KYPROLIS® + daratumumab + dexamethasone
Response that lasts when it matters most
DKd vs Kd study design (CANDOR): Phase 3, randomized, open-label, multicenter trial that compared KYPROLIS® plus daratumumab and dexamethasone (DKd) to KYPROLIS® plus dexamethasone (Kd) in patients with relapsed or refractory multiple myeloma who had received 1 to 3 prior lines of therapy. 466 patients were randomized 2:1 to receive DKd (n=312) or Kd (n=154) with KYPROLIS® 56 mg/m² twice weekly for 28-day cycles until disease progression or unacceptable toxicity. The primary endpoint was PFS. Select secondary endpoints included ORR, MRD-negative CR rate at 12 months, and safety.1,2
The power to sustain patients’ PFS for a median of nearly 2.5 years1
DKd reduced the risk of progression or death by 41% vs Kd at a median follow-up of nearly 28 months (HR=0.59; 95% CI: 0.45-0.78)1,*
*Primary results were reported after a median follow-up of ~17 months. Median PFS was not reached for DKd vs 15.8 months for Kd (HR=0.63; 95% CI: 0.46-0.85; P=0.0014, one-sided).
DKd = carfilzomib + daratumumab + dexamethasone; PFS = progression-free survival; Kd = carfilzomib + dexamethasone; mPFS = median progression-free survival; HR = hazard ratio; CI = confidence interval.
DKd delivered deep responses with high MRD negativity rates*
With a median follow-up of ~17 months, DKd delivered higher ORR, ≥ VGPR, CR, and MRD negative CR than Kd, beginning at first relapse2
12% of patients achieved MRD negative CR at 12 months with DKd vs 1.3% with Kd (P < 0.0001, one-sided)2,*
MRD tests detect residual tumor cells in the bone marrow at 100x-10,000x lower concentration than conventional methods of assessing CR3,4,‡
*MRD negative CR (at the 10-5 level) is defined as achievement of CR per the IMWG-URC and MRD negative status assessed by the next generation sequencing assay (ClonoSEQ) at the 12-month landmark (from 8 months to 13 months window).
†ORR was defined as the proportion of patients with PR or better.
‡Based on sensitivity limits of detecting < 1 in 104 to 106 cells for MRD negative CR vs < 5% for CR.
DKd = carfilzomib + daratumumab + dexamethasone; MRD = minimal residual disease; ORR = overall response rate; VGPR = very good partial response; CR = complete response; Kd = carfilzomib + dexamethasone; IMWG-URC = International Myeloma Working Group-uniform response criteria; PR = partial response.
IMWG uniform response criteria
Minimal residual disease-negative complete response (MRD negative CR)
Multiple myeloma response criteria: Complete response plus absence of clonal plasma cells by NGS on bone marrow aspirate. Presence of a clone is defined as < 2 identical sequencing reads obtained after DNA sequencing of bone marrow aspirates using the LymphoSIGHT platform (or validated equivalent method) with a minimum sensitivity of 1 in 105 nucleated cells or higher.4
NGS = next-generation sequencing; DNA = deoxyribonucleic acid.
IMWG uniform response criteria
Complete response (CR)
Multiple myeloma response criteria: Negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and < 5% plasma cells in bone marrow aspirates.4
IMWG uniform response criteria
Very good partial response (VGPR)
Multiple myeloma response criteria: Serum and urine M-protein detectable by immunofixation but not on electrophoresis or ≥ 90% reduction in serum M-protein plus urine M-protein level < 100 mg/24 hours.4
M-protein = monoclonal protein.
IMWG uniform response criteria
Partial response (PR)
Multiple myeloma response criteria: ≥ 50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥ 90% or to < 200 mg/24 hours.
If the serum and urine M-protein are unmeasurable, a ≥ 50% decrease in the difference between involved and uninvolved FLC levels is required in place of the M-protein criteria.
If serum and urine M-protein are unmeasurable, and serum-free light assay is also unmeasurable, ≥ 50% reduction in plasma cells is required in place of the M-protein, provided baseline bone marrow plasma cell percentage was ≥ 30%. In addition to these criteria, if present at baseline, a ≥ 50% reduction in the size (SPD)* of soft tissue plasmacytomas is also required.4
*Plasmacytoma measurements should be taken from the CT portion of the PET/CT, MRI scans, or dedicated CT scans where applicable. For patients with only skin involvement, skin lesions should be measured with a ruler. Measurement of tumor size will be determined by the SPD.
M-protein = monoclonal protein; FLC = free light chain; SPD = sum of the products of the maximal perpendicular diameters of measured lesions; CT = computed tomography; PET = positron emission tomography; MRI = magnetic resonance imaging.
Exploratory analysis for specific patient populations
PFS favorability was consistent across clinically important subgroups1,3
PFS in predefined subgroups, including prior lenalidomide-exposed, lenalidomide-refractory, and prior PI-exposed.1
These results represent prespecified subgroup analyses of the CANDOR study; however, these analyses were not study objectives and the study was therefore not powered or adjusted for multiplicity to assess efficacy in these subgroups.3
With a median follow-up of nearly 28 months, median PFS was 28.6 months with DKd vs 15.2 months with Kd (HR = 0.59; 95% CI: 0.45-0.78).1
*New updates for this subgroup are currently not available at this time.
†High-risk defined as a patient with cytogenetic abnormalities that are considered high-risk, including t(4;14), t(14;16), or del17p.
‡Standard-risk defined as a patient without cytogenetic abnormalities that are considered high risk.
DKd = carfilzomib + daratumumab + dexamethasone; PFS = progression-free survival; Kd = carfilzomib + dexamethasone; HR = hazard ratio; CI = confidence interval; Len = lenalidomide; PI = proteasome inhibitor; ECOG PS = Eastern Cooperative Oncology Group Performance Status; ISS = International Staging System.
DKd Patient Profile*
Meet Diane, a fit, standard risk patient with multiple myeloma at first relapse
*Hypothetical patient profile.
DKd vs Kd (CANDOR)
Key eligibility criteria (N = 466):
Key exclusion criteria (N = 466):
*Carfilzomib at 56 mg/m2 administered twice weekly; 20 mg/m2 administered on Days 1 and 2 of Cycle 1 only.
†The first dose of daratumumab is split over Days 1 and 2 of Cycle 1 (8 mg/kg each day).
‡For patients > 75 years of age, 20 mg of dexamethasone was administered weekly after the first week, and the entire 20-mg dose was given as a daratumumab pre-infusion medication on days when daratumumab was administered. Dosing of dexamethasone was otherwise split across days when KYPROLIS® was administered in both study arms.
§NYHA classification of heart failure III is defined as: Marked limitation of physical activity. Comfortable at rest. Less than ordinary activity causes fatigue, palpitation, or dyspnea (shortness of breath). IV is defined as: Unable to carry out any physical activity without discomfort. Symptoms of heart failure at rest. If any physical activity is undertaken, discomfort increases.
DKd = carfilzomib + daratumumab + dexamethasone; Kd = carfilzomib + dexamethasone; R = randomization; mg/m2 = milligrams per meter squared body surface area; BIW = twice a week; mg/kg = milligrams per kilogram; mg = milligram; PFS = progression-free survival; ORR = overall response rate; MRD = minimal residual disease; CR = complete response; OS = overall survival; PR = partial response; ECOG PS = Eastern Cooperative Oncology Group Performance Status; CrCl = creatinine clearance; LVEF = left ventricular ejection fraction; COPD = chronic obstructive pulmonary disease; FEV1 = forced expiratory volume in 1 second; NYHA = New York Heart Association.
Baseline disease characteristics and prior treatments were balanced between study arms2
*FISH analysis was conducted by the central lab. The high-risk group consisted of patients with the genetic subtypes t(4;14), t(14;16), or deletion 17p. The standard-risk group consisted of patients without cytogenetic abnormalities that are considered high risk. The unknown-risk group consisted of patients with FISH results that failed or were canceled.
†Patients were considered refractory to a drug received in previous regimens if any of the following criteria were met: (1) best response to any regimen containing the drug was stable disease or progressive disease; (2) reason the drug was stopped was progression in any regimen; (3) date of relapse/progression was after start date and within 60 days after stop date of the drug in any regimen.
DKd = carfilzomib + daratumumab + dexamethasone; Kd = carfilzomib + dexamethasone; ECOG PS = Eastern Cooperative Oncology Group Performance Status; ISS = International Staging System; IxRS = interactive voice-web response system; FISH = fluorescence in situ hybridization; ASCT = autologous stem cell transplant.
DKd = carfilzomib + daratumumab + dexamethasone, Kd = carfilzomib + dexamethasone.
References: 1. Usmani S, Quach H, Mateos MV, et al. Carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone for patients with relapsed or refractory multiple myeloma (CANDOR): updated outcomes from a randomised, multicentre, open-label, phase 3 study. Lancet Oncol. 2022;23(1):65-76. 2. KYPROLIS® (carfilzomib) prescribing information, Onyx Pharmaceuticals Inc., an Amgen Inc. subsidiary. 3. Dimopoulos M, Quach H, Mateos MV, et al. Carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone for patients with relapsed or refractory multiple myeloma (CANDOR): results from a randomized, multicentre, open-label, phase 3 study. Lancet. 2020;396:186-197. 4. Kumar S, Paiva B, Anderson K, et al. International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma. Lancet Oncol. 2016;17:e328-346.