Efficacy and safety of weekly carfilzomib (70 mg/m²), dexamethasone, and daratumumab (KdD70) is comparable to twice-weekly KdD56 while being a more convenient dosing option: a cross-study comparison of the CANDOR and EQUULEUS studies

Figures & data

Figure 1. Overall response rate (ORR) and progression-free survival (PFS) analyses. (A) Unadjusted and adjusted ORR and PFS. The ORR and PFS and associated 95% confidence intervals (CIs) are shown for twice-weekly (BIW) KdD56 and once-weekly (QW) KdD70. Also shown are the odds ratios (ORs; for ORR) and hazard ratios (HRs; for PFS) and associated 95% CIs. Sensitivity analyses for ORR (B) and PFS (C), with corresponding OR for ORR and HR for PFS, and associated 95% CIs are shown for BIW KdD56 and QW KdD70. Progression-free survival (PFS) for unadjusted primary analysis (D) and IPTW-IRC analysis (E).

BIW: twice-weekly; CI: confidence interval; HR: hazard ratio; IRC: Independent Review Committee; IPTW: inverse probability of treatment weighting; KdD: carfilzomib, dexamethasone, and daratumumab; NE: not estimable; QW: once weekly.

Table 1. Unadjusted baseline demographics and disease characteristics.

	CANDOR Subset Bortezomib and IMiD Exposure 20/56 mg/m^2 KdD BIW (N = 185)	EQUULEUS 20/70 mg/m^2 KdD QW (N = 85)
Sex, male, n (%)	105 (57%)	46 (54%)
Age group, n (%)
<65 years	100 (54%)	36 (42%)
65–74 years	73 (40%)	41 (48%)
≥75 years	12 (7%)	8 (9%)
Race, n (%)
Asian	33 (18%)	3 (4%)
Black or African American	6 (3%)	3 (4%)
White	132 (71%)	68 (80%)
Other	14 (8%)	0 (0%)
Missing	0 (0%)	11 (13%)
ECOG performance status, 0 / 1–2, %	48% / 52%	38% / 62%
Creatinine clearance, n (%)
<50 mL/min	19 (10%)	15 (18%)
50–79 mL/min	57 (31%)	28 (33%)
≥80 mL/min	108 (58%)	42 (49%)
Risk group by FISH, %
High risk	16%	15%
t(4;14) / t(14;16) / del(17p)	6.5% / 0.5% / 9.7%	7.1% / 2.4% / 8.2%
Standard risk	31%	64%
Unknown	53%	21%
Time from diagnosis, months, mean (SD)	46 (30)	57 (30)
Time from diagnosis, months, median (range)	37 (0.3–157)	49 (8.7–145)
Prior regimens, 1 / ≥2, n (%)	62 (34%) / 123 (66%)	20 (24%) / 65 (76%)
Prior transplant, n (%)	129 (70%)	62 (73%)
Refractory to last prior treatment, n (%)	124 (67%)	53 (62%)
Time from last relapse, months, mean (SD)	3.2 (6.3)	2.7 (5.9)
Received prior IMiD, n (%)	185 (100%)	85 (100%)
Received thalidomide	102 (55%)	21 (25%)
Received lenalidomide	115 (62%)	81 (95%)
Refractory to prior lenalidomide	94 (51%)	50 (59%)
Received prior PI, n (%)	185 (100%)	85 (100%)
Refractory to prior bortezomib, n (%)	57 (31%)	27 (32%)

BIW: twice weekly; ECOG: Eastern Cooperative Oncology Group; FISH: fluorescence in situ hybridization; IMiD: immunomodulatory imide drug; KdD: carfilzomib, dexamethasone, and daratumumab; PI: proteasome inhibitor; QW: once weekly; SD: standard deviation.

Table 2. Baseline demographics and disease characteristics of adjusted BIW KdD56 and QW KdD70 groups after using propensity score.

	CANDOR, 20/56 mg/m^2 KdD BIW, Bortezomib and IMiD exposed (N = 89.3)^a	EQUULEUS 20/70 mg/m^2 KdD QW (N = 85.0)	Absolute Standard Difference
Age group, n (%)
<65 years	34.2 (38.3%)	36.0 (42.4%)
65–74 years	45.8 (51.3%)	41.0 (48.2%)	0.06
≥75 years	9.3 (10.4%)	8.0 (9.4%)	0.03
ECOG performance status, %, 0 / 1–2	34.6% / 65.4%	37.6% / 62.4%	0.06
Time from initial diagnosis, months, mean (SD)	57.2 (21.8)	57.3 (29.8)	<0.01
Creatinine clearance, n (%)
<50 mL/min	16.0 (17.9%)	15.0 (17.6%)
50–79 mL/min	34.2 (38.3%)	28.0 (32.9%)	0.11
≥80 mL/min	39.1 (43.8%)	42.0 (49.4%)	0.11
Prior regimens, 1 / ≥2, %	28.0% / 72.0%	23.5% / 76.5%	0.10
Prior transplant, %	73.6%	72.9%	0.01
Refractory to last prior treatment, %	60.0%	62.4%	0.05
Time from last relapse, months, mean (SD)	2.81 (2.44)	2.72 (5.94)	0.02
Received lenalidomide, n (%)	85.3 (95.6%)	81.0 (95.3%)	0.01
Refractory to prior lenalidomide, n (%)	47.9 (53.6%)	50.0 (58.8%)	0.10
Refractory to prior bortezomib, n (%)	26.7 (29.9%)	27.0 (31.8%)	0.04

BIW: twice weekly; ECOG: Eastern Cooperative Oncology Group; IMiD: immunomodulatory imide drug; KdD: carfilzomib, dexamethasone, and daratumumab; QW: once weekly; SD: standard deviation. Absolute standard difference was a prespecified method used to quantify the balance for each covariate; an absolute standard difference of ≤0.1 signifies little or no imbalance between KdD BIW and KdD QW for that variable.

a The N = 89.3 is not a whole number as it represents a weighted sum of the 185 KdD56 CANDOR patients included in the analysis. Specifically, each patient of the KdD56 arm was weighted according to the inverse probability of treatment weighting (IPTW) based on the propensity score to have received KdD70, balancing for the baseline covariates included in this table. As these weights were not whole numbers, the sum of these weights was also not necessarily a whole number (in this case, the sum was 89.3).

Table 3. Unadjusted and adjusted ORR and PFS.

	Unadjusted analysis		Adjusted analysis
	CANDOR BIW KdD56 (n = 185)	EQUULEUS QW KdD70 (n = 85)	CANDOR BIW KdD56 (n = 89.3)^a	EQUULEUS QW KdD70 (n = 85)
ORR, % (95% CI)	83.2 (77.1–88.3)	81.2 (71.2–88.8)	79.6 (71.2–87.9)	81.2 (72.9–89.5)
OR (QW/BIW) (95% CI)	–		1.11 (0.50–2.45)
Median PFS, months (95% CI)	NE (18.4–NE)	25.8 (19.4–NE)	NE (12.0–NE)	25.8 (19.4–NE)
HR (QW/BIW) (95% CI)	–		0.80 (0.49–1.32)

BIW: twice weekly; CI: confidence interval; HR: hazard ratio; KdD: carfilzomib, dexamethasone, and daratumumab; NE: not estimable; OR: odds ratio; ORR: overall response rate; PFS: progression-free survival; QW: once weekly.

a The N = 89.3 is not a whole number as it represents a weighted sum of the 185 KdD56 CANDOR patients included in the analysis. Specifically, each patient of the KdD56 arm was weighted according to the inverse probability of treatment weighting (IPTW) based on the propensity score to have received KdD70, balancing for the baseline covariates included in this table. As these weights were not whole numbers, the sum of these weights was also not necessarily a whole number (in this case, the sum was 89.3).

Table 4. Efficacy results for selected subgroups.

	Unadjusted (QW/BIW KdD)	Adjusted (IPTW-IRC) (QW/BIW KdD)
Overall response rate odds ratio (95% CI)
All patients in analysis	0.87 (0.45–1.69)	1.11 (0.50–2.45)
Refractory to lenalidomide
Yes	0.72 (0.32–1.62)	0.64 (0.28–1.46)
No	1.62 (0.43–6.13)	3.18 (0.67–15.11)
Prior stem cell transplant^a
Yes	0.77 (0.35–1.69)	1.17 (0.45–3.02)
No	1.16 (0.33–4.11)	0.93 (0.24–3.53)
Progression-free survival hazard ratio (95% CI)
All patients in analysis	0.87 (0.57–1.32)	0.80 (0.49–1.32)
Refractory to lenalidomide
Yes	1.22 (0.70–2.10)	1.25 (0.71–2.20)
No	0.54 (0.27–1.05)	0.43 (0.19–1.00)
Prior stem cell transplant
Yes	0.82 (0.51–1.34)	0.77 (0.42–1.40)
No	0.94 (0.42–2.14)	0.87 (0.36–2.11)

BIW: twice weekly; CI: confidence interval; IPTW: inverse probability of treatment weighting; IRC: Independent Review Committee; KdD: carfilzomib, dexamethasone, and daratumumab; QW: once weekly.

a For CANDOR patients, prior transplant includes autologous and allogeneic transplant; for EQUULEUS patients, prior transplant includes autologous transplant only.

Table 5. Safety.

	CANDOR Subset Bortezomib and IMiD Exposure KdD 20/56 mg/m^2 BIW (N = 185)		EQUULEUS KdD 20/70 mg/m^2 QW  (N = 85)
	n (%)	# per 100 patient-years (95% CI)	n (%)	# per 100 patient-years (95% CI)
All treatment-emergent adverse events	185 (100.0)	NC	85 (100.0)	NC
Grade ≥3	156 (84.3)	229 (196–268)	70 (82.4)	173 (137–219)
Serious adverse events	109 (58.9)	85 (70–102)	41 (48.2)	46 (34–62)
Leading to D/C carfilzomib	39 (21.1)	22 (16–30)	16 (18.8)	15.1 (9.3–24.6)
Leading to D/C daratumumab	15 (8.1)	8.2 (4.9–13.5)	7 (8.2)	6.1 (2.9–12.8)
Fatal adverse events	20 (10.8)	10.6 (6.8–16.4)	3 (3.5)	2.6 (0.8–7.9)
Adverse events of interest, grade ≥3
Cardiac failure	2 (1.1)	1.1 (0.3, 4.3)	2 (2.4)	1.8 (0.4, 7.0)
Acute renal failure	1 (0.5)	0.5 (0.1, 3.8)	3 (3.5)	2.6 (0.8, 8.0)
Hypertension	34 (18.4)	20.8 (14.8, 29.1)	17 (20.0)	17.6 (11.0, 28.3)
Respiratory tract infections	5 (2.7)	2.7 (1.1, 6.5)	0 (0.0)	0.00 (NA, NA)
Infections / infestations^a	68 (36.8)	44.5 (35.1, 56.4)	18 (21.2)	18.3 (11.5, 29.0)

BIW: twice weekly; CI: confidence interval; D/C: discontinuation of; KdD: carfilzomib, dexamethasone, and daratumumab; NA: not applicable; QW: once weekly. NC indicates that exposure-adjusted adverse event rates were not calculated as collection of adverse events can vary across studies, making interpretation of rates of all adverse events across studies infeasible. Safety data were compared side-by-side without any propensity score adjustment.

a By system organ class category; other adverse events are preferred terms.