DARZALEX FASPRO® is a combination of daratumumab, a CD38-targeted antibody, and hyaluronidase, an endoglycosidase, indicated for the treatment of adult patients with multiple myeloma2:
- In combination with the medicines bortezomib, lenalidomide, and dexamethasone for induction and consolidation in newly diagnosed patients who are eligible for autologous stem cell transplant
- In combination with the medicines bortezomib, melphalan and prednisone in newly diagnosed patients who are ineligible for autologous stem cell transplant
- In combination with the medicines lenalidomide and dexamethasone in newly diagnosed patients who are ineligible for autologous stem cell transplant and in patients with relapsed or refractory multiple myeloma who have received at least one prior therapy
- In combination with the medicines bortezomib, thalidomide, and dexamethasone in newly diagnosed patients who are eligible for autologous stem cell transplant
- In combination with the medicines bortezomib and dexamethasone in patients who have received at least one prior therapy
- In combination with the medicines pomalidomide and dexamethasone in patients who have received at least one prior line of therapy including lenalidomide and a proteasome inhibitor
- In combination with the medicines carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma who have received one to three prior lines of therapy
- As monotherapy, in patients who have received at least three prior lines of therapy including a proteasome inhibitor and an immunomodulatory agent or who are double-refractory to a proteasome inhibitor and an immunomodulatory agent
Contraindications2:
DARZALEX FASPRO ® is contraindicated in patients with a history of severe hypersensitivity to daratumumab, hyaluronidase, or any of the components of the formulation.
Warnings and precautions2:
Hypersensitivity and other administration reactions
- Both systemic administration-related reactions, including severe or life-threatening reactions, and local injection-site reactions can occur with DARZALEX FASPRO ®
- Fatal reactions have been reported with daratumumab-containing products, including DARZALEX FASPRO ®
- In a pooled safety population of 1249 patients with multiple myeloma (N=1056) or light chain (AL) amyloidosis (N=193) who received DARZALEX FASPRO ® as monotherapy or as part of a combination therapy, 7% of patients experienced a systemic administration-related reaction (Grade 2: 3.2%, Grade 3: 0.7%, Grade 4: 0.1%)
- Systemic administration-related reactions occurred in 7% of patients with the first injection, 0.2% with the second injection, and cumulatively 1% with subsequent injections
- The median time to onset was 2.9 hours (range: 5 minutes to 3.5 days)
- Of the 165 systemic administration-related reactions that occurred in 93 patients, 144 (87%) occurred on the day of DARZALEX FASPRO ® administration
- Delayed systemic administration-related reactions have occurred in 1% of the patients
- Severe reactions included hypoxia, dyspnea, hypertension, tachycardia, and ocular adverse reactions, including choroidal effusion, acute myopia, and acute angle closure glaucoma
- Other signs and symptoms of systemic administration-related reactions may include respiratory symptoms, such as bronchospasm, nasal congestion, cough, throat irritation, allergic rhinitis, and wheezing, as well as anaphylactic reaction, pyrexia, chest pain, pruritus, chills, vomiting, nausea, hypotension, and blurred vision
- Pre-medicate patients with histamine-1 receptor antagonist, acetaminophen, and corticosteroids
- Monitor patients for systemic administration-related reactions, especially following the first and second injections
- For anaphylactic reaction or life-threatening (Grade 4) administration-related reactions, immediately and permanently discontinue DARZALEX FASPRO®
- Consider administering corticosteroids and other medications after the administration of DARZALEX FASPRO® depending on dosing regimen and medical history to minimize the risk of delayed (defined as occurring the day after administration) systemic administration‑related reactions
- Ocular adverse reactions, including acute myopia and narrowing of the anterior chamber angle due to ciliochoroidal effusions with potential for increased intraocular pressure or glaucoma, have occurred with daratumumab-containing products
- If ocular symptoms occur, interrupt DARZALEX FASPRO® and seek immediate ophthalmologic evaluation prior to restarting DARZALEX FASPRO®
- In this pooled safety population, injection-site reactions occurred in 7% of patients, including Grade 2 reactions in 0.8%
- The most frequent (>1%) injection-site reaction was injection-site erythema
- These local reactions occurred a median of 5 minutes (range: 0 minutes to 6.5 days) after starting administration of DARZALEX FASPRO ®
- Monitor for local reactions and consider symptomatic management
Neutropenia
- Daratumumab may increase neutropenia induced by background therapy
- Monitor complete blood cell counts periodically during treatment according to manufacturer’s prescribing information for background therapies
- Monitor patients with neutropenia for signs of infection
- Consider withholding DARZALEX FASPRO® until recovery of neutrophils
- In lower body weight patients receiving DARZALEX FASPRO®, higher rates of Grade 3-4 neutropenia were observed
Thrombocytopenia
- Daratumumab may increase thrombocytopenia induced by background therapy
- Monitor complete blood cell counts periodically during treatment according to manufacturer’s prescribing information for background therapies
- Consider withholding DARZALEX FASPRO® until recovery of platelets
Embryo-fetal toxicity
- Based on the mechanism of action, DARZALEX FASPRO® can cause fetal harm when administered to a pregnant woman
- DARZALEX FASPRO® may cause depletion of fetal immune cells and decreased bone density
- Advise pregnant women of the potential risk to a fetus
- Advise females with reproductive potential to use effective contraception during treatment with DARZALEX FASPRO® and for 3 months after the last dose
- The combination of DARZALEX FASPRO® with lenalidomide, thalidomide, or pomalidomide is contraindicated in pregnant women because lenalidomide, thalidomide, and pomalidomide may cause birth defects and death of the unborn child
- Refer to the lenalidomide, thalidomide, or pomalidomide prescribing information on use during pregnancy
Interference with serological testing
- Daratumumab binds to CD38 on RBCs and results in a positive Indirect Antiglobulin Test (Indirect Coombs test)
- Daratumumab-mediated positive indirect antiglobulin test may persist for up to 6 months after the last daratumumab administration
- Daratumumab bound to RBCs masks detection of antibodies to minor antigens in the patient’s serum
- The determination of a patient’s ABO and Rh blood type are not impacted
- Notify blood transfusion centers of this interference with serological testing and inform blood banks that a patient has received DARZALEX FASPRO®
- Type and screen patients prior to starting DARZALEX FASPRO®
Interference with determination of complete response
- Daratumumab is a human IgG kappa monoclonal antibody that can be detected on both the serum protein electrophoresis and immunofixation assays used for the clinical monitoring of endogenous M‑protein
- This interference can impact the determination of complete response and of disease progression in some DARZALEX FASPRO ®-treated patients with IgG kappa myeloma protein
Adverse reactions
- In multiple myeloma, the most common adverse reaction (≥20%) with DARZALEX FASPRO® monotherapy is upper respiratory tract infection. The most common adverse reactions with combination therapy (≥20% for any combination) include fatigue, nausea, diarrhea, dyspnea, insomnia, headache, pyrexia, cough, muscle spasms, back pain, vomiting, hypertension, upper respiratory tract infection, peripheral neuropathy, peripheral sensory neuropathy, constipation, pneumonia, edema, peripheral edema, musculoskeletal pain, and rash
- The most common adverse reactions (≥20%) in patients with AL amyloidosis are upper respiratory tract infection, diarrhea, peripheral edema, constipation, fatigue, peripheral sensory neuropathy, nausea, insomnia, dyspnea, and cough
- The most common hematology laboratory abnormalities (≥40%) with DARZALEX FASPRO® are decreased leukocytes, decreased lymphocytes, decreased neutrophils, decreased platelets, and decreased hemoglobin
Key eligibility1
- TIE NDMM or refused ASCT as initial therapya
- <80 years of age
- Myeloma frailty index score <2b
- ECOG PS score 0-2
- CrCl ≥30 mL/min
Stratification factors1
- ISS disease stage (I, II, or III)
- Age/transplant eligibility:
- <70 years/TIE
- <70 years/refused ASCT as initial therapy
- ≥70 years
aPatients were not considered candidates for high-dose chemotherapy with stem-cell transplantation due to age (≥70 years) or were age 18 to 70 years with the presence of underlying medical conditions likely to have a negative impact on tolerability of high-dose chemotherapy with stem-cell transplantation making them transplant ineligible or refused high-dose chemotherapy with stem-cell transplantation as initial treatment (transplant deferred).
bTotal additive frailty is scored on a scale of 0 to 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.
Design: Open-label, multicenter, randomized phase 3 study with enrollment from December 2018 to October 2019 across 92 sites in 13 countries1
CEPHEUS study design1
aPatients received 20 mg PO or IV on Days 1, 4, 8, and 11 if aged >75 years or had a BMI <18.5.
bPatients received 20 mg weekly if aged >75 or had a BMI <18.5.
- CEPHEUS enrolled only 27 patients in the United States, limiting the generalizability of results to the US population.1
- Black or African American patients represented 4.8% of the total population, which may be an underrepresentation in some countries; however, the trial was partly conducted in countries where race is “not reported” (7.3% of the study population) based on trial regulations. This may limit the generalizability of results for this patient subpopulation.1
- CEPHEUS did not enroll patients above the age of 80 and those with a Myeloma Frailty Index score ≥ 2, thereby limiting how the data can be extrapolated to these patients.1
- CEPHEUS enrolled both TIE as well as patients who refused ASCT as initial therapy, making it a more heterogeneous patient population.1
- The small sample size of the transplant deferred sub-population does not allow for the demonstration of statistical significance on the clinical safety or efficacy of D-VRd in this sub-population.
- The primary endpoint of MRD negativity currently hasn’t been accepted as a regulatory endpoint by the FDA. However, it was recently (April 12, 2024) reviewed at an FDA ODAC meeting where the panel voted unanimously in favor of utilizing MRD as an endpoint for accelerated approval.3
- The incidence of Grade 5 TEAEs was higher in the D-VRd group vs VRd group, due to more Grade 5 COVID-19 events and nearly 2 years of additional treatment exposure in the D-VRd arm. Note that, due to the timing of study enrollment during the peak of the COVID-19 pandemic, patients in CEPHEUS were likely to still be on study treatment and at higher risk for COVID-19 infection prior to the availability of vaccines.1
Primary endpoint1
- Overall MRD-negativitya,b
Major secondary endpoints1
- Sustained MRD negativity ratec
- ≥ CR rate
- PFS
- Patient-reported outcomes: EORTC QLQ-C30
aDefined as the proportion of patients achieving ≥CR who had a MRD-negative status at or below a sensitivity threshold of 10-5 after randomization but prior to disease progression, subsequent antimyeloma therapy, or both.
b2-sided alpha of 0.05; 80% power was estimated to be needed to detect 15% improvement, or N = 360.
cDefined as the proportion of patients who achieved ≥CR and MRD-negative status (10-5) at two exams ≥1 year apart; the 2 exams should be prior to disease progression, subsequent antimyeloma therapy, or both, without MRD-positive status in between.
- Median follow-up was 58.7 months
- At the clinical cutoff (May 7, 2024), 51.8% of D-VRd patients and 34.4% of VRd patients remained on treatment
- The most common reason for treatment discontinuation was progressive disease (D-VRd, 13.7%; VRd, 26.2%)
| D-VRd | VRd | |
|---|---|---|
| Randomized (ITT) | 197 | 198 |
| Number of patients treated | 197 | 195 |
| Median treatment duration, months | 56.3 | 34.3 |
| Patients who discontinued study treatment, n (%) | 95 (48.2) | 128 (65.6) |
| Reason for treatment discontinuation, n (%) | ||
| Progressive disease | 27 (13.7) | 51 (26.2) |
| Adverse events | 16 (8.1) | 32 (16.4) |
| Deatha | 12 (6.1) | 6 (3.1) |
| Death due to COVID-19 | 75 (52.1) | 78 (53.8) |
| Otherb | 18 (9.1) | 21 (10.8) |
| Patients remaining on study | 135 (68.5) | 125 (64.6) |
aTreatment discontinuations due to death are different than grade 5 TEAEs.
b“Other” included patients who refused further treatment, physician decision, and patients who received concurrent treatment for multiple myeloma prior to disease progression.
Patient demographics1:
| Characteristic |
D-VRd (n = 197) |
VRd (n = 198) |
|---|---|---|
| Age | ||
| Median (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/transplant eligibility, n (%) | ||
| <70 years and TIE | 35 (17.8) | 35 (17.7) |
| <70 years and refused ASCT as initial therapy | 53 (26.9) | 53 (26.8) |
| >70 years | 109 (55.3) | 110 (55.6) |
| Sex | ||
| Male | 87 (44.2) | 111 (56.1) |
| ECOG PS score,a n (%) | ||
| 0 | 71 (36.0) | 84 (42.4) |
| 1 | 103 (52.3) | 100 (50.5) |
| 2 | 23 (11.7) | 14 (7.1) |
| Race,b n (%) | ||
| White | 162 (82.2) | 156 (78.8) |
| Black or African American | 10 (5.1) | 9 (4.5) |
| Time since MM diagnosis, months | ||
| Median (range) | 1.2 (0.4-5.8) | 1.3 (0.3-8.0) |
| ISS disease stage,c n (%) | ||
| I | 68 (34.5) | 68 (34.3) |
| II | 73 (37.1) | 75 (37.9) |
| III | 56 (28.4) | 55 (27.8) |
| Frailty score,d n (%) | ||
| 0 (fit) | 124 (62.9) | 132 (66.7) |
| 1 (intermediate fitness) | 73 (37.1) | 66 (33.3) |
| Cytogenetic risk profile,e n (%) | ||
| Standard risk | 149 (75.6) | 149 (75.3) |
| High risk | 25 (12.7) | 27 (13.6) |
| Indeterminate | 23 (11.7) | 22 (11.1) |
| 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) |
| Otherf | 4 (2.0) | 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 FLC only | 16 (8.1) | 21 (10.6) |
|
aECOG PS is scored on a scale from 0 to 5, with 0 indicating no symptoms and higher scores indicating increasing disability. bSex and race were reported by the patient. cThe ISS disease stage is based on the combination of serum β2-microglobulin and albumin levels. Higher stages indicate more advanced disease. 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. eCytogenetic risk was assessed by fluorescence in situ hybridization; high risk was defined as the presence of del(17p), t(4;14), or t(14;16). Indeterminate includes patients with missing or unevaluable samples. fOther includes IgD, IgM, IgE, and biclonal. |
||
- Median duration of treatment was 22 months longer and median number of treatment cycles was greater for patients who received D-VRd compared to VRd
- Relative dose intensities were similar between treatment arms
| Treatment exposure |
D-VRd (n = 197) |
VRd (n = 195) |
|||
|---|---|---|---|---|---|
| Median (range) duration of treatment, months | 56.3 (0.1-64.6) | 34.3 (0.5-63.8) | |||
| Median (range) no. of treatment cycles | 59 (1-71) | 37 (1-70) | |||
| Median (range) relative dose intensityb | |||||
|
100 (33.3-105.6) | NA | |||
|
100 (33.3-101.1) | NA | |||
|
100 (10.0-100.4) | NA | |||
|
84.5 (12.7-104.3) | 81.6 (22.4-102.1) | |||
|
80.6 (2.5-248.2) | 83.8 (25.7-246.0) | |||
|
81.5 (19.6-177.0) | 77.9 (23.4-173.4) | |||
aThe safety analysis population included all randomized patients who received ≥1 dose of study treatment.
bDose intensity was defined as the ratio of total administered dose to total planned dose.
cn = 191.
dn = 175.
Overall MRD negativity & sustained MRD negativity1
At a median follow-up of 58.7 months, CEPHEUS demonstrated an improvement in overall MRD negativity rate in the D-VRd treatment arm (60.9%) vs the VRd treatment arm (39.4%) (odds ratio, 2.37; 95% confidence interval (CI), 1.58–3.55; P<0.0001).
aOverall MRD-negativity rate was defined as the proportion of patients who achieved ≥CR and MRD negativity (at or below a sensitivity threshold of 10-5) after randomization but prior to disease progression, subsequent antimyeloma therapy, or both. MRD status is based on the assessment of bone marrow samples by next-generation sequencing in accordance with International Myeloma Working Group criteria. An odds ratio >1 indicates an advantage for D-VRd. P value was calculated using a Fisher’s exact test.
- The following figure shows overall MRD-negativity (10-5) ratesa with D-VRd versus VRd across clinically relevant subgroups
- This analysis was not adjusted for multiple comparisons and no conclusion should be drawn
aOverall MRD-negativity rate was defined as the proportion of patients who achieved ≥CR and MRD negativity (at or below a sensitivity threshold of 10-5) after randomization but prior to disease progression, subsequent antimyeloma therapy, or both. MRD status is based on the assessment of bone marrow samples by next-generation sequencing in accordance with International Myeloma Working Group criteria. An odds ratio >1 indicates an advantage for D-VRd.
bHigh-risk cytogenetics are defined based on fluorescence in situ hybridization testing as ≥1 of the following: del(17p), t(4;14), and/or t(14;16). Indeterminate includes patients with missing or unevaluable samples.
- Median follow-up: 58.7 months
- The following figure shows the time to initial achievement of MRD negativity (10-5)
- This analysis was not adjusted for multiple comparisons and no conclusion should be drawn
PFS in the ITT population1
- Median follow-up: 58.7 months
- Median PFS was not reached for D-VRd versus 52.6 months for VRd
- In patients receiving D-VRd versus VRd, there was a 43% reduction in the risk of disease progression or death
- Disease progression or death had occurred in 63 patients (32.0%) in the D-VRd group and 91 patients (46.0%) in the VRd group
aHazard ratio and 95% CI are estimated from a stratified Cox regression model with treatment as the sole explanatory variable and stratified with ISS staging (I, II, and III) and age/transplant eligibility (<70 years transplant ineligible, <70 years transplant deferred, or ≥70 years). A hazard ratio <1 indicates an advantage for D-VRd. The final PFS analysis was performed after 162 events of disease progression or death occurred; 8 of these were censored due to missing ≥2 consecutive disease evaluations preceding the event. The P value was calculated using the stratified log-rank test.
- The following figure shows PFS with D-VRd versus VRd across clinically relevant subgroups
- This analysis was not adjusted for multiple comparisons and no conclusion should be drawn
A hazard ratio of <1 indicates an advantage for D-VRd.
aHigh-risk cytogenetics are defined based on fluorescence in situ hybridization testing as ≥1 of the following: del(17p), t(4;14), and/or t(14;16). Indeterminate includes patients with missing or unevaluable samples.
PFS2 in the ITT population1,a
- Median follow-up: 58.7 months
- PFS2 data are immature, and follow-up is ongoing to evaluate this endpoint
- Among patients who received subsequent therapy, an anti-CD38–based subsequent therapy was received by 3 of 22 (13.6%) patients in the D-VRd group and 39 of 65 (60.0%) patients in the VRd group
- This analysis was not adjusted for multiple comparisons and no conclusion should be drawn
aPFS2 was defined as the time from randomization to progression on the next line of treatment or death (due to any cause), whichever came first. Disease progression was based on investigator judgement.
- This figure shows a sensitivity analysis of PFS2 that adjusted for the impact of COVID-19 deaths for D-VRd versus VRd
- This analysis was not adjusted for multiple comparisons and no conclusion should be drawn
aPFS2 was defined as the time from randomization to progression on the next line of treatment or death (due to any cause), whichever came first. Disease progression was based on investigator judgement.
a≥CR rate was defined as the proportion of patients achieving CR or sCR based on International Myeloma Working Group response criteria, during or after the study treatment prior to the start of subsequent antimyeloma therapy. An odds ratio >1 indicates an advantage for D-VRd. P value was calculated using the stratified Cochran-Mantel-Haenszel chi-square test.
OS in the ITT population1,a
- Median follow-up: 58.7 months
- Median OS was not reached for either group
- A total of 111 patients died overall (D-VRd, n = 51; VRd, n = 60)
- 24 patients (21.6%) died due to COVID-19 (D-VRd, n = 15; VRd, n = 9)b
- OS data are immature, and follow-up is ongoing to evaluate this endpoint
- This analysis was not adjusted for multiple comparisons and no conclusion should be drawn
aOS was defined as the time from the date of randomization to the date of the patient’s death due to any cause. A hazard ratio <1 indicates an advantage for D-VRd.
b21 patient deaths occurred during the peak of global pandemic fatalities in 2020 and 2021, with only 3 more occurring in 2022 (after availability of COVID-19 vaccines) and none in 2023 or 2024.
- These figures show 2 sensitivity analyses of OS that adjusted for the impact of COVID-19 deaths for D-VRd versus VRd
- This analysis was not adjusted for multiple comparisons and no conclusion should be drawn
aOS was defined as the time from the date of randomization to the date of the patient’s death due to any cause. A hazard ratio <1 indicates an advantage for D-VRd.
b(ie, considers COVID death as a competing event and non-COVID death as the event of interest).
Quality of life by EORTC QLQ-C3011,a
- The following figure shows changes from baseline in EORTC QLQ-C30 Global Health Status domain scores between baseline and cycle 24
- In both groups, EORTC QLQ-C30 Global Health Status domain scores improved over time
- This analysis was not adjusted for multiple comparisons and no conclusion should be drawn
aScores range from 0 to 100, with higher scores indicating a better health status and quality of life.
Most common AEs1,a
| Most common TEAEs, n (%) |
D-VRd (n = 197) |
VRd (n = 195) |
|---|---|---|
| Any grade | Any grade | |
| Hematologicb | ||
| Neutropenia | 110 (55.8) | 76 (39.0) |
| Thrombocytopenia | 92 (46.7) | 66 (33.8) |
| Anemia | 73 (37.1) | 62 (31.8) |
| Lymphopenia | 36 (18.3) | 34 (17.4) |
| Nonhematologic | ||
| Diarrhea | 112 (56.9) | 115 (59.0) |
| Peripheral sensory neuropathy | 110 (55.8) | 119 (61.0) |
| Peripheral edema | 83 (42.1) | 76 (39.0) |
| Constipation | 75 (38.1) | 82 (42.1) |
| Insomnia | 63 (32.0) | 63 (32.3) |
| Fatigue | 63 (32.0) | 60 (30.8) |
| Hypokalemia | 58 (29.4) | 25 (12.8) |
| Cataract | 55 (27.9) | 51 (26.2) |
| Back pain | 55 (27.9) | 43 (22.1) |
| Cough | 53 (26.9) | 38 (19.5) |
| Asthenia | 51 (25.9) | 40 (20.5) |
| Rash | 50 (25.4) | 48 (24.6) |
| Infection | 181 (91.9) | 167 (85.6) |
| Upper respiratory tract infection | 78 (39.6) | 64 (32.8) |
| COVID-19 | 75 (38.1) | 48 (24.6) |
- The incidence of second primary malignancies was 7.6% [n = 15] in the D-VRd group and 9.2% [n = 18] in the VRd group
- Injection-related reactions occurred in 3.6% (n = 7) of patients who received D-VRd
aAny grade TEAEs occurring in ≥25% of patients in either group are listed. The safety analysis population included all randomized patients who received ≥1 dose of the study treatment.
bHematologic second primary malignancies occurred in 0.5% of patients.
cNot applicable to patients who received VRd.
Most common grade 3/41,a,b
| Most common grade 3/4 TEAEs, n (%) |
D-VRd (n = 197) |
VRd (n = 195) |
|---|---|---|
| Grade 3/4 | Grade 3/4 | |
| Hematologic | ||
| Neutropenia | 87 (44.2) | 58 (29.7) |
| Thrombocytopenia | 56 (28.4) | 39 (20.0) |
| Anemia | 26 (13.2) | 23 (11.8) |
| Lymphopenia | 24 (12.2) | 20 (10.3) |
| Nonhematologic | ||
| Diarrhea | 24 (12.2) | 18 (9.2) |
| Hypokalemia | 24 (12.2) | 12 (6.2) |
| Infection | 79 (40.1) | 62 (31.8) |
| COVID-19 | 22 (11.2) | 9 (4.6) |
| Pneumonia | 28 (14.2) | 25 (12.8) |
Most common grade serious TEAEs1,c
| Most common grade 3/4 TEAEs, n (%) |
D-VRd (n = 197) |
VRd (n = 195) |
|---|---|---|
| Serious TEAEs | Serious TEAEs | |
| Infections | 78 (39.6) | 69 (35.4) |
| Pneumonia | 27 (13.7) | 25 (12.8) |
| COVID-19 | 22 (11.2) | 16 (8.2) |
| Pulmonary embolism | 11 (5.6) | 5 (2.6) |
| Diarrhea | 10 (5.1) | 6 (3.1) |
- Serious TEAEs occurred in 72.1% (n = 142) of patients who received D-VRd and 67.2% (n = 131) of patients who received VRd
- The most common serious TEAE was pneumonia (D-VRd, 13.7% [n = 27]; VRd, 12.8% [n = 25])
aThe safety analysis population included all randomized patients who received ≥1 dose of study treatment.
bTEAEs of grade 3/4 occurring in ≥10% of the patients in the safety analysis population are shown.
cSerious TEAEs occurring in ≥5% of the patients in the safety analysis population are shown.
Additional safety information1
- The rate of treatment discontinuation due to AEs was 7.6% with D-VRd and 15.9% with VRd
- Discontinuations and dose modifications of all/any study treatment due to peripheral neuropathy occurred at similar rates between groups
- Non-COVID–related grade 5 TEAEs occurred in 10.7% of patients who received D-VRd and 7.7% who received VRd
- COVID-related grade 5 TEAEs occurred in 6.1% and 3.1% of patients, respectively
- Most grade 5 TEAEs occurred after discontinuation of bortezomib
- Rate of grade 5 TEAEs was similar for D-VRd (0.39/100 patient-months) and VRd (0.31/100 patient-months) after adjusting for treatment exposure
|
D-VRd (n = 197) |
VRd (n = 195) |
|
|---|---|---|
| Due to treatment-emergent peripheral neuropathy, n (%) | ||
| Discontinuation of all study treatment | 16 (8.1) | 19 (9.7) |
| Discontinuation of bortezomib | 14 (7.1) | 17 (8.7) |
| Dose modification of any study treatment | 12 (6.1) | 15 (7.7) |
| Primary causes of all deaths on study,a n (%) | ||
| AE | 37 (18.7) | 25 (12.8) |
| Progressive disease | 8 (4.1) | 16 (8.2) |
| Other | 6 (3.0) | 19 (9.7) |
aUp until the clinical cutoff.
Impact of COVID-191
The COVID-19 pandemic impacted OS in CEPHEUS, with more deaths occurring during the peak of global pandemic fatalities (2020-2021) and fewer deaths occurring after COVID-19 vaccine availability (2022-2024)
| COVID-19 deaths,a n (%) |
D-VRd (n = 197) |
VRd (n = 195) |
|---|---|---|
| Patients with COVID-19 deaths | 15 (7.6) | 9 (4.6) |
| Proportion of COVID-19 deaths by calendar yearb | ||
| 2020 | 3 (20.0) | 1 (11.1) |
| 2021 | 10 (66.7) | 7 (77.8) |
| 2022 | 2 (13.3) | 1 (11.1) |
| 2023 | 0 | 0 |
| Progressive disease | 8 (4.1) | 16 (8.2) |
| Other | 6 (3.0) | 19 (9.7) |
| COVID-19 serious AEs,a n (%) |
D-VRd (n = 197) |
VRd (n = 195) |
|---|---|---|
| Patients with COVID-19 serious AEs | 30 (15.2)c | 20 (10.3) |
| Proportion of COVID-19 serious AEs by calendar yearb | ||
| 2020 | 10 (33.3) | 6 (30.0) |
| 2021 | 12 (40.0) | 9 (45.0) |
| 2022 | 7 (23.3) | 4 (20.0) |
| 2023 | 1 (3.3) | 1 (5.0) |
| 2024 | 1 (3.3) | 0 |
aThe safety population included all randomized patients who received ≥1 dose of study treatment.
bPercentages per year calculated using the number of patients with COVID-19 deaths/serious AEs in the corresponding column as the denominator.
cSerious AE occurrence includes 1 patient who had a COVID-19 serious AE in 2021 and 2022.
Conflict of interest:
- The CEPHEUS study is sponsored by Janssen Research & Development, LLC.
- The authors’ conflict of interest disclosures are as follows:
- Saad Z. Usmani, Nizar J. Bahlis, Yael C. Cohen, Morio Matsumoto, and Sonja Zweegman received research funding from Janssen; Saad Z. Usmani, Nizar J. Bahlis, Yael C. Cohen, Meral Beksac, and Angelo Maiolino have served as consultants for Janssen; Vania Hungria, Nizar J. Bahlis, Yael C. Cohen, and Sonja Zweegman have served on scientific advisory boards for Janssen; Vania Hungria, Marc Braunstein, Kenshi Suzuki, and Meral Beksac have been involved with speaker engagement for Janssen; Vania Hungria, Nizar J. Bahlis, Christopher P. Venner, Yael C. Cohen, Morio Matsumoto, Angelo Maiolino, and Hiroyuki Takamatsu have received honoraria from Janssen; Saad Z. Usmani, Vania Hungria, Nizar J. Bahlis, Christopher P. Venner, Marc Braunstein, Josep M. Marti, Yael C. Cohen, Morio Matsumoto, Kenshi Suzuki, Meral Beksac, Angelo Maiolino, Hiroyuki Takamatsu, Aurore Perrot, Tahamtan Ahmadi, and Sonja Zweegman have disclosures with other companies; Thierry Facon, Ludek Pour, Supratik Basu, Cyrille Hulin, Sebastian Grosicki, Wojciech Legiec, and Mehmet Turgut have no conflicts of interest to disclose
- Weiping Liu, Jianping Wang, Katherine Chastain, Jessica Vermeulen, Maria Krevvata, Lorena Lopez-Masi, Jodi Carey, Melissa Rowe, and Robin Carson are authors of this publication and also employees of Janssen
- Full disclosures are available in the publication
The following additional information can be found in the publication:
- Patient disposition
The following additional information can be found in the supplement:
- Study enrollment by region and country in the intention-to-treat population
- Second primary malignancies in the safety population
- Serious TEAEs in the safety population
- Treatment modifications and discontinuations in the safety population
- Patients with treatment discontinuation or dose modification due to treatment-emergent peripheral neuropathy in the safety population
- List of deaths on study in the ITT population
- Usmani SZ, Thierry Facon, Hungria V, et al. Daratumumab plus bortezomib, lenalidomide and dexamethasone for transplant-ineligible or transplant-deferred newly diagnosed multiple myeloma: the randomized phase 3 CEPHEUS study.Nature Medicine. 2025 Apr;31(4):1195-1202. doi: https://doi.org/10.1038/s41591-024-03485-7
- DARZALEX FASPRO ® [Prescribing Information]. Horsham, PA: Janssen Biotech, Inc.
- April 12, 2024, Meeting of the Oncologic Drugs Advisory Committee (ODAC). Streamed live April 12, 2024. Accessed April 12, 2024. https://tinyurl.com/2tbe3f4k
| ASCT | autologous stem cell transplant | NDMM | newly diagnosed multiple myeloma |
|---|---|---|---|
| BMI | Body mass index | NYHA | New York Heart Association |
| CI | confidence interval | ODAC | Oncologic Drugs Advisory Committee |
| COVID-19 | coronavirus disease 2019 | OS | odds ratio |
| CR | complete response | ORR | overall response rate |
| CrCl | creatinine clearance | PFS | progression-free survival |
| D | daratumumab and hyaluronidase-fihj | PO | oral |
| d | dexamethasone | PR | partial response |
| D-VRd | daratumumab and hyaluronidase-fihj plus bortezomib/lenalidomide/dexamethasone | QW | every week |
| ECOG PS | Eastern Cooperative Oncology Group performance status | Q3W | every 3 weeks |
| EORTC QLQ-C30 | European Organisation for Research and Treatment of Cancer quality of life questionnaire-C30 version | Q4W | every 4 weeks |
| FDA | US Food and Drug Administration | R | lenalidomide |
| FLC | free light chain | RBC | red blood cell |
| Ig | immunoglobulin | SC | subcutaneous |
| ISS | International Staging System | sCR | stringent complete response |
| ITT | intent-to-treat | TEAE | treatment-emergent adverse event |
| IV | intravenous | TIE | transplant ineligible |
| kg | kilograms | V | bortezomib |
| MRD | minimal residual disease | VGPR | very good partial response |
| MM | multiple myeloma | VRd | bortezomib/lenalidomide/dexamethasone |
| US | United States |