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Age-based subgroup analysis of CASTOR and POLLUX
Introduction
Multiple myeloma (MM) is a disease of the elderly, which is evidenced by an increasing incidence with advancing age and a median onset age of 69 years.1,2 Treatment regimens including proteasome inhibitors and immunomodulatory drugs have significantly improved survival for patients with MM;3 however, survival benefits are less pronounced in patients aged >60 years.4 Among patients with MM, median survival times were shown to decrease steadily over each decade from age <50 years (5.2 years) to age ≥80 years (2.6 years).5 Aging is associated with organ dysfunction, reduced functional status, poor resilience to physiologic stressors, an increased burden of comorbidities, and an increased risk of frailty, which affects the ability of elderly patients to tolerate MM treat- ment regimens.6 Furthermore, higher age correlates with more advanced International Staging System (ISS) stage.5 Based on the challenges of treating MM in elderly patients, a need exists for effective treatment regimens that exhibit a favorable benefit/risk profile in this age group.
Daratumumab is a human immunoglobulin G1 (IgG1κ) monoclonal antibody targeting CD38 with a direct on- tumor7-10 and immunomodulatory11-13 mechanism of action. Tumor cell death is induced by daratumumab via several CD38 immune-mediated actions, including com- plement-dependent cytotoxicity, antibody-dependent cel- lular cytotoxicity, antibody-dependent cellular phagocyto- sis, apoptosis, and modulation of CD38 enzymatic activity.7-10 Daratumumab exhibits immunomodulatory effects through reduction of CD38+ immunosuppressive cellular populations, including myeloid-derived suppres- sor cells, regulatory B cells and regulatory T cells; induc- tion of helper and cytotoxic T-cell expansion; increased T-cell clonality, and production of interferon in response to viral peptides.11
In two randomized, open-label, active-controlled, phase 3 studies (POLLUX and CASTOR), daratumumab in combination with standard-of-care regimens (lenalido- mide and dexamethasone [RD] or bortezomib and dexam- ethasone [VD]) demonstrated superior clinical benefit compared with Rd or Vd alone in patients with MM who had received ≥1 prior line of therapy. In POLLUX, daratu- mumab in combination with Rd (D-Rd) reduced the risk of disease progression or death by 63% compared with Rd after a median follow-up of 13.5 months.14 Similarly, in CASTOR, the risk of the progression or death was reduced by 61% with daratumumab in combination with Vd (D-Vd) versus Vd after a median follow-up of 7.4 months.15 Findings from these pivotal studies led to the approval of daratumumab in combination with Rd or Vd in many countries for the treatment of patients with MM who received ≥1 prior line of therapy.16 This analysis reports the efficacy and safety of daratumumab in patients aged 65 to 74 years or ≥75 years from POLLUX and CAS- TOR after further median follow-up of 25.4 and 19.4 months, respectively.
Methods
Study design and patients
POLLUX and CASTOR were multicenter, randomized, open- label, active-controlled, phase 3 studies of patients with relapsed
or refractory MM (RRMM). Trials were approved by an institu- tional review board or independent ethics committee at each site. Study protocols were conducted in accordance with the principles of the Declaration of Helsinki and the International Conference on Harmonisation Good Clinical Practice guidelines. Detailed study designs were published previously.14,15 Briefly, patients received ≥1 prior line of therapy, had at least a partial response to ≥1 prior ther- apy, and had documented progressive disease, according to the International Myeloma Working Group (IMWG) criteria.14,15,17,18 Patients refractory or intolerant to lenalidomide were excluded from POLLUX. Patients refractory or intolerant to bortezomib, or refractory to another proteasome inhibitor were excluded from CASTOR.
Procedures
Patients were randomized 1:1 to D-Rd or Rd in POLLUX and D-Vd or Vd in CASTOR.14,15 Stratification was described previous- ly and did not include age.14,15 In POLLUX, all patients received 28- day cycles of lenalidomide (25 mg orally [PO] on days 1-21 of each cycle) and dexamethasone (40 mg PO weekly in patients aged ≤75 years; 20 mg PO weekly in patients aged >75 years) with or with- out daratumumab (16 mg/kg intravenously [IV] weekly during cycles 1 and 2, every 2 weeks during cycles 3-6, and every 4 weeks thereafter until disease progression, unacceptable toxicity, or with- drawal of consent). Patients in the D-Rd group received a split dose of dexamethasone during daratumumab dosing weeks (20 mg before infusion; 20 mg the following day). Patients aged >75 years received the entire 20-mg dose prior to infusion.
In CASTOR, patients received eight, 21-day cycles of borte- zomib (1.3 mg/m2 subcutaneously (SC) on days 1, 4, 8, and 11) and dexamethasone (20 mg PO or IV on days 1, 2, 4, 5, 8, 9, 11, and 12; for a total dose of 160 mg/cycle during cycles 1-8) with or without daratumumab (16 mg/kg IV weekly in cycles 1-3, every three weeks during cycles 4-8, and every four weeks thereafter until withdrawal of consent, disease progression, or unacceptable toxicity). In patients aged >75 years, dexamethasone could be reduced to 20 mg weekly. In both studies, daratumumab-treated patients received pre- and post-infusion medications to prevent the onset of infusion-related reactions (IRR).14,15
Outcomes and statistical analyses
Frailty score was not assessed as these studies were initiated before this metric was adopted.19 The safety analysis set included all patients who received ≥1 administration of study treatment. Efficacy was assessed by progression-free survival (PFS) and response rates,14,15 which were based on the intent-to-treat (ITT) and response-evaluable populations, respectively. A stratified log- rank test compared PFS between groups. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using a stratified Cox regression model, with treatment as the sole explanatory variable. Distributions were estimated using the Kaplan-Meier method. A stratified Cochran-Mantel-Haenszel chi-square test measured treatment differences in overall response rate (ORR) and rates of very good partial response (VGPR) or better and complete response (CR) or better.
Results
At the clinical cut-off date of March 7, 2017, the median (range) duration of follow-up was 25.4 (0-32.7) months for POLLUX. Of the 569 patients enrolled, 29/286 (D-Rd) and 35/283 (Rd) were aged ≥75 years, and 124/286 (D-Rd) and 108/283 (Rd) were aged 65 to 74 years. The clinical cut-off date for CASTOR was January 11, 2017, conferring a
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