Introduction
Methods
Patients and Study Designs
Compliance with Ethics Guidelines
Population PK and Exposure–Response Analysis
Results
Patient and Disease Characteristics
Comparison of PK of Daratumumab Following Monotherapy and Combination Therapy Regimens
Effects of Patient and Disease Characteristics on Daratumumab Exposure
Covariate | Monotherapy | Combination therapies |
---|---|---|
Renal function | ||
Mild vs. normal | 1.15 (0.86–1.54) | 0.99 (0.91–1.07) |
Moderate vs. normal | 0.96 (0.71–1.30) | 0.97 (0.89–1.06) |
Severe vs. normal | 1.00 (0.47–2.12) | 1.02 (0.78–1.32) |
Hepatic function | ||
Mild vs. normal | 0.71 (0.51–0.98) | 1.01 (0.91–1.12) |
Moderate/severe vs. normal | NE | 0.95 (0.63–1.41) |
Age, years | ||
≥ 65 vs. < 65 | 1.07 (0.84–1.35) | 1.06 (0.99–1.13) |
≥ 75 vs. < 75 | 1.09 (0.71–1.69) | 1.01 (0.90–1.13) |
Sex | ||
Male vs. female | 0.86 (0.68–1.09) | 0.96 (0.90–1.03) |
Race | ||
White vs. non-white | 0.88 (0.61–1.27) | 1.10 (1.01–1.19) |
Body weighta, kg | ||
Q3 vs. Q4 | 1.06 (0.76–1.47) | 0.98 (0.90–1.08) |
Q2 vs. Q4 | 0.90 (0.65–1.25) | 0.89 (0.81–0.98) |
Q1 vs. Q4 | 0.76 (0.54–1.06) | 0.81 (0.74–0.90) |
Albumin, g/L | ||
< 35 vs. ≥ 35 (normal) | 0.72 (0.57–0.92) | 0.79 (0.74–0.86) |
Prior line of therapy | ||
2 vs. 1 | NA | 0.98 (0.90–1.06) |
3 vs. 1 | NA | 0.97 (0.88–1.07) |
> 3 vs. 1 | NA | 0.84 (0.75–0.93) |
> 3 vs. ≤ 3 | 0.83 (0.63–1.11) | NA |
Refractory status | ||
PI only vs. none | NA | 0.93 (0.82–1.06) |
IMiD only vs. none | NA | 0.95 (0.84–1.08) |
Double vs. none | NA | 0.92 (0.81–1.05) |
Double vs. other | 1.08 (0.80–1.46) | NA |
ECOG status | ||
1 vs. 0 | 0.88 (0.68–1.15) | 0.99 (0.92–1.06) |
2 vs. 0 | 0.85 (0.51–1.43) | 0.95 (0.82–1.11) |
Type of myeloma | ||
IgG vs. non-IgG | 0.50 (0.40–0.62) | 0.77 (0.73–0.83) |
Relationship Between Daratumumab Exposure and Efficacy
Relationship Between Daratumumab Exposure and Safety
TEAE | Control | Exposure quartiles, % (95% CI) | |||
---|---|---|---|---|---|
% (95% CI) | 1st | 2nd | 3rd | 4th | |
Combined POLLUX and GEN503 | Rd, N = 281 | D-Rd, N = 82 | D-Rd, N = 81 | D-Rd, N = 81 | D-Rd, N = 82 |
IRRsa | NA | 69.5 (59.1–78.8) | 45.7 (35.1–56.5) | 38.3 (28.2–49.1) | 39.0 (28.9–49.8) |
Grade ≥ 3 | NA | 9.8 (4.6–17.4) | 1.2 (0.1–5.3) | 7.4 (3–14.4) | 1.2 (0.1–5.3) |
Thrombocytopenia | 27.4 (22.4–32.8) | 31.7 (22.3–42.2) | 28.4 (19.4–38.8) | 25.9 (17.2–36.1) | 25.6 (17.0–35.7) |
Grade ≥ 3 | 13.5 (9.9–17.8) | 15.9 (9.1–24.8) | 13.6 (7.3–22.1) | 12.3 (6.4–20.6) | 9.8 (4.6–17.4) |
Neutropenia | 43.1 (37.4–48.9) | 70.7 (60.3–79.8) | 65.4 (54.7–75.2) | 54.3 (43.5–64.9) | 59.8 (49.0–69.9) |
Grade ≥ 3 | 37.0 (31.5–42.8) | 63.4 (52.7–73.3) | 59.3 (48.4–69.5) | 46.9 (36.3–57.8) | 51.2 (40.5–61.9) |
Anemia | 34.9 (29.5–40.6) | 31.7 (22.3–42.2) | 30.9 (21.5–41.4) | 29.6 (20.4–40.1) | 28.0 (19.1–38.3) |
Grade ≥ 3 | 19.6 (15.2–24.5) | 19.5 (11.9–29.0) | 14.8 (8.2–23.6) | 4.9 (1.6–11.1) | 8.5 (3.8–15.9) |
Lymphopenia | 5.3 (3.1–8.4) | 4.9 (1.5–11.0) | 6.2 (2.3–12.8) | 4.9 (1.6–11.1) | 9.8 (4.6–17.4) |
Grade ≥ 3 | 3.6 (1.8–6.2) | 4.9 (1.5–11.0) | 6.2 (2.3–12.8) | 3.7 (0.9–9.3) | 8.5 (3.8–15.9) |
Infections | 72.6 (67.2–77.6) | 81.7 (72.4–89.0) | 84.0 (75.0–90.8) | 85.2 (76.4–91.8) | 85.4 (76.7–91.9) |
Grade ≥ 3 | 22.8 (18.1–27.9) | 31.7 (22.3–42.2) | 27.2 (18.3–37.5) | 29.6 (20.4–40.1) | 23.2 (15.0–33.0) |
CASTOR | Vd, N = 237 | D-Vd, N = 60 | D-Vd, N = 60 | D-Vd, N = 60 | D-Vd, N = 60 |
---|---|---|---|---|---|
IRRsa | NA | 75.0 (63.1–84.8) | 38.3 (26.7–50.9) | 40.0 (28.2–52.6) | 28.3 (18.0–40.5) |
Grade ≥ 3 | NA | 16.7 (8.7–27.4) | 5.0 (1.3–12.5) | 8.3 (3.1–17.1) | 5.0 (1.3–12.5) |
Thrombocytopenia | 43.9 (37.7–50.2) | 61.7 (49.1–73.3) | 61.7 (49.1–73.3) | 53.3 (40.8–65.6) | 58.3 (45.7–70.3) |
Grade ≥ 3 | 32.9 (27.1–39.1) | 55.0 (42.4–67.2) | 50.0 (37.5–62.5) | 36.7 (25.2–49.2) | 40.0 (28.2–52.6) |
Neutropenia | 9.3 (6.0–13.4) | 23.3 (13.9–35.0) | 13.3 (6.3–23.4) | 15.0 (7.5–25.4) | 20.0 (11.3–31.3) |
Grade ≥ 3 | 4.2 (2.1–7.3) | 16.7 (8.7–27.4) | 10.0 (4.1–19.2) | 10.0 (4.1–19.2) | 15.0 (7.5–25.4) |
Anemia | 31.2 (25.5–37.3) | 38.3 (26.7–50.9) | 21.7 (12.6–33.1) | 21.7 (12.6–33.1) | 21.7 (12.6–33.1) |
Grade ≥ 3 | 16.0 (11.7–21.1) | 25.0 (15.2–36.9) | 16.7 (8.7–27.4) | 8.3 (3.1–17.1) | 5.0 (1.3–12.5) |
Lymphopenia | 3.8 (1.8–6.7) | 10.0 (4.1–19.2) | 10.0 (4.1–19.2) | 16.7 (8.7–27.4) | 15.0 (7.5–25.4) |
Grade ≥ 3 | 2.5 (1.0–5.1) | 10.0 (4.1–19.2) | 5.0 (1.3–12.5) | 11.7 (5.2–21.3) | 10.0 (4.1–19.2) |
Infections | 53.2 (46.8–59.5) | 63.3 (50.8–74.8) | 63.3 (50.8–74.8) | 68.3 (56.0–79.2) | 75.0 (63.1–84.8) |
Grade ≥ 3 | 19.4 (14.7–24.8) | 33.3 (22.3–45.8) | 20.0 (11.3–31.3) | 11.7 (5.2–21.3) | 18.3 (10.0–29.3) |
EQUULEUS | D-Pd, N = 25 | D-Pd, N = 24 | D-Pd, N = 25 | D-Pd, N = 25 | |
---|---|---|---|---|---|
IRRsa | NE | 72.0 (52.8–86.9) | 41.7 (23.5–61.5) | 48.0 (29.3–67.1) | 36.0 (19.2–55.5) |
Grade ≥ 3 | NE | 8.0 (1.4–22.7) | 0 (NE–NE) | 0 (NE–NE) | 8.0 (1.4–22.7) |
Thrombocytopenia | NE | 60.0 (40.5–77.5) | 41.7 (23.5–61.5) | 44.0 (25.8–63.3) | 16.0 (5.3–33.3) |
Grade ≥ 3 | NE | 28.0 (13.1–47.2) | 16.7 (5.5–34.6) | 20.0 (7.7–38.2) | 4.0 (0.2–16.5) |
Neutropenia | NE | 72.0 (52.8–86.9) | 87.5 (70.7–96.7) | 76.0 (57.2–89.7) | 76.0 (57.2–89.7) |
Grade ≥ 3 | NE | 68.0 (48.6–83.9) | 83.3 (65.4–94.5) | 76.0 (57.2–89.7) | 76.0 (57.2–89.7) |
Anemia | NE | 68.0 (48.6–83.9) | 58.3 (38.5–76.5) | 48.0 (29.3–67.1) | 36.0 (19.2–55.5) |
Grade ≥ 3 | NE | 44.0 (25.8–63.3) | 45.8 (27.1–65.4) | 16.0 (5.3–33.3) | 4.0 (0.2–16.5) |
Lymphopenia | NE | 16.0 (5.3–33.3) | 25.0 (10.8–44.3) | 20.0 (7.7–38.2) | 20.0 (7.7–38.2) |
Grade ≥ 3 | NE | 12.0 (3.1–28.2) | 12.5 (3.3–29.3) | 8.0 (1.4–22.7) | 16.0 (5.3–33.3) |
Infections | NE | 48.0 (29.3–67.1) | 62.5 (42.6–79.9) | 76.0 (57.2–89.7) | 100.0 (NE–NE) |
Grade ≥ 3 | NE | 32.0 (16.1–51.4) | 25.0 (10.8–44.3) | 28.0 (13.1–47.2) | 32.0 (16.1–51.4) |