DARZALEX FASPRO®
(daratumumab and hyaluronidase-fihj)
Medical inquiries
This information is intended for US healthcare professionals to access current scientific information about J&J Innovative Medicine products. It is prepared by Medical Information and is not intended for promotional purposes, nor to provide medical advice.
DARZALEX FASPRO® (daratumumab and hyaluronidase-fihj)
Medical Information
DARZALEX FASPRO - MMY3019 (CEPHEUS) Study
Last Updated: 02/07/2025
SUMMARY
- DARZALEX FASPRO for subcutaneous (SC) use is not approved by the regulatory agencies for use in combination with bortezomib, lenalidomide, and dexamethasone (VRd) for the treatment of multiple myeloma (MM) in newly diagnosed multiple myeloma (NDMM) patients for whom transplant is not intended as initial therapy. Janssen does not recommend the use of DARZALEX FASPRO in a manner that is inconsistent with the approved labeling.
- CEPHEUS (MMY3019) is a phase 3 study evaluating the efficacy and safety of DARZALEX FASPRO in combination with bortezomib, lenalidomide, and dexamethasone (D-VRd) or VRd in patients with NDMM who are
transplant ineligible (TIE) or for whom transplant is not planned as initial therapy (transplant deferred). The trial has enrolled 395 patients in 13 countries.1 - 3 - Usmani et al (2025)3 reported results from the phase 3 CEPHEUS study. At a median follow-up of 58.7 months (range, 0.1-64.7), the overall minimal residual disease (MRD)-negativity (10-5
sensitivity with complete response or better [≥CR]) rate was significantly higher with D-VRd vs VRd (60.9% vs 39.4%; odds ratio [OR], 2.37; 95% confidence interval [CI], 1.58-3.55; P<0.0001). Similarly, the sustained MRD-negativity (10-5 sensitivity; ≥12 months) rate was significantly higher in the D-VRd vs VRd arm (48.7% vs 26.3%; OR, 2.63; 95% CI, 1.73-4; P<0.0001). The overall ≥CR rate was significantly higher with D-VRd vs VRd (81.2% vs 61.6%; OR, 2.73; 95% CI, 1.71-4.34; P<0.0001). Further, D-VRd significantly improved the progression-free survival (PFS; hazard ratio [HR], 0.57; 95% CI, 0.41-0.79; P=0.0005) with 43% reduction in the risk of progression or death vs VRd. The overall survival (OS) rate favored the D-VRd vs VRd arm (HR, 0.85; 95% CI, 0.58-1.24). Serious treatment-emergent adverse events (TEAEs) occurred in 142 (72.1%) vs 131 (67.2%) of patients from the D-VRd vs VRd arm, respectively, with the most common serious TEAE being pneumonia (D-VRd, 13.7%; VRd, 12.8%). The overall safety data were consistent with the established safety profile of each individual drug. - Zweegman et al (2024)4
presented (at the 66th American Society of Hematology [ASH] Annual Meeting) an expanded analysis of MRD outcomes from CEPHEUS study in NDMM patients who were ineligible for stem cell transplant (SCT) or transplant deferred. The addition of DARZALEX FASPRO to VRd improved cumulative MRD-negativity rates (both 10-5 and 10-6 sensitivity) vs VRd alone at all prespecified timepoints. At 54 months, among patients who achieved both MRD negativity
(10-6) and ≥CR, >85% were alive and progression free.D-VRd vs VRd analyses of MRD-negativity (with ≥CR) rates in prespecified subgroups were generally consistent across prespecified subgroups.
- Usmani et al (2025)3 reported results from the phase 3 CEPHEUS study. At a median follow-up of 58.7 months (range, 0.1-64.7), the overall minimal residual disease (MRD)-negativity (10-5
PRODUCT LABELING
- DARZALEX FASPRO (daratumumab and hyaluronidase-fihj) [Prescribing Information]. Horsham, PA: Janssen Biotech, Inc.; https://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/DARZALEX+Faspro-pi.pdf
CLINICAL DATA
Study Design/Methods
- The trial has enrolled 395 patients from 13 different countries including the United States.
- The study design has been presented in the Figure: CEPHEUS Study Design.
Abbreviations: CR, complete response; d, dexamethasone; D, daratumumab and hyaluronidase; ECOG PS, Eastern Cooperative Oncology Group performance status; MRD, minimal residual disease; NCI-CTCAE, National Cancer Institute - Common Terminology Criteria for Adverse Events; NDMM, newly diagnosed multiple myeloma; ORR, overall response rate; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PFS2, PFS on next line of therapy; PO, orally; PS, performance status; QW, once a week; Q3W, three times a week; Q4W, four times a week; R, lenalidomide; SC, subcutaneously; V, bortezomib; TIE, transplant ineligible; VGPR, very good partial response.
a
Results
Patient Characteristics
- A total of 395 patients were randomized into the D-VRd (n=197) and VRd (n=198) arms.3
- The baseline demographics and clinical characteristics of the intention-to-treat (ITT) population are presented in Table: Baseline Demographics and Clinical Characteristics of the ITT Population.
- The median follow-up was 58.7 months (range, 0.1-64.7).3
| Characteristic | D-VRd (n=197) | VRd (n=198) | |
|---|---|---|---|
| Median age (range), years | 70 (42-79) | 70 (31-80) | |
| <65 years, n (%) | 36 (18.3) | 35 (17.7) | |
| 65 to <70 years, n (%) | 52 (26.4) | 53 (26.8) | |
| ≥70 years, n (%) | 109 (55.3) | 110 (55.6) | |
| Age or transplant eligibility, n (%) | |||
| <70 years and transplant ineligible | 35 (17.8) | 35 (17.7) | |
| <70 years and transplant deferred | 53 (26.9) | 53 (26.8) | |
| ≥70 years | 109 (55.3) | 110 (55.6) | |
| Maleb | 87 (44.2) | 111 (56.1) | |
| Raceb, n (%) | |||
| White | 162 (82.2) | 156 (78.8) | |
| Black or African American | 10 (5.1) | 9 (4.5) | |
| Asian | 11 (5.6) | 14 (7.1) | |
| Native Hawaiian or other Pacific Islander | 0 (0) | 1 (0.5) | |
| Other | 1 (0.5) | 2 (1) | |
| Not reported | 13 (6.6) | 16 (8.1) | |
| ECOG PSc | |||
| 0 | 71 (36) | 84 (42.4) | |
| 1 | 103 (52.3) | 100 (50.5) | |
| 2 | 23 (11.7) | 14 (7.1) | |
| Frailty scored | |||
| 0 (fit) | 124 (62.9) | 132 (66.7) | |
| 1 (intermediate fitness) | 73 (37.1) | 66 (33.3) | |
| Type of measurable disease, n (%) | |||
| Detected in serum only | 120 (60.9) | 108 (54.5) | |
| IgG | 89 (45.2) | 76 (38.4) | |
| IgA | 27 (13.7) | 31 (15.7) | |
| Othere | 4 (2) | 1 (0.5) | |
| Detected in serum and urine | 41 (20.8) | 45 (22.7) | |
| Detected in urine only | 20 (10.2) | 24 (12.1) | |
| Detected in serum FLCs only | 16 (8.1) | 21 (10.6) | |
| ISS disease stagef | |||
| I | 68 (34.5) | 68 (34.3) | |
| II | 73 (37.1) | 75 (37.9) | |
| III | 56 (28.4) | 55 (27.8) | |
| Cytogenetic risk profileg | |||
| Standard risk | 149 (75.6) | 149 (75.3) | |
| High risk | 25 (12.7) | 27 (13.6) | |
| Indeterminateh | 23 (11.7) | 22 (11.1) | |
| Median time since diagnosis of MM (range), months | 1.2 (0.4-5.8) | 1.3 (0.3-8) | |
| Abbreviations: D-VRd, DARZALEX FASPRO + bortezomib + lenalidomide + dexamethasone; ECOG PS, Eastern Cooperative Oncology Group performance status; FLC, free light chain; Ig, immunoglobulin; ISS, International Staging System; ITT, intention-to-treat; MM, multiple myeloma; VRd, bortezomib + lenalidomide + dexamethasone. aThe ITT population was defined as all patients who underwent randomization. bSex and race were reported by the patient.cECOG PS is scored on a scale of 0-5, with 0 indicating no symptoms and higher scores indicating increasing disability. dTotal additive frailty is scored on a scale of 0-5 based on age, comorbidities, and cognitive and physical conditions, with 0 indicating fit, 1 indicating intermediate fitness, and ≥2 indicating frail, per the Myeloma Geriatric Assessment score (http://www.myelomafrailtyscorecalculator.net/). eIncludes IgD, IgM, IgE, and biclonal.fBased on the combination of serum β2-microglobulin and albumin levels. Higher stages indicate more advanced disease. gAssessed by fluorescence in situ hybridization; high risk was defined as the presence of del(17p), t(4;14), and/or t(14;16). hIndeterminate includes patients with missing or unevaluable samples. | |||
Efficacy
The duration of treatment and relative dose intensities are summarized in Table: Duration of Treatment and Relative Dose Intensities in the Safety Population. - As of the clinical cutoff date of May 7, 2024, 102 (51.8%) vs 67 (34.4%) patients from the D-VRd vs VRd arm, respectively, continued their treatment.3
- A summary of the MRD status and response rates in the ITT population is presented in Table: Summary of MRD Status and Response Rates in the ITT Population.
- D-VRd vs VRd significantly increased the overall MRD-negativity rate (10-5 sensitivity with ≥CR; 60.9% vs 39.4%) and ≥CR rate (81.2% vs 61.6%).3
- Patients in the D-VRd vs VRd arm showed a higher MRD-negativity rate at 10-6 sensitivity (46.2% vs 27.3%) and a significantly higher sustained (≥12 months) MRD-negativity rate at 10-5 sensitivity (48.7% vs 26.3%).3
- The treatment effect on the overall MRD-negativity rate remained consistent across the predefined subgroups and is summarized in Table: Prespecified Subgroup Analysis of Overall MRD-Negativity Rates.
- At a median follow-up duration of 58.7 months, the median PFS was not reached in the D-VRd arm, while it was 52.6 months in the VRd arm.3
- D-VRd significantly improved PFS with a 43% reduction in the risk of progression or death (HR, 0.57; 95% CI, 0.41-0.79; P=0.0005).3
- At 54 months, the estimated PFS for D-VRd vs VRd was 68.1% (95% CI, 60.8-74.3) vs 49.5% (95% CI, 41.8-56.8).3
- The treatment effect on PFS remained consistent across the predefined subgroups and is summarized in Table: PFS in Prespecified Subgroups.
- Data for PFS on the subsequent line of therapy are still immature. However, HR favored D-VRd over VRd (HR, 0.78; 95% CI, 0.54-1.14) and further improved when censoring for death due to coronavirus disease 2019 (COVID-19; HR, 0.60; 95% CI, 0.40-0.93).3
OS for intent-to-treat (ITT) population favored the D-VRd vs VRd arm (HR, 0.85; 95% CI, 0.58-1.24) and further improved when censoring for death due to COVID-19 (HR, 0.69; 95% CI, 0.45-1.05).3 - OS data were immature, and follow-up is ongoing.3
- A lower proportion of patients who received subsequent therapy received an anti-cluster of differentiation 38 (CD38)-based therapy in the D-VRd arm (3 of 22 patients [13.6%]) vs the VRd arm (39 of 65 patients [60%]).3
- The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 global (EORTC QLQ-C30) health status domain score improved over time in both arms, with no negative impact from the addition of DARZALEX FASPRO.3
| Parameter | D-VRd (n=197) | VRd (n=195) |
|---|---|---|
| Median duration of treatment (range), months | 56.3 (0.1-64.6) | 34.3 (0.5-63.8) |
| Median number of treatment cycles (range) | 59 (1-71) | (1-70) |
| Median relative dose intensity (range) | ||
| Bortezomib | 84.5 (12.7-104.3) | 81.6 (22.4-102.1) |
| Lenalidomide | 80.6 (2.5-248.2) | 83.8 (25.7-246) |
| Dexamethasone | 81.5 (19.6-177) | 77.9 (23.4-173.4) |
| DARZALEX FASPRO | ||
| Cycles 1 and 2 (n=197) | 100 (33.3-105.6) | - |
| Cycles 3 to 8 (n=191) | 100 (33.3-101.1) | - |
| Cycle 9+ (n=175) | 100 (10-100.4) | - |
| Abbreviations: D-VRd, DARZALEX FASPRO + bortezomib + lenalidomide + dexamethasone; VRd, bortezomib + lenalidomide + dexamethasone. aDose intensity was defined as the ratio of total administered dose to total planned dose.bThe safety population included all patients who received ≥1 dose of study treatment. | ||
| Parameter | D-VRd (n=197) | VRd (n=198) | OR (95% CI) | P Value |
|---|---|---|---|---|
| Overall MRD-negativitya, % | ||||
| 10-5 sensitivity | 60.9 | 39.4 | 2.37 (1.58-3.55) | <0.0001 |
| 10-6 sensitivity | 46.2 | 27.3 | 2.24 (1.48-3.40) | 0.0001 |
| Sustained MRD-negativity (10‒5 | 48.7 | 26.3 | 2.63 (1.73-4) | <0.0001 |
| Responseb, n | 191 | 184 | - | - |
| ORR, % (95% CI) | 97 (93.5-98.9) | 92.9 (88.4-96.1) | - | 0.0698 |
| sCR, n (%) | 128 (65) | 88 (44.4) | - | <0.0001 |
| CR, n (%) | 32 (16.2) | 34 (17.2) | - | - |
| VGPR, n (%) | 23 (11.7) | 50 (25.3) | - | - |
| PR, n (%) | 8 (4.1) | 12 (6.1) | - | - |
| ≥CR, n (%) | 160 (81.2) | 122 (61.6) | 2.73 (1.71-4.34) | <0.0001 |
| ≥VGPR, n (%) | 183 (92.9) | 172 (86.9) | - | 0.0495 |
| SD, n (%) | 5 (2.5) | 7 (3.5) | - | - |
| PD, n (%) | 0 (0) | 0 (0) | - | - |
| Response could not be evaluated, n (%) | 1 (0.5) | 7 (3.5) | - | - |
| Abbreviations: CI, confidence interval; CR, complete response; D-VRd, DARZALEX FASPRO + bortezomib + lenalidomide + dexamethasone; IMWG, International Myeloma Working Group; ITT, intention-to-treat; MRD, minimal residual disease; OR, odds ratio; ORR, overall response rate; PD, progressive disease; PR, partial response; sCR, stringent complete response; SD, stable disease; VGPR, very good partial response; VRd, bortezomib + lenalidomide + dexamethasone. aMRD-negativity rate was defined as the proportion of patients who achieved both MRD-negativity (10-5 threshold) and ≥CR. bResponse rates at any time during the study. Response was assessed based on IMWG response criteria. P values were calculated using the stratified Cochran-Mantel-Haenszel chi-squared test. | ||||
| Subgroup | D-VRd | VRd | OR (95% CI) |
|---|---|---|---|
| Number of Patients With MRD-Negativity/ Total Number of Patients (%) | |||
| Sex | |||
| Male | 54/87 (62.1) | 39/111 (35.1) | 3.02 (1.69-5.41) |
| Female | 66/110 (60) | 39/87 (44.8) | 1.85 (1.04-3.26) |
| Age | |||
| <70 years | 59/88 (67) | 36/88 (40.9) | 2.94 (1.59-5.44) |
| ≥70 years | 61/109 (56) | 42/110 (38.2) | 2.06 (1.20-3.53) |
| Region | |||
| Europe | 69/120 (57.5) | 46/116 (39.7) | 2.06 (1.23-3.46) |
| North America | 21/37 (56.8) | 13/31 (41.9) | 1.82 (0.69-4.77) |
| Other | 30/40 (75) | 19/51 (37.3) | 5.05 (2.03-12.60) |
| Weight | |||
| ≤65 kg | 40/58 (69) | 22/63 (34.9) | 4.14 (1.94-8.86) |
| >65-85 kg | 58/101 (57.4) | 31/88 (35.2) | 2.48 (1.38-4.47) |
| >85 kg | 22/38 (57.9) | 25/47 (53.2) | 1.21 (0.51-2.87) |
| ISS staging | |||
| I | 45/68 (66.2) | 30/68 (44.1) | 2.48 (1.24-4.96) |
| II | 47/73 (64.4) | 29/75 (38.7) | 2.87 (1.47-5.59) |
| III | 28/56 (50) | 19/55 (34.5) | 1.89 (0.88-4.07) |
| Cytogenetic risk | |||
| High risk | 12/25 (48) | 15/27 (55.6) | 0.74 (0.25-2.20) |
| Standard risk | 95/149 (63.8) | 57/149 (38.3) | 2.84 (1.78-4.54) |
| Indeterminate | 13/23 (56.5) | 6/22 (27.3) | 3.47 (0.99-12.09) |
| ECOG PS score | |||
| 0 | 41/71 (57.7) | 36/84 (42.9) | 1.82 (0.96-3.45) |
| ≥1 | 79/126 (62.7) | 42/114 (36.8) | 2.88 (1.71-4.87) |
| Abbreviations: CI, confidence interval; D-VRd, DARZALEX FASPRO + bortezomib + lenalidomide + dexamethasone; ECOG PS, Eastern Cooperative Oncology Group performance status; ISS, International Staging System; MRD, minimal residual disease; OR, odds ratio; VRd, bortezomib + lenalidomide + dexamethasone. | |||
| Subgroups | D-VRd | VRd | D-VRd | VRd | HR (95% CI) |
|---|---|---|---|---|---|
| Number of Disease Progression Events or Deaths/Total Number of Patients | Median PFS, months | ||||
| Sex | |||||
| Male | 24/87 | 53/111 | NE | 49.2 | 0.46 (0.29-0.75) |
| Female | 39/110 | 38/87 | NE | NE | 0.73 (0.47-1.15) |
| Age | |||||
| <70 years | 30/88 | 38/88 | NE | NE | 0.72 (0.44-1.16) |
| ≥70 years | 33/109 | 53/110 | NE | 49.4 | 0.50 (0.33-0.78) |
| Region | |||||
| Europe | 37/120 | 54/116 | NE | 51.1 | 0.54 (0.36-0.82) |
| North America | 10/37 | 13/31 | NE | 50.2 | 0.51 (0.22-1.17) |
| Other | 16/40 | 24/51 | NE | NE | 0.87 (0.46-1.64) |
| Weight | |||||
| ≤65 kg | 17/58 | 24/63 | NE | NE | 0.62 (0.34-1.16) |
| >65-85 kg | 34/101 | 40/88 | NE | 51.1 | 0.65 (0.41-1.02) |
| >85 kg | 12/38 | 27/47 | NE | 41.9 | 0.46 (0.23-0.91) |
| ISS staging | |||||
| I | 21/68 | 28/68 | NE | 60.6 | 0.66 (0.37-1.16) |
| II | 18/73 | 37/75 | NE | 45.6 | 0.36 (0.21-0.64) |
| III | 24/56 | 26/55 | NE | 49.2 | 0.84 (0.48-1.46) |
| Cytogenetic risk | |||||
| High risk | 13/25 | 17/27 | 39.8 | 31.7 | 0.88 (0.42-1.84) |
| Standard risk | 43/149 | 60/149 | NE | 60.6 | 0.61 (0.41-0.91) |
| Indeterminate | 7/22 | 14/22 | NE | 47.9 | 0.33 (0.13-0.82) |
| ECOG PS score | |||||
| 0 | 16/71 | 30/84 | NE | NE | 0.53 (0.29-0.97) |
| ≥1 | 47/126 | 61/114 | NE | 43.8 | 0.59 (0.40-0.86) |
| Abbreviations: CI, confidence interval; D-VRd, DARZALEX FASPRO + bortezomib + lenalidomide + dexamethasone; ECOG PS, Eastern Cooperative Oncology Group performance status; HR, hazard ratio; ISS, International Staging System; NE, not estimated; PFS, progression-free survival; VRd, bortezomib + lenalidomide + dexamethasone. | |||||
Safety
- A total of 95 vs 128 patients from the D-VRd vs VRd arm, respectively, discontinued treatment.3
- Reasons for treatment discontinuation in the D-VRd vs VRd arm, respectively, included:
- Progressive disease: 27 (13.7%) vs 51 (26.2%) patients.
- Adverse events (AEs): 16 vs 32 patients.
- Deaths: 34 vs 24 patients.
- COVID-19-related deaths: 12 (6.1%) vs 6 (3.1%) patients.
- Refused further treatment: 15 vs 8 patients.
- Physician decision: 3 vs 12 patients.
- Received concurrent treatment for MM prior to disease progression: 0 vs 1 patient.
- Treatment discontinuation due to TEAEs was observed in 7.6% vs 15.9% of patients from the D-VRd vs VRd arm, respectively.
- Reasons for treatment discontinuation in the D-VRd vs VRd arm, respectively, included:
- The safety data were consistent with the established safety profile of each individual drug.3 TEAEs in the safety population are summarized in Table: Most Common TEAEs in the Safety Population.
- Overall, deaths were reported in 51 vs 60 patients from the D-VRd vs VRd arm, respectively and are summarized in Table: Summary of Deaths in the ITT Population.
- The COVID-19 pandemic impacted OS with 24 (21.6%) of all deaths in the study attributed to COVID-19 (D-VRd, n=15 vs VRd, n=9).
- Overall, 21 COVID-19 deaths occurred during the peak of the pandemic in 2020 and 2021, with 3 additional deaths in 2022 (post-vaccine availability), and none in 2023 or 2024.
- Overall, deaths were reported in 51 vs 60 patients from the D-VRd vs VRd arm, respectively and are summarized in Table: Summary of Deaths in the ITT Population.
- Regional variations were observed in pandemic impact. Brazil reported 54.2% of COVID-19 deaths (17.5% of the study population), while Poland had 16.7% of deaths (18.7% of the study population).
- Two sensitivity analyses of OS adjusting for COVID-19 deaths showed a stronger treatment effect for D-VRd vs VRd (censoring COVID-19 deaths [HR, 0.69; 95% CI, 0.45-1.05] and considering COVID-19 deaths as a competing risk [HR for non-COVID mortality, 0.67; 95% CI, 0.44-1.03]).
- Grade 5 non-COVID-related TEAEs occurred in 10.7% vs 7.7% of patients from the D-VRd vs VRd arm, respectively.
- Serious TEAEs occurred in 142 (72.1%) vs 131 (67.2%) of patients from the D-VRd vs VRd arm, respectively, with the most common serious TEAE being pneumonia (D-VRd, 13.7%; VRd, 12.8%). A summary of the serious TEAEs is presented in Table: Serious TEAEs (≥2%) in the Safety Population.
- Most grade 5 TEAEs occurred after the discontinuation of bortezomib (cycle 8) in both arms (D-VRd, 13%; VRd, 9%). When adjusted for treatment exposure, the rate of grade 5 TEAEs was similar between the two arms (D-VRd, 0.39 per 100 patient-months; VRd, 0.31 per 100 patient-months).
| TEAE, n (%) | D-VRd (n=197) | VRd (n=195) | ||
|---|---|---|---|---|
| Any Grade | Grade 3/4 | Any Grade | Grade 3/4 | |
| Hematologic | ||||
| Neutropenia | 110 (55.8) | 87 (44.2) | 76 (39) | 58 (29.7) |
| Thrombocytopenia | 92 (46.7) | 56 (28.4) | 66 (33.8) | 39 (20) |
| Anemia | 73 (37.1) | 26 (13.2) | 62 (31.8) | 23 (11.8) |
| Lymphopenia | 36 (18.3) | 24 (12.2) | 34 (17.4) | 20 (10.3) |
| Nonhematologic | ||||
| Diarrhea | 112 (56.9) | 24 (12.2) | 115 (59) | 18 (9.2) |
| Peripheral sensory neuropathy | 110 (55.8) | 16 (8.1) | 119 (61) | 16 (8.2) |
| Peripheral edema | 83 (42.1) | 4 (2) | 76 (39) | 1 (0.5) |
| Constipation | 75 (38.1) | 4 (2) | 82 (42.1) | 5 (2.6) |
| Insomnia | 63 (32) | 4 (2) | 63 (32.3) | 2 (1) |
| Fatigue | 63 (32) | 18 (9.1) | 60 (30.8) | 16 (8.2) |
| Hypokalemia | 58 (29.4) | 24 (12.2) | 25 (12.8) | 12 (6.2) |
| Cataract | 55 (27.9) | 17 (8.6) | 51 (26.2) | 17 (8.7) |
| Back pain | 55 (27.9) | 6 (3) | 43 (22.1) | 6 (3.1) |
| Cough | 53 (26.9) | 1 (0.5) | 38 (19.5) | 2 (1) |
| Asthenia | 51 (25.9) | 7 (3.6) | 40 (20.5) | 5 (2.6) |
| Rash | 50 (25.4) | 5 (2.5) | 48 (24.6) | 3 (1.5) |
| Nausea | 49 (24.9) | 0 (0) | 48 (24.6) | 4 (2.1) |
| Pyrexia | 46 (23.4) | 2 (1) | 30 (15.4) | 1 (0.5) |
| Arthralgia | 45 (22.8) | 3 (1.5) | 39 (20) | 0 (0) |
| Decreased appetite | 42 (21.3) | 2 (1) | 39 (20) | 5 (2.6) |
| Dizziness | 41 (20.8) | 1 (0.5) | 41 (21) | 2 (1) |
| Infections | 181 (91.9) | 79 (40.1) | 167 (85.6) | 62 (31.8) |
| Upper respiratory tract infection | 78 (39.6) | 1 (0.5) | 64 (32.8) | 1 (0.5) |
| COVID-19 | 75 (38.1) | 22 (11.2) | 48 (24.6) | 9 (4.6) |
| Pneumonia | 48 (24.4) | 28 (14.2) | 39 (20) | 25 (12.8) |
| Urinary tract | 41 (20.8) | 7 (3.6) | 29 (14.9) | 5 (2.6) |
| Second primary malignancyb | 15 (7.6) | - | 18 (9.2) | - |
| Any injection-related reaction | 7 (3.6) | 1 (0.5)c | - | - |
| Abbreviations: AE, adverse event; COVID-19, coronavirus disease 2019; D-VRd, DARZALEX FASPRO + bortezomib + lenalidomide + dexamethasone; TEAE, treatment-emergent adverse event; VRd, bortezomib + lenalidomide + dexamethasone. aThe safety population included patients who received ≥1 dose of study treatment. AEs of any grade that were reported in ≥20% of patients in either treatment arm and grade 3/4 AEs that were reported in ≥10% of patients in either treatment arm are listed. bOf all second primary malignancies, cutaneous malignancies were reported in 7 (3.6%) vs 7 (3.6%) patients from the D-VRd vs VRd arm, respectively.cGrade 3. | ||||
| Parameter, n | D-VRd (n=197) | VRd (n=195) |
|---|---|---|
| Overall deaths | 51 | 60 |
| PD | 8 | 16 |
| AEb | 37 | 25 |
| COVID-19 | 7 | 5 |
| COVID-19 pneumonia | 5 | 1 |
| Pneumonia | 3 | 4 |
| Death/sudden death | 3 | 1 |
| Cardiac arrest | 2 | 1 |
| General physical health deterioration | 2 | - |
| Drug induced liver injury | 1 | - |
| COVID-19, multiple organ dysfunction syndrome, and pulmonary embolism | 1 | - |
| Colitis | 1 | - |
| Sudden cardiac death | 1 | - |
| Respiratory failure | 1 | - |
| Acute kidney injury/failure | 1 | 1 |
| Dyspnea | 1 | - |
| Pulmonary embolism | 1 | - |
| Pulmonary fibrosis | - | 1 |
| Myocardial infarction | 1 | 1 |
| Acute myocardial infarction, cardiogenic shock | - | 1 |
| Multiple organ dysfunction syndrome | - | 1 |
| Lung neoplasm malignant | - | 1 |
| Completed suicide | - | 1 |
| Hypovolemic shock | - | 1 |
| Septic shock | 1 | 1 |
| Sepsis | - | 2 |
| Urinary tract infection | - | 1 |
| Cerebrovascular accident | 1 | - |
| Cardiopulmonary failure | 1 | - |
| Hepatic failure | - | 1 |
| Febrile neutropenia | 1 | - |
| Abdominal pain | 1 | - |
| Esophageal adenocarcinoma | 1 | - |
| Otherb | 6 | 19 |
| Unknown | 3 | 10 |
| COVID-19 or COVID-19 positive/infection | 1 | 2 |
| Acute hypoxic respiratory failure due to COVID-19 | 1 | - |
| COVID-19 bronchopneumonia bilat. | - | 1 |
| Severe acute hepatitis | 1 | - |
| No more information available | - | 1 |
| Pneumocystosis infection | - | 1 |
| Ischemic bowel stroke | - | 1 |
| Acute kidney injuryc | - | 1 |
| Cholengiocellular carcinoma intrahepatic metastasis | - | 1 |
| Renal failure, possibility of PD | - | 1 |
| Abbreviations: AE, adverse event; COVID-19, coronavirus disease 2019; D-VRd, DARZALEX FASPRO + bortezomib + lenalidomide + dexamethasone; PD, progressive disease; VRd, bortezomib + lenalidomide + dexamethasone. aUntil the clinical cutoff. bSubcategory terms are listed as originally entered in the database by the investigator.cPatient died following admission and was outside AE reporting window. | ||
| TEAE, n (%) | D-VRd (n=197) | VRd (n=195) |
|---|---|---|
| Serious TEAEs | 142 (72.1) | 131 (67.2) |
| Infections | 78 (39.6) | 69 (35.4) |
| Pneumonia | 27 (13.7) | 25 (12.8) |
| COVID-19 | 22 (11.2) | 16 (8.2) |
| COVID-19 pneumonia | 8 (4.1) | 4 (2.1) |
| Sepsis | 7 (3.6) | 4 (2.1) |
| Urinary tract infection | 7 (3.6) | 4 (2.1) |
| Septic shock | 6 (3 ) | 1 (0.5) |
| Gastroenteritis | 4 (2) | 4 (2.1) |
| Influenza | 4 (2) | 1 (0.5) |
| Pulmonary embolism | 11 (5.6) | 5 (2.6) |
| Diarrhea | 10 (5.1) | 6 (3.1) |
| Atrial fibrillation | 7 (3.6) | 7 (3.6) |
| Acute kidney injury | 6 (3) | 3 (1.5) |
| Asthenia | 6 (3) | 2 (1) |
| Anemia | 6 (3) | 2 (1) |
| Cataract | 5 (2.5) | 4 (2.1) |
| Pvrexia | 5 (2.5) | 3 (1.5) |
| Hypokalemia | 5 (2.5) | 3 (1.5) |
| Hyponatremia | 5 (2.5) | 1 (0.5) |
| Febrile neutropenia | 4 (2) | 4 (2.1) |
| Thrombocytopenia | 4 (2) | 2 (1) |
| Deep vein thrombosis | 4 (2) | 2 (1) |
| Syncope | 3 (1.5) | 6 (3.1) |
| Hypotension | 3 (1.5) | 4 (2.1) |
| Orthostatic hypotension | 2 (1) | 5 (2.6) |
| Dehydration | 0 (0) | 5 (2.6) |
| Abbreviations: COVID-19, coronavirus disease 2019; D-VRd, DARZALEX FASPRO + bortezomib + lenalidomide + dexamethasone; TEAE, treatment-emergent adverse event; VRd, bortezomib + lenalidomide + dexamethasone. aThe safety population included patients who received ≥1 dose of study treatment. | ||
Expanded Analysis of MRD Outcomes
Results
Efficacy
- A summary of the cumulative and sustained MRD-negativity (≥CR) rates is presented in Table: Summary of Cumulative and Sustained MRD-negativity (≥CR) Rates.
- The addition of DARZALEX FASPRO to VRd improved cumulative MRD-negativity rates (both 10-5 and 10-6 sensitivity) vs VRd alone at all prespecified timepoints.4
- D-VRd almost doubled sustained MRD-negativity (≥CR) rates at 12, 24, and 36 months.4
- Among patients who achieved both MRD negativity (10-6 sensitivity) and ≥CR with D-VRd, >85% were alive and progression free at 54 months.4
- D-VRd vs VRd showed PFS benefit regardless of MRD-negativity status (10-6 sensitivity).4
- The overall MRD-negativity rates (10-6 sensitivity) for D-VRd vs VRd were 46.2% vs 27.3% and the MRD-positivity rates (10-6 sensitivity) were 53.8% vs 72.7%, respectively.
- At 54 months, the estimated PFS by MRD-negativity status (10-6 sensitivity) was 86.2% vs 79% and by MRD-positivity status was 51% vs 36.5% for D-VRd vs VRd, respectively.
- Analyses of MRD-negativity (with ≥CR) rates in prespecified subgroups appeared to consistently favor D-VRd over VRd across prespecified subgroups and is summarized in Table: MRD-negativity (≥CR) Rates in Prespecified Subgroups.
| Parameter | D-VRd (n=197) | VRd (n=198) | OR (95% CI) | P Value |
|---|---|---|---|---|
| Cumulative MRD-negativity (10-5 sensitivity; ≥CR), % | ||||
| 12 months | 43.1 | 28.3 | - | - |
| 24 months | 56.9 | 35.9 | - | - |
| 36 months | 59.9 | 37.4 | - | - |
| 48 months | 60.9 | 38.4 | - | - |
| Cumulative MRD-negativity (10-5 sensitivity; ≥CR), % | ||||
| 12 months | 22.8 | 11.1 | - | - |
| 24 months | 38.1 | 22.2 | - | - |
| 36 months | 40.6 | 25.3 | - | - |
| 48 months | 45.2 | 27.3 | - | - |
| Sustained MRD-negativity (10-5)a, % | ||||
| ≥12 monthsb | 49.2 | 27.3 | 2.56 (NR) | <0.0001 |
| ≥24 monthsc | 42.1 | 22.7 | 2.47 (NR) | <0.0001 |
| ≥36 monthsd | 29.9 | 15.2 | 2.37 (NR) | 0.0005 |
| Sustained MRD-negativity (10-6)a, % | ||||
| ≥12 monthsb | 34 | 16.2 | NR | NR |
| ≥24 monthsc | 27.9 | 13.6 | NR | NR |
| ≥36 monthsd | 18.8 | 8.6 | NR | NR |
| Abbreviations: CI, confidence interval; CR, complete response; D-VRd, DARZALEX FASPRO + bortezomib + lenalidomide + dexamethasone; MRD, minimal residual disease; NR, not reported; OR, odds ratio; VRd, bortezomib + lenalidomide + dexamethasone. aAt any time on study. bProportion of patients who achieved CR or better response and achieved MRD-negative status at 2 bone marrow assessments that are 1 year apart with an allotted window of +/- 1 month, without any MRD-positive status in between.cAchieving MRD-negative status at 2 bone marrow assessments that are 24 months apart with an allotted window of +/- 3 months, without any MRD-positive status in between. dAchieving MRD-negative status at 2 bone marrow assessments that are 36 months apart, with an allotted window of +/- 3 months, without any MRD-positive status in between. | ||||
| Subgroups, n/N (%) | D-VRd | VRd | ORa (95% CI) | D-VRd | VRd | ORa (95% CI) |
|---|---|---|---|---|---|---|
| 10-5 sensitivity | 10-6 sensitivity | |||||
| Sex | ||||||
| Male | 54/87 (62.1) | 39/111 (35.1) | 3.02 (1.69-5.41) | 42/87 (48.3) | 28/111 (25.2) | 2.77 (1.52-5.04) |
| Female | 66/110 (60) | 39/87 (44.8) | 1.85 (1.04-3.26) | 49/110 (44.5) | 26/87 (29.9) | 1.88 (1.04-3.41) |
| Age | ||||||
| <70 years | 59/88 (67) | 36/88 (40.9) | 2.94 (1.59-5.44) | 44/88 (50) | 25/88 (28.4) | 2.52 (1.35-4.70) |
| ≥70 years | 61/109 (56) | 42/110 (38.2) | 2.06 (1.20-3.53) | 47/109 (43.1) | 29/110 (26.4) | 2.12 (1.20-3.74) |
| Region | ||||||
| Europe | 69/120 (57.5) | 46/116 (39.7) | 2.06 (1.23-3.46) | 57/120 (47.5) | 34/116 (29.3) | 2.18 (1.28-3.73) |
| North America | 21/37 (56.8) | 13/31 (41.9) | 1.82 (0.69-4.77) | 14/37 (37.8) | 9/31 (29) | 1.49 (0.54-4.13) |
| Other | 30/40 (75) | 19/51 (37.3) | 5.05 (2.03-12.60) | 20/40 (50) | 11/51 (21.6) | 3.64 (1.46-9.04) |
| Weight | ||||||
| ≤65 kg | 40/58 (69) | 22/63 (34.9) | 4.14 (1.94-8.86) | 31/58 (53.4) | 18/63 (28.6) | 2.87 (1.35-6.09) |
| >65-85 kg | 58/101 (57.4) | 31/88 (35.2) | 2.48 (1.38-4.47) | 45/101 (44.6) | 19/88 (21.6) | 2.92 (1.54-5.54) |
| >85 kg | 22/38 (57.9) | 25/47 (53.2) | 1.21 (0.51-2.87) | 15/38 (39.5) | 17/47 (36.2) | 1.15 (0.48-2.78) |
| ISS staging | ||||||
| I | 45/68 (66.2) | 30/68 (44.1) | 2.48 (1.24-4.96) | 32/68 (47.1) | 22/68 (32.4) | 1.86 (0.93-3.73) |
| II | 47/73 (64.4) | 29/75 (38.7) | 2.87 (1.47-5.59) | 37/73 (50.7) | 17/75 (22.7) | 3.51 (1.73-7.13) |
| III | 28/56 (50) | 19/55 (34.5) | 1.89 (0.88-4.07) | 22/56 (39.3) | 15/55 (27.3) | 1.73 (0.78-3.84) |
| Cytogenetic risk | ||||||
| High riskb | 12/25 (48) | 15/27 (55.6) | 0.74 (0.25-2.20) | 8/25 (32) | 12/27 (44.4) | 0.59 (0.19-1.83) |
| Standard risk | 95/149 (63.8) | 57/149 (38.3) | 2.84 (1.78-4.54) | 71/149 (47.7) | 37/149 (24.8) | 2.76 (1.69-4.50) |
| ECOG PS score | ||||||
| 0 | 41/71 (57.7) | 36/84 (42.9) | 1.82 (0.96-3.45) | 28/71 (39.4) | 27/84 (32.1) | 1.37 (0.71-2.66) |
| ≥1 | 79/126 (62.7) | 42/114 (36.8) | 2.88 (1.71-4.87) | 63/126 (50) | 27/114 (23.7) | 3.22 (1.85-5.61) |
| Abbreviations: CI, confidence interval; D-VRd, DARZALEX FASPRO + bortezomib + lenalidomide + dexamethasone; ECOG PS, Eastern Cooperative Oncology Group performance status; FISH, fluorescence in situ hybridization; HR, hazard ratio; ISS, International Staging System; MRD, minimal residual disease; VRd, bortezomib + lenalidomide + dexamethasone. aMantel-Haenszel estimate of the commons odds ratio for unstratified tables is used. An odds ratio >1 indicates an advantage for D-VRd. bHigh-risk was defined as the presence of del(17p), t(4,14), and/or t(14;16), as assessed by FISH testing. | ||||||
Literature Search
A literature search of MEDLINE®
References
| 1 | Zweegman S, Usmani S, Chastian K, et al. Bortezomib, lenalidomide, and dexamethasone (VRd) ± daratumumab in patients with newly diagnosed multiple myeloma for whom transplant is not planned as initial therapy: a multicenter, randomized, phase 3 study (CEPHEUS). Poster presented at: The Annual Meeting of the American Society of Clinical Oncology (ASCO). May 31-June 4, 2019; Chicago, IL. |
| 2 | |
| 3 | |
| 4 |