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M.-V. Mateos et al.
Table 4. Most common IRR among patients aged 65-74 years and ≥75 years in POLLUX and CASTOR.
TEAE (>5%): POLLUXa
Patients with IRR, n (%) Dyspnea
Chills
Feeling cold Wheezing
Vomiting Bronchospasm Cough
Nausea
TEAE (>5%): CASTORa
Patients with IRR, n (%) Bronchospasm Throat irritation Dyspnea
Any grade
57 (46.3) 13 (10.6) 8 (6.5) 2 (1.6) 3 (2.4) 8 (6.5) 7 (5.7) 7(5.7) 7(5.7)
Any grade
43 (45.7) 11 (11.7) 2 (2.1) 10 (10.6) 8 (8.5)
65-74 years D-Rd (n=123)
≥75 years D-Rd (n=29)
65-74 years D-Vd (n=94)
Grade 3/4
8 (8.5) 1 (1.1) 0
4 (4.3) 0
Any grade
13 (65.0) 4 (20.0) 4 (20.0) 3 (15.0) 3 (15.0)
≥75 years D-Vd (n=20)
Grade 3/4
2 (10.0) 1 (5.0) 0
0
0
0
0
0
Grade 3/4
6 (4.9) 1 (0.8) 0
0
1 (0.8) 1 (0.8)
Any grade
12 (41.4) 4 (13.8) 3 (10.3) 2 (6.9) 2 (6.9) 2 (6.9)
Grade 3/4
4 (13.8) 1 (3.4) 1 (3.4) 1 (3.4) 1 (3.4) 0
000 0 0 0 0 0 0
Cough
Nausea 6(6.4) 0 0 Hypertension 6 (6.4) 5 (5.3) 0 Chills 3 (3.2) 0 2 (10.0)
IRR: infusion-related reaction; D-Rd: daratumumab/lenalidomide/dexamethasone; Rd: lenalidomide/dexamethasone; D-Vd: daratumumab/bortezomib/dexamethasone; Vd: bortezomib/dexamethasone. aThe safety analysis set included all patients who received ≥1 administration of study treatment.
patients, including 11% CR and 12.5% VGPR. The most common adverse events included peripheral neuropathy (47% of patients), gastrointestinal symptoms (22.2%), thrombocytopenia (11.1%), and anemia (7.4%). Overall, these results are comparable with studies of Vd in younger patients.23
Sub-analyses of the phase 3 ASPIRE and ENDEAVOR studies demonstrated a benefit for carfilzomib in elderly patients with MM. The ASPIRE study of carfilzomib, lenalidomide, and dexamethasone (KRd) versus Rd demon- strated prolonged PFS with KRd in patients with relapsed multiple myeloma aged ≥70 years (median: 23.8 versus 16.0 months; HR, 0.75, 95% CI, 0.53-1.08) and an improved ORR (90.3% versus 66.1%, respectively).24 While cardiovascular events occurred more frequently in the elderly population compared with patients aged <70 years, KRd demonstrated a favorable benefit-risk profile in elderly patients.25 The ENDEAVOR study of carfilzomib and dexamethasone (Kd) versus Vd demonstrated pro- longed PFS with Kd in patients with RRMM who received 1 to 3 prior lines of therapy and were aged 65 to 74 years (median: 15.6 versus 9.5 months; HR, 0.528, 95% CI, 0.382-0.728) or ≥75 years (median: 18.7 versus 8.9 months; HR, 0.383; 95% CI, 0.227-0.647).26 While hypertension was the most common grade ≥3 TEAE in patients aged 65 to 74 years and ≥75 years who received Kd, the safety results were similar to the overall population in ENDEAV- OR.
Due to the nature of drug development, clinical trials and regulatory approvals usually proceed with patients with more advanced disease. Ideally, moving these regi- mens into front-line treatment may provide the best
opportunity for patients to mount prolonged responses and delay relapse. Newly diagnosed elderly patients are usually excluded from receiving stem cell transplants due to their age. The VISTA phase 3 study of bortezomib, mel- phalan, and prednisone (VMP) established this regimen as a standard of care in transplant-ineligible newly diagnosed MM patients.27 Of interest is whether the benefit of dara- tumumab-based regimens in RRMM could be extended to these patients. In the phase 3 ALCYONE study, daratu- mumab in combination with VMP reduced the risk of dis- ease progression or death by 50% compared with VMP alone (HR, 0.50; 95% CI, 0.38-0.65).28 Over 90% of patients were aged ≥65 years, and 30% were aged ≥75 years. In a prespecified subgroup analysis, the HR for the primary endpoint of PFS were similar for patients aged ≥75 years (0.53) and <75 years (0.49). The addition of daratumumab to VMP produced no new safety signals except for a higher rate of infections that resolved with few discontinuations.28 Furthermore, Rd is also a standard treatment regimen for patients with transplant-ineligible newly diagnosed MM. Recently, in the phase 3 MAIA study, D-Rd significantly reduced the risk of disease pro- gression or death and nearly doubled the rate of CR or better.29 MAIA enrolled patients aged ≥65 years, 44% of whom were aged ≥75 years.29
MM is a disease of the elderly with 35 to 40% of patients aged ≥75 years at diagnosis.22 One of the limitations of the current analysis is that the subgroup of patients aged ≥75 years in POLLUX and CASTOR was relatively small (<15% of the overall study population was ≥75 years of age). Comorbidities and other ailments, including frailty, that are often associated with elderly patients may have compro-
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