Page 170 - 2018_12-Haematologica-web

M.A. Dimopoulos et al.
Table 3. Most common all grade (≥15%) and grade 3/4 (≥5%) treatment-emergent adverse events in the safety population
D-Rd (n=283)
Rd (n=281)
Event, n (%)
Total
Hematologic
Neutropenia Febrile neutropenia Anemia Thrombocytopenia Lymphopenia
Nonhematologic
Diarrhea
Fatigue
Upper respiratory tract infection Cough
Constipation Muscle spasms Nasopharyngitis Nausea Insomnia Pyrexia Dyspnea
Back pain Pneumonia Bronchitis Edema peripheral Vomiting Asthenia Headache
All grade
281 (99.3)
172 (60.8) 17 (6.0) 104 (36.7) 81 (28.6) 18 (6.4)
144 (50.9) 103 (36.4) 105 (37.1) 91 (32.2) 88 (31.1) 81 (28.6) 84 (29.7) 76 (26.9) 67 (23.7) 67 (23.7) 59 (20.8) 58 (20.5) 58 (20.5) 53 (18.7) 53 (18.7) 52 (18.4) 51 (18.0) 43 (15.2)
Grade 3/4
251 (88.7)
153 (54.1) 17 (6.0) 44 (15.5) 39 (13.8) 15 (5.3)
20 (7.1) 18 (6.4) 4 (1.4) 1 (0.4) 3 (1.1) 3 (1.1) 0 (0.0) 5 (1.8) 4 (1.4) 7 (2.5) 12 (4.2) 6 (2.1) 34 (12.0) 6 (2.1) 2 (0.7) 3 (1.1) 10 (3.5) 0 (0.0)
All grade
274 (97.5)
127 (45.2) 8 (2.8) 109 (38.8) 87 (31.0) 16 (5.7)
89 (31.7) 85 (30.2) 74 (26.3) 40 (14.2) 74 (26.3) 59 (21.0) 54 (19.2) 50 (17.8) 61 (21.7) 36 (12.8) 35 (12.5) 53 (18.9) 42 (14.9) 46 (16.4) 43 (15.3) 19 (6.8) 43 (15.3) 22 (7.8)
Grade 3/4
216 (76.9)
112 (39.9) 8 (2.8) 60 (21.4) 44 (15.7) 11 (3.9)
9 (3.2) 10 (3.6) 4 (1.4) 0 (0.0) 2 (0.7) 4 (1.4) 0 (0.0) 2 (0.7) 4 (1.4) 5 (1.8) 2 (0.7) 5 (1.8) 24 (8.5) 7 (2.5) 4 (1.4) 4 (1.4) 8 (2.8) 0 (0.0)
D-Rd: daratumumab/lenalidomide/dexamethasone; Rd: lenalidomide/dexamethasone.
genetic risk status. As one of the first studies to prospec- tively assess MRD in a phase 3 trial of RRMM, MRD-negativity rates were also significantly higher with D-Rd across all patient subgroups, including patients with high cytogenetic risk. These findings reinforce observa- tions that highlight the depth, durability, and robustness of responses achieved with daratumumab-based regi- mens.24
These findings compare favorably with other studies of IMiD-containing regimens with subgroup analyses based on prior lines of therapy and/or prior treatment exposure (Appendix Table 2). In a large phase 3 study (ASPIRE) of carfilzomib-Rd (KRd) compared with Rd alone, a consis- tent PFS benefit was observed with KRd versus Rd among patients who received 1 and 2 to 3 prior lines of therapy.25 Prespecified PFS subgroup analyses showed a modest ben- efit with KRd over Rd for patients who previously received lenalidomide and patients nonresponsive to bortezomib in any previous regimen.26 The magnitude of benefit for KRd versus Rd was similar in patients with early disease relapse (≤12 months from starting the first prior regimen; ORR: 79% vs. 61%).27 In a phase 3 study of elotuzumab (ELOQUENT-2), the PFS benefit in combina- tion with Rd was maintained among patients who received 2 to 3 prior lines of therapy or had prior exposure
to bortezomib but not among patients who received 1 prior line of therapy or prior lenalidomide.28,29 Ixazomib in combination with lenalidomide and dexamethasone in the phase 3 TOURMALINE-MM1 study demonstrated a modest PFS benefit versus Rd in patients who received 1 or 2 prior lines, were previously treated with an IMiD or a PI, and were refractory to their last line of therapy; interest- ingly, patients who received 3 prior lines of therapy demonstrated an HR of 0.37.30
D-Rd improved responses, including MRD negativity in patients with high-risk cytogenetic status, suggesting that targeting CD38 in combination with Rd may improve outcomes for this challenging-to-treat population. Moreover, despite the small number of patients with high-risk disease, D-Rd demonstrated significantly higher MRD-negativity rates compared with standard-risk patients receiving Rd. While PFS was not statistically dif- ferent between D-Rd versus Rd for patients with high-risk disease, a numerical improvement in PFS was observed in high-risk patients who received D-Rd versus Rd. As the magnitude of benefit for D-Rd was lower among high-risk patients, these findings suggest that while D-Rd is able to provide improvements in efficacy, it is not able to overcome the greater risk of progression and poor outcomes associated
2094
haematologica | 2018; 103(12)