or clinical TLS. Based on preliminary PK (n=21), the mean Cmax and AUC24 were ~dose-proportional at all studied doses (300, 600, 1200 mg) except 900 mg, and dose-normalized venetoclax exposure in MM was similar to that in CLL and NHL pts. Thirty-two of the 37 patients were evaluable for preliminary efficacy (Table). Two patients, both t(11;14), achieved a complete response (1 at 600 mg and 1 at 900 mg). Responses were first achieved at 1.8 and 1.1 months and were maintained for 9.7 and 9.0 months, respectively (900 mg pt remains in CR). Among the 16 patients receiving 1200 mg in the DE or SE cohort, 6 of whom had t(11;14), 5 achieved SD, 6 experienced PD, and 5 are not yet evaluable. Conclusions: Venetoclax monotherapy had a tolerable safety profile in heavily-pretreated relapsed/refractory MM, and no new safety signals were observed compared to other venetoclax studies. The study continues to enroll in the SE cohort at 1200 mg. Responses (including CR) and longer time on venetoclax were observed in t(11;14) patients. These early results suggest that venetoclax has single agent activity, most prominently in t(11;14) patients. Figure 1. Figure 1. Disclosures Kumar: Celgene: Research Funding; Millenium/Takeda: Research Funding; Onyx: Research Funding; AbbVie: Research Funding; Janssen: Research Funding; Sanofi: Research Funding; Celgene, Millenium, Sanofi, Skyline, BMS, Onyx, Noxxon,: Other: Consultant, no compensation,; Skyline, Noxxon: Honoraria. Off Label Use: Venetoclax is an investigational drug that is not yet approved in this indication.. Vij:Takeda, Onyx: Research Funding; Celgene, Onyx, Takeda, Novartis, BMS, Sanofi, Janssen, Merck: Consultancy. Kaufman:Janssen: Consultancy; Spectrum: Consultancy; Merck: Research Funding; Celgene: Consultancy; Onyx: Consultancy; Novartis: Consultancy; Novartis: Research Funding; Onyx: Research Funding. Mikhael:Sanofi: Research Funding; AbbVie: Research Funding; Celgene: Research Funding; Onyx: Research Funding. Moreau:Takeda: Other: Adboard; Janssen: Other: Adboard; Celgene: Other: Adboard; Novartis: Other: Adboard; Amgen: Other: Adboard. Alzate:AbbVie: Employment, Equity Ownership. Morris:AbbVie: Employment, Equity Ownership. Ross:AbbVie: Employment, Equity Ownership. Dunbar:AbbVie: Employment, Equity Ownership. Zhu:AbbVie: Employment, Equity Ownership. Maciag:AbbVie: Employment, Equity Ownership. Agarwal:AbbVie: Employment, Equity Ownership. Leverson:AbbVie: Employment, Equity Ownership. Enschede:AbbVie: Employment, Equity Ownership. Humerickhouse:AbbVie: Employment, Equity Ownership. Touzeau:AbbVie: Research Funding.

Download Full-text

Real-World Outcomes for Transplant-Ineligible Patients with Newly Diagnosed Multiple Myeloma Treated with Lenalidomide, Bortezomib, and Dexamethasone, or Bortezomib and Dexamethasone: An Enhanced Electronic Health Records Database Analysis

Blood ◽

10.1182/blood-2018-99-111121 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2243-2243

Author(s):

Ajai Chari ◽

Brian Ung ◽

Marc Tian ◽

Amit Agarwal ◽

Kejal Parikh

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Real World ◽

Research Funding ◽

Second Line ◽

Second Line Therapy ◽

Employment Equity ◽

Advisory Committees ◽

Line Therapy ◽

Equity Ownership

Abstract Background: For transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM), the only category 1 regimens recommended by the National Comprehensive Cancer Network (NCCN) are lenalidomide and dexamethasone (Rd)-based, including triplet therapy with lenalidomide, bortezomib, and dexamethasone (RVd) (NCCN Myeloma v4.2018). Other doublet regimens, such as bortezomib and dexamethasone (Vd), are still a first-line option for patients with NDMM, especially for those who are elderly and/or frail. However, the latter population is either excluded or markedly underrepresented in clinical trials. Using an electronic health records (EHRs) database, we compared outcomes when either RVd or Vd were used in the treatment of transplant-ineligible patients with NDMM in a real-world practice setting, after adjusting for baseline demographic and clinical differences between the two cohorts. Methods: A retrospective observational study of patients with NDMM was conducted using EHRs from a nationally representative database (Flatiron Health). The Flatiron Network database is an enhanced oncology EHR database of patients treated at 265 clinics throughout the USA. Patients diagnosed with multiple myeloma, ICD-9 (203.0x) or ICD-10 (C90.xx), between January 2011 and May 2018 who were treated with RVd or Vd and did not undergo stem cell transplantation were included in the analysis. The primary comparison was time to next therapy (TTNT) in the overall population and in a subset of frail patients, as determined by a composite score based on age, Eastern Cooperative Oncology Group performance status (ECOG PS) score, and Charlson Comorbidity Index (CCI). Data regarding overall and progression-free survival (PFS) were limited as patient data prior to adoption of the Flatiron Network database were incomplete. Treatment-free interval (TFI) for patients who initiated a second-line therapy was defined as time from start of first-line to start of second-line therapy minus the duration of therapy (DOT). The Kaplan-Meier and Cox proportional hazard methods were used to calculate TTNT after adjusting for differences in patient baseline demographic and clinical characteristics. Results: Of the 8,470 transplant-ineligible patients with NDMM in the database, 2,369 were treated with either RVd (n = 1,309) or Vd (n = 1,060) and met the criteria for inclusion in this analysis. Patients treated with Vd were more likely to be older (median age 75 vs 70 years; P < 0.0001), frail (76.3% vs 65.4%; P = 0.0002), have creatinine clearance < 30 mL/min (23.9% vs 10.7%, P < 0.0001), have a higher ECOG PS score (P = 0.0031), and have International Staging System stage III disease (45.1% vs 28.8%; P < 0.0001). There were no significant differences in baseline neutropenia, anemia, or thrombocytopenia, or in median CCI. The proportion of patients with high-risk cytogenetics was lower in the Vd group (19.7% vs 26.0%; P < 0.0001). The mean DOT was longer for RVd (11.4 ± standard deviation [SD] 13.3 months) than for Vd (7.7 ± SD 9.7 months). However, the median adjusted TTNT was significantly longer with RVd than Vd (40.9 vs 14.8 months; hazard ratio [HR] 0.43; 95% confidence interval [CI] 0.33-0.55; P < 0.0001). The proportion of patients initiating a new treatment was lower in the RVd group (24.8% vs 40.6%; P < 0.0001). Among those who initiated a second-line therapy, the mean TFI for RVd compared with Vd was 42.6 versus 39.3 days, respectively (P = 0.2214). Among the 735 frail patients (416 RVd and 319 Vd), the median TTNT was significantly longer with RVd (32.6 vs 17.1 months; HR 0.40; 95% CI 0.29-0.54; P < 0.0001; Figure). Similar to the overall population, there were no significant differences in TFI (54.9 vs 29.6 days, P = 0.2598) and a significantly higher proportion of Vd patients initiated a new treatment (22.1% vs 36.4%; P < 0.001). Conclusions: In this real-world practice setting where PFS cannot be measured directly, triplet therapy with RVd significantly prolonged TTNT compared with Vd by 26.1 months in the overall patient population, and by 15.5 months in frail transplant-ineligible patients with NDMM. Disclosures Chari: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnology: Membership on an entity's Board of Directors or advisory committees; The Binding Site: Consultancy; Array Biopharma: Research Funding; Bristol Myers Squibb: Consultancy. Ung:Celgene Corporation: Employment, Equity Ownership. Tian:Celgene Corporation: Employment. Agarwal:Celgene Corporation: Employment, Equity Ownership. Parikh:Celgene Corporation: Employment, Equity Ownership.

Download Full-text

Safety in Patients with Multiple Myeloma Treated with Pomalidomide in a Real-World Setting According to Last Prior Treatment: A European Post-Authorization Safety Study

Blood ◽

10.1182/blood-2018-99-111906 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3286-3286

Author(s):

Niels Abildgaard ◽

Marie-Christiane Vekemans ◽

Barbara Gamberi ◽

Francesco Di Raimondo ◽

Angel Ramirez Payer ◽

...

Keyword(s):

Multiple Myeloma ◽

Adverse Events ◽

Real World ◽

Safety Profile ◽

Research Funding ◽

Interventional Study ◽

Employment Equity ◽

Safety Study ◽

Real World Setting ◽

Equity Ownership

Abstract BACKGROUND The combination of pomalidomide (POM) and dexamethasone (DEX) for the treatment (Tx) of relapsed or refractory multiple myeloma (RRMM) in patients (pts) who have received ≥ 2 prior Tx regimens, including lenalidomide (LEN) and bortezomib (BORT), was approved in Europe in August 2013. POM-DEX is now a standard Tx for pts with RRMM. These pts are at an increased risk for adverse events (AEs) due to prior exposure to multiple lines of Tx and a high disease burden. The European Union post-authorization safety study (EU PASS; NCT02164955) is a prospective, observational, non-interventional study (method: registry) designed to characterize the safety profile of POM-based Tx in pts with RRMM in a real-world setting. AIM To report the incidence of key AEs with POM-based Tx, such as neutropenia, thrombocytopenia, venous thromboembolism (VTE), peripheral neuropathy (PN), and second primary malignancies (SPMs), in pts with RRMM treated with POM according to the last prior Tx before starting POM Tx in a post-marketing setting. METHODS Pts with symptomatic RRMM initiating POM-based Tx were enrolled at the investigator's discretion. Thromboprophylaxis was administered per local standard practice. AEs were graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (v4.0). The study is ongoing and open for recruitment in centers across Europe. This analysis focused on the safety profile according to the last prior Tx received before starting POM Tx. RESULTS As of July 12, 2018, 596 pts across 100 institutions in 8 European countries were included in the safety population. At the time of data cutoff, Tx was ongoing in 122 pts (20.5%). Median age was 70 yrs (range, 37-92 yrs), with 28.4% of pts aged < 65 yrs, 38.4% between age 65 and 75 yrs, and 33.2% aged ≥ 75 yrs; 54.2% were male. Median time from diagnosis was 4.8 yrs (range, 0.3-26.9 yrs). Median number of prior Txs was 3; 72.1% of pts had ≥ 3 prior lines. Most pts received prior LEN (99.2%) and BORT (99.0%). In 343 pts assessed for Eastern Cooperative Oncology Group performance status (PS), 277 had a PS of 0 or 1 at baseline. Among 595 pts whose prior Tx was entered into the database at the time of data cutoff, the last prior Tx before starting POM was LEN in 340 pts (57.1%), BORT in 134 pts (22.5%), a combination of LEN and BORT in 16 pts (2.7%), and any other drug in 105 pts (17.6%). Tx duration of POM was slightly longer in pts treated with prior BORT than in those treated with prior LEN, with a median Tx duration of 18.7 wks (range, 0.9-150.0 wks) in the LEN group vs 23.7 wks (range, 0.1-148.0 wks) in the BORT group. Across all subgroups, hematologic AEs and infections represented most of all AEs (Table). CONCLUSIONS This ongoing, prospective, non-interventional study in pts with RRMM continues to demonstrate that POM-based Tx is generally well tolerated in the real-world setting and that the safety profile is not impacted by the Tx administered immediately before starting a POM-based Tx. Of all pts included in this trial, more pts were treated with LEN immediately before starting POM than any other drug. This analysis shows that AEs are almost similar in pts treated with LEN or BORT or both or any other drug immediately before starting POM Tx. In addition, the reported VTEs, PNs, and SPMs were generally low in all subgroups. Updated data will be presented at the meeting. Table. Table. Disclosures Abildgaard: Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding. Di Raimondo:Celgene: Honoraria; Takeda: Honoraria, Research Funding. Kueenburg:Celgene Corporation: Consultancy, Honoraria. Rosettani:Celgene International: Employment, Equity Ownership. Bacon:Celgene: Employment. Atiba-Davies:Celgene Corporation: Employment, Equity Ownership. Plesner:Janssen: Consultancy; Celgene: Other: Independent Response Assessment Comittee.

Download Full-text

An Adjusted Treatment Comparison of Bortezomib/Cyclophosphamide /Dexamethasone and Bortezomib/Thalidomide/Dexamethasone from Real-World Data in Patients with Newly Diagnosed Multiple Myeloma Who Are Transplant-Eligible

Blood ◽

10.1182/blood-2019-123512 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2142-2142

Author(s):

Maneesha Mehra ◽

Sarah Cote ◽

Tobias Kampfenkel ◽

Sandhya Nair

Keyword(s):

United States ◽

Multiple Myeloma ◽

Real World ◽

The United States ◽

Induction Treatment ◽

Newly Diagnosed ◽

Real World Data ◽

Employment Equity ◽

Equity Ownership ◽

Baseline Characteristics

Introduction: For patients with newly diagnosed multiple myeloma (NDMM) who are eligible for autologous stem-cell transplantation (ASCT), two standard of care (SoC) induction regimens are bortezomib/cyclophosphamide/dexamethasone (VCd) and bortezomib/thalidomide/dexamethasone (VTd), each followed by ASCT. While VCd and VTd are both treatment options according to international guidelines, treatment selection varies by country. Additionally, while some clinical studies have evaluated the efficacy and safety of these therapies, direct comparisons have been limited to response endpoints post-induction and post-transplant (Moreau P, et al. Blood. 2016;127[21]2569-2574; Cavo M, et al. Blood. 2014;124[21]197; Cavo M, et al. Leukemia. 2015;29[12]2429-31). Herein we describe real-world treatment patterns in the United States for patients with NDMM who are transplant-eligible, and report results from a matched adjusted comparison to evaluate real-world long-term efficacy (overall survival, OS) for VCd +ASCT versus VTd +ASCT. Methods: Data for the VCd and VTd real-world evidence (RWE) cohorts were identified from 3 US data sources collectively covering the period January 2000 to March 2017: the OPTUM™ Commercial Claims database, the OPTUM™ Integrated (CLAIMS+EMR) database, and the Surveillance, Epidemiology, and End Results (SEER)-Medicare Linked database. RWE data were from patients with an index MM diagnosis on or after 1 January 2007, medical prescription coverage in place at diagnosis, no prior malignancies in the 1-year period prior to index diagnosis, a 1-year look-back period prior to index diagnosis, received ≥1 line of therapy, and received stem cell transplantation with induction as frontline treatment. The Kaplan-Meier method and Cox proportional hazard model compared outcomes with and without adjustments for baseline characteristics (age, sex, renal impairment, and anemia) and induction treatment duration; comparisons were also conducted with inverse probability of treatment weighting (IPTW). Results: Analysis of RWE from the United States demonstrated that bortezomib (V)-based regimens were the most common induction treatment (together accounting for approximately 75% of therapies), with bortezomib/lenalidomide/dexamethasone (VRd) being the most common (31%). Use of VCd (13%) and VTd (5%) was limited. Comparisons were conducted for VCd (n = 135) and VTd (n = 51). Baseline characteristics were generally similar between groups, except for fewer male patients in the VCd group than the VTd group (57% vs 65%), and lower rates of renal impairment in the VCd group than the VTd group (29% vs 43%; Table 1). The naïve and adjusted comparisons of OS for VCd versus VTd therapy showed these treatments were not statistically different (adjusted hazard ratio, 1.180 [95%: 0.468-2.972]; P = 0.7260; Figure 1). The IPTW method generated similar results. Conclusions: Real-world data from the United States show that V-based induction regimens are the most commonly used for treatment of patients with NDMM who are transplant-eligible. Results from the naïve, adjusted, and IPTW comparisons all showed that OS was not significantly different for VCd + ASCT versus VTd + ASCT. Survival data for VTd from RWE are generally consistent with VTd data reported in the recent phase 3 CASSIOPEIA study, although OS data from CASSIOPEIA remain immature (Moreau P, et al. Lancet. 2019;394[10192]:29-38). Disclosures Cote: Janssen: Employment, Equity Ownership. Kampfenkel:Janssen: Employment, Equity Ownership. Nair:Janssen: Employment, Equity Ownership.

Download Full-text

PFS2 In Elderly Patients With Newly Diagnosed Multiple Myeloma (NDMM): Results From The MM-015 Study

Blood ◽

10.1182/blood.v122.21.405.405 ◽

2013 ◽

Vol 122 (21) ◽

pp. 405-405 ◽

Cited By ~ 3

Author(s):

Meletios A. Dimopoulos ◽

Maria Teresa Petrucci ◽

Robin Foà ◽

John V. Catalano ◽

Martin Kropff ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Research Funding ◽

Employment Equity ◽

Advisory Committees ◽

Long Term Treatment ◽

Equity Ownership ◽

Line Setting ◽

The Impact

Abstract Introduction In a phase 3 trial of transplant non-eligible elderly (≥ 65 yrs) patients (pts) with NDMM, the combination of melphalan-prednisone-lenalidomide (LEN) followed by LEN maintenance (MPR-R) reduced the risk of progression by 60% compared with 9 cycles of MP (HR=0.40; P < 0.001) and by 51% compared with 9 cycles of MPR (HR=0.49; P < 0.001) (Palumbo, NEJM. 2012). The progression-free survival (PFS) benefit was seen in all patient types. With a median follow-up of 53 mos, the median overall survival (OS) was similar across the 3 treatment (Tx) groups (54 mos for MPR-R vs. 52 mos for MPR vs. 55 mos for MP) (Dimopoulos, ASH 2012; abstract 944). The similar OS benefit seen across the 3 arms could be due in part to the availability of more effective Tx options in subsequent lines of therapy. Assessment of PFS2, defined as the time from initial randomization to time of objective disease progression (PD) after next-line of therapy or death from any cause, has recently been proposed as a surrogate for OS, particularly for trials evaluating maintenance Tx (EMA guideline, www.ema.europa.eu). Therefore, data from MM-015 were analyzed to estimate PFS2 in pts treated with MPR-R, MPR, or MP. Methods The MM-015 study design has been previously described (Palumbo, NEJM. 2012). Refractory multiple myeloma pts who progressed during MM-015 study could receive LEN 25 mg (D1–21/28-day cycle) ± dexamethasone 40 mg (on days 1–4, 9–12, and 17–20) as part of an open-label extension phase, or any other anti-myeloma Tx outside of the protocol as part of the follow-up phase. The data of PD following 2nd-line Tx was not collected prospectively; therefore, the start of 3rd-line Tx was used as a surrogate for analyzing the PFS2 endpoint. The assessment included data up to July 31, 2012 (median follow-up: 53 mos after initial randomization). Results A total of 459 pts were randomized to MPR-R (n= 152), MPR (n= 153), or MP (n= 154). At the time of the data cut-off, fewer pts in the MPR-R group had started 2nd-line Tx (53%) compared with the MPR and MP groups (77% and 82%, respectively) due to the improved PFS seen with MPR-R in the 1st-line setting. Most pts in the MP group “crossed over” to receive LEN as 2nd-line Tx (72%); choice of 2nd-line Tx in the MPR-R group was heterogeneous (Table). Median PFS2 was significantly higher with MPR-R (39.7 mos) vs. MP (28.5 mos; HR=0.71; log-rank P = 0.013) (Figure). The safety profile of continuous therapy with LEN was predictable and manageable with little evidence of cumulative toxicity and low second primary malignancy risk (Delforge, IMW 2013: abstract O-17). Conclusion PFS2 was markedly improved in the MPR-R group vs. the MP group. LEN provided a durable progression-free interval also when including the impact of 2nd-line Tx, confirming the clinical benefits of continuous LEN Tx. The benefit of MPR-R was apparent regardless of subsequent Tx; long-term treatment with LEN did not affect the efficacy of subsequent therapy. Use of continuous LEN in the 1st-line setting in combination with MP is more beneficial than sequential use of MP and LEN. PFS and PFS2 were improved with MPR-R; OS was similar among the 3 Tx groups; the reason for this is unclear, but may be related to the impact of subsequent Tx (i.e., 3rd and 4th line), which was more frequently needed in the MPR and MP groups. Disclosures: Dimopoulos: Orthobiotech: Honoraria; Celgene Corporation: Honoraria. Off Label Use: Lenalidomide in the frontline and maintenance treatment of multiple myeloma. Petrucci:Celgene Corporation: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria. Catalano:Celgene Corporation: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Yu:Celgene Corporation: Employment, Equity Ownership. Grote:Celgene Corporation: Employment, Equity Ownership. Jacques:Celgene Corporation: Employment, Equity Ownership. Palumbo:Amgen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen Pharmaceuticals: Consultancy, Honoraria; Millenium: Consultancy, Honoraria; Onyx: Consultancy, Honoraria.

Download Full-text