Burden of Treatment Among Older Adults With Newly Diagnosed Multiple Myeloma

Abstract

We used the Surveillance, Epidemiology, and End Results–Medicare linked database to understand the treatment burden among 3065 newly diagnosed adults with multiple myeloma between 2007 and 2013, and factors associated with high treatment burden. There is a substantial burden of treatment, with over 2 months of cumulative interaction with health care in the first year. Future tailored interventions are required to optimize this burden whenever possible.

Background:

Multiple myeloma is an incurable hematologic malignancy with significant recent treatment advances; however, the magnitude of treatment burden among patients in the first year after diagnosis has yet to be fully researched and reported.

Patients and Methods:

Patients with multiple myeloma newly diagnosed between 2007 and 2013 were identified in the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked databases. Treatment burden was captured as the number of total days with a health care encounter (including acute care and outpatient visits), oncology and nononcology physician visits, and the number of new prescriptions within the first year after diagnosis. Logistic regression was used to identify factors associated with high treatment burden.

Results:

A total of 3065 patients were included in the analysis. There was a substantial burden of treatment within the first year after diagnosis (median, 77 days; interquartile range, 55-105 days), which was highest during the first 3 months. Patients with high comorbidities (adjusted odds ratio [aOR] 1.27 per 1-point increase in Charlson comorbidity index, P < .001), poor performance status (aOR 1.85, P < .001), myeloma-related end organ damage, particularly bone disease (aOR 2.28, P < .001), and those who underwent autologous stem-cell transplantation (aOR 2.41, P < .001) were more likely to have a higher treatment burden.

Conclusion:

There is considerable burden of treatment in patients with newly diagnosed multiple myeloma within the first year after diagnosis, particularly within the first 3 months. Future tailored interventions aimed at optimizing this treatment burden when possible while simultaneously providing support to manage it may improve patient-centered care.

Introduction

Multiple myeloma (MM), the second most common hematologic malignancy, is a disease of aging, with a median age at diagnosis of 69 years.¹ It is associated with significant morbidity and mortality, especially among older patients. Although MM remains an incurable disease, novel therapeutic agents have substantially improved the outcomes of adults with MM, with ongoing improvement expected over the next several years.²

As continuous and novel therapeutic agents enter into the landscape for the treatment of patients with MM, there is an increasing need to understand the impact of this treatment using a patient-centered lens.³ Previous studies in the area have focused on the economic impact of health care utilization among adults with MM, as individuals undergo different treatments and at various time point during the disease trajectory.^4–7 This traditional concept of “burden” relies on cost as the central measure of health care utilization associated with treatment efficacy and outcome.⁸ An alternative framework for treatment burden has recently emerged that shifts the focus away from the economic impact and instead toward the effect of treatment on an individual patient’s “workload” and its subsequent impact on the patient’s well-being and functioning.^9,10 Treatment burden includes all aspects of care required by an individual patient, including visits to health care providers, medical laboratory and diagnostic tests, treatment prescription management, and any required lifestyle modifications. Increased treatment burden can have negative consequences both for the intended treatment plan, where it has been correlated with poor treatment adherence,¹¹ and for the individual patient’s well-being, as it correlates with lower patient satisfaction.^12,13

Patients with cancer are particularly susceptible to the adverse effects of treatment burden, as they may concurrently already be experiencing a disruption in their lives as a result of the burden of symptoms from the cancer itself, subsequently leading to decreased capacity to navigate the additional burden imposed by the cancer treatment.⁹ Specifically, in adults with newly diagnosed MM (NDMM), who at baseline are known to have multiple comorbidities and aging-associated vulnerabilities¹⁴ along with a high burden of symptoms,¹⁵ the impact of treatment burden may be particularly challenging for individual patients to navigate. Understanding this treatment burden is an essential first step in the future development of strategies that focus both on optimizing this burden if possible, while increasing the support and capacity for patients to navigate this burden to improve the overall patient treatment experience.

In this study, we aimed to understand the treatment burden within the first year after diagnosis among adults with NDMM in the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked administrative database. We also aimed to investigate factors associated with high treatment burden in order to identify future strategies aimed at potentially reducing this burden.

Patients and Methods

Data Source

The data source for this study was the SEER-Medicare linked database, which provides cancer registry data from 18 geographic areas covering approximately 28% of the US population and is linked to billing claims for Medicare beneficiaries.¹⁶ This linked database contains information regarding patient demographics, tumor characteristics, and survival for those with a cancer diagnosis who reside in the coverage area. This data source broadly represents the health care experience of older patients in the United States diagnosed with cancer and who are insured through traditional fee-for-service Medicare plans. This study was performed under a protocol approved by the Washington University School of Medicine human subject committee.

Participants

Using the SEER-Medicare linked database, we identified older adults (age > 65 years) with NDMM (International Classification of Disease for Oncology, 3rd edition, code 9732) diagnosed between the years 2007 and 2013. Medicare eligibility before age 65 is restricted to those with severe illness or disability, which limits the generalizability of this subset of patients, and therefore patients diagnosed with MM before age 65 were not included. Those who did not have Medicare Parts A (inpatient), B (outpatient), and D (prescription) were excluded, as were those enrolled in Medicare Health Maintenance Organization plans, as claims are not available in the data set for these patients.

To limit the population to patients with symptomatic NDMM, only those with treatment occurring within 6 months after diagnosis were included. Patients with less than 1 year of follow-up, including those who died, were excluded because the characteristics and overall treatment burden of those patients are likely to be substantially different. Demographic and clinical characteristics collected included the following: age, gender, ethnicity, marital status, Medicaid enrollment and previously established proxies for poor performance status,¹⁷ and Charlson comorbidity index.^18,19 We also collected available disease characteristics (myeloma-related end organ damage including renal impairment, anemia, and bone disease within 6 months before the diagnosis date, defined by a previously established algorithm²⁰), details of the treatment (stemcell transplantation [SCT] and protease inhibitor [PI]/immuno-modulatory agent [IMID] utilization), and overall survival (OS; defined from the date of diagnosis).

Treatment Burden

Treatment burden has no universally accepted definition. In our study, we defined it as the cumulative number of days that patients were in contact with the health care system (total health care encounter days), as defined by Presley et al.²¹ To allow for lag between diagnostic assessment and formal date of diagnosis, the follow-up period included all claims within 30 days before the diagnosis through 1 year after diagnosis. A day of treatment burden was defined as each day the patient had a claim for an interaction with the medical system, as either an inpatient or outpatient, excluding days with only home health visits, durable medical equipment, or prescription dispensations. We categorized these days as acute care days (emergency department visits and short-stay hospitalization) or outpatient visits (all outpatient visits, including those for diagnostic testing and receipt of radiotherapy).

Using the treatment burden definition described above, patients were categorized into quartiles on the basis of the cumulative number of treatment burden days. Patients in the highest quartile were defined as having a high treatment burden. In addition, we described the frequency of oncology physician visits and nononcology physician visits as well as the number of new, unique prescriptions dispensed through Medicare Part D. To determine if treatment burden changed during the follow-up period, outcomes were described monthly and categorized as early burden (diagnosis to day 90) versus late burden (day 91 to day 365).

Statistical Analysis

Patient baseline demographic factors were summarized using measures of central tendency and proportions. To investigate factors associated with high treatment burden (defined as those in the highest quartile by the number of total health care encounters days), a multivariable logistic regression model was created using baseline characteristics and MM-directed treatments. P < .05 was considered statistically significant. All analyses were performed by SAS Enterprise Guide 5.1 software (SAS Institute, Cary, NC).

Results

A total of 3065 adults with NDMM were included in the analysis data set. Participant selection is outlined in Figure 1. The baseline characteristics of the patients are described in Table 1. The median age was 74 years (interquartile range [IQR], 70-79), with 46.3% of the patients 75 or older. Most patients (62.9%) had one or more comorbidities, and 14.7% had indicators of poor performance status. Many patients were affected by myeloma-related end organ damage; renal impairment, anemia, and bone disease were present in 45.6%, 61.7%, and 35.6% of the patients, respectively. The median time from diagnosis to treatment was just over 1 month (41 days; IQR 28-64). With regards to treatment, the majority of patients (94.4%) were treated with novel agents including PIs and/or IMIDs during first-line therapy. Only 7.8% of the cohort underwent treatment with SCT. The median OS was approximately 4 years.

Figure 1.

Selection of Study Cohort

Table 1.

Baseline Patient Characteristics

Characteristic	Total (N = 3065)	Treatment Burden Quartile
		Lowest	Third	Second	Highest
Demographic Characteristics
Age (years), median (IQR)	74 (70-79)	75 (70-80)	73 (70-79)	73 (69-79)	73 (69-79)
≥ 75 years	46.3	52.3	45.3	43.2	44.6
Gender
Male	51.3	48.1	49.8	53.0	54.2
Female	48.7	51.9	50.2	47.0	45.8
Ethnicity
White	79.4	72.3	81.3	82.6	81.1
Black	14.0	18.6	11.7	11.5	14.4
Other	6.6	9.2	7.0	5.9	4.5
Marital status
Married/domestic partner	55.3	51.4	56.1	57.6	56.0
Divorced/widowed/other	37.6	40.2	36.5	35.2	38.8
Unknown	7.1	8.5	7.4	7.2	5.2
Medicaid enrollment	25.8	29.9	23.6	23.2	27.0
CCI and performance status	37.1	49.7	40.0	35.5	23.7
0	21.1	20.2	23.8	21.3	19.2
1-2	41.8	30.1	36.2	43.3	57.1
>2	14.7	10.5	10.4	14.3	23.5
Poor performance status
Disease characteristics
Myeloma-related end organ damage
Renal impairment	45.6	28.3	42.9	48.5	61.6
Anemia	61.7	51.8	61.5	66.2	66.7
Bone disease	35.6	23.8	31.1	37.6	49.3
Treatment Characteristics
Time from diagnosis to treatment (days), median (IQR)	41 (28-64)	43 (28-67)	41 (27-63)	40 (27-60)	41 (28-64)
Stem-cell transplantation	7.8	0.7	5.6	12.0	12.3
First-line treatment
PI based	33.5	17.2	33.0	37.9	44.9
IMID based	36.0	61.6	36.5	26.5	20.8
PI + IMID	25.0	11.5	24.8	32.5	30.2
Other	5.6	9.7	5.6	3.1	4.2
Overall survival (months), median (95% CI)	47.8 (45.8-50.1)	52.1 (47.7-58.0)	53.5 (48.9-58.1)	47.3 (42.8-53.0)	38.1 (34.9-42.8)

Data are shown as percentages unless otherwise indicated.

Abbreviations: CCI = Charlson comorbidity index; CI = confidence interval; IMID = immunomodulatory agents; IQR = interquartile range; PI = protease inhibitor.

The cumulative impact of treatment burden is shown in Table 2. Individual patients spent a median of 77 days (IQR 55-105) interacting with the health care system in the first 12 months. Patients spent a median of 10 days (IQR 2-21) in the emergency department and/or were admitted to the hospital. Outpatient visit days (median 59, IQR 42-76) and oncology physician visits (median 16, IQR 11-24) corresponded to areas of high treatment burden among the cohort. Nononcology physician days corresponded to a median of 12 visits (IQR 7-20) in the first year, with 5 of those visits occurring within the first 3 months. The median number of unique medications dispensed was 18 (range, 13-24), with over half of them prescribed within the first 3 months alone (median, 10 medications; range, 7-14 medications).

Table 2.

Health Care Encounters Among Adults With Newly Diagnosed Multiple Myeloma in First 12 Months After Diagnosis

Variable	Total	Early Burden	Late Burden
Total days	77 (55-105)	27 (19-37)	49 (32-68)
Acute care days	10 (2-21)	3 (0-11)	2 (0-11)
Outpatient visit days	59 (42-76)	19 (13-25)	39 (27-53)
Oncology physician visits	16 (11-24)	5 (3-7)	11 (7-17)
Nononcology physician visits	12 (7-20)	5 (2-7)	7 (4-13)
Prescriptions	18 (13-24)	10 (7-14)	14 (10-19)

Data are presented as median (interquartile range). Early burden was defined as 30 days before until 90 days after diagnosis; late burden, > 90 days until 365 days after diagnosis.

Treatment burden was highest during the first 3 months, as illustrated in Figure 2, with a peak of approximately 5 total health care encounters per month, decreasing to 4 per month from months 4 to 7, then plateauing at 3 per month by month 12 after diagnosis. Factors found by multivariate analysis to be significantly associated with high health care burden in the first 12 months are shown in Table 3. Factors included greater comorbidities (adjusted odds ratio [aOR] 1.27; 95% confidence interval [CI], 1.20-1.35; P < .001 per 1-unit increase in Charlson comorbidity index) and poor performance status (aOR, 1.85; 95% CI, 1.45-2.35; P < .001), along with myeloma-related renal impairment (aOR, 1.63; 95% CI, 1.34-1.98; P < .001), anemia (aOR, 1.23; 95% CI, 1.01-1.48; P = .037), and bone disease (aOR, 2.28; 95% CI, 1.90-2.73; P < .001). Regarding treatment, SCT was associated with a significantly high treatment burden (aOR, 2.41; 95% CI, 1.75-3.30; P < .001). Age had no impact on treatment burden; however, race other than white or black (aOR, 0.66; 95% CI, 0.44-0.99; P = .048), more recent year of diagnosis (aOR, 0.94 per year; 95% CI, 0.90-0.99; P = .011), and IMID-based therapy (aOR, 0.37; 95% CI, 0.29-0.46; P < .001) were associated with a lower treatment burden. The median OS varied between 52.1 months (95% CI, 47.7-58.0) and 38.1 months (95% CI, 34.9-42.8) among those with the lowest and highest treatment burden, respectively.

Figure 2.

Number of Total Health Care Encounters Among Adults With NDMM in First 12 Months After Diagnosis. Data are shown as mean with standard deviation

Abbreviation: NDMM = newly diagnosed multiple myeloma.

Table 3.

Multivariate Logistic Regression Variables for Predicting High Health Care Utilization Burden

Characteristic	Adjusted Odds Ratioa	95% Confidence Interval	P b
Demographic Characteristics
Age (per year)	1.00	0.99-1.02	.775
Gender
Male	Ref
Female	0.97	0.81-1.16	.708
Race
White	Ref
Black	0.91	0.70-1.19	.508
Other	0.66	0.44-0.99	.048
Medicaid enrollment	0.98	0.79-1.22	.888
Year of diagnosis (per year)	0.94	0.90-0.99	.013
Comorbidities and functional status
CCI (per unit)	1.27	1.20-1.35	<.001
Poor performance status	1.85	1.45-2.35	<.001
Disease Characteristics
Myeloma-related renal impairment	1.63	1.34-1.98	<.001
Myeloma-related anemia	1.23	1.01-1.48	.037
Myeloma-related bone disease	2.28	1.90-2.73	<.001
Treatment Characteristics
Stem-cell transplantation	2.41	1.75-3.30	<.001
First-line treatment
PI based	Ref
IMID based	0.37	0.29-0.46	<.001
PI + IMID	0.92	0.74-1.15	.465
Other	0.50	0.32-0.76	.002

Abbreviations: CCI = Charlson comorbidity index; IMID = immunomodulatory agents; PI = protease inhibitor.

^aAdjusted for all listed covariates.

^bLikelihood ratio test.

Discussion

In our cohort of 3065 adults with NDMM, we found a considerable health care burden, especially within the first 3 months after diagnosis. Patients spend approximately 5 days a month during the first 3 months and 3 to 4 days a month from months 4 to 12 after diagnosis interacting with the health care system. In total, this corresponded to a substantial burden of treatment within the first year after diagnosis, with over 2 months of cumulative interaction with the health care system (median, 77 days).

The concept of treatment burden among patient with chronic conditions and those with cancer is increasingly being recognized as a key consideration of patient-centered care.⁹ It is also a central component of minimally disruptive medicine, which emphasizes individual patient preference and focuses on reducing the workload of being a patient and a care partner.²² Although this concept is important for all patients, older patients with cancer are particularly susceptible to the adverse events of treatment burden as a result of concurrent aging-associated vulnerabilities, cancer-associated symptom burden, and treatment toxicity. Previous studies performed in early stage non–small-cell lung cancer and breast cancer show high treatment burden among patients, with wide variability depending on patient baseline comorbidities, disease stage, and treatment modality.^21,23

Although MM may have other similarities to both other hematologic and solid organ malignancies, understanding this treatment burden in MM is particularly relevant, particularly for clinicians who care for older adults with myeloma, because it is a cancer of older patients, in whom there may be competing age-associated vulnerabilities and functional limitations.^14,24 There may also be variations among different cancers due to the patient population and type and duration of therapy, as shown by a previous breast cancer study in which the median number of encounter days was 44, compared to 77 days in our study.²¹ Additionally, patients with myeloma have a high symptom burden, including pain from the cancer itself,¹⁵ which may further stress the capacity of these patients to manage the health care burden. Last, because myeloma is an incurable cancer with often continuous and prolonged treatment, the additive effect of ongoing treatment burden may exceed a patient’s capacity threshold.

Many of the previous analyses in myeloma highlighting burden have focused on viewing this problem through an economic lens. Teitelbaum et al⁴ used a commercial claims database in the United States to compare the health care costs and resource utilization, including patient out-of-pocket expenses associated with novel and nonnovel drugs during various lines of treatment among patients with myeloma during 2005-2010. In their analysis, the number of ambulatory visits was 69; however, it ranged between 63 and 84 visits per year after treatment initiation, with various therapies including bortezomib, thalidomide, and lenalidomide. Similarly, Hagiwara et al²⁵ reported the health care utilization rate and its impact on economic burden among transplantation-ineligible patients with myeloma during 2006-2016 during each line of treatment using a different commercial claims database. Their study reported approximately 30 to 35 outpatient visits per year during each line of treatment, with numbers higher for patients with progressive disease. Our study reported a median of 59 (range, 42-76) outpatient visits per year; our different results compared to the previously mentioned studies may be because of the more homogenous population in our study, which included treatment burden only among newly diagnosed patients, including those receiving SCT, specifically during the first year after diagnosis. Additionally, the variation across these studies from as low as 30 to as high as 84 outpatient visits per year emphasizes the heterogeneity in the treatment burden experienced by different subgroups of patients in different health care settings. This wide range in treatment burden may also provide potential opportunities in minimizing this burden, such as improved care coordination and scheduling, or increasing capacity to manage this burden among those experiencing the highest such burden.

In our study, factors identified with high treatment burden included baseline comorbidities and poor performance status. This is similar to other studies performed in other chronic diseases as well as in cancer, where increased comorbidities are related to high treatment burden.²¹ Interestingly, in our study, chronological age alone was not associated with higher treatment burden, thus emphasizing the heterogeneity found in aging, which is becoming increasingly recognized in myeloma.^26,27 There was also variation in patient race noted in our study, with a lower treatment burden among those identified as being of “other” race. The reasons for this are likely multifactorial; however, disparities in different therapeutic options and supportive care among those with different racial backgrounds²⁸ may have contributed to the heterogeneity in treatment burden. Additionally, a more recent year of diagnosis was associated with a decreasing treatment burden, which may be due to improved myeloma control with newer agents in later years. Patients presenting with myeloma-related end organ damage, including anemia, renal impairment, and bone disease, were at significantly higher risk of greater treatment burden. Bone disease in particular was associated with an over 2-fold risk of high treatment burden, consistent with previous literature that describes its association with high health care utilization.²⁹ Treatment-related factors that affected treatment burden included SCT, as would be expected, along with IMID-based therapy, which was associated with significantly lower treatment burden compared to Pi-based therapy, likely due to its oral administration.

Because the SEER-Medicare database does not provide detailed information regarding the reason and time associated with each encounter, as may be present in specific institutional electronic medical health records,²³ we could not capture the magnitude of burden associated with each encounter, which could range from a simple blood count check lasting a few minutes to a lengthy intravenous chemotherapy infusion. Additionally, we could not distinguish treatment burden and the associated magnitude that is necessary and unavoidable versus the burden that may be decreased with alternative strategies, such as improved care coordination. While not all treatment burdens may be avoidable, understanding the components may enhance shared decision making and prompt increased support. Knowledge of the high treatment burden experienced by patients with comorbidities and poor performance status, for example, may prompt health care providers to ensure extra supports or provide tailored interventions to increase capacity to manage the treatment workload. The capacity of each patient may be unique to individual circumstances, so tailored interventions may be required. Furthermore, timely diagnosis and initiation of treatment may decrease the risk of myeloma-related end organ damage, which is associated with high burden. Treatment burden related to the initiation of new prescription medications is also important to recognize and address, as polypharmacy has been associated with poor medication adherence as well as adverse drug events with associated increased morbidity.³⁰

Additionally, decision making regarding treatment modalities should not just emphasize traditional parameters such as response rates and progression-free survival but should also include a discussion regarding the workload burden placed on the patient and the care partner in order to ensure that informed and patient-centered decision making is prioritized. This may be particularly relevant among certain subgroups such as older patients with cancer who may prioritize quality of life over aggressive disease control and OS.³¹ In MM specifically, two recent patient preference studies indicate that patients consider the mode, frequency, and duration of administration of therapies, in addition to outcomes and toxicity, in their treatment choices.^32,33 Our study supports the notion that specific regimens such as IMID-based treatments, which are orally administered, may be associated with a lower treatment burden and may therefore be preferable for certain patients.

There are several limitations to this study. While our study did capture many demographic and baseline factors, we did not have access to some myeloma-specific factors, such as disease stage, cytogenetic results, treatment response, and therapy-related toxicities, which may affect the overall treatment burden. The myelomadefining CRAB (increased calcium level, renal dysfunction, anemia, destructive bone lesions) features may also be underreported or overreported compared to previous prospectively conducted studies³⁴ as a result of the limitations of the diagnosis and billing codes in the administrative database. The magnitude of treatment burden between the different visit types such as acute care visits versus routine outpatient visits versus prolonged chemotherapy infusions is also not comparable and was not measured or quantified in our study. This magnitude of treatment burden, including the time spent waiting for appointments/procedures or even to commute to these different encounters, would also be helpful to patients in order to understand the anticipated amount of disruption to their lives caused by treatment that was not captured in our study. Treatment burden that is necessary or unavoidable versus that which may have the potential to be decreased could also not be identified from our study. Additionally, not all aspects of treatment burden could be captured in our study, including the cognitive, psychological, and financial aspects. The burden faced by care partners and their unique challenges was also not captured in our study and will require future studies. It is unknown how treatment burden may have further changed over time with the introduction of additional therapeutic agents such as daratumumab or carfilzomib in the up-front setting, as our study did not include those agents. Last, the SEER-Medicare database is largely representative of the older adult patients in the United States enrolled in traditional fee-for-service Medicare; however, the results may not generalize to other populations, including younger adults in the United States, who would largely have coverage from private insurers, or in older adults in other geographic locations.

Conclusion

Our study highlights the considerable treatment burden experienced by adults with NDMM. Future interventions aimed at optimizing this treatment burden whenever possible while simultaneously providing support to manage the burden may improve patient-centered care.

Clinical Practice Points.

• Multiple myeloma (MM) is an incurable hematologic malignancy that has seen significant treatment advances over the last decade. While many previous studies have focused on the economic burden, the impact of this treatment on treatment burden remains unknown. In order to understand this treatment burden and factors associated with high treatment burden, we conducted an analysis of 3065 adults with newly diagnosed MM (NDMM) using the Surveillance, Epidemiology, and End Results–Medicare linked database.

• Our results indicate that there is considerable health care burden, especially within the first 3 months after diagnosis among patients with NDMM. Patients spend approximately 5 days per month during the first 3 months and 3 or 4 days a month from months 4 to 12 after diagnosis interacting with the health care system. In total, this corresponded to a substantial burden of treatment within the first year, with over 2 months of cumulative interaction with the health care system (median, 77 days). High comorbidities, poor performance status, myeloma-related end organ damage, particularly bone disease, and stem-cell transplantation were all associated with a higher treatment burden.

• Our study is important and novel because it highlights that there is a considerable treatment burden experienced by adults with NDMM. Future interventions aimed at optimizing this treatment burden when possible will be an essential step in shifting the focus of care toward a patient-centered approach in MM.