Just Accepted by Current Medical Research & Opinion Original Article Patterns of total cost and economic consequences of progression for patients with newly diagnosed multiple myeloma Steven R. Arikian, Dejan Milentijevic, Gary Binder, Craig J. Gibson, X. Henry Hu, Yasir Nagarwala, Mohamad Hussein, Frank A. Corvino, Andy Surinach, Saad Z. Usmani doi: 10.1185/03007995.2015.1031732
Curr Med Res Opin Downloaded from informahealthcare.com by Georgian Court University on 04/11/15 For personal use only.
Abstract Background: Few studies have addressed the cost patterns of patients with multiple myeloma (MM) before and after first relapse. This US claims analysis evaluated, from a US health plan perspective, patterns of total direct costs of care from treatment initiation to progression for patients with MM treated with novel agents, using time to next therapy (TTNT) as a proxy measure for progression. Methods: A retrospective study was conducted using a large US claims database, evaluating patients with claims for MM between 2006 and 2013. Patients with claims for stem cell transplant (SCT) were excluded. The analysis focused on patients receiving lenalidomide (LEN)- or bortezomib (BORT)-based treatment, for whom complete claim history was available through initiation of subsequent treatment. Average patient monthly direct costs were determined, including medical and pharmacy costs, and total cost patterns over quarterly time periods were calculated. Results: The study population comprised 2843 patients with NDMM and 1361 with relapsed MM. Total monthly cost for patients with NDMM declined steadily, from $15,734 initially to $5082 at 18+ months after therapy. Upon initiation of second-line therapy, total monthly costs rose to $13,876 and declined to $6446 18 months later. Although NDMM cost levels for individual ordinal months were similar between the LEN and BORT groups, TTNT was longer for LEN-based treatments (37 months). The BORT-treated cohort had higher average monthly total costs for NDMM and for the common time period through 37 months after initiation of therapy ($7534 vs $10,763 for LEN and BORT, respectively). Key limitations of this study, in addition to the lack of mortality and staging information available from claims data, include the definition of TTNT based on change in treatment or a defined gap in therapy prior to retreatment, which may differ from actual time of progression in some patients. Conclusions: For patients with NDMM receiving either LEN- or BORT-based treatment without SCT, followed until TTNT, total direct monthly costs (drug + medical) declined steadily over time. Monthly costs returned near initial levels when patients began second-line therapy and then followed a similar pattern of decline. Due to the longer TTNT for patients initiated on LEN and the associated longer period of below-average costs, patients initiated with LEN-based treatments had mean monthly total costs > $3200 lower than total costs for patients initiated on BORT during the first 3 years after starting treatment, cumulating to nearly $120,000 in lower costs for patients initiated on LEN.
© 2014 Informa UK Ltd. This provisional PDF corresponds to the article as it appeared upon acceptance. Fully formatted PDF and full text (HTML) versions will be made available soon. DISCLAIMER: The ideas and opinions expressed in the journal’s Just Accepted articles do not necessarily reflect those of Informa Healthcare (the Publisher), the Editors or the journal. The Publisher does not assume any responsibility for any injury and/or damage to persons or property arising from or related to any use of the material contained in these articles. The reader is advised to check the appropriate medical literature and the product information currently provided by the manufacturer of each drug to be administered to verify the dosages, the method and duration of administration, and contraindications. It is the responsibility of the treating physician or other health care professional, relying on his or her independent experience and knowledge of the patient, to determine drug dosages and the best treatment for the patient. Just Accepted articles have undergone full scientific review but none of the additional editorial preparation, such as copyediting, typesetting, and proofreading, as have articles published in the traditional manner. There may, therefore, be errors in Just Accepted articles that will be corrected in the final print and final online version of the article. Any use of the Just Accepted articles is subject to the express understanding that the papers have not yet gone through the full quality control process prior to publication.
ORIGINAL ARTICLE Patterns of total cost and economic consequences of progression for patients with newly diagnosed multiple myeloma
Steven R. Arikian,1 Dejan Milentijevic,2 Gary Binder,3 Craig J. Gibson,3 X. Henry Hu,3 Yasir
Curr Med Res Opin Downloaded from informahealthcare.com by Georgian Court University on 04/11/15 For personal use only.
Nagarwala,3 Mohamad Hussein,3 Frank A. Corvino,1 Andy Surinach,1 Saad Z. Usmani4
1
Genesis Research, Hoboken, NJ, USA
2
D. Milentijevic, Springfield, NJ, USA
3
Celgene Corporation, Summit, NJ, USA
4
Levine Cancer Institute/Carolinas Healthcare System, Charlotte, NC, USA
Address for correspondence: Steven R. Arikian, Managing Director, Genesis Research, 50 Harrison Street , Hoboken, New Jersey 07030 USA. [email protected]
Key words: Myeloma , cost analysis , cost comparison , newly-diagnosed , Lenalidomide , Bortezomib , economic analysis
[Short title: Cost patterns and consequences of progression in myeloma]
1
ABSTRACT Background: Few studies have addressed the cost patterns of patients with multiple myeloma (MM) before and after first relapse. This US claims analysis evaluated, from a US health plan perspective, patterns of total direct costs of care from treatment initiation to progression for patients with MM treated with novel agents, using time to next therapy (TTNT) as a proxy
Curr Med Res Opin Downloaded from informahealthcare.com by Georgian Court University on 04/11/15 For personal use only.
measure for progression.
Methods: A retrospective study was conducted using a large US claims database, evaluating patients with claims for MM between 2006 and 2013. Patients with claims for stem cell transplant (SCT) were excluded. The analysis focused on patients receiving lenalidomide (LEN)or bortezomib (BORT)-based treatment, for whom complete claim history was available through initiation of subsequent treatment. Average patient monthly direct costs were determined, including medical and pharmacy costs, and total cost patterns over quarterly time periods were calculated.
Results: The study population comprised 2843 patients with NDMM and 1361 with relapsed MM. Total monthly cost for patients with NDMM declined steadily, from $15,734 initially to $5082 at 18+ months after therapy. Upon initiation of second-line therapy, total monthly costs rose to $13,876 and declined to $6446 18 months later. Although NDMM cost levels for individual ordinal months were similar between the LEN and BORT groups, TTNT was longer for LEN-based treatments (37 months). The BORT-treated cohort had higher average monthly total costs for NDMM and for the common time period through 37 months after initiation of therapy ($7534 vs $10,763 for LEN and BORT, respectively). Key limitations of this study, in
2
addition to the lack of mortality and staging information available from claims data, include the definition of TTNT based on change in treatment or a defined gap in therapy prior to retreatment, which may differ from actual time of progression in some patients.
Conclusions: For patients with NDMM receiving either LEN- or BORT-based treatment without
Curr Med Res Opin Downloaded from informahealthcare.com by Georgian Court University on 04/11/15 For personal use only.
SCT, followed until TTNT, total direct monthly costs (drug + medical) declined steadily over time. Monthly costs returned near initial levels when patients began second-line therapy and then followed a similar pattern of decline. Due to the longer TTNT for patients initiated on LEN and the associated longer period of below-average costs, patients initiated with LEN-based treatments had mean monthly total costs > $3200 lower than total costs for patients initiated on BORT during the first 3 years after starting treatment, cumulating to nearly $120,000 in lower costs for patients initiated on LEN.
INTRODUCTION Over the past decade, the treatment paradigm for multiple myeloma (MM) has shifted, with the introduction of novel agents, such as the immunomodulatory drugs thalidomide and lenalidomide (LEN; Revlimid®) and the proteasome inhibitor bortezomib (BORT; Velcade®), as standard treatment options for newly diagnosed MM (NDMM) and for relapsed disease1,2. In the US, clinical practice guidelines from the National Comprehensive Cancer Network (NCCN) include category 1 recommendations for BORT -based and LEN -based regimens as first-line and second-line therapy in MM patients3. Evidence from large randomized clinical trials has
3
mounted in support of these agents as well as for longer treatment for patients with NDMM4–7. Median survival in patients with NDMM has increased to 6.1 years, a gain attributed to the impact of initial therapy with these novel agents8. Extending time without progression is a primary focus of treatment, and progression-free survival (PFS) or time to progression (TTP) have been primary endpoints in phase III studies of
Curr Med Res Opin Downloaded from informahealthcare.com by Georgian Court University on 04/11/15 For personal use only.
both agents.9,10 Progression is defined by the International Myeloma Workgroup to reflect specific measures including 25% worsening in paraprotein levels and/or other evidence of end organ damage including hypercalcemia, renal impairment, anemia, or bone lesions2. A patient’s prognosis worsens with each progression, and there is a shorter expected time to the next progression. BORT and LEN demonstrated significant improvement in extending TTP and PFS in patients with NDMM in the VISTA (Velcade as Initial Standard Therapy in Multiple Myeloma: Assessment with Melphalan and Prednisone) and FIRST (Frontline Investigation of Revlimid + Dexamethasone Versus Standard Thalidomide) trials, respectively11,12. Achieving these improvements in the outcomes of patients with MM with these new therapies raises questions regarding the costs of care among patients with NDMM, including the economic impact of extending TTP vs not extending TTP in these patients, and the cost consequences when patients relapse and move to a second line of treatment. Given the constrained resources for healthcare delivery, assessing the cost patterns of these agents will be valuable in evaluating the economic benefits of therapies. A recent retrospective chart review in the Netherlands showed that patients with relapsed myeloma incurred higher monthly costs upon advancing to later lines of therapy13. However, few published studies have examined the cost patterns of patients with MM before and after the first
4
relapse, using real-world cost data. The present study evaluated from the perspective of a US health plan, the patterns of total direct costs of care, from treatment initiation until progression, for patients with NDMM (first-line) and for patients with relapsed MM receiving second-line administration of LEN- or BORT-based treatments, using a large US healthcare claims database.
Curr Med Res Opin Downloaded from informahealthcare.com by Georgian Court University on 04/11/15 For personal use only.
METHODS Study design and data A retrospective study was conducted using the MarketScan Commercial Claims and Encounters (commercial) and the Medicare Supplemental and Coordination of Benefits (Medicare) databases. The commercial database contains US pharmacy and medical claims for healthcare services performed in inpatient as well as outpatient settings and enrollment data from employer-sponsored health insurance plans, covering more than 25 million lives annually. Medical claims and enrollment data are linked to outpatient prescription drug claims through the use of unique enrollee identifiers. The Medicare database contains inpatient medical, outpatient medical, and outpatient prescription drug claims of retirees with Medicare supplemental insurance paid for by Medicare and the employer. Both databases contain demographic and eligibility information, including age, sex, geographic region, coverage type, and pre-existing comorbidities. This analysis evaluated patients with NDMM or relapsed MM receiving LEN- or BORTbased treatment, with a complete claim history from treatment onset to initiation of subsequent treatment, between January 2006 and December 2013.
Study population
5
Patients with NDMM were identified as individuals with ≥ 2 outpatient claims or ≥ 1 inpatient medical claim associated with a diagnosis of MM (ICD-9-CM code 203.0X) between January 1, 2006, and December 31, 2013. The index date was defined as the date of the first claim with an MM diagnosis code in the specified study period. Patients were included in the study if they had continuous enrollment for (1) ≥ 12 months before the index date, (2) ≥ 6
Curr Med Res Opin Downloaded from informahealthcare.com by Georgian Court University on 04/11/15 For personal use only.
months after the index date, and (3) ≥ 6 months after initiation of the first treatment. Patients with claims for stem cell transplant (SCT) were excluded to avoid confounding results from various factors based on timing, costs, and site of care of SCT.
Definition of variables First-line treatment included the first LEN- or BORT-based treatment that a patient with NDMM received after the index date and excluded any of the following: SCT plus maintenance therapy or BORT plus LEN combined therapy (with a minimum overlap of 30 days). The patient group “other” referred to patients who received ≥ 60 days of treatment with agents other than BORT and/or LEN. Time to next therapy (TTNT) was defined as the time between the start of the first therapy and the start of the second therapy and was used as a proxy for progression (ie, TTP). For any given line of therapy, the end of treatment was defined as either the first day of any gap in treatment > 90 days or initiation of a new regimen (BORT plus LEN, BORT, LEN, or other). Patients who received the above treatments were followed until TTNT. Thereafter, those patients receiving BORT, LEN, or other as subsequent therapy (ie, second-line treatment) were evaluated using similar methods, until their subsequent TTNT. To be considered on other therapy, patients needed ≥ 60 days of other therapy with no evidence of LEN or BORT.
6
Analysis Patient demographics and clinical characteristics were examined and defined as of the index date. These variables include age, sex, geographic region, and insurance plan type. The primary outcome in this study was direct healthcare costs. Healthcare costs in patients with MM were assessed using paid amounts on included claims and by component of
Curr Med Res Opin Downloaded from informahealthcare.com by Georgian Court University on 04/11/15 For personal use only.
care, medical (ie, inpatient, ambulatory, emergency department [ED]) costs, and pharmacy (ie, index and other prescription drug) costs for each patient. Total costs were determined as the sum of medical- and pharmacy-related costs, were adjusted appropriately using the US Consumer Price Index, and are reported in 2014 US$. Cost analyses were performed exclusively on patients with MM who completed a line of therapy to avoid underestimation of the cost consequences of progression. Consistent with methods described by Gaultney et al13, monthly total costs were calculated by summing total direct costs incurred by all patients in each successive month and dividing by the sum of patientmonths; the costs were then stratified by components of care. In addition, to provide a clearer basis for evaluating temporal trends, quarterly cost patterns of monthly costs for each line of therapy were evaluated by summing total costs and dividing by the sum of patient-months within each quarter. To determine a single average monthly cost for each treatment through to TTNT, each quarter’s monthly costs were cumulated up to the median TTNT, as calculated via a Kaplan-Meier analysis, for each cohort and divided by the median number of months. The resulting average costs for each treatment group were then weighted by the number of patients in each group to determine the pooled average monthly costs.
7
To avoid ascribing lower cumulative costs to a regimen solely due to a shorter period of successful outcomes, costs for patient cohorts initiated on each regimen were also evaluated over a consistent elapsed time period. Average Charlson Comorbidity Index (CCI) was determined to compare baseline measures of burden of disease and case mix between patient groups. To generate this, presence
Curr Med Res Opin Downloaded from informahealthcare.com by Georgian Court University on 04/11/15 For personal use only.
of comorbidities of interest for each patient during the 6 month baseline period was recorded and scores were tallied using methods described by Quan et al.14 The significance of each month’s average per-patient monthly cost for each treatment was evaluated with the Wilcoxon rank-sum test. Additionally, multivariate regression analysis was performed when direct costs were compared between treatments to control for possible confounding factors, such as age, sex, quantity of prescriptions for all medications before the index date, history of cancer or renal disease before the baseline period, and CCI. By means of a generalized linear model with a γ error distribution and log-link function, unadjusted and adjusted total monthly direct costs, pharmacy costs, and medical costs were compared between patients receiving LEN or BORT. Data management and statistical analyses were conducted using SAS version 9.4 (SAS Institute Inc, Cary, NC).
RESULTS Characteristics of the patient population From 2006 through 2013, 2843 patients with NDMM (1281 patients receiving LENbased treatments and 1562 patients receiving BORT-based treatments) and 1361 patients with
8
MM receiving second-line therapy (832 and 529 patients receiving LEN- and BORT-based treatments, respectively) were identified. summarizes demographic and clinical characteristics of the study population by treatment regimen and line of treatment. Sex distribution was similar between the cohorts, with a larger proportion of men (range,
Curr Med Res Opin Downloaded from informahealthcare.com by Georgian Court University on 04/11/15 For personal use only.
55%-58%). The mean age of both NDMM and relapsed MM study cohorts was similar between treatments, with > 50% of the patients aged ≥ 65 years. The most common comorbidities found in the study population before the index date were diabetes, other nonmyeloma cancers (eg, breast cancer, prostate cancer, melanoma, leukemia), and chronic pulmonary disease. CCI scores were similar between treatment groups in both patients with NDMM and those with relapsed disease. Patient characteristics were similar between treatment groups, both in first- and secondline treatment groups. Differences were most noted among patients receiving second-line therapy, including average age (1.8 years older for BORT treatment) and a 0.36 difference in CCI score (largely due to higher rates of renal disease and vascular diseases for BORT-treated patients; Table 1).
Time to next treatment For the overall study population, the median TTNT for patients with NDMM was 28.1 months. Patients with NDMM receiving LEN-based treatments (LEN first-line cohort) had a longer median TTNT than those receiving BORT-based treatments (BORT first-line cohort); 36.9 months [95% confidence interval (CI), 34.6 to 40.7] vs 20.0 months ( [95% CI, 18.0 to 22.1], p
Curr Med Res Opin Downloaded from informahealthcare.com by Georgian Court University on 04/11/15 For personal use only.
Abstract Background: Few studies have addressed the cost patterns of patients with multiple myeloma (MM) before and after first relapse. This US claims analysis evaluated, from a US health plan perspective, patterns of total direct costs of care from treatment initiation to progression for patients with MM treated with novel agents, using time to next therapy (TTNT) as a proxy measure for progression. Methods: A retrospective study was conducted using a large US claims database, evaluating patients with claims for MM between 2006 and 2013. Patients with claims for stem cell transplant (SCT) were excluded. The analysis focused on patients receiving lenalidomide (LEN)- or bortezomib (BORT)-based treatment, for whom complete claim history was available through initiation of subsequent treatment. Average patient monthly direct costs were determined, including medical and pharmacy costs, and total cost patterns over quarterly time periods were calculated. Results: The study population comprised 2843 patients with NDMM and 1361 with relapsed MM. Total monthly cost for patients with NDMM declined steadily, from $15,734 initially to $5082 at 18+ months after therapy. Upon initiation of second-line therapy, total monthly costs rose to $13,876 and declined to $6446 18 months later. Although NDMM cost levels for individual ordinal months were similar between the LEN and BORT groups, TTNT was longer for LEN-based treatments (37 months). The BORT-treated cohort had higher average monthly total costs for NDMM and for the common time period through 37 months after initiation of therapy ($7534 vs $10,763 for LEN and BORT, respectively). Key limitations of this study, in addition to the lack of mortality and staging information available from claims data, include the definition of TTNT based on change in treatment or a defined gap in therapy prior to retreatment, which may differ from actual time of progression in some patients. Conclusions: For patients with NDMM receiving either LEN- or BORT-based treatment without SCT, followed until TTNT, total direct monthly costs (drug + medical) declined steadily over time. Monthly costs returned near initial levels when patients began second-line therapy and then followed a similar pattern of decline. Due to the longer TTNT for patients initiated on LEN and the associated longer period of below-average costs, patients initiated with LEN-based treatments had mean monthly total costs > $3200 lower than total costs for patients initiated on BORT during the first 3 years after starting treatment, cumulating to nearly $120,000 in lower costs for patients initiated on LEN.
© 2014 Informa UK Ltd. This provisional PDF corresponds to the article as it appeared upon acceptance. Fully formatted PDF and full text (HTML) versions will be made available soon. DISCLAIMER: The ideas and opinions expressed in the journal’s Just Accepted articles do not necessarily reflect those of Informa Healthcare (the Publisher), the Editors or the journal. The Publisher does not assume any responsibility for any injury and/or damage to persons or property arising from or related to any use of the material contained in these articles. The reader is advised to check the appropriate medical literature and the product information currently provided by the manufacturer of each drug to be administered to verify the dosages, the method and duration of administration, and contraindications. It is the responsibility of the treating physician or other health care professional, relying on his or her independent experience and knowledge of the patient, to determine drug dosages and the best treatment for the patient. Just Accepted articles have undergone full scientific review but none of the additional editorial preparation, such as copyediting, typesetting, and proofreading, as have articles published in the traditional manner. There may, therefore, be errors in Just Accepted articles that will be corrected in the final print and final online version of the article. Any use of the Just Accepted articles is subject to the express understanding that the papers have not yet gone through the full quality control process prior to publication.
ORIGINAL ARTICLE Patterns of total cost and economic consequences of progression for patients with newly diagnosed multiple myeloma
Steven R. Arikian,1 Dejan Milentijevic,2 Gary Binder,3 Craig J. Gibson,3 X. Henry Hu,3 Yasir
Curr Med Res Opin Downloaded from informahealthcare.com by Georgian Court University on 04/11/15 For personal use only.
Nagarwala,3 Mohamad Hussein,3 Frank A. Corvino,1 Andy Surinach,1 Saad Z. Usmani4
1
Genesis Research, Hoboken, NJ, USA
2
D. Milentijevic, Springfield, NJ, USA
3
Celgene Corporation, Summit, NJ, USA
4
Levine Cancer Institute/Carolinas Healthcare System, Charlotte, NC, USA
Address for correspondence: Steven R. Arikian, Managing Director, Genesis Research, 50 Harrison Street , Hoboken, New Jersey 07030 USA. [email protected]
Key words: Myeloma , cost analysis , cost comparison , newly-diagnosed , Lenalidomide , Bortezomib , economic analysis
[Short title: Cost patterns and consequences of progression in myeloma]
1
ABSTRACT Background: Few studies have addressed the cost patterns of patients with multiple myeloma (MM) before and after first relapse. This US claims analysis evaluated, from a US health plan perspective, patterns of total direct costs of care from treatment initiation to progression for patients with MM treated with novel agents, using time to next therapy (TTNT) as a proxy
Curr Med Res Opin Downloaded from informahealthcare.com by Georgian Court University on 04/11/15 For personal use only.
measure for progression.
Methods: A retrospective study was conducted using a large US claims database, evaluating patients with claims for MM between 2006 and 2013. Patients with claims for stem cell transplant (SCT) were excluded. The analysis focused on patients receiving lenalidomide (LEN)or bortezomib (BORT)-based treatment, for whom complete claim history was available through initiation of subsequent treatment. Average patient monthly direct costs were determined, including medical and pharmacy costs, and total cost patterns over quarterly time periods were calculated.
Results: The study population comprised 2843 patients with NDMM and 1361 with relapsed MM. Total monthly cost for patients with NDMM declined steadily, from $15,734 initially to $5082 at 18+ months after therapy. Upon initiation of second-line therapy, total monthly costs rose to $13,876 and declined to $6446 18 months later. Although NDMM cost levels for individual ordinal months were similar between the LEN and BORT groups, TTNT was longer for LEN-based treatments (37 months). The BORT-treated cohort had higher average monthly total costs for NDMM and for the common time period through 37 months after initiation of therapy ($7534 vs $10,763 for LEN and BORT, respectively). Key limitations of this study, in
2
addition to the lack of mortality and staging information available from claims data, include the definition of TTNT based on change in treatment or a defined gap in therapy prior to retreatment, which may differ from actual time of progression in some patients.
Conclusions: For patients with NDMM receiving either LEN- or BORT-based treatment without
Curr Med Res Opin Downloaded from informahealthcare.com by Georgian Court University on 04/11/15 For personal use only.
SCT, followed until TTNT, total direct monthly costs (drug + medical) declined steadily over time. Monthly costs returned near initial levels when patients began second-line therapy and then followed a similar pattern of decline. Due to the longer TTNT for patients initiated on LEN and the associated longer period of below-average costs, patients initiated with LEN-based treatments had mean monthly total costs > $3200 lower than total costs for patients initiated on BORT during the first 3 years after starting treatment, cumulating to nearly $120,000 in lower costs for patients initiated on LEN.
INTRODUCTION Over the past decade, the treatment paradigm for multiple myeloma (MM) has shifted, with the introduction of novel agents, such as the immunomodulatory drugs thalidomide and lenalidomide (LEN; Revlimid®) and the proteasome inhibitor bortezomib (BORT; Velcade®), as standard treatment options for newly diagnosed MM (NDMM) and for relapsed disease1,2. In the US, clinical practice guidelines from the National Comprehensive Cancer Network (NCCN) include category 1 recommendations for BORT -based and LEN -based regimens as first-line and second-line therapy in MM patients3. Evidence from large randomized clinical trials has
3
mounted in support of these agents as well as for longer treatment for patients with NDMM4–7. Median survival in patients with NDMM has increased to 6.1 years, a gain attributed to the impact of initial therapy with these novel agents8. Extending time without progression is a primary focus of treatment, and progression-free survival (PFS) or time to progression (TTP) have been primary endpoints in phase III studies of
Curr Med Res Opin Downloaded from informahealthcare.com by Georgian Court University on 04/11/15 For personal use only.
both agents.9,10 Progression is defined by the International Myeloma Workgroup to reflect specific measures including 25% worsening in paraprotein levels and/or other evidence of end organ damage including hypercalcemia, renal impairment, anemia, or bone lesions2. A patient’s prognosis worsens with each progression, and there is a shorter expected time to the next progression. BORT and LEN demonstrated significant improvement in extending TTP and PFS in patients with NDMM in the VISTA (Velcade as Initial Standard Therapy in Multiple Myeloma: Assessment with Melphalan and Prednisone) and FIRST (Frontline Investigation of Revlimid + Dexamethasone Versus Standard Thalidomide) trials, respectively11,12. Achieving these improvements in the outcomes of patients with MM with these new therapies raises questions regarding the costs of care among patients with NDMM, including the economic impact of extending TTP vs not extending TTP in these patients, and the cost consequences when patients relapse and move to a second line of treatment. Given the constrained resources for healthcare delivery, assessing the cost patterns of these agents will be valuable in evaluating the economic benefits of therapies. A recent retrospective chart review in the Netherlands showed that patients with relapsed myeloma incurred higher monthly costs upon advancing to later lines of therapy13. However, few published studies have examined the cost patterns of patients with MM before and after the first
4
relapse, using real-world cost data. The present study evaluated from the perspective of a US health plan, the patterns of total direct costs of care, from treatment initiation until progression, for patients with NDMM (first-line) and for patients with relapsed MM receiving second-line administration of LEN- or BORT-based treatments, using a large US healthcare claims database.
Curr Med Res Opin Downloaded from informahealthcare.com by Georgian Court University on 04/11/15 For personal use only.
METHODS Study design and data A retrospective study was conducted using the MarketScan Commercial Claims and Encounters (commercial) and the Medicare Supplemental and Coordination of Benefits (Medicare) databases. The commercial database contains US pharmacy and medical claims for healthcare services performed in inpatient as well as outpatient settings and enrollment data from employer-sponsored health insurance plans, covering more than 25 million lives annually. Medical claims and enrollment data are linked to outpatient prescription drug claims through the use of unique enrollee identifiers. The Medicare database contains inpatient medical, outpatient medical, and outpatient prescription drug claims of retirees with Medicare supplemental insurance paid for by Medicare and the employer. Both databases contain demographic and eligibility information, including age, sex, geographic region, coverage type, and pre-existing comorbidities. This analysis evaluated patients with NDMM or relapsed MM receiving LEN- or BORTbased treatment, with a complete claim history from treatment onset to initiation of subsequent treatment, between January 2006 and December 2013.
Study population
5
Patients with NDMM were identified as individuals with ≥ 2 outpatient claims or ≥ 1 inpatient medical claim associated with a diagnosis of MM (ICD-9-CM code 203.0X) between January 1, 2006, and December 31, 2013. The index date was defined as the date of the first claim with an MM diagnosis code in the specified study period. Patients were included in the study if they had continuous enrollment for (1) ≥ 12 months before the index date, (2) ≥ 6
Curr Med Res Opin Downloaded from informahealthcare.com by Georgian Court University on 04/11/15 For personal use only.
months after the index date, and (3) ≥ 6 months after initiation of the first treatment. Patients with claims for stem cell transplant (SCT) were excluded to avoid confounding results from various factors based on timing, costs, and site of care of SCT.
Definition of variables First-line treatment included the first LEN- or BORT-based treatment that a patient with NDMM received after the index date and excluded any of the following: SCT plus maintenance therapy or BORT plus LEN combined therapy (with a minimum overlap of 30 days). The patient group “other” referred to patients who received ≥ 60 days of treatment with agents other than BORT and/or LEN. Time to next therapy (TTNT) was defined as the time between the start of the first therapy and the start of the second therapy and was used as a proxy for progression (ie, TTP). For any given line of therapy, the end of treatment was defined as either the first day of any gap in treatment > 90 days or initiation of a new regimen (BORT plus LEN, BORT, LEN, or other). Patients who received the above treatments were followed until TTNT. Thereafter, those patients receiving BORT, LEN, or other as subsequent therapy (ie, second-line treatment) were evaluated using similar methods, until their subsequent TTNT. To be considered on other therapy, patients needed ≥ 60 days of other therapy with no evidence of LEN or BORT.
6
Analysis Patient demographics and clinical characteristics were examined and defined as of the index date. These variables include age, sex, geographic region, and insurance plan type. The primary outcome in this study was direct healthcare costs. Healthcare costs in patients with MM were assessed using paid amounts on included claims and by component of
Curr Med Res Opin Downloaded from informahealthcare.com by Georgian Court University on 04/11/15 For personal use only.
care, medical (ie, inpatient, ambulatory, emergency department [ED]) costs, and pharmacy (ie, index and other prescription drug) costs for each patient. Total costs were determined as the sum of medical- and pharmacy-related costs, were adjusted appropriately using the US Consumer Price Index, and are reported in 2014 US$. Cost analyses were performed exclusively on patients with MM who completed a line of therapy to avoid underestimation of the cost consequences of progression. Consistent with methods described by Gaultney et al13, monthly total costs were calculated by summing total direct costs incurred by all patients in each successive month and dividing by the sum of patientmonths; the costs were then stratified by components of care. In addition, to provide a clearer basis for evaluating temporal trends, quarterly cost patterns of monthly costs for each line of therapy were evaluated by summing total costs and dividing by the sum of patient-months within each quarter. To determine a single average monthly cost for each treatment through to TTNT, each quarter’s monthly costs were cumulated up to the median TTNT, as calculated via a Kaplan-Meier analysis, for each cohort and divided by the median number of months. The resulting average costs for each treatment group were then weighted by the number of patients in each group to determine the pooled average monthly costs.
7
To avoid ascribing lower cumulative costs to a regimen solely due to a shorter period of successful outcomes, costs for patient cohorts initiated on each regimen were also evaluated over a consistent elapsed time period. Average Charlson Comorbidity Index (CCI) was determined to compare baseline measures of burden of disease and case mix between patient groups. To generate this, presence
Curr Med Res Opin Downloaded from informahealthcare.com by Georgian Court University on 04/11/15 For personal use only.
of comorbidities of interest for each patient during the 6 month baseline period was recorded and scores were tallied using methods described by Quan et al.14 The significance of each month’s average per-patient monthly cost for each treatment was evaluated with the Wilcoxon rank-sum test. Additionally, multivariate regression analysis was performed when direct costs were compared between treatments to control for possible confounding factors, such as age, sex, quantity of prescriptions for all medications before the index date, history of cancer or renal disease before the baseline period, and CCI. By means of a generalized linear model with a γ error distribution and log-link function, unadjusted and adjusted total monthly direct costs, pharmacy costs, and medical costs were compared between patients receiving LEN or BORT. Data management and statistical analyses were conducted using SAS version 9.4 (SAS Institute Inc, Cary, NC).
RESULTS Characteristics of the patient population From 2006 through 2013, 2843 patients with NDMM (1281 patients receiving LENbased treatments and 1562 patients receiving BORT-based treatments) and 1361 patients with
8
MM receiving second-line therapy (832 and 529 patients receiving LEN- and BORT-based treatments, respectively) were identified. summarizes demographic and clinical characteristics of the study population by treatment regimen and line of treatment. Sex distribution was similar between the cohorts, with a larger proportion of men (range,
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55%-58%). The mean age of both NDMM and relapsed MM study cohorts was similar between treatments, with > 50% of the patients aged ≥ 65 years. The most common comorbidities found in the study population before the index date were diabetes, other nonmyeloma cancers (eg, breast cancer, prostate cancer, melanoma, leukemia), and chronic pulmonary disease. CCI scores were similar between treatment groups in both patients with NDMM and those with relapsed disease. Patient characteristics were similar between treatment groups, both in first- and secondline treatment groups. Differences were most noted among patients receiving second-line therapy, including average age (1.8 years older for BORT treatment) and a 0.36 difference in CCI score (largely due to higher rates of renal disease and vascular diseases for BORT-treated patients; Table 1).
Time to next treatment For the overall study population, the median TTNT for patients with NDMM was 28.1 months. Patients with NDMM receiving LEN-based treatments (LEN first-line cohort) had a longer median TTNT than those receiving BORT-based treatments (BORT first-line cohort); 36.9 months [95% confidence interval (CI), 34.6 to 40.7] vs 20.0 months ( [95% CI, 18.0 to 22.1], p
