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DARZALEX® (daratumumab)

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DARZALEX - CANDOR Study

Last Updated: 06/27/2024

SUMMARY

  • CANDOR is an ongoing, randomized, open-label, multicenter, phase 3 study evaluating the efficacy and safety of DARZALEX for intravenous (IV) use in combination with carfilzomib and dexamethasone (DKd; n=312) vs carfilzomib and dexamethasone (Kd; n=154) in patients with relapsed or refractory multiple myeloma (RRMM).1,2
    • Dimopoulos et al (2020)2 reported the primary results of the CANDOR study with a median progression-free survival (PFS) follow-up of 16.9 months for DKd and
      16.3 months for Kd. The median PFS in the DKd arm was not estimable (NE) vs 15.8 months in the Kd arm (hazard ratio [HR], 0.63; 95% confidence interval [CI], 0.46-‍0.85; two-sided P=0.0027).
      • The overall response rate (ORR) in the DKd arm was 84% vs 75% in the Kd arm (P=0.0080). The 12-month minimal residual disease (MRD)-negative complete response (CR) rate was achieved by 13% of patients in the DKd arm vs 1% of patients in the Kd arm (P<0.0001). The median overall survival (OS) was NE in either arm after a median follow-up time of 17.2 months with DKd and 17.1 months for Kd.
      • The DKd vs Kd arm had a greater incidence of any grade adverse events (AEs; 99% vs 96%), grade ≥3 AEs (82% vs 74%), serious AEs (SAEs; 56% vs 46%), and fatal AEs (10% vs 5%).
    • Usmani et al (2023)3 reported the final efficacy and safety results of the CANDOR study after a median follow-up of approximately 50 months. The median PFS was 28.4 vs 15.2 months in patients treated with DKd vs Kd (HR, 0.64; 95% CI, 0.490.83). The DKd vs Kd arm had a greater incidence of any grade treatment-emergent adverse events (TEAEs; 99% vs 97%), grade ≥3 TEAEs (89% vs 78%), serious TEAEs (68% vs 52%), and fatal TEAEs (11% vs 6%).
  • Dimopoulous et al (2023)4 reported the results of a subgroup analysis of efficacy and safety by baseline renal function in patients with RRMM receiving DKd vs Kd in the CANDOR study. Consistent clinical benefit was seen in median PFS, ORR, and OS regardless of baseline renal function in DKd vs KD. Median PFS for patients with CrCl ≥15-<60 mL/min, ≥60-<90 mL/min, and ≥90 mL/min was 24.9 months vs 8.4 months (HR, 0.61; 95% CI, 0.35-1.06), 31.6 months vs 19.9 months (HR, 0.63; 95% CI 0.41-0.96), and 27.4 months vs 15.3 months (HR 0.64; 95% CI, 0.43-0.95), respectively. ORRs were 87% vs 50% (Odds ratio [OR], 8.02; 95% CI, 2.84-22.65); 85% vs 82% (OR 1.26; 95% CI 0.49-3.27); and 86% vs 80% (OR 1.59; 95% CI 0.69-3.68), respectively. Safety finding were consistent with the overall study population.
  • Quach et al (2022)5reported the results of a subgroup analysis across frailty subgroups in patients with RRMM treated with DKd vs Kd. Efficacy and safety results were consistent with the primary analysis favoring DKd. Median PFS and ORR in DKd vs Kd was 18.5 vs 9.3 months (HR 0.66, 95% CI 0.38-1.14) and 75% vs 54% (OR 2.39, 95% CI 1.09-5.22) for frail patients, respectively.
  • Landgren et al (2022)6 reported efficacy results of a subgroup analysis based on cytogenic risk in patients with RRMM in the CANDOR study. ORR was 81% vs 56% in high-risk and 87% vs 79% in standard-risk groups for DKd vs Kd, respectively. Median PFS was 11.2 vs 7.4 months in high-risk (HR, 0.56 [95% CI, 0.34, 0.93]) and not reached vs 16.6 months in standard-risk groups (0.56[95% CI, 0.39, 0.80)] for DKd vs Kd, respectively.
  • Quach et al (2021)7reported the results of a subgroup analysis by prior lines of therapy. Efficacy and safety results by subgroup were generally consistent with the primary analysis favoring DKd over Kd. PFS HRs for DKd vs Kd ranged from 0.47 to 0.84 across prior treatment subgroups. ORR and MRD-negative CR rates were higher for DKd vs Kd arms regardless of prior drug exposure or refractory status.
  • Mateos et al (2021)8 presented (at the 18th International Myeloma Workshop in September 2021) the efficacy and safety results of DKd vs Kd in patients with RRMM with or without prior autologous stem cell transplantation (ASCT) subdivided by lenalidomide-refractory and/or lenalidomide-exposed status. In patients with vs without prior ASCT, PFS HR was 0.54 vs 0.68 overall, 0.35 vs 0.62 for lenalidomide-exposed patients, and 0.30 vs 0.62 for lenalidomide-refractory patients. In patients with vs without prior ASCT, grade ≥3 AEs were reported in 89.6% vs 82.8% of patients in the DKd arm and in 78.7% vs 73.1% of patients in the Kd arm, with consistent rates across lenalidomide subgroups.
  • Suzuki et al (2021)9 reported the efficacy and safety results of DKd vs Kd from a post hoc analysis of the CANDOR study conducted in Asian patients with RRMM. PFS was NE for both the treatment arms. Grade ≥3 TEAEs occurred in 95.7% and 90.0% of patients in the DKd and Kd arms, respectively.
  • Siegel et al (2021)10reported the results of patient-reported outcome (PRO) data collected during treatment. Health-related quality of life (HRQoL) scores were measured using the Global Health Status (GHS)/Quality of Life (QoL) domain of the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item (EORTC QLQ-C30). GHS/QoL completion rates were >81% for both arms. Overall, the least squares mean estimate (95% CI) of the difference between the two treatment arms was 0.06 (-2.39-2.50).
  • Chari et al (2021)11 presented naïve comparison (without adjustments) and matching-adjusted indirect comparisons (MAIC) of PFS for DKd vs pomalidomide in combination with bortezomib and dexamethasone (PVd) vs DARZALEX in combination with pomalidomide and dexamethasone (DPd) in patients with RRMM. After naïve comparison, PFS benefit was observed for DKd vs PVd (median, 25.9 months vs 11.5 months; HR, 0.629; 95% CI, 0.397-0.747) and DKd vs DPd (median, 25.9 months vs 12.8 months; HR, 0.629; 95% CI, 0.445-0.890). After MAIC, PFS benefit was observed for DKd vs PVd (median: 25.0 months vs 11.5 months; HR, 0.539; 95% CI, 0.395-0.736) and DKd vs DPd (median, 25.0 months vs 12.8 months; HR, 0.677; 95% CI, 0.474-0.966). This analysis is referenced below.
  • Landgren et al (2020)12 presented (at the 62nd American Society of Hematology [ASH] Annual Meeting & Exposition in December 2020) results from a post-hoc analyses of the best overall MRD-negative status at any time point and MRD-negative CR at various cutoffs from the CANDOR study. In each analysis, MRD-negativity rates were higher in the DKd arm. At the 12month landmark, DKd vs Kd treatment resulted in greater proportion of CR rates (26.9% vs 9.7%) and deeper MRD responses. With a median follow-up of 6 months from the 12-month landmark, no patient with MRD-negative CR response progressed.
  • Weisel et al (2020)13 presented (at the 62nd ASH Annual Meeting & Exposition in December 2020) the results of a subgroup analysis in patients with early or late relapse after the most recent prior line of therapy. PFS HRs in DKd vs Kd arms were consistent in both early and late relapse subgroups. Rates of ≥CR were higher with DKd vs Kd among patients with early relapse. The safety profile was consistent with the overall DKd and Kd cohorts.

PRODUCT LABELING

CLINICAL DATA

CANDOR (clinicaltrials.gov identifier: NCT03158688) is a randomized, open-label, multicenter, phase 3 study evaluating the efficacy and safety of DKd vs Kd in patients with RRMM.1-3

Study Design/Methods

  • Patients were randomized 2:1 to receive either of the following as 28-day cycles until disease progression:
    • DKd:
      • DARZALEX 16 mg/kg IV weekly cycles 1-2 (first dose split over days 1 and 2 [8 mg/kg each] of cycle 1); every 2 weeks cycles 3-6; every 4 weeks thereafter
      • Carfilzomib 56 mg/m2 IV on days 1, 2, 8, 9, 15, and 16 of each 28-day cycle (20 mg/m2 on days 1, 2 of cycle 1, 56 mg/m2 thereafter)
      • Dexamethasone 40 mg orally or IV weekly (or 20 mg if ≥75 years starting on the second week)
    • Kd: Carfilzomib and dexamethasone as above.
  • Key eligibility criteria: RRMM; 1-3 prior therapies with ≥ partial response to ≥1 prior therapy; Eastern Cooperative Oncology Group performance status of 0-2; creatinine clearance ≥20 mL/min; left ventricular ejection fraction ≥40%
  • MRD samples were collected at baseline and analyzed at 12 months for MRD-negativity (10-5) CR rate.
  • Primary endpoint: PFS
  • Key secondary endpoints: ORR, MRD (10-5), safety, rate of ≥CR and OS

Primary Efficacy and Safety Results of CANDOR

Dimopoulos et al (2020)2 reported the primary results of CANDOR at a median follow-up of approximately 17 months.

Results

Patient Characteristics

Baseline Patient and Disease Characteristics1,2
Characteristic
DKd (n=312)
Kd (n=154)
Median age (range), years
64 (57-70)
65 (59-71)
ECOG PS, n (%)
0-1
295 (95)
147 (95)
2
15 (5)
7 (5)
ISS stage, n (%)
I
147 (47)
79 (51)
II
103 (33)
48 (31)
III
61 (20)
27 (18)
Cytogenetic risk by FISH, n (%)
Standard riska
104 (33)
52 (34)
High riskb
48 (15)
26 (17)
Unknownc
160 (51)
76 (49)
Number of prior therapies, n (%)
1
144 (46)
70 (45)
≥2
168 (54)
83 (55)
Prior therapies, n (%)
Bortezomib
287 (92)
134 (87)
Refractory to prior bortezomib
88 (28)
47 (31)
Lenalidomide
123 (39)
74 (48)
Refractory to prior lenalidomide
99 (32)
55 (36)
Abbreviations: DKd, DARZALEX + carfilzomib + dexamethasone; ECOG PS, Eastern Cooperative Oncology Group Performance Status; FISH, fluorescence in-situ hybridization; ISS, International Staging System; Kd, carfilzomib + dexamethasone.aPatients without t(4;14), t(14;16), and del(17p).bGenetic subtypes t(4;14), t(14;16), or del(17p).cPatients with FISH not done, failed, or of insufficient quantity.
Efficacy
  • Median PFS follow-up for the DKd vs Kd arms: 16.9 months vs 16.3 months
  • Treatment with DKd resulted in a 37% reduction in the risk of progression or death (HR, 0.63; 95% CI, 0.460.85; two-sided P=0.0027).
  • Median PFS for the DKd vs Kd arms: NE vs 15.8 months.
  • Number of events that resulted in progression/death for the DKd vs Kd arms: 110 (35%) vs 68 (44%).
  • The HR for PFS favored the DKd arm across other prespecified subgroups including age, International Staging System stage, cytogenetic risk status, number of prior lines of therapy, lenalidomide-exposed patients, and lenalidomide-refractory patients. See Table: Progression-Free Survival in Prespecified Subgroups.
  • The response rates and MRD-negativity rates (10-5) are summarized in the Table: Response Rates and MRD-Negative Rates.
  • After a median follow-up of 17.2 and 17.1 months in the DKd and Kd arms, respectively, the median OS was NE in both arms (HR, 0.75; 95% CI, 0.49-1.13; P=0.17).

Progression-Free Survival in Prespecified Subgroups1,2
Subgroup
DKd
(n=312)
Kd
(n=154)
HR for DKd vs Kd
(95% CI)
All randomized patients
312
154
0.63 (0.46-0.85)
ISS stage per IXRS at screening
1 or 2
252
127
0.61 (0.43-0.86)
3
60
27
0.72 (0.38-1.39)
Age at baseline, years
≤65
178
80
0.57 (0.38-0.86)
>65
134
74
0.76 (0.48-1.22)
Cytogenetic risk group
High risk
48
26
0.70 (0.36-1.40)
Standard risk
104
52
0.50 (0.28-0.90)
Unknown
160
76
0.66 (0.43-1.02)
Number of prior lines of therapy
1
133
67
0.68 (0.40-1.14)
≥2
179
87
0.61 (0.42-0.88)
Prior lenalidomide exposure
Yes
123
74
0.53 (0.34-0.82)
No
189
80
0.71 (0.45-1.12)
Refractory to lenalidomide
Yes
99
55
0.47 (0.29-0.78)
No
213
99
0.74 (0.49-1.11)
Abbreviations: CI, confidence interval; DKd, DARZALEX + carfilzomib + dexamethasone; ECOG PS, Eastern Cooperative Oncology Group Performance Status; HR, hazard ratio; ISS, International Staging System; IXRS, interactive response system; Kd, carfilzomib + dexamethasone.

ResponseRatesa and MRD-Negative Rates1,2
Response rates, %
DKd (n=312)
Kd (n=154)
P value
ORR
84
75
0.0080
≥VGPR
69
49
-
CR
29
10
-
MRD-negativity (10-5)
MRD-negativity at 12 months
18
4
<0.0001
MRD-negative CR at 12 months
13
1
<0.0001
Best MRD-negative CR
14
3
-
Abbreviations: CR, complete response; DKd, DARZALEX + carfilzomib + dexamethasone; Kd, carfilzomib + dexamethasone; MRD, minimal residual disease; ORR, overall response rate; PR, partial response; VGPR, very good partial response.aMedian time to first response was 1 month in both arms.
Safety

Treatment Exposure1
Parameter
DKd (n=308)
Kd (n=153)
Median duration of treatment, weeks
Carfilzomib
58.4
40.3
Dexamethasone
69.1
40.0
DARZALEX
68.1
-
Median relative dose intensity (range), %
Carfilzomib
90.8 (21.6-106.0)
93.3 (40.1-105.9)
Dexamethasone
90.6 (28.0-102.6)
91.9 (29.1-170.0)
DARZALEX
95.6 (24.0-102.4)
-
Abbreviations: DKd, DARZALEX + carfilzomib + dexamethasone; Kd, carfilzomib + dexamethasone.

Treatment-Emergent Adverse Events1,2
Adverse events, n (%)
DKd (n=308)
Kd (n=153)
All Grades (≥20%)
Grade 3 (≥5%)
Grade 4 (≥5%)
All Grades (≥20%)
Grade 3 (≥5%)
Grade 4 (≥5%)
TEAEs
306 (99)
-
-
147 (96)
-
-
Hematologica
   Thrombocytopenia
115 (37)
49 (16)
26 (8)
45 (29)
19 (12)
6 (4)
   Anemia
101 (33)
48 (16)
3 (1)
48 (31)
21 (14)
1(1)
   Neutropenia
43 (14)
24 (8)
2 (1)
15 (10)
7 (5)
2 (1)
   Lymphopenia
27 (9)
9 (3)
12 (4)
12 (8)
9 (6)
2(1)
Nonhematologica
   Diarrhea
97 (31)
12 (4)
0
22 (14)
1 (1)
0
   Hypertension
94 (31)
54 (18)
0
42 (27)
20 (13)
0
   URTI
90 (29)
7 (2)
1 (<1)
35 (23)
2 (1)
0
   Fatigue
75 (24)
23 (7)
1(<1)
28 (18)
7 (5)
0
   Dyspnea
61 (20)
12 (4)
0
34 (22)
4 (3)
0
   Pneumonia
55 (18)
32 (10)
5 (2)
19 (12)
12(8)
1 (1)
   Serious
173 (56)
-
-
70 (46)
-
-
Leading to treatment discontinuation
69 (22)
-
-
38 (25)
-
-
Leading to treatment dose reduction
119 (39)
-
-
53 (35)
-
-
Abbreviations: DKd, DARZALEX + carfilzomib + dexamethasone; Kd, carfilzomib + dexamethasone; TEAE, treatment-emergent adverse event; URTI, upper respiratory tract infection.aHematologic and nonhematologic adverse events of all grades were reported for those that occurred in ≥20% of patients in either arm. Grade ≥3 events reported for those that occurred in >5% of patients in either arm.

Adverse Events of Interest1,2
Adverse events, n (%)
DKd (n=308)
Kd (n=153)
All Grades
Grade 3 (≥5%)
Grade 4 (≥5%)
All Grades
Grade 3 (≥5%)
Grade 4 (≥5%)
Respiratory tract infection
225 (73)
77 (25)
7 (2)
84 (55)
22 (14)
1 (1)
Viral infections
63 (20)
19 (6)
0
22 (14)
2 (1)
0
DARZALEX-related infusion reactions
56 (18)
7 (2)
0
0
0
0
Peripheral neuropathy
53 (17)
3 (1)
0
13 (8)
0
0
Cardiac failurea
23 (7)
9 (3)
1 (<1)
16 (10)
10 (7)
3 (2)
Acute renal failure
18 (5.8)
5 (2)
4 (1)
12 (8)
6(4)
4 (3)
Ischemic heart disease
13 (4)
7 (2)
2 (1)
5 (3)
4 (3)
0
Abbreviations: DKd, DARZALEX + carfilzomib + dexamethasone; Kd, carfilzomib + dexamethasone; IRR, infusion-related reaction.aIncidence of cardiac failure leading to carfilzomib discontinuation was 3.9% in the DKd arm vs 4.6% in Kd arm.

Adverse Events Leading to Treatment Discontinuation1,2
DKd (n=308)
Kd (n=153)
Adverse Events leading to treatment discontinuation, n (%)
69 (22)
38 (25)
Adverse Events leading to carfilzomib discontinuation, n (%)
65 (21)
33 (22)
Adverse Events leading to DARZALEX discontinuation, n (%)
28 (9)
-
Abbreviations: DKd, DARZALEX + carfilzomib + dexamethasone; Kd, carfilzomib + dexamethasone.

Fatal Events2
Fatal events, n (%)
DKd (n=308)
Kd (n=153)
Treatment-emergent
30 (10)a
8 (5)
Treatment-related
5 (1.6)b
0
Abbreviations: DKd, DARZALEX + carfilzomib + dexamethasone; Kd, carfilzomib + dexamethasone.aGenerally reported in older and more frail patients.bDue to pneumonia, sepsis with Clostridium difficile enterocolitis, septic shock in the setting of Pneumocystis carinii pneumonia; Acinetobacter infection, and cardiorespiratory arrest (n=1 each).

Final Efficacy and Safety Results of CANDOR

Usmani et al (2023)3 reported the final efficacy and safety results of the CANDOR study after a median follow-up of approximately 50 months.

Results

Efficacy
  • In the DKd vs Kd arm, median follow-up duration was 50.6 (range, 0-57) months vs 50.1 (range, 0-58) months.
  • Survival and MRD-negativity rates are summarized in Table: Overall Survival and MRD-Negativity (10-5) Rates.
  • Prespecified subgroup analyses showed an OS improvement in the DKd vs Kd arm in most subgroups.
    • The greatest OS benefit of DKd was observed in patients with high-risk cytogenetics (HR, 0.52; 95% CI, 0.29-0.94) and International Staging System (ISS) stage III at screening (HR, 0.58; 95% CI, 0.35-0.99).
  • In the DKd vs Kd arm, 49% (n=153) vs 68% (n=105) of patients received subsequent antimyeloma therapy, respectively.

Overall Survival and MRD-Negativity (10-5) Rates3
Parameter
DKd, % (95% CI)
(n=312)
Kd, % (95% CI)
(n=154)
MRD-negativity rate at 12 months
n=57
n=8
18.3 (14.1-23.0)
5.2 (2.3-10.0)
   OR (95% CI)
4.403 (2.007-9.656)
MRD-negative CR rate at 12 months
n=40
n=3
12.8 (9.3-17.0)
1.9 (0.4-5.6)
   OR (95% CI)
7.819 (2.364-25.858)
MRD-negativity rate at any time
n=87
n=14
27.9 (23.0-33.2)
9.1 (5.1-14.8)
   OR (95% CI)
4.222 (2.277-7.829)
MRD-negative CR rate at any time
n=68
n=12
21.8 (17.3-26.8)
7.8 (4.1-13.2)
   OR (95% CI)
3.551 (1.833-6.877)
Median PFS (95% CI), months
28.4 (22.7-36.2)a
15.2 (11.1-19.9)
   HR (95% CI)
0.64 (0.49-0.83)
Median OS (95% CI), months
50.8 (44.7-NE)
43.6 (35.3-NE)
   HR (95% CI); P value
0.784 (0.595-1.033); 0.0417b
Median TTNT (95% CI), months
37.4 (30.1-47.8)
17.8 (13.5-23.1)
Median dPFS2, months
44.6
35.5
   HR (95% CI)
0.800 (0.614-1.044)
Abbreviations: CI, confidence interval; CR, complete response; DKd, DARZALEX + carfilzomib + dexamethasone; dPFS2, derived time to subsequent disease progression or death; HR, hazard ratio; Kd, carfilzomib + dexamethasone; MRD, minimal residual disease; NE, not estimable; OR, odds ratio; OS, overall survival; PFS, progression-free survival; TTNT, time to next treatment.aMedian follow-up was ~39 months in the DKd arm.bAlthough there was a difference of 7.2 months in OS in favor of DKd, the 1-sided P value of 0.0417 did not meet the prespecified statistical significance level of 0.021 (1-sided). These results were generally consistent across the 4 prespecified OS sensitivity analyses.
Safety
  • The treatment exposure is summarized in the Table: Treatment Exposure.
  • The safety results were consistent with previous reports, and no new safety signals were identified with the longer follow-up. See Table: Safety Overview.
  • Grade ≥3 infections and infestations occurred in 46% (n=142) vs 32% (n=49) of patients in the DKd vs Kd arm and led to carfilzomib discontinuation in 22% (n=69) vs 20% (n=30) of patients, respectively.
  • TEAEs related to COVID-19 occurred in 11% (n=33) vs 4% (n=6) of patients in the DKd vs Kd arm, and deaths related to COVID-19 occurred in 2% (n=6) vs 1% (n=1) of patients, respectively.
  • The incidence of carfilzomib and DARZALEX discontinuation due to TEAEs decreased over time, with most discontinuations due to TEAEs occurring in the first 18 months. See Table: TEAEs Leading to Treatment Discontinuation.
  • The most common causes of fatal TEAEs were infections (DKd, 7% [n=21]; Kd, 3% [n=5]) and cardiac disorders (DKd, 2% [n=6]; Kd, 0%).
    • In the DKd vs Kd arm, the exposure-adjusted rates of fatal TEAEs were 6.5 vs 5.6 per 100 patients-years, respectively.
    • In the DKd vs Kd arm, the fatal infection rates were 7% (n=21) vs 3% (n=5), and the exposure-adjusted fatal infection rates were 3.5 vs 2.55 per 100 patient-years, respectively.
  • TEAEs are summarized in Tables: TEAEs in the Safety Population, TEAEs of Interest, and Fatal TEAEs.

Treatment Exposure3
Parameter
DKd (n=308)
Kd (n=153)
Median duration of treatment, weeks (range)
79 (0.3-236) 
40 (0.3-236)
   Carfilzomib
61 (0.3236)
40 (0.3-235)
   DARZALEX
79 (0.1-236)
-
Median relative dose intensity (range),a %
   Carfilzomib
88.3 (21.6-106.0)
91.4 (34.3-105.9)
   DARZALEX
94.9 (24.0-102.3)
-
Abbreviations: DKd, DARZALEX + carfilzomib + dexamethasone; Kd, carfilzomib + dexamethasone.aRelative dose intensity is the actual dose intensity/planned dose intensity×100, where actual (planned) dose intensity is the actual (planned) cumulative dose (mg/kg) divided by the actual (planned) duration of drug administration (weeks).

Safety Overview14
Parameter 
DKd (n=308)
Kd (n=153)
Median relative dose intensity (range),a %
   Carfilzomib
88.3 (21.6-106.0)
91.4 (34.3-105.9)
   DARZALEX
94.9 (24.0-102.3)
-
Dose reductions due to TEAE, n (%)
141 (45.8)
59 (38.6)
   Carfilzomib
95 (30.8)
38 (24.8)
   DARZALEX
4 (1.3)
-
Grade ≥3 TEAEs, n (%)
273 (88.6)
120 (78.4)
   Exposure-adjusted rate (95% CI), per PY
149.6 (132.9-168.5)
144.7 (121.0-173.1)
Serious TEAEs, n (%)
211 (68.5)
80 (52.3)
   Exposure-adjusted rate (95% CI)
60.4 (52.7-69.1)
59.0 (47.4-73.4)
Abbreviations: CI, confidence interval; DKd, DARZALEX + carfilzomib + dexamethasone; Kd, carfilzomib + dexamethasone; PY, patient years; TEAE, treatment-emergent adverse event.aRelative dose intensity is the actual dose intensity/planned dose intensity×100, where actual (planned) dose intensity is the actual (planned) cumulative dose (mg/kg) divided by the actual (planned) duration of drug administration (weeks).

TEAEs in the Safety Population3
Adverse Events, n (%)
DKd (n=308)
Kd (n=153)
Any Gradea
Grade ≥3b
Any Gradea
Grade ≥3b
All TEAEs
306 (99.4)
273 (88.6)
149 (97.4)
120 (78.4)
Hematologic
   Thrombocytopenia
119 (38.6)
76 (24.7)
46 (30.1)
25 (16.3)
   Anemia
114 (37.0)
54 (17.5)
52 (34.0)
25 (16.3)
   Neutropenia
49 (15.9)
31 (10.1)
15 (9.8)
10 (6.5)
   Lymphopenia
29 (9.4)
22 (7.1)
13 (8.5)
11 (7.2)
Nonhematologic
   Diarrhea
118 (38.3)
18 (5.8)
28 (18.3)
1 (0.7)
   Hypertension
115 (37.3)
72 (23.4)
49 (32.0)
27 (17.6)
   Upper respiratory tract infection
105 (34.1)
12 (3.9)
37 (24.2)
2 (1.3)
   Fatigue
81 (26.3)
25 (8.1)
29 (19.0)
7 (4.6)
   Pneumonia
79 (25.6)
57 (18.5)
24 (15.7)
14 (9.2)
   Dyspnea
70 (22.7)
16 (5.2)
35 (22.9)
4 (2.6)
   Pyrexia
66 (21.4)
6 (1.9)
27 (17.6)
2 (1.3)
   Insomnia
64 (20.8)
16 (5.2)
19 (12.4)
3 (2.0)
   Back pain
63 (20.5)
7 (2.3)
21 (13.7)
2 (1.3)
   Nausea
62 (20.1)
0
22 (14.4)
1 (0.7)
   Hyperglycemia
31 (10.1)
16 (5.2)
13 (8.5)
5 (3.3)
   Cataract
34 (11.0)
15 (4.9)
13 (8.5)
8 (5.2)
Abbreviations: DKd, DARZALEX + carfilzomib + dexamethasone; Kd, carfilzomib + dexamethasone; TEAE, treatment-emergent adverse event.aAny grade TEAEs occurring in ≥20% of patients.bGrade ≥3 TEAEs occurring in ≥5% of patients.

TEAEs of Interest3
Adverse Events, n (%)
DKd (n=308)
Kd (n=153)
Any Gradea
Grade ≥3b
Any Gradea
Grade ≥3b
Respiratory tract infection
243 (78.9)
117 (38.0)
90 (58.8)
27 (17.6)
Infusion reaction (on same day as any carfilzomib dosing)
142 (46.1)
47 (15.3)
50 (32.7)
12 (7.8)
Peripheral neuropathy
66 (21.4)
6 (1.9)
15 (9.8)
1 (0.7)
Cardiac failure
29 (9.4)
12 (3.9)
17 (11.1)
13 (8.5)
Acute renal failure
25 (8.1)
11 (3.6)
14 (9.2)
10 (6.5)
Ischemic heart disease
19 (6.2)
16 (5.2)
8 (5.2)
5 (3.3)
Abbreviations: DKd, DARZALEX + carfilzomib + dexamethasone; Kd, carfilzomib + dexamethasone; TEAE, treatment-emergent adverse event.
aAny grade TEAEs occurring in ≥20% of patients.
bGrade ≥3 TEAEs occurring in ≥5% of patients.

TEAEs Leading to Treatment Discontinuation14
Parameter 
DKd (n=308)
Kd (n=153)
Discontinuation due to TEAE, n (%)
105 (34.1)
41 (26.8)
   Carfilzomib
98 (31.8)
37 (24.2)
   DARZALEX
43 (14.0)
-
Abbreviations: DKd, DARZALEX + carfilzomib + dexamethasone; Kd, carfilzomib + dexamethasone; TEAE, treatment-emergent adverse event.

Fatal Events3,14
Fatal AEs, n (%)
DKd (n=308)
Kd (n=153)
Treatment-emergenta
35 (11.4)
9 (5.9)
Treatment-related
5 (2%)b
-
Abbreviations: CI, confidence interval; DKd, DARZALEX + carfilzomib + dexamethasone; Kd, carfilzomib + dexamethasone.aExcludes the fatal TEAE of plasma cell myeloma.bDue to pneumonia, sepsis, septic shock, Acinetobacter infection, and cardiorespiratory arrest (n=1 each).

Subgroup Analysis by Baseline Renal Function

Dimopoulous et al (2023)4 conducted a subgroup analysis of efficacy and safety by baseline renal function in patients in the CANDOR study.

Results

Patient Characteristics
  • A total of 466 patients were randomized with baseline characteristics generally balanced between treatment arms and renal subgroups and are detailed in Table: Baseline Characteristics by Renal Subgroups.
  • One patient in the DKd arm was excluded due to missing baseline CrCl.

Baseline Characteristics by Renal Subgroups4
Characteristic
≥15-<60 mL/min
≥60-<90 mL/min
≥90 mL/min
DKd (n=67)
Kd
(n=36)
DKd (n=112)
Kd
(n=57)
DKd (n=132)
Kd
(n=61)
ISS stage at baseline*, n (%)
I
2 (3)
3 (8)
14 (13)
7 (12)
21 (16)
15 (25)
II
19 (28)
13 (36)
29 (26)
16 (28)
34 (26)
11 (18)
III
13 (19)
7 (19)
7 (6)
7 (12)
5 (4)
0
Unknown
33 (49)
13 (36)
62 (55)
27 (47)
72 (55)
35 (57)
High risk cytogenetics1, n (%)
15 (22)
9 (25)
16 (14)
11 (19)
17 (13)
6 (10)
Number of prior transplants, n (%)
1
23 (34)
8 (22)
57 (51)
26 (46)
81 (61)
32 (52)
2
7 (10)
1 (3)
9 (8)
4 (7)
16 (12)
4 (7)
>2
0
0
0
0
1 (1)
0
Number of prior therapies, n (%)
1
30 (45)
14 (39)
52 (46)
30 (53)
61 (46)
26 (43)
2-3
37 (55)
22 (61)
60 (54)
27 (47)
71 (54)
34 (56)
>3
0
0
0
0
0
1 (2)
Prior therapies, n (%)
Bortezomib
62 (93)
31 (86)
101 (90)
47 (82)
123 (93)
56 (92)
Lenalidomide
24 (36)
21 (58)
52 (46)
24 (42)
47 (36)
29 (48)
PI
63 (94)
33 (92)
103 (92)
49 (86)
123 (93)
57 (93)
IMiD
33 (49)
26 (72)
82 (73)
39 (68)
90 (68)
45 (74)
Abbreviations: DKd, DARZALEX + carfilzomib + dexamethasone; FISH, fluorescence in situ; IMiD, Immunomodulatory drugs; ISS, International Staging System; Kd, carfilzomib + dexamethasone; LDH, lactate dehydrogenase; PI, proteasome inhibitor.
Excluded patient whose baseline renal impairment with missing value (DKd, n=1; Kd, n=0).
*Revised ISS stage: R-Stage 1 and standard risk group by FISH and morla LDH; R-Stage 2: neither R-ISS stage 1 nor 3; and R-Stage 3: ISS stage 3 and (either high-risk group by FISH or high LDH).
1The high-risk group consisted of the genetic subtypes t(4; 14); t(14; 16), or deletion17p.
Efficacy
  • After a median follow up of approximately 50 months (data cutoff: April 15, 2022), DKd showed consistent clinical benefit irrespective of baseline renal function vs Kd in median PFS, ORR, and OS as detailed within the Table: Efficacy Outcomes by Renal Subgroups.

Efficacy Outcomes by Renal Subgroups4
Parameter
≥15-<60 mL/min
≥60-<90 mL/min
≥90 mL/min
DKd (n=67)
Kd
(n=36)
DKd (n=112)
Kd
(n=57)
DKd (n=132)
Kd
(n=61)
Median PFS, mo (95% CI)
24.9
(13.0-41.8)
8.4
(3.3-32.8)
31.6
(20.3-43.2)
19.9
(11.1-33.2)
27.4
(18.7-35.1)
15.3
(10.8-20.3)
HR, (DKd/KD) (95% CI)
0.61 (0.35-1.06)
0.63 (0.41-0.96)
0.64 (0.43-0.95)
Median OS, mo (95% CI)
44.6
(24.2-NE)
25.2
(12.4-NE)
48.0
(39.4-NE)
43.7
(35.4-NE)
NE
(44.9-NE)
NE
(34.6-NE)
HR, (DKd/KD) (95% CI)
0.58 (0.32-1.03)
0.91 (0.58-1.43)
0.74 (0.46-1.20)
ORR*, n (%)
58 (87)
18 (50)
95 (85)
47 (82)
113 (86)
49 (80)
OR (DKd/Kd) (95% CI)
8.02 (2.84-22.65)
1.26 (0.49-3.27)
1.59 (0.69-3.68)
CR Rate1, n (%)
24 (36)
3 (8)
49 (44)
12 (21)
50 (38)
13 (21)
OR (DKd/Kd) (95% CI)
7.43 (1.85-29.74)
3.17 (1.47-6.87)
2.20 (1.08-4.49)
Treatment duration, wks, median (range)
67
(0-227)
21
(0-222)
90
(1-236)
56
(1-222)
76
(0-236)
47
(1.3-236)
Abbreviations: DKd, DARZALEX + carfilzomib + dexamethasone; FISH, fluorescence in situ; IMiD, Immunomodulatory drugs; ISS, International Staging System; Kd, carfilzomib + dexamethasone; LDH, lactate dehydrogenase; PI, proteasome inhibitor.
Excluded patient whose baseline renal impairment with missing value (DKd, n=1; Kd, n=0).
*ORR is defined as the proportion of intent-to-treat patients who achieve stringent CR, CR, very good partial response, or partial response per the International Myeloma Working Group Uniform Response Criteria (IMWG-URC) as their best response.
1CR rate is defined as the proportion of intent-to-treat patients who achieve stringent CR or CR per International Myeloma Working Group Uniform Response Criteria (IMWG-URC) as their best response.
Safety

Most Common TEAEs by Renal Subgroups4
Most common TEAEs1
≥15-<60 mL/min
≥60-<90 mL/min
≥90 mL/min
DKd (n=66)
Kd
(n=35)
DKd (n=110)
Kd
(n=57)
DKd (n=131)
Kd
(n=61)
Grade ≥3, n (%)
59 (89)
32 (91)
96 (87)
45 (79)
117 (89)
43 (70)
Thrombocytopenia
25 ()38)
8 (23)
23 (21)
10 (18)
28 (21)
7 (11)
Hypertension
16 (24)
7 (20)
24 (22)
13 (23)
32 (24)
7 (11)
Anemia
16 (24)
10 (29)
20 (18)
7 (12)
18 (14)
8 (13)
Pneumonia
15 (23)
3 (9)
20 (18)
6 (11)
22 (17)
5 (8)
TEAEs of interest, n (%)
Respiratory tract infections
21 (32)
5 (14)
46 (42)
11 (19)
49 (37)
11 (18)
Hypertension
17 (26)
7 (20)
25 (23)
14 (25)
32 (24)
7 (11)
Infusion reaction (on same date of any carfilzomib dosing)
9 (14)
4 (11)
16 (15)
5 (9)
22 (17)
3 (5)
Cardiac failure
3 (5)
4 (11)
5 (5)
6 (11)
4 (3)
3 (5)
Viral infection
3 (5)
0
10 (9)
0
9 (7)
3 (5)
Acute renal failure
4 (6)
4 (11)
4 (4)
4 (7)
3 (2)
2 (3)
Dyspnea
6 (9)
1 (3)
4 (4)
2 (4)
6 (5)
1 (2)
Abbreviations: DKd, DARZALEX + carfilzomib + dexamethasone; FISH, fluorescence in situ; Kd, carfilzomib + dexamethasone; TEAE, treatment emergent adverse event.
Excluded patient whose baseline renal impairment with missing value (DKd, n=1; Kd, n=0).
1Grade ≥3 TEAEs include those reported in ≥15% of patients. TEAEs of interest include those reported in ≥5% of patients

Impact of Frailty on Efficacy and Safety in the CANDOR Study

Quach et al (2022)5conducted a subgroup analysis of frailty status in patients in the CANDOR study.

Study Design/Methods

  • Patients were categorized as fit, intermediate (int), or frail based on a frailty score of 0, 1, or ≥2.
  • Scoring used an algorithm based on the International Myeloma Working Group (IMWG) frailty index: the final score is based on age (0 if ≤75 years, 1 if 76-80 years, 2 if >80 years), modified Charlson Comorbidity Index (CCI; 0 if CCI ≤1, 1 if CCI >1), and Easter Cooperative Oncology Group performance status (ECOG PS; 0 if ECOG PS=0, 1 if ECOG PS=1, and 2 if ECOG PS=2).

Results

Patient Characteristics
  • Patients were stratified based on frailty status:
    • Frail patients: 25% vs 27% for DKd vs Kd, respectively.
    • Int patients: 43% vs 36% for DKd vs Kd, respectively.
    • Fit patients: 27% vs 35% for DKd vs Kd, respectively.
  • Median duration of treatment among frailty status:
    • Frail patients: 51 weeks vs 21 weeks for DKd vs Kd, respectively.
    • Int patients: 82 weeks vs 31 weeks for DKd vs Kd, respectively.
    • Fit patients: 99 weeks vs 68 week for DKd vs Kd, respectively.
  • Patients with prior transplant were more prevalent in the DKd vs Kd arms for frail (41% vs 27%) and int (65% vs 36%) subgroups, respectively.
  • Fewer patients among the frail subgroup were lenalidomide exposed (37% vs 61%) and lenalidomide refractory (25% vs 46%) in the DKd vs Kd arm, respectively.
Efficacy
  • Median PFS in DKd vs Kd was 18.5 vs 9.3 months (HR 0.66; 95% CI, 0.38-1.14) for frail patients, not reached vs 11.1 months (HR 0.44; 95% CI, 0.285-0.69) for int patients, not reached vs 17.6 months (HR 0.64; 95% CI, 0.38-1.07) for fit patients.
  • Response rates for DKd vs Kd arms are summarized in the Table: Response Rates.

Response Rates5
Response Rates, n (%)
Frail
Intermediate
Fit
DKd (n=79)
Kd (n=41)
OR
(95% CI)
DKd (n=135)
Kd (n=56)
OR
(95% CI)
DKd (n=84)
Kd (n=54)
OR
(95% CI)
ORR
59 (75)
22 (54)
2.39
(1.09-5.22)
117 (87)
39 (70)
2.95
(1.31-6.62)
75 (89)
48 (89)
1.09
(0.35-3.38)
CR
15 (19)
3 (7)
-
46 (34)
6 (11)
-
37 (44)
9 (17)
-
VGPR
29 (37)
13 (32)
-
52 (39)
18 (32)
-
28 (33)
21 (39)
-
PR
15 (19)
6 (15)
-
19 (14)
15 (27)
-
10 (12)
18 (33)
-
Abbreviations: CR, complete response; DKd, DARZALEX + carfilzomib + dexamethasone; Kd, carfilzomib + dexamethasone; OR, odds ratio; ORR, overall response rate; PR, partial response; VGPR, very good partial response.
Safety

Treatment-Emergent Adverse Events in the Safety Population5
Events, n (%)
Frail
Intermediate
Fit
DKd (n=84)
Kd (n=54)
DKd (n=134)
Kd (n=56)
DKd (n=77)
Kd (n=40)
All TEAEs
 84 (100)
52 (96)
134 (100)
54 (96)
76 (99)
39 (98)
   Grade ≥3 TEAE
73 (87)
38 (70)
113 (84)
40 (71)
70 (91)
36 (90)
   Fatal TEAEa
3 (4)
1 (2)
15 (11)
5 (9)
12 (16)
3 (8)
   Carfilzomib
   discontinuation due to
   TEAE
21 (25)
9 (17)
30 (22)
16 (29)
27 (35)
9 (23)
TEAEs of interest,b grade ≥3
   Acute renal failure
0 (0)
0 (0)
4 (3)
8 (14)
6 (8)
2 (5)
   Cardiac arrhythmias
3 (4)
0 (0)
1 (1)
3 (5)
6 (8)
1 (3)
   Cardiac failure
2 (2)
3 (6)
5 (4)
4 (7)
4 (5)
6 (15)
   Dyspnea
2 (2)
1 (2)
6 (5)
2 (4)
6 (8)
1 (3)
   Hypertension
20 (24)
6 (11)
29 (22)
10 (18)
14 (18)
7 (18)
   Infusion reactionc
13 (16)
1 (2)
18 (13)
2 (4)
11 (14)
5 (13)
   Peripheral neuropathy
5 (6)
0 (0)
1 (1)
0 (0)
0 (0)
0 (0)
   Respiratory tract
   infection
25 (30)
11 (20)
49 (37)
8 (14)
26 (34)
5 (13)
   Viral infection
7 (8)
1 (2)
12 (9)
1 (2)
2 (3)
1 (3)
DARZALEX-related infusion reactiond
2 (2)
0 (0)
2 (2)
0 (0)
3 (4)
0 (0)
Abbreviations: DKd, DARZALEX + carfilzomib + dexamethasone; Kd, carfilzomib + dexamethasone; TEAE, treatment-emergent adverse event.
aIncludes patients with TEAE of disease progression/plasma cell myeloma.
bBy preferred term.
cEvent on same date of any carfilzomib dosing.dEvent on same date or next date of any DARZALEX dosing.

Subgroup Analysis Based on Cytogenetic Risk in the CANDOR Study

Landgren et al (2022)6 reported efficacy results of a subgroup analysis based on cytogenic risk in patients with RRMM in the CANDOR study.

Results


Overall Response Rates of Patients Across Cytogenetic Risk Subgroups6
DKd (n=312)
Kd (n=154)
OR
(95% CI)a
P Value
(2-sided)b
n/N
ORR, %
CR, n (%)
VGFR, n (%)
PR, n (%)
n/N
ORR, %
CR, n (%)
VGFR, n (%)
PR, n (%)
All randomized patients
263/312
84.3
103 (33.0)
113 (36.2)
47 (15.1)
112/154
72.7
20 (13.0)
53 (34.4)
39 (25.3)
2.148
(1.328-3.475)
-
   Cytogenetic risk group
      High riskc
56/69
81.2
16 (23.2)
26 (37.7)
14 (20.3)
20/36
55.6
0
11 (30.6)
9 (25.0)
3.73
(1.348-8.440)
0.5775
      Standard riskd
154/178
86.5
62 (34.8)
68 (38.2)
24 (13.5)
78/99
78.8
18 (18.2)
34 (34.3)
26 (26.3)
1.864
(0.958-3.624)
-
      Unknowne
53/65
81.5
25 (38.5)
19 (29.2)
9 (13.8)
14/19
73.7
2 (10.5)
8 (42.1)
4 (21.1)
2.679
(0.677-10.610)
-
With prior lenalidomide exposure
   All Patients
97/123
78.9
38 (30.9)
41 (33.3)
18 (14.6)
53/74
71.6
8 (10.8)
28 (37.8)
17 (23.0)
1.565
(0.782-3.132)
-
   Cytogenetic risk group
      High riskc
22/26
84.6
7 (26.9)
9 (34.6)
6 (23.1)
10/15
66.7
0
6 (40.0)
4 (26.7)
3.012
(0.635-14.290)
0.6809
      Standard riskd
57/72
79.2
22 (30.6)
26 (36.1)
9 (12.5)
38/52
73.1
6 (11.5)
19 (36.5)
13 (25.0)
1.437
(0.611-3.380)
-
      Unknowne
18/25
72.0
9 (36.0)
6 (24.0)
3 (12.0)
5/7
71.4
2 (28.6)
3 (42.9)
0
1.178
(0.136-10.172)
-
Without prior lenalidomide exposure
   All Patients
166/189
87.8
65 (34.4)
72 (38.1)
29 (15.3)
59/80
73.8
12 (15.0)
25 (31.3)
22 (27.5)
2.770
(1.395-5.501)
-
   Cytogenetic risk group
      High riskc
34/43
79.1
9 (20.9)
17 (39.5)
8 (18.6)
10/21
47.6
0
5 (23.8)
5 (23.8)
3.650
(1.155-11.535)
0.7284
      Standard riskd
97/106
91.5
40 (37.7)
42 (39.6)
15 (14.2)
40/47
85.1
12 (25.5)
15 (31.9)
13 (27.7)
2.049
(0.671-6.259)
-
      Unknowne
35/40
87.5
16 (40.0)
13 (32.5)
6 (15.0)
9/12
75.0
0
5 (41.7)
4 (33.3)
4.028
(0.577-28.112)
-
Abbreviations: CI, confidence interval; CR, complete response; DKd, DARZALEX + carfilzomib + dexamethasone; FISH, fluorescent in-situ hybridization; Kd, carfilzomib + dexamethasone; OR, odds ratio; ORR, overall response rate; PR, partial response; VGPR, very good partial response.
aOdds ratio and corresponding 95% CIs were estimated using a stratified Mantel-Haenszel method as specified.
bP values were calculated using Gail and Simon quantitative interaction tests.
cIncludes patients who have any mutation of t(4;14), t(14;16); or deletion 17p13, while the other test may be unknown.
dIncludes patients who have valid results without evidence of mutation of t(4;14), t(14;16); or deletion 17p13, while the other test may be unknown.
eIncludes patients without FISH or seqFISH results, or with failed or insufficient sample quantity.

Summary of Cytogenetic Risk Groups15
DKd (n=312)
Kd (n=154)
Total (n=466)
Patients with samples tested and valid results, n (%)
247 (79.2)
135 (87.7)
382 (82.0)
High riska
69 (22.1)
36 (23.4)
105 (22.5)
   t(4; 14)
28 (9.0)
15 (9.7)
43 (9.2)
   t(14; 16)
3 (1.0)
3 (1.9)
6 (1.3)
   del(17p13)
44 (14.1)
23 (14.9)
67 (14.4)
Standard riskb
178 (57.1)
99 (64.3)
277 (59.4)
Unknownc
65 (20.8)
19 (12.3)
84 (18.0)
Abbreviations: DKd, DARZALEX + carfilzomib + dexamethasone; FISH, fluorescent in-situ hybridization; Kd, carfilzomib + dexamethasone.
aIncludes genetic subtypes t(4;14); t(14;16); or del(17p13).
bIncludes patients without t(4;14); t(14;16); or del(17p13).
cIncludes patients without FISH or seqFISH results, or with failed or insufficient sample quantity.

PFS Hazard Ratios Across Cytogenetic Risk Groups6
DKd (n=312)
Kd (n=154)
HR
(95% CI)b
P value (2-sided)c
n/N (%)
Median PFS
(95% CI),a months
n/N (%)
Median PFS
(95% CI),a months
All randomized patients
140/312 (44.9)
28.6 (22.7-NE)
85/154 (55.2)
15.2 (11.1-19.9)
0.59 (0.45-0.78)
   Cytogenetic risk group
0.7575
      High riskd
45/69 (65.2)
11.2 (6.5-17.0)
26/36 (72.2)
7.4 (3.3-11.1)
0.56 (0.37-0.93)
      Standard riske
69/178 (38.8)
NE (26.3-NE)
51/99 (51.5)
16.6 (12.3-28.0)
0.56 (0.39-0.80)
      Unknownf
26/65 (40.0)
NE (21.7-NE)
8/19 (42.1)
NE (9.9-NE)
0.79 (0.33-1.88)
With prior lenalidomide exposure
   All Patients
57/123 (46.3)
25.9 (20.3-NE)
47/74 (63.5)
11.1 (7.6-14.9)
0.49 (0.33-0.74)
   Cytogenetic risk group
0.4867
      High riskd
14/26 (53.8)
22.6 (6.5-NE)
12/15 (80.0)
9.3 (3.3-12.0)
0.35 (0.15-0.83)
      Standard riske
32/72 (44.4)
28.1 (18.5-NE)
32/52 (61.5)
12.3 (7.6-15.7)
0.51 (0.31-0.85)
      Unknownf
11/25 (44.0)
NE (4.2-NE)
3/7 (42.9)
21.7 (2.1-NE)
0.93 (0.24-3.59)
Without prior lenalidomide exposure
   All Patients
83/189 (43.9)
NE (19.2-NE)
38/80 (47.5)
21.3 (14.6-NE)
0.64 (0.43-0.96)
   Cytogenetic risk group
0.9421
      High riskd
31/43 (72.1)
10.3 (5.8-16.8)
14/21 (66.7)
4.7 (1.9-19.9)
0.73 (0.37-1.42)
      Standard riske
37/106 (34.9)
NE (27.4-NE)
19/47 (40.4)
28.0 (16.6-NE)
0.63 (0.35-1.13)
      Unknownf
15/40 (37.5)
NE (18.7-NE)
5/12 (41.7)
NE (7.4-NE)
0.72 (0.22-2.32)
Abbreviations: CI, confidence interval; DKd, DARZALEX + carfilzomib + dexamethasone; FISH, fluorescent in-situ hybridization; Kd, carfilzomib + dexamethasone; NE, not estimable; PD, progressive disease; PFS, progression free survival.
aPFS is defined as time (in months) from randomization until PD or death due to any cause, whichever occurs first; medians were estimated using Kaplan-Meier method. Corresponding 95% CIs were estimated.
bHazard ratios and corresponding 95% CIs were estimated using a stratified Cox proportional hazards model as specified.
cP values were calculated using Gail and Simon quantitative interaction test.
dIncludes patients who have any mutation t(4;14), t(14;16); or deletion 17p13.eIncludes patients who have valid results without evidence of mutation of t(4;14), t(14;16), or deletion 17p13, while the other test may be unknown.
fIncludes patients without FISH or seqFISH results, or with failed or insufficient sample quantity.

Subgroup Analysis by Prior Lines of Therapy

Quach et al (2021)7,16 reported the results of a subgroup analysis by prior lines of therapy at a median follow-up of approximately 17 months.

Results

Patient Characteristics


Baseline Characteristics by Number of Prior Lines of Therapy16
Characteristic 
1 Prior Line
≥2 Prior Lines
DKd (n=133)
Kd (n=67)
DKd (n=179)
Kd (n=87)
Median age (range), years
63.0 (29-83)
66.0 (35-81)
65.0 (33-84)
63.0 (35-83)
ISS stage, n (%)
   I
64 (48.1)
35 (52.2)
83 (46.4)
44 (50.6)
   II
45 (33.8)
21 (31.3)
58 (32.4)
27 (31.0)
   III
23 (17.3)
11 (16.4)
38 (21.2)
16 (18.4)
   Unknown
1 (0.8)
0
0
0
Cytogenetic risk by FISH, n (%)
   High riska
24 (18.0)
11 (16.4)
24 (13.4)
15 (17.2)
   Standard riskb
45 (33.8)
23 (34.3)
59 (33.0)
29 (33.3.)
   Unknownc
64 (48.1)
33 (49.3)
96 (53.6)
43 (49.4)
Median prior lines of therapy (range)
1.0 (1-2)
1.0 (1-1)
2.0 (1-3)
2.0 (1-4)
Prior therapies, n (%)
   Bortezomib or ixazomib
117 (88.0)
55 (82.1)
172 (96.1)
82 (94.3)
      Refractory to bortezomib
      or ixazomibd
21 (15.8)
14 (20.9)
79 (44.1)
41 (47.1)
   Lenalidomide
29 (21.8)
17 (25.4)
94 (52.5)
57 (65.5)
      Refractory to lenalidomide
19 (14.3)
6 (9.0)
80 (44.7)
49 (56.3)
Abbreviations: DKd, DARZALEX + carfilzomib + dexamethasone; FISH, fluorescence in-situ hybridization; ISS, International Staging System; Kd, carfilzomib + dexamethasone.aGenetic subtypes t(4;14), t(14;16), or del(17p).bPatients without t(4;14), t(14;16), and del(17p).cPatients with FISH not done, failed, or of insufficient quantity.dFive patients in the prior bortezomib/ixazomib subgroups were exposed to ixazomib (DKd, n=2; Kd, n=3)

Baseline Characteristics of Patients Either Refractory to Lenalidomide or Bortezomib/Ixazomib16
Characteristic
Lenalidomide-Refractory
Bortezomib/Ixazomib-Refractory
DKd (n=99)
Kd (n=55)
DKd (n=100)
Kd (n=55)
Median age (range), years
65.0 (37-83)
64.0 (35-82)
64.0 (33-84)
64.0 (36-77)
ISS stage, n (%)
   I
53 (53.5)
27 (49.1)
43 (43.0)
27 (49.1)
   II
29 (29.3)
18 (32.7)
29 (29.0)
15 (27.3)
   III
17 (17.2)
10 (18.2)
28 (28.0)
13 (23.6)
   Unknown
0
0
0
0
Cytogenetic risk by FISH, n (%)
   High riska
13 (13.1)
8 (14.5)
14 (14.0)
11 (20.0)
   Standard riskb
29 (29.3)
23 (41.8)
33 (33.0)
19 (34.5)
   Unknownc
57 (57.6)
24 (43.6)
53 (53.0)
25 (45.5)
Median prior lines of therapy (range)
2.0 (1-3)
2.0 (1-3)
2.0 (1-3)
2.0 (1-4)
Prior therapies, n (%)
   Bortezomib or
   ixazomib
96 (97.0)
50 (90.9)
100 (100.0)
55 (100.0)
      Refractory to
      bortezomib or
      ixazomibd
43 (43.4)
22 (40.0)
100 (100.0)
55 (100.0)
   Lenalidomide
99 (100.0)
55 (100.0)
46 (46.0)
29 (52.7)
      Refractory to
      lenalidomide
99 (100.0)
55 (100.0)
43 (43.0)
22 (40.0)
Abbreviations: DKd, DARZALEX + carfilzomib + dexamethasone; FISH, fluorescence in-situ hybridization; ISS, International Staging System; Kd, carfilzomib + dexamethasone.aGenetic subtypes t(4;14), t(14;16), or del(17p).bPatients without t(4;14), t(14;16), and del(17p).cPatients with FISH not done, failed, or of insufficient quantity.dFive patients in the prior bortezomib/ixazomib subgroups were exposed to ixazomib (DKd, n=2; Kd, n=3).

Efficacy


Progression-Free Survival in Prior Treatment Subgroups7
Subgroup
DKd (n=312)
Kd (n=67)
HR for DKd vs Kd
(95% CI)
P value (two-sided)
Events/ Patients
Median (95% CI), months
Events/ Patients
Median (95% CI), months
All patients
110/312
NE (NE-NE)
68/154
15.8 (12.1-NE)
0.630
(0.464-0.854)
Number of prior lines of therapy
0.7230
   1
39/133
NE (NE-NE)
23/67
NE (11.1-NE)
0.679
(0.404-1.142)
   ≥2
71/179
NE (17.0-NE)
45/87
14.9 (9.3-17.5)
0.605
(0.415-0.881)
Prior lenalidomide exposure
0.3656
   Yes
44/123
NE (18.5-NE)
40/74
12.1 (8.4-15.3)
0.529
(0.342-0.818)
   No
66/189
NE (NE-NE)
28/80
NE (15.8-NE)
0.708
(0.448-1.120)
Refractory to lenalidomide
0.1772
   Yes
34/99
NE (18.5-NE)
32/55
11.1 (7.4-14.9)
0.474
(0.288-0.781)
   No
76/213
NE (NE-NE)
36/99
NE (15.7-NE)
0.738
(0.492-1.108)
Prior bortezomib/ixazomib exposurea
0.9262
   Yes
105/289
NE (NE-NE)
63/137
15.3 (11.1-NE)
0.619
(0.452-0.849)
   No
5/23
NE (NE-NE)
5/17
NE (11.1-NE)
0.583
(0.165-2.055)
Refractory to bortezomib/ixazomib
0.1510
   Yes
48/100
14.2 (9.2-NE)
26/55
14.9 (6.5-NE)
0.840
(0.518-1.361)
   No
62/212
NE (NE-NE)
42/99
17.5 (12.3-NE)
0.531
(0.357-0.790)
Abbreviations: CI, confidence interval; DKd, DARZALEX + carfilzomib + dexamethasone; HR, hazard ratio; Kd, carfilzomib + dexamethasone; NE, not estimable.aFive patients in the prior bortezomib/ixazomib subgroups were exposed to ixazomib (DKd, n=2; Kd, n=3).

ORR and MRD-Negative CR by Number of Prior Lines of Therapy7
Response, %
1 Prior Line of Therapy
≥2 Prior Lines of Therapy
DKd (n=133)
Kd (n=67)
Odds Ratio (95% CI)
P value
DKd (n=179)
Kd (n=87)
Odds Ratio (95% CI)
P value
ORR
90.2
76.1
2.90
(1.30-6.46)
0.0052
79.9
73.6
1.43
(0.78-2.60)
0.1360
MRD-negative CR
16.5
1.5
13.08
(1.72-99.31)
0.0004
9.5
1.1
9.03
(1.18-68.97)
0.0044
Abbreviations: CI, confidence interval; CR, complete response; DKd, DARZALEX + carfilzomib + dexamethasone; Kd, carfilzomib + dexamethasone; MRD, minimal residual disease; ORR, overall response rate.

ORR and MRD-Negative CR by Prior Lenalidomide Exposure7
Response, %
Prior Lenalidomide Exposure
No Prior Lenalidomide Exposure
DKd (n=123)
Kd (n=74)
Odds Ratio (95% CI)
P value
DKd (n=189)
Kd (n=80)
Odds Ratio (95% CI)
P value
ORR
78.9
74.3
1.29
(0.65-2.54)
0.2434
87.8
75.0
2.41
(1.23-4.69)
0.0055
MRD-negative CR
11.4
0.0
NE
(NE-NE)
NE
13.2
2.5
5.95
(1.37-25.74)
0.0034
Abbreviations: CI, confidence interval; CR, complete response; DKd, DARZALEX + carfilzomib + dexamethasone; Kd, carfilzomib + dexamethasone; MRD, minimal residual disease; NE, not estimable; ORR, overall response rate.

ORR and MRD-Negative CR by Lenalidomide Refractory Status7
Response, %
Lenalidomide Refractory
Lenalidomide Non-refractory
DKd (n=123)
Kd (n=74)
Odds Ratio (95% CI)
P value
DKd (n=189)
Kd (n=80)
Odds Ratio (95% CI)
P value
ORR
79.8
72.7
1.48
(0.69-3.20)
0.1617
86.4
75.8
-
0.0118
MRD-negative CR
13.1
0.0
NE
(NE-NE)
NE
12.2
2.0
-
0.0012
Abbreviations: CI, confidence interval; CR, complete response; DKd, DARZALEX + carfilzomib + dexamethasone; Kd, carfilzomib + dexamethasone; MRD, minimal residual disease; NE, not estimable; ORR, overall response rate.

ORR and MRD-negative CR by Prior Bortezomib/Ixazomib Exposure7
Response, %
Prior Bortezomib/Ixazomib Exposure
No Prior Bortezomib/Ixazomib Exposure
DKd (n=123)
Kd (n=74)
Odds Ratio (95% CI)
P value
DKd (n=189)
Kd (n=80)
Odds Ratio (95% CI)
P value
ORR
83.4
73.7
1.79
(1.10-2.92)
0.0131
95.7
82.4
4.71
(0.45-49.94)
0.1470
MRD-negative CR
11.8
1.5
9.00
(2.13-38.03)
<0.0001
21.7
0.0
NE
(NE-NE)
NE
Abbreviations: CI, confidence interval; CR, complete response; DKd, DARZALEX + carfilzomib + dexamethasone; Kd, carfilzomib + dexamethasone; MRD, minimal residual disease; NE, not estimable; ORR, overall response rate.

ORR and MRD-negative CR by Bortezomib/Ixazomib Refractory Status7
Response, %
Bortezomib/Ixazomib Refractory
Bortezomib/Ixazomib Non-refractory
DKd (n=123)
Kd (n=74)
Odds Ratio (95% CI)
P value
DKd (n=189)
Kd (n=80)
Odds Ratio (95% CI)
P value
ORR
79.0
69.1
1.68
(0.80-3.55)
0.0890
86.8
77.8
-
0.0241
MRD-negative CR
7.0
1.8
4.07
(0.49-33.93)
0.1304
15.1
1.0
-
<0.0001
Abbreviations: CI, confidence interval; CR, complete response; DKd, DARZALEX + carfilzomib + dexamethasone; Kd, carfilzomib + dexamethasone; MRD, minimal residual disease; ORR, overall response rate.

Safety


Treatment Exposure by Subgroup7
1 Prior Line
≥2 Prior Lines
Lenalidomide-Refractory
Bortezomib/ Ixazomib-Refractory
DKd (n=131)
Kd (n=66)
DKd (n=117)
Kd (n=87)
DKd (n=98)
Kd (n=55)
DKd (n=99)
Kd
(n=55)
Median duration of treatment, weeks (range)
71.4
(0.3-103.1)
47.0
(1.3-88.4)
65.4
(0.3-97.4)
36.3
(0.3-97.4)
69.3
(0.3-98.3)
34.3
(0.3-97.1)
47.3
(0.3-96.3)
33.3
(1.3-97.3)
Abbreviations: DKd, DARZALEX + carfilzomib + dexamethasone; Kd, carfilzomib + dexamethasone.

Safety Summary by Number of Prior Lines of Therapy16
Characteristic, n (%)
1 Prior Line
≥2 Prior Lines
DKd (n=131)
Kd (n=66)
DKd (n=177)
Kd (n=87)
Any AE
129 (98.5)
63 (95.5)
177 (100.0)
84 (96.6)
   Grade ≥3 AE
108 (82.4)
49 (74.2)
145 (81.9)
64 (73.6)
   Serious AE
74 (56.5)
31 (47.0)
99 (55.9)
39 (44.8)
   Fatal AE
9 (6.9)
4 (6.1)
21 (11.9)
4 (4.6)
Carfilzomib discontinuation due to AEs
30 (22.9)
16 (24.2)
35 (19.8)
17 (19.5)
DARZALEX discontinuation due to AEs
12 (9.2)
0
16 (9.0)
0
Abbreviations: AE, adverse event; DKd, DARZALEX + carfilzomib + dexamethasone; Kd, carfilzomib + dexamethasone.

Safety Summary by Refractory Status to Lenalidomide or Bortezomib/Ixazomib16
Characteristic, n (%)
Lenalidomide-refractory
Bortezomib/Ixazomib-refractory
DKd (n=98)
Kd (n=55)
DKd (n=99)
Kd (n=55)
Any AE
98 (100.0)
53 (96.4)
99 (100.0)
53 (96.4)
Grade ≥3 AE
81 (82.7)
41 (74.5)
80 (80.8)
41 (74.5)
Serious AE
53 (54.1)
26 (47.3)
57 (57.6)
24 (43.6)
Fatal AE
11 (11.2)
4 (7.3)
15 (15.2)
3 (5.5)
Carfilzomib discontinuation due to AEs
19 (19.4)
13 (23.6)
17 (17.2)
6 (10.9)
DARZALEX discontinuation due to AEs
8 (8.2)
0
10 (10.1)
0
Abbreviations: AE, adverse event; DKd, DARZALEX + carfilzomib + dexamethasone; Kd, carfilzomib + dexamethasone.

Subgroup Analysis by Prior ASCT

Mateos et al (2021)8 presented the efficacy and safety results of DKd vs Kd in patients with RRMM with or without prior ASCT subdivided by lenalidomide-refractory and/or lenalidomide-exposed status.

Results

  • Overall, 269 patients (DKd arm, n=194; Kd arm, n=75) received prior ASCT.
Efficacy

PFS in Patients With and Without Prior ASCT8
Parameter
Prior ASCT
Without Prior ASCT
Overall
LEN-exposed
LEN-refractory
Overall
LEN-exposed
LEN-refractory
PFS HR (95% CI)
0.54
(0.37-0.77)
0.35
(0.20-0.61)
0.30
(0.15-0.59)
0.68
(0.44-1.05)
0.62
(0.33-1.15)
0.62
(0.31-1.22)
2-year PFS rate - DKd arm, %
55
57
57
55
53
54
2-year PFS rate - Kd arm, %
31
15
12
44
41
39
Abbreviations: ASCT, autologous stem cell transplantation; CI, confidence interval; DKd, DARZALEX + carfilzomib + dexamethasone; HR, hazard ratio; Kd, carfilzomib + dexamethasone; LEN, lenalidomide; PFS, progression-free survival.
Safety
  • In the DKd vs Kd arms:
    • Grade ≥3 AEs were reported in 89.6% vs 78.7% of patients with prior ASCT and 82.8% vs 73.1% of patients without prior ASCT, respectively, with consistent rates across lenalidomide subgroups.
    • TEAEs leading to treatment discontinuation were reported in 28.6% vs 21.3% of patients with prior ASCT and 25.9% vs 28.2% of patients without prior ASCT, respectively.

Subgroup Analysis in Asian Patients

Suzuki et al (2021)9 reported the efficacy and safety results of DKd vs Kd from a post hoc analysis of the CANDOR study conducted in Asian patients with RRMM.

Results

Patient Characteristics

Baseline Patient and Disease Characteristics9
Characteristic
DKd (n=312)
Kd (n=154)
Total (N=66)
Median age (range), years
64 (32.0-80.0)
66 (50.0-77.0)
 65 (32.0-80.0)
Male, n (%)
26 (56.5)
12 (60.0)
 38 (57.6)
ECOG performance status, n (%)
   0 or 1
46 (100.0)
19 (95.0)
65 (98.5)
   2
0 (0.0)
1 (5.0)
1 (1.5)
ISS stagea at baseline, n (%)
   I
32 (69.6)
13 (65.0)
45 (68.2)
   II
13 (28.3)
3 (15.0)
16 (24.2)
   III
1 (2.2)
4 (20.0)
5 (7.6)
Cytogenetics,b n (%)
   High-risk
8 (17.4)
5 (25.0)
13 (19.7)
   Standard-risk
15 (32.6)
12 (60.0)
27 (40.9)
   Missing or unknown
23 (50.0)
3 (15.0)
26 (39.4)
Number of patients by prior lines of therapy, n (%)
   1
24 (52.2)
8 (40.0)
32 (48.5)
   2
14 (30.4)
4 (20.0)
18 (27.3)
   3
8 (17.4)
8 (40.0)
16 (24.2)
Prior therapies, n (%)
   Transplant
31 (67.4)
13 (65.0)
44 (66.7)
   PI
40 (87.0)
16 (80.0)
56 (84.8)
   IMiD
38 (82.6)
19 (95.0)
57 (86.4)
   Bortezomib
40 (87.0)
16 (80.0)
56 (84.8)
      Refractoryc to prior bortezomib
13 (28.3)
11 (55.0)
24 (36.4)
   Lenalidomide
20 (43.5)
10 (50.0)
30 (45.5)
      Refractoryc to prior lenalidomide
16 (34.8)
7 (35.0)
23 (34.8)
   PI-including and IMiD-including regimen
33 (71.7)
15 (75.0)
48 (72.7)
      Refractoryc to prior PI-including and IMiD-
      including regimen
10 (21.7)
8 (40.0)
18 (27.3)
Abbreviations: DKd, DARZALEX + carfilzomib + dexamethasone; ECOG, Eastern Cooperative Oncology Group; IMiD, immunomodulatory drug; ISS, International Staging System; Kd, carfilzomib + dexamethasone; PI, proteasome inhibitor.aISS stage: stage 1, beta-2 microglobulin < 3.5 mg/L and albumin ≥ 3.5 g/dL; stage 2, neither stage 1 nor 3; stage 3, beta-2 microglobulin ≥ 5.5 mg/L.bThe high-risk group consists of the genetic subtypes t(4;14), t(14;16), or deletion 17p and the standard-risk group consists of patients without t(4;14), t(14;16), and deletion 17p.cPatients were considered refractory to a drug received in prior regimens if any of the following criteria were met: best response to any regimen containing the drug was stable disease or progressive disease, reason for treatment discontinuation was progression in any regimen, date of relapse/progression was after start date and within 60 days after stop date of the drug in any regimen.
Efficacy
  • HR for progression or death observed in the Asian subgroup (HR, 0.750; 95% CI, 0.259-2.168) was consistent with that observed in the overall CANDOR trial (HR, 0.630; 95% CI, 0.464-0.854). Efficacy outcomes are summarized in the Table: Efficacy Outcomes in the Asian Subgroup.

Efficacy Outcomes in the Asian Subgroup9
Parameter
DKd (n=46)
Kd (n=20)
HR for progression or death (95% CI)
0.750 (0.259-2.168)
Median PFS
NE
NE
ORR, % (95% CI)
93.5 (82.1-98.6)
75.0 (50.9-91.3)
   Odds ratio (95% CI)
2.150 (0.321-14.386)
Best overall response, n (%)
   CR
21 (45.7)
3 (15.0)
      Odds ratio(95% CI)
3.756 (0.940-15.006)
      MRD-negative CRa
11 (23.9)
2 (10.0)
   VGPR
18 (39.1)
8 (40.0)
   PR
4 (8.7)
4 (20.0)
   NR
2 (4.3)
3 (15.0)
   PD
1 (2.2)
0 (0.0)
   NE
0 (0.0)
2 (10.0)
MRD-negative CRa rate at 12 months, % (95% CI)
19.6 (9.4-33.9)
5.0 (0.1-24.9)
   Odds ratio (95% CI)
3.525 (0.408-30.463)
Mean (SD) time to overall response,b months
1.2 (0.3)
1.5 (0.7)
Median time to overall response,b months
1.0
1.1
Mean (SD) time to CR,c months
8.1 (3.2)
5.6 (2.3)
Median time to CR,c months
7.7
5.6
Median (95% CI) duration of overall response, months
NE (NE-NE)
NE (7.4-NE)
Abbreviations: CI, confidence interval; CR, complete response; DKd, DARZALEX + carfilzomib + dexamethasone; HR, hazard ratio; IMWG-URC, International Myeloma Working Group Uniform Response Criteria; Kd, carfilzomib + dexamethasone; MRD, minimal residual disease; NE, not estimable; NGS, next-generation sequencing; NR, no response (same as stable disease); ORR, overall response rate; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, standard deviation; VGPR, very good partial response.aDefined as achievement of CR per IMWG-URC by independent review committee and MRD-negative status as assessed by NGS at a 10-5 level.bTime to overall response is defined as the time from randomization to the earliest of CR, VGPR, or PR per IMWG-URC.cTime to CR is defined as the time from randomization to the earliest of CR per IMWG-URC.
Safety
  • The safety population included all patients who received at least 1 dose of study treatment. TEAEs are summarized in Tables: Summary of Any Grade (≥20%) or Grade ≥3 (>5%) TEAEs and TEAEs of Interest.
  • Overview of exposure-adjusted rate of TEAEs in the Asian subgroup is summarized in the Table: Exposure-Adjusted Rate of TEAEs.
  • Treatment-emergent fatalities were reported in 2 patients in the DKd arm due to infections, of which one was due to pneumonia (not related to DKd) and the other due to septic shock (related to carfilzomib and DARZALEX).

Summary of Any Grade (≥20%) or Grade ≥3 (>5%) TEAEs9
Events, n (%)
DKd (n=46)
Kd (n=20)
Any Grade
Grade ≥3
Any Grade
Grade ≥3
TEAEs
46 (100.0)
44 (95.7)
20 (100.0)
18 (90.0)
Hematologic TEAEs
   Thrombocytopenia
27 (58.7)
23 (50.0)
11 (55.0)
6 (30.0)
   Anemia
23 (50.0)
15 (32.6)
7 (35.0)
4 (20.0)
   Lymphopenia
18 (39.1)
18 (39.1)
9 (45.0)
8 (40.0)
   Neutropenia
11 (23.9)
10 (21.7)
4 (20.0)
3 (15.0)
   Leukopenia
11 (23.9)
6 (13.0)
3 (15.0)
2 (10.0)
Nonhematologic TEAEs
   Hypertension
20 (43.5)
9 (19.6)
7 (35.0)
5 (25.0)
   Diarrhea
19 (41.3)
2 (4.3)
8 (40.0)
1 (5.0)
   Upper respiratory tract infection
18 (39.1)
1 (2.2)
6 (30.0)
1 (5.0)
   Insomnia
16 (34.8)
1 (2.2)
6 (30.0)
1 (5.0)
   Nasopharyngitis
14 (30.4)
0 (0.0)
4 (20.0)
1 (5.0)
   Nausea
14 (30.4)
NA
1 (5.0)
NA
   Fatigue
13 (28.3)
5 (10.9)
3 (15.0)
2 (10.0)
   Vomiting
13 (28.3)
NA
2 (10.0)
NA
   Decreased appetite
12 (26.1)
1 (2.2)
2 (10.0)
0 (0.0)
   Headache
12 (26.1)
NA
6 (30.0)
NA
   Pneumonia
11 (23.9)
9 (19.6)
3 (15.0)
2 (10.0)
   Pyrexia
11 (23.9)
NA
8 (40.0)
NA
   Constipation
8 (17.4)
NA
5 (25.0)
NA
   Cataract
6 (13.0)
3 (6.5)
3 (15.0)
2 (10.0)
   Dyspnea
6 (13.0)
0 (0.0)
4 (20.0)
1 (5.0)
   Hyperglycemia
3 (6.5)
2 (4.3)
3 (15.0)
2 (10.0)
   Muscular weakness
2 (4.3)
2 (4.3)
4 (20.0)
0 (0.0)
   Cardiac failure congestive
2 (4.3)
0 (0.0)
2 (10.0)
2 (10.0)
   Acute kidney injury
1 (2.2)
0 (0.0)
2 (10.0)
2 (10.0)
Abbreviations: DKd, DARZALEX + carfilzomib + dexamethasone; Kd, carfilzomib + dexamethasone; NA, not applicable; TEAE, treatment-emergent adverse event.

TEAEs of Interest9
Events, n (%)
DKd (n=46)
Kd (n=20)
Any Grade
Grade ≥3
Any Grade
Grade ≥3
TEAEs of interest
46 (100.0)
41.0 (89.1)
19 (95.0)
16 (80.0)
   Respiratory tract infections
38 (82.6)
12 (26.1)
11 (55.0)
4 (20.0)
   IRR (event on same day as any
   carfilzomib dosing)
30 (65.2)
6 (13.0)
9 (45.0)
1 (5.0)
   Hematopoietic thrombocytopenia
27 (58.7)
24 (52.2)
12 (60.0)
6 (30.0)
   Hematopoietic leukopenia
25 (54.3)
25 (54.3)
10 (50.0)
9 (45.0)
   Hematopoietic erythropenia
23 (50.0)
15 (32.6)
7 (35.0)
4 (20.0)
   Hypertension
21 (45.7)
9 (19.6)
7 (35.0)
5 (25.0)
   DARZALEX-related infusion reactiona
12 (26.1)
0 (0.0)
2 (4.3)
0 (0.0)
   Viral infections
9 (19.6)
2 (10.0)
2 (4.3)
0 (0.0)
   Peripheral neuropathy
9 (19.6)
NA
1 (5.0)
NA
   Dyspnea
9 (19.6)
0 (0.0)
4 (20.0)
1 (5.0)
   Cardiac arrhythmiasa
3 (6.5)
1 (2.2)
1 (5.0)
0 (0.0)
   Cardiac failurea
3 (6.5)
0 (0.0)
3 (15.0)
3 (15.0)
   Acute renal failurea
2 (4.3)
0 (0.0)
3 (15.0)
3 (15.0)
   Ischemic heart diseasea
0 (0.0)
0 (0.0)
2 (10.0)
1 (5.0)
Abbreviations: DKd, DARZALEX + carfilzomib + dexamethasone; IRR, infusion-related reaction; Kd, carfilzomib + dexamethasone; NA, not applicable; TEAE, treatment-emergent adverse event.aEvent on same day or next day of any DARZALEX dosing.

Exposure-Adjusted Rate of TEAEs9
TEAEs
DKd (n=46)
Kd (n=20)
Risk Ratio in DKd vs Kd arms
Total number of patients with events (%)
Total patient-yearsa
Exposure-adjusted risk estimate (95% CI)b
Total number of patients with events (%)
Total patient-yearsa
Exposure-adjusted risk estimate (95% CI)b
Grade ≥3
44 (95.7)
5.5
801.55
(596.49-1077.09)
18 (90.0)
3.0
590.17
(371.83-936.72)
1.4
Serious
27 (58.7)
31.2
86.65
(59.42-126.35)
8 (40.0)
13.4
59.83
(29.92-119.63)
1.4
Fatal
2 (4.3)
49.2
4.07
(1.02-16.26)
0 (0.0)
17.2
0.00
(NE-NE)
NE
Abbreviations: CI, confidence interval; DKd, DARZALEX + carfilzomib + dexamethasone; Kd, carfilzomib + dexamethasone; NE, not estimable; TEAE, treatment-emergent adverse event.
aTotal patient-years is the sum of the time to first TEAE for all patients in each treatment group. If a patient has no event, then the entire exposure time to study treatment is considered in the sum.
bPer 100 patient-years.

PRO Data in Patients in CANDOR Study

Siegel et al (2021)10 reported the results of PRO data collected during treatment.

Results

  • GHS/QoL completion rates were >81% in both arms for randomized patients who remained on treatment from baseline through Cycle 26.
  • Overall, the least squares mean estimate (95% CI) of the difference between the two treatment arms was 0.06 (-2.39 to 2.50).
  • From Cycle 7-26, higher GHS/QoL scores were observed with DKd vs Kd and mean differences in GHS/QoL scores increased between treatment arms. See Table: Least Squares Mean Estimate Over Time in Change from Baseline GHS/QoL Score.
  • The percentage of PRO responders (calculated as the proportion of subjects who had an improvement of ≥10 points in GHS/QoL score from baseline) for DKd vs Kd overall was 55.5% vs 43.0%, respectively (OR, 1.65; 95% CI, 1.10-2.45).

Least Squares Mean Estimate Over Time in Change From Baseline GHS/QoL Score10
Time Point
Least Squares Mean Estimate
Mean difference in score (DKd vs Kd)
95% CI
DKd (n=281)
Kd (n=128)
Cycle 3
0.78
1.35
-0.57
-3.14 to 2.01
Cycle 6
1.34
1.43
-0.10
-2.55 to 2.35
Cycle 9
1.89
1.52
0.37
-2.10 to 2.84
Cycle 12
2.45
1.61
0.84
-1.81 to 3.49
Cycle 15
3.00
1.69
1.31
-1.63 to 4.25
Cycle 18
3.55
1.78
1.78
-1.55 to 5.11
Cycle 21
4.11
1.86
2.25
-1.53 to 6.02
Cycle 24
4.66
1.95
2.72
-1.55 to 6.98
Overall
1.95
1.89
0.06
-2.39 to 2.50
Abbreviations: CI, confidence interval; DKd, DARZALEX + carfilzomib + dexamethasone; GHS/QoL, Global Health Status/Quality of Life; Kd, carfilzomib + dexamethasone.

MRD-Negative CR and Best Overall MRD-Negative Results of CANDOR

Landgren et al (2020)12 presented results from a post-hoc analyses of the best overall MRD-negative status at any time point and MRD-negative CR at various cutoffs from the CANDOR study.


Summary of MRD-Negative Rates in Key Secondary and Exploratory Analyses12
Rate Type, %
DKd
Kd
OR
(95% CI)
P value
(1-sided)a
Best overall MRD-negative rate at any time
22.8
5.8
5.15
<0.0001
12-month MRD-negative rate
17.6
3.9
5.8
(2.4-14.0)
<0.0001
Best overall MRD-negative CR rate at any time
13.8
3.2
4.95
<0.0001
12-month MRD-negative CR rateb
12.5
1.3
11.3
(2.7-47.5)
<0.0001
Abbreviations: CI, confidence interval; CR, complete response; DKd, DARZALEX + carfilzomib + dexamethasone; Kd, carfilzomib + dexamethasone; MRD, minimal residual disease; OR, odds ratio.aP values were calculated using the stratified Cochran-Mantel-Haenszel test for ”All randomized patients,” and the Fisher’s exact test for subgroups.bPrespecified secondary endpoint.

MRD-negative CR rates at 12-month Landmark by Subgroup12
Group
DKd
Kd
OR (95% CI)
n/N
MRD-negative CR
n/N
MRD-negative CR
Prior lines of therapy per IXRS
   1
1/67
1.5%
22/133
16.5%
13.1 (1.7, 99.3)
   ≥2
1/87
1.1%
17/179
9.5%
9.0 (1.2, 69.0)
Age at baseline, years
   ≤75
1/136
0.7%
37/287
12.9%
20.0 (2.7, 147.2)
   >75
1/18
5.6%
2/25
8.0%
1.5 (0.1, 17.7)
Baseline CrCl, mL/min
   ≥15-49
0/27
0.0%
4/38
10.5%
NE
   ≥50-79
1/50
2.0%
14/97
14.4%
8.3 (1.1, 64.8)
   ≥80
1/77
1.3%
21/176
11.9%
10.3 (1.4, 78.0)
Prior lenalidomide exposure
   Yes
0/74
0.0%
14/123
11.4%
NE
   No
2/80
2.5%
25/189
13.2%
5.9 (1.4, 25.7)
Refractory to lenalidomide
   Yes
0/55
0.0%
13/99
13.1%
NE
   No
2/99
2.0%
26/213
12.2%
6.7 (1.6, 29.0)
Prior bortezomib or ixazomib exposure
   Yes
2/137
1.5%
34/289
11.8%
9.0 (2.1, 38.0)
   No
0/17
0.0%
5/23
21.7%
NE
Refractory to bortezomib or ixazomib
   Yes
1/55
1.8%
7/100
7.0%
4.1 (0.5, 33.9)
   No
1/99
1.0%
32/212
15.1%
17.4 (2.3, 129.4)
Prior IMiD exposure
   Yes
0/110
0.0%
24/206
11.7%
NE
   No
2/44
4.5%
15/106
14.2%
3.5 (0.8, 15.8)
Refractory to IMiD
   Yes
0/65
0.0%
16/130
12.3%
NE
   No
2/89
2.2%
23/182
12.6%
6.3 (1.4, 27.3)
Abbreviations: CI, confidence interval; CR, complete response; CrCl, creatinine clearance; DKd, DARZALEX + carfilzomib + dexamethasone; IMiD, immunomodulatory imide drugs; IXRS, interactive voice/web response system; Kd, carfilzomib + dexamethasone; MRD, minimal residual disease; NE, not evaluated; OR, odds ratio.

Level of Residual Disease in Patients with CR at 12-month Landmark12
Patients with CR, n (%)
DKd
(n=84)
Kd
(n=15)
<10-6
19 (22.6)
0 (0)
10-5 to 10-6
20 (23.8)
2 (13.3)
10-4 to 10-5
14 (16.7)
2 (13.3)
10-4
31 (36.9)
11 (73.3)
Abbreviations: CR, complete response; DKd, DARZALEX + carfilzomib + dexamethasone; Kd, carfilzomib + dexamethasone; MRD, minimal residual disease; NGS, next-generation sequencing.aDepth of response measured by NGS MRD level.

Subgroup Analysis in Patients with Early or Late Relapse After Previous Therapy

Weisel et al (2020)13 presented the results of a subgroup analysis in patients with early or late relapse after the most recent prior line of therapy. Outcomes from this subgroup analysis are from the CANDOR primary analysis dataset.

Results

Patient Characteristics


Baseline Characteristics of Patients With Early or Late Relapse After 1 Line of Therapy13
Characteristic
Early Relapse
Late Relapse
DKd (n=59)
Kd (n=33)
DKd (n=82)
Kd (n=36)
Median age, years
63.0
64.0
65.0
69.0
ISS stage at screening, n (%)
   I or II
46 (78.0)
26 (78.8)
71 (86.6)
32 (88.9)
   III
13 (22.0)
7 (21.2)
11 (13.4)
4 (11.1)
Cytogenetic risk group per FISH, n (%)
   High riska
15 (25.4)
5 (15.2)
9 (11.0)
6 (16.7)
   Standard riskb
21 (35.6)
10 (30.3)
28 (34.1)
14 (38.9)
   Unknownc
23 (39.0)
18 (54.5)
45 (54.9)
16 (44.4)
Refractory to bortezomib or ixazomib, n (%)
18 (30.5)
9 (27.3)
3 (3.7)
7 (19.4)
Abbreviations: DKd, DARZALEX + carfilzomib + dexamethasone; FISH, fluorescence in-situ hybridization; ISS, International Staging System; Kd, carfilzomib + dexamethasone.aGenetic subtypes t(4;14), t(14;16), or del(17p).bPatients without t(4;14), t(14;16), and del(17p).cIncludes samples that failed or were cancelled.

Baseline Characteristics of Patients With Early or Late Relapse After ≥2 Lines of Therapy13
Characteristic 
≥2 Prior Lines of Therapy
Early Relapse
Late Relapse
DKd (n=81)
Kd (n=43)
DKd (n=82)
Kd (n=36)
Median age, years
63.0
61.0
65.0
67.5
ISS stage at screening, n (%)
   I or II
62 (76.5)
31 (72.1)
67 (81.7)
34 (94.4)
   III
19 (23.5)
12 (27.9)
15 (18.3)
2 (5.6)
Cytogenetic risk group per FISH, n (%)
   High riska
12 (14.8)
12 (27.9)
11 (13.4)
3 (8.3)
   Standard riskb
22 (27.2)
13 (30.2)
28 (34.1)
14 (38.9)
   Unknownc
47 (58.0)
18 (41.9)
43 (52.4)
19 (52.8)
Refractory to bortezomib or ixazomib, n (%)
54 (66.7)
24 (55.8)
22 (26.8)
14 (38.9)
Abbreviations: DKd, DARZALEX + carfilzomib + dexamethasone; FISH, fluorescence in-situ hybridization; ISS, International Staging System; Kd, carfilzomib + dexamethasone.aGenetic subtypes t(4;14), t(14;16), or del(17p).bPatients without t(4;14), t(14;16), and del(17p).cIncludes samples that failed or were cancelled.
Efficacy

PFS by Relapse Subgroup13
Subgroup
DKd (n=304)a
Kd (n=148)b
HR for DKd vs Kd
(95% CI)
Events/ Patients
Median PFS, months
Events/ Patients
Median PFS, months
≥1 prior lines of therapy
   Early relapse (<12 months)
51/116
18.5
32/64
11.1
0.6
(0.4, 1.0)
   Late relapse (≥12 months)
56/188
NE
34/84
NE
0.7
(0.4, 1.0)
1 prior line of therapy
   Early relapse (<18 months)
23/59
NE
13/33
13.2
0.6
(0.3, 1.2)
   Late relapse (≥18 months)
17/82
NE
11/36
NE
0.7
(0.3, 1.4)
≥2 prior lines of therapy
   Early relapse (<12 months)
38/81
18.5
24/43
12.0
0.7
(0.4, 1.1)
   Late relapse (≥12 months)
29/82
NE
18/36
15.8
0.6
(0.4, 1.2)
Prior ASCTc
   Early relapse (<12 months)
12/25
16.0
6/8
4.3
0.4
(0.2, 1.1)
   Late relapse (≥12 months)
27/92
NE
12/31
NE
0.7
(0.4, 1.5)
Abbreviations: ASCT, autologous stem cell transplantation; CI, confidence interval; DKd, DARZALEX + carfilzomib + dexamethasone; HR, hazard ratio; Kd, carfilzomib + dexamethasone; NE, not estimable; PFS, progressionfree survival.aFrom the intention-to-treat population, n=8 patients in the DKd arm had missing data or did not receive treatment per randomization and were excluded.bFrom the intention-to treat population, n=6 patients in the Kd arm had missing data or did not receive treatment per randomization and were excluded.cIncludes patients with ≥1 prior lines of therapy.

Response Rates in the Early Relapse Subgroup13

Response, %
1 Prior Line
≥2 Prior Lines
Prior ASCTa
DKd
(n=59)
Kd
(n=33)
DKd (n=81)
Kd (n=43)
DKd (n=25)
Kd
(n=8)
Overall Response Rateb
86.4
57.6
75.3
65.1
68.0
37.5
Rate of ≥CR
28.8
3.0
19.8
4.7
16.0
0
Abbreviations: ASCT, autologous stem cell transplantation; CR, complete response; DKd, DARZALEX + carfilzomib + dexamethasone; IMWG, International Myeloma Working Group; Kd, carfilzomib + dexamethasone.aIncludes patients with ≥1 prior lines of therapy.bDisease assessments were made by an independent review committee using IMWG Uniform Response Criteria.

Response Rates in the Late Relapse Subgroup13
Response, %
1 Prior Line
≥2 Prior Lines
Prior ASCTa
DKd
(n=82)
Kd
(n=36)
DKd (n=82)
Kd (n=36)
DKd (n=92)
Kd
(n=31)
Overall Response Rateb
93.9
88.9
82.9
86.1
94.6
87.1
Rate of ≥CR
39.0
16.7
28.0
16.7
35.9
19.4
Abbreviations: ASCT, autologous stem cell transplantation; CR, complete response; DKd, DARZALEX + carfilzomib + dexamethasone; IMWG, International Myeloma Working Group; Kd, carfilzomib + dexamethasone.aIncludes patients with ≥1 prior lines of therapy.bDisease assessments were made by an independent review committee using IMWG Uniform Response Criteria.
Safety
  • The safety profile was consistent with the overall DKd and Kd cohorts.
  • The safety population included all patients with ≥1 study treatment dose and data are summarized in Table: TEAEs by Relapse Subgroup.

TEAEs by Relapse Subgroup13
TEAEs, n (%)
1 Prior Line
≥2 Prior Lines
Prior ASCTa
Early Relapse
DKd
(n=58)
Kd
(n=32)
DKd
(n=81)
Kd (n=43)
DKd
(n=25)
Kd
(n=8)
   TEAEs
57 (98.3)
29 (90.6)
81 (100.0)
42 (97.7)
25 (100.0)
8 (100.0)
   Grade ≥3 TEAEs
49 (84.5)
20 (62.5)
70 (86.4)
33 (76.7)
22 (88.0)
8 (100.0)
   Treatment discontinuation due to
   TEAEs
14 (24.1)
7 (21.9)
18 (22.2)
11 (25.6)
6 (24.0)
3 (37.5)
   Fatal TEAEs
5 (8.6)
3 (9.4)
11 (13.6)
4 (9.3)
1 (4.0)
2 (25.0)
Late Relapse
DKd
(n=81)
Kd
(n=36)
DKd (n=81)
Kd (n=36)
DKd (n=91)
Kd
(n=31)
   TEAEs
80 (98.8)
35 (97.2)
81 (100.0)
35 (97.2)
90 (98.9)
30 (96.8)
   Grade ≥3 TEAEs
63 (77.8)
28 (77.8)
64 (79.0)
27 (75.0)
74 (81.3)
22 (71.0)
   Treatment discontinuation due to
   TEAEs
19 (23.5)
11 (30.6)
16 (19.8)
6 (16.7)
23 (25.3)
7 (22.6)
   Fatal TEAEs
3 (3.7)
1 (2.8)
9 (11.1)
0 (0.0)
3 (3.3)
0 (0.0)
Abbreviations: ASCT, autologous stem cell transplantation; CR, complete response; DKd, DARZALEX + carfilzomib + dexamethasone; Kd, carfilzomib + dexamethasone; TEAE, treatment-emergent adverse event.aIncludes patients with ≥1 prior lines of therapy.

Literature Search

A literature search of MEDLINE®, Embase®, BIOSIS Previews®, and Derwent Drug File (and/or other resources, including internal/external databases) was conducted on 12 June 2024.

 

References

Show
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5 Quach H, Leleu X, Mateos M, et al. P907: Carfilzomib, dexamethasone, and daratumumab (Kdd) vs carfilzomib and dexamethasone (Kd) in relapsed/refractory multiple myeloma (RRMM): Frailty Subgroup Analysis of the Candor Study. Hemasphere. 2022;6(Suppl):798-799.  
6 Landgren O, Weisel K, Rosinol L, et al. Subgroup analysis based on cytogenetic risk in patients with relapsed or refractory multiple myeloma in the CANDOR study. Br J Haematol. 2022;198(6):988-993.  
7 Quach H, Nooka A, Samoylova O, et al. Carfilzomib, dexamethasone and daratumumab in relapsed or refractory multiple myeloma: results of the phase III study CANDOR by prior lines of therapy. British Journal of Haematology. 2021;194:784-788.  
8 Mateos M, Usmani S, Quach H, et al. Carfilzomib, dexamethasone, and daratumumab (KdD) vs Kd: subgroup analysis of the CANDOR study by prior autologous stem cell transplantation, lenalidomide exposure, or lenalidomide refractory disease. Abstract presented at: 18th International Myeloma Workshop (IMW); September 8-11, 2021; Vienna, Austria.  
9 Suzuki K, Min C, Kim K, et al. Carfilzomib, dexamethasone, and daratumumab in Asian patients with relapsed or refractory multiple myeloma: post hoc subgroup analysis of the phase 3 CANDOR trial. Int J Hematol. 2021;114(6)(suppl 34410635):653-663.  
10 Siegel D, Weisel K, Zahlten-Kumeli A, et al. Health-related quality of life outcomes from the CANDOR study in patients with relapsed or refractory multiple myeloma. Leukemia & Lymphoma. 2021;:1-9.  
11 Chari A, Dimopoulos M, Beksac M, et al. Comparison of efficacy outcomes for carfilzomib plus dexamethasone and daratumumab (KdD) versus pomalidomide plus bortezomib and dexamethasone (PVd) and D-Pd in relapsed or refractory multiple myeloma. Poster presented at: 18th International Myeloma Workshop (IMW); September 08-11, 2021; Vienna, Austria.  
12 Landgren O, Weisel K, Dachs L, et al. Evaluation of Minimal Residual Disease (MRD) Negativity in Patients with Relapsed or Refractory Multiple Myeloma Treated in the CANDOR Study. Poster presented at: 62nd American Society of Hematology (ASH) Annual Meeting & Exposition; December 5-8, 2020; Virtual.  
13 Weisel K, Geils G, Karlin L, et al. Carfilzomib, Dexamethasone, and Daratumumab Versus Carfilzomib and Dexamethasone in Relapsed or Refractory Multiple Myeloma: Subgroup Analysis of the Phase 3 CANDOR Study in Patients With Early or Late Relapse. presented at: 62nd American Society of Hematology (ASH) Annual Meeting & Exposition; December 5-8, 2020; Virtual.  
14 Usmani S, Quach H, Mateos M, et al. Supplement to: Final analysis of carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone in the CANDOR Study. Blood Adv. 2023;7(14):3739-3748.  
15 Landgren O, Weisel K, Rosinol L, et al. Supplement to: Subgroup analysis based on cytogenetic risk in patients with relapsed or refractory multiple myeloma in the CANDOR study. Br J Haematol. 2022;198(6):988-993.  
16 Quach H, Nooka A, Samoylova O, et al. Supplementary Appendix for: Carfilzomib, dexamethasone and daratumumab in relapsed or refractory multiple myeloma: results of the phase III study CANDOR by prior lines of therapy. British Journal of Haematology. 2021;194:784-788.