Abstract
This cohort study compares the use of different bone-modifying agents among Medicare beneficiaries with multiple myeloma.
The US Food and Drug Administration (FDA) approved denosumab to prevent skeletal-related events in patients with multiple myeloma on January 5, 2018, based on the results of a noninferiority trial.1 However, denosumab requires a more frequent dosing schedule and is much more expensive than standard bisphosphonate therapy.2 Denosumab discontinuation is associated with rapid bone loss, and patients who discontinue denosumab therapy will likely require subsequent treatment with bisphosphonates to limit anticipated bone loss.2,3 Therefore, its routine use is difficult to justify except in patients with renal dysfunction or in those unable to tolerate bisphosphonates. In light of these issues, we describe the uptake in use of denosumab after FDA approval.
Methods
We performed a retrospective analysis of the use of bone-modifying agents using Medicare fee-for-service claims from January 1, 2017, through March 31, 2019. We included patients with multiple myeloma (International Classification of Diseases, Tenth Revision, Clinical Modification [ICD-10-CM] code C90.0) who received at least 1 dose of a bone-modifying agent during the study period: denosumab (Current Procedural Terminology [CPT] code J0897) or bisphosphonates (zoledronic acid [CPT code J3489] or pamidronate [CPT code J2430]). We calculated rates of denosumab use before and after FDA approval. We used a Poisson regression model with cluster-robust standard errors calculated at the patient level to evaluate patient characteristics associated with denosumab use. We defined renal dysfunction as any of 60 codes according to the International Classification of Diseases, Ninth Revision, Clinical Modification or ICD-10-CM dating back to 2010, and treated it as a time-varying exposure. Independent variables included patient age, sex, race, US Census Bureau region of residence, population density of residence, FDA approval period, renal dysfunction, and an interaction term for approval period with renal dysfunction. The logarithm of at-risk person-months was included as an offset variable. This study was approved by the Johns Hopkins University School of Medicine Institutional Review Board. Patient consent was not required because only administrative claims data were used.
Results
We identified 15 872 patients (mean [SD] age, 72.7 [8.4] years; 48.9% women) with 329 595.6 person-months of follow-up (Table). Overall, the rate of denosumab use was 3.8 doses per 1000 person-months in the preapproval period and 84.1 doses per 1000 person-months in the postapproval period. Of the total number of bone-modifying agent doses, the percentage of denosumab doses increased from 0.1% throughout 2017 to 38.1% in March 2019 (Figure).
Table. Characteristics of Medicare Beneficiaries With Multiple Myeloma Receiving Bone-Modifying Agents Between January 2017 and March 2019a.
| Characteristic | No. (%) | |||
|---|---|---|---|---|
| Patients Without Renal Dysfunction | Patients With Renal Dysfunction | |||
| Preapproval (January 1, 2017, through January 4, 2018) | Postapproval (January 5, 2018, through March 31, 2019) | Preapproval (January 1, 2017, through January 4, 2018) | Postapproval (January 5, 2018, through March 31, 2019) | |
| No. of patients | ||||
| With multiple myeloma (patient-months) | 6590 (62 206.6) | 6641 (75 406.7) | 7914 (77 647.6) | 9730 (114 334.7) |
| With any denosumab use | 48 (0.7%) | 1129 (17.0%) | 138 (1.7%) | 2594 (26.7%) |
| No. of doses administered | ||||
| Denosumab | 108 | 4682 | 430 | 11 268 |
| Zoledronic acid | 20 808 | 17 763 | 27 875 | 23 611 |
| Pamidronate | 1341 | 862 | 3206 | 1945 |
| Age at study entry, mean (SD), y | 71.3 (8.4) | 70.4 (8.4) | 74.5 (8.0) | 73.8 (8.0) |
| ≤64 | 1175 (17.8) | 1534 (23.1) | 720 (9.1) | 1075 (11.1) |
| 65-74 | 3338 (50.7) | 3249 (48.9) | 3440 (43.5) | 4371 (44.9) |
| 75-84 | 1709 (25.9) | 1564 (23.6) | 2996 (37.9) | 3479 (35.8) |
| 85-94 | 366 (5.6) | 292 (4.4) | 743 (9.4) | 792 (8.1) |
| ≥95 | 2 (0.03) | 2 (0.03) | 15 (0.2) | 13 (0.1) |
| Sex | ||||
| Male | 3126 (47.4) | 3092 (46.6) | 4283 (54.1) | 5261 (54.1) |
| Female | 3464 (52.6) | 3549 (53.4) | 3631 (45.9) | 4469 (45.9) |
| Race | ||||
| White | 5308 (80.6) | 5309 (79.9) | 6196 (78.3) | 7643 (78.6) |
| Black | 787 (11.9) | 766 (11.5) | 1208 (15.3) | 1435 (14.8) |
| Asian | 98 (1.5) | 107 (1.6) | 109 (1.4) | 135 (1.4) |
| Hispanic | 122 (1.9) | 141 (2.1) | 130 (1.6) | 162 (1.7) |
| North American Native | 33 (0.5) | 33 (0.5) | 41 (0.5) | 47 (0.5) |
| Other or unknown | 242 (3.7) | 285 (4.3) | 230 (2.9) | 308 (3.2) |
| Population density of residence | ||||
| Urban | 5612 (85.2) | 5647 (85.0) | 6722 (84.9) | 8227 (84.6) |
| Rural | 978 (14.8) | 994 (15.0) | 1192 (15.1) | 1503 (15.5) |
Abbreviation: FDA, US Food and Drug Administration.
Adjusted incidence rate ratios were calculated using a Poisson regression model with patient age, sex, race, US Census Bureau region of residence, population density of residence, FDA approval period, renal dysfunction, and an interaction term for approval period with renal dysfunction.
Figure. Proportion of Denosumab Doses Administered to Medicare Beneficiaries With Multiple Myeloma.
Proportion is of the total number of bone-modifying agent doses (ie, denosumab, zoledronic acid, and pamidronate) by month.
The adjusted incidence rate ratio of postapproval (vs preapproval) denosumab use was 36.0 (95% CI, 24.3-53.4) in patients without renal dysfunction and 17.9 (95% CI, 14.2-22.5) in patients with renal dysfunction. Other characteristics associated with denosumab use included age of 85 to 94 years vs 64 years or younger (incidence rate ratio, 1.26; 95% CI, 1.06-1.50) and residing in rural areas vs urban areas (incidence rate ratio, 1.12; 95% CI, 1.01-1.24).
Discussion
In patients with multiple myeloma, FDA approval of denosumab was associated with rapid uptake, quickly reaching almost 40% of the bone-modifying agent market within 15 months. We also observed that its use increased in patients without renal dysfunction, despite a lack of evidence of superiority compared with standard therapy.
Concerns regarding the value of denosumab in lieu of bisphosphonate therapy were raised when it was approved for preventing skeletal-related events in patients with solid tumors.4 On the basis of a noninferiority trial,1 the only reasonable explanation for prescribing denosumab—an agent that costs approximately $24 000 more per patient per year than zoledronic acid (the standard of care) but is neither more convenient nor less toxic—is its potential to preserve renal function compared with zoledronic acid.5 However, since FDA approval, its use has extended to patients with multiple myeloma who do not have renal dysfunction.
These findings highlight the need for reflection. Noninferiority trials should ideally be conducted in a patient population where a potential modest loss of efficacy is justified by other benefits.6 Clinicians and patients should be aware that a new drug approved on the basis of a noninferiority trial may not be more effective than existing, often less expensive therapy. Further research should examine the role of rebates and reimbursements as incentives for the widespread adoption of more costly drugs that have not demonstrated superiority.
References
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