DARZALEX FASPRO®
(daratumumab and hyaluronidase-fihj)
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DARZALEX FASPRO® (daratumumab and hyaluronidase-fihj)
Medical Information
DARZALEX + DARZALEX FASPRO- Use in Older Patients With Multiple Myeloma
Last Updated: 06/23/2025
Summary
- Janssen does not recommend the use of DARZALEX for intravenous (IV) use or DARZALEX FASPRO for subcutaneous (SC) use in a manner that is inconsistent with the approved labeling.
- DARZALEX and DARZALEX FASPRO: No overall differences in effectiveness were observed based on age. The incidence of serious adverse reactions was higher in older patients than in younger patients.1
, 2 - DARZALEX:
- Among patients with relapsed and refractory multiple myeloma (RRMM; n=1213), the most common serious adverse reactions that occurred more frequently in patients ≥65 years of age were pneumonia and sepsis. Among patients with newly diagnosed multiple myeloma (NDMM) who were ineligible for an autologous stem cell transplant (ASCT; n=710), the most common serious adverse reaction that occurred more frequently in patients ≥75 years of age was pneumonia.1
- Based on population pharmacokinetic (PK) analyses in patients receiving monotherapy or various combinations therapies, age (range, 31-93 years) had no clinically important effect on the PK of daratumumab, and the exposure of daratumumab was similar between younger (aged <65 years: n=706) and older (aged ≥65 to <75 years: n=913; aged ≥75 years: n=369) patients.1
- DARZALEX FASPRO:
- Among patients with RRMM (n=2042), the most common serious adverse reactions that occurred more frequently in patients
≥65 years of age were pneumonia and sepsis. Among patients with NDMM who were ineligible for ASCT (n=777), the most common serious adverse reaction that occurred more frequently in patients ≥75 years of age was pneumonia.2 - Among patients with NDMM who were eligible for ASCT (n=351), the most common serious adverse reaction that occurred more frequently in patients ≥65 years of age was pneumonia. Among patients with NDMM for whom ASCT was not planned as initial therapy or who were ineligible for a transplant (n=197), the most common serious adverse reaction that occurred more frequently in patients ≥65 years of age was pneumonia.2
- Based on population PK analyses in patients (33-92 years) receiving monotherapy or various combination therapies, age had no statistically significant effect on the PK of daratumumab and hyaluronidase. No individualization is necessary for patients on the basis of age.2
- Among patients with RRMM (n=2042), the most common serious adverse reactions that occurred more frequently in patients
- CANDOR: phase 3 study evaluating the efficacy and safety of
DARZALEX in combination with carfilzomib and dexamethasone (D-Kd) vs carfilzomib and dexamethasone (Kd) in patients with RRMM.3 - Dimopoulos et al (2020)3 reported the efficacy and safety analysis of elderly patients aged <75 and ≥75 years with RRMM from the CANDOR study. The hazard ratio (HR) for progression-free survival (PFS) favored the D-Kd arm in the prespecified subgroup of patients aged >65 years (HR, 0.76; 95% confidence interval [CI], 0.48-1.22). The most common grade 3/4 (≥5%) treatment-emergent adverse event (TEAE) was thrombocytopenia (D-Kd, 24%; Kd, 16%).
- Usmani et al (2023)4
reported the updated efficacy and safety results after a median duration of follow-up of approximately 50 months. The HR for median overall survival (OS) favored the D-Kd arm in the prespecified subgroup of patients aged ≥65 years (HR, 0.912; 95% CI, 0.603-1.381). The most common (≥15%) grade ≥3 TEAEs were thrombocytopenia (D-Kd, 24.7%; Kd, 16.3%), hypertension (D-Kd, 23.4%; Kd, 17.6%), pneumonia (D-Kd, 18.5%; Kd, 9.2%), and anemia (D-Kd, 17.5%; Kd, 16.3%).
- MAIA: phase 3 study evaluating the efficacy and safety
of DARZALEX in combination with lenalidomide and dexamethasone (D-Rd) vs lenalidomide and dexamethasone (Rd) in patients with NDMM.5 ,6 - Usmani et al (2019)6 evaluated the effect of age (≥75 years vs <75 years) on the efficacy and safety of D-Rd vs Rd in patients with NDMM ineligible for high-dose chemotherapy and ASCT in the MAIA study at a median duration of follow-up of 28.0 months. For patients aged ≥75 years, PFS was not reported (NR) with D-Rd vs 31.9 months with Rd (HR, 0.63; 95% CI, 0.44-0.92; P=0.0146). The reduction of risk of progressive disease (PD) or death was 37% and the minimal residual disease (MRD)-negativity rate (10-5
sensitivity threshold) was increased (D-Rd arm, 19.4% vs Rd arm, 7.5%; P=0.0018) with D-Rd vs Rd, in patients aged ≥75 years. The response rates are summarized in the Table: Response Rate of ITT Population by Age Group (MAIA). Serious TEAEs occurred in 65.6% vs 70.4% patients and treatment discontinuation due to TEAEs were reported in 10.2% vs 20.8% patients aged ≥75 years from the D-Rd vs Rd arm, respectively. Infusion-related reactions (IRRs) in the D-Rd arm occurred in 35.7% of patients aged ≥75 years. No new safety concerns were observed, and grade 3/4 infection rates were consistent with the overall population. - Facon et al (2025)7
reported the updated efficacy and safety results from the MAIA study at a long-term median follow-up of 64.5 months. As of the clinical cutoff date of October 21, 2021, PFS improved with D-Rd vs Rd across subgroups of patients based on age (see Table: PFS and OS Based on Age Subgroups) and this benefit was consistent across prespecified subgroups based on baseline characteristics (see Table: Analysis of PFS in Prespecified Patient Subgroups). OS improved with D-Rd vs Rd across subgroups of patients based on age (see Table: PFS and OS Based on Age Subgroups) and this benefit was consistent across prespecified patient subgroups based on baseline characteristics (see Table: Analysis of OS in Prespecified Patient Subgroups). The overall response rate (ORR), complete response (CR) or better (≥CR) rate, very good partial response (VGPR) or better (≥VGPR) rate, and MRD-negativity rate were higher for the D-Rd vs Rd arm across all age subgroups and are summarized in Table: Response Rates Based on Age Subgroups. No new safety concerns were observed with a longer follow-up. Grade 3/4 TEAEs occurred in 95.5% vs 95.0% of patients aged ≥75 years and in 92.3% vs 95.7% of patients aged ≥80 years from the D-Rd vs Rd arm, respectively. The rate of common grade 3/4 TEAEs in patients aged ≥75 years and those aged ≥80 years was similar to that in the overall study population. Serious TEAEs occurred in 80.9% vs 79.2% of patients aged ≥75 years and in 81.5% vs 82.9% of patients aged ≥80 years from the D-Rd vs Rd arm, respectively; pneumonia was the most common serious TEAE (age ≥75 years: 19.7% vs 12.6%, respectively; age ≥80 years: 24.6% vs 8.6%, respectively). Treatment discontinuation due to TEAEs was reported in 15.3% vs 27.7% of patients aged ≥75 years and in 6.2% vs 20.0% of patients aged ≥80 years from the D-Rd vs Rd arm, respectively. TEAEs leading to death were reported in 11.5% vs 13.2% of patients aged ≥75 years and in 12.3% vs 11.4% of patients aged ≥80 years from the D-Rd vs Rd arm, respectively. - Moreau et al (2022)8
presented the efficacy and safety results in clinically important subgroups of patients from the MAIA study. The median PFS was longer (54.3 months vs 31.4 months) in the D-Rd vs Rd arm in the patient subgroup of ≥75 years of age. Among patients aged ≥75 years, grade 3/4 TEAEs were reported in 95.5% vs 95.0% patients in the D-Rd vs Rd arm. The most common (≥20%) grade 3/4 TEAEs were neutropenia (D-Rd, 62.4%; Rd, 41.5%), lymphopenia (D-Rd, 21.0%; Rd, 12.6%), anemia (DRd, 20.4%; Rd, 25.2%), and pneumonia (D-Rd, 20.4%; Rd, 14.5%). TEAEs resulting in treatment discontinuation were reported in 15.3% vs 27.7% of patients in the D-Rd vs Rd arm.
- Usmani et al (2019)6 evaluated the effect of age (≥75 years vs <75 years) on the efficacy and safety of D-Rd vs Rd in patients with NDMM ineligible for high-dose chemotherapy and ASCT in the MAIA study at a median duration of follow-up of 28.0 months. For patients aged ≥75 years, PFS was not reported (NR) with D-Rd vs 31.9 months with Rd (HR, 0.63; 95% CI, 0.44-0.92; P=0.0146). The reduction of risk of progressive disease (PD) or death was 37% and the minimal residual disease (MRD)-negativity rate (10-5
- ALCYONE: phase 3 study evaluating the efficacy and safety of elderly patients aged <75 and
≥75 years with NDMM ineligible for ASCT who were treated DARZALEX in combination with bortezomib, melphalan, and prednisone (D-VMP) vs bortezomib, melphalan, and prednisone (VMP).9 - Cavo et al (2018)9 reported the efficacy and safety data of elderly patients aged <75 and ≥75 years from the ALCYONE study. The median PFS for patients aged ≥75 years was NR in the D-VMP arm and 20.4 months in the VMP arm (HR, 0.53; 95% CI, 0.32-0.85). The most common grade 3/4 (≥10%) TEAEs in patients aged ≥75 years were neutropenia (D-VMP, 52%; VMP, 42%) and thrombocytopenia (D-VMP, 51%; VMP, 43%).
- Mateos et al (2025)10
reported the final efficacy and safety analysis results of the ALCYONE study at a median follow-up of 86.7 months (interquartile range [IQR], 28.5-85.2). The median age at randomization was 71 years (range, 40-93), with 30% of patients aged ≥75 years. The median PFS on the next line of therapy in the D-VMP vs VMP group was 66.7 months (95% CI, 58.6-80.1) vs 42.4 months (95% CI, 37.3-47.1), respectively (HR, 0.56; 95% CI, 0.46-0.68; P<0.0001). The MRD-negativity rate at the 10-5 sensitivity level in the D-VMP vs VMP group was 28% vs 7%, respectively (odds ratio [OR], 5.23; 95% CI, 3.27-8.36; P<0.0001). The most common grade 3 or 4 TEAEs in the D-VMP vs VMP group were neutropenia (40% vs 39%, respectively), thrombocytopenia (35% vs 38%, respectively), and anemia (18% vs 20%, respectively). Pneumonia was the most common grade 3 or 4 infection, reported by 16% of patients in the D-VMP group and 5% of patients in the VMP group.
- APOLLO: phase 3 study evaluating the efficacy and safety of DARZALEX in combination with pomalidomide and dexamethasone (D-Pd) vs pomalidomide and dexamethasone (Pd) in patients with RRMM who received ≥1 prior treatment with both lenalidomide and a proteasome inhibitor.11
- Dimopoulos et al (2021)11 reported the impact of age (<65 years vs ≥65 years) on the efficacy and safety of D-Pd vs Pd in patients with RRMM from the APOLLO study. The median PFS for prespecified subgroup of patients aged ≥65 years was 14.2 months in the D-Pd arm and 7 months in the Pd arm (HR, 0.55; 95% CI, 0.38-0.81). The most common grade 3/4 TEAEs (≥5%) for patients aged ≥65 years was neutropenia (D-Pd, 72.7%; Pd, 55.4%) and infections (D-Pd, 30.7%; Pd, 21.7%).
- Sonneveld et al (2021)12
presented updated efficacy and safety results of the APOLLO study, with a median duration of follow-up of 30.7 months. The median PFS for the D-Pd vs Pd arm in patients aged ≥65 years was 13.11 vs 7.23 months (HR, 0.60; 95% CI, 0.42-0.85) and that in patients aged <65 years was 8.34 vs 6.54 months (HR, 0.63; 95% CI, 0.41-0.96). The most common grade 3/4 TEAEs (≥5%) were neutropenia (D-Pd, 69.1%; Pd, 50.7%) and infections (D-Pd, 31.5%; Pd, 23.3%).
- COLUMBA: phase 3 study evaluating the efficacy, PK, and IRRs of daratumumab and hyaluronidase vs daratumumab in adults patients with heavily pre-treated RRMM.13
- Usmani et al (2019)13 presented efficacy results for patients aged ≥75 years treated in the COLUMBA study. The ORR in patients aged ≥75 years was 44.7% in the DARZALEX FASPRO arm vs 45.8% in the DARZALEX arm (relative risk [RR], 0.98; 95% CI, 0.63-1.48). The most common grade 3/4 TEAEs (>5%) were anemia (DARZALEX FASPRO, 14%; DARZALEX, 15%), thrombocytopenia (14% in both arms), and neutropenia (DARZALEX FASPRO, 13%; DARZALEX, 8%).
- Mateos et al (2019)14
conducted an efficacy and safety analysis of patients aged 65-74 and ≥75 years with RRMM treated in the POLLUX (Rd alone compared to D-Rd) and CASTOR ( DARZALEX + bortezomib + dexamethasone [D-Vd] compared with bortezomib + dexamethasone [Vd]) studies. In the POLLUX study, prolonged PFS was observed in the D-Rd arm vs Rd arm in patients aged ≥75 years (median, 28.9 vs 11.4 months; HR, 0.27; 95% CI, 0.10-0.69; P=0.0042) and in patients aged 65-74 years (median, NR vs 17.1 months; HR, 0.40; 95% CI, 0.27-0.60; P<0.0001). In the POLLUX study, neutropenia was the most common grade 3/4 TEAE (≥10%) in patients aged ≥75 years (D-Rd, 44.8%; Rd, 31.4%) and in patients aged 65-74 years (D-Rd, 55.3%; Rd, 39.8%). In the CASTOR study, prolonged PFS was observed in the D-Vd arm vs Vd arm in patients aged ≥75 years (median, 17.9 vs 8.1 months; HR, 0.26; 95% CI, 0.10-0.65; P=0.0022) and in patients aged 65-74 years (median, 18.9 vs 6.1 months; HR, 0.25; 95% CI, 0.16-0.40; P<0.0001). In the CASTOR study, thrombocytopenia was the most common grade 3/4 TEAE (≥10%) in patients aged ≥75 years (D-Vd, 45%; Vd, 37.1%) and in patients aged 65-74 years (D-Vd, 52.1%; Vd, 32.6%). - Mateos et al (2022)15
presented the results of a post hoc subgroup analysis of the CASTOR and POLLUX studies, evaluating the efficacy of D-Vd vs Vd alone (CASTOR) and D-Rd vs Rd alone (POLLUX) in patients with RRMM. In the subgroup of patients aged ≥75 years, improvement in PFS and OS was observed in the pooled intention-to-treat (ITT) population from CASTOR and POLLUX. PFS benefit of the DARZALEX vs control arm was observed in patients with ≥75 years of age in the ITT populations of each of the CASTOR and POLLUX studies. - AURIGA: phase 3 study evaluating the conversion rate to MRD-negativity after maintenance treatment with DARZALEX FASPRO in combination with lenalidomide (D-R) vs lenalidomide (R) alone in patients with NDMM who are anti-cluster of differentiation (CD) 38 naïve, have
≥VGPR, and are MRD-positive following ASCT after standard-of-care induction/consolidation.16 - 18 - Foster et al (2024)19
presented a post hoc analysis of the phase 3 AURIGA study that evaluated clinically relevant subgroups in patients with NDMM at a median follow-up of 32.3 months. The clinically relevant subgroups included elderly and Black patients; patients with high-risk disease per International Staging System (ISS) disease staging; and patients with a high cytogenetic risk per standard, revised, and International Myeloma Society (IMS) 2024 high-risk criteria. A subgroup analysis of MRD-negativity (10-5 sensitivity) conversion rates by 12 months of maintenance showed improvement for D-R vs R regardless of age. No additional safety concerns were observed in patients aged ≥65 years. DARZALEX FASPRO in combination with lenalidomide (D-R) maintenance did not increase grade 3/4 infection or cytopenia rates in patients ≥65 years of age.
- Foster et al (2024)19
- PERSEUS: phase 3 study evaluating the safety and efficacy of DARZALEX FASPRO in combination with bortezomib, lenalidomide, and dexamethasone (D-VRd) vs VRd induction and consolidation followed by maintenance with DARZALEX FASPRO in combination with lenalidomide (D-R) in the D-VRd group or lenalidomide (R) in the VRd group in patients with NDMM eligible for ASCT.20
- Sonneveld et al (2024)20 reported primary results from the phase 3 PERSEUS study at a median follow-up of 47.5 months. The median PFS was not estimable. However, 20 vs 19 events of disease progression or deaths were reported in patients aged ≥65 years from the D-VRd (n=94) vs VRd (n=87) groups, respectively (HR, 0.97; 95% CI, 0.52-1.81).
- Rodriguez-Otero et al (2024)21
presented MRD-negativity results from the phase 3 PERSEUS study in patients aged ≥65 years. The overall MRD-negativity rates were higher in the D-VRd vs VRd group at 10-5 sensitivity (67.0% [63/94] vs 49.4% [43/87]; OR, 2.08; 95% CI, 1.14-3.79) and 10-6 sensitivity (57.4% [54/94] vs 35.6% [37/87]; OR, 2.44; 95% CI, 1.34-4.44). The sustained (≥12 months) MRD-negativity rates were higher in the D-VRd vs VRd group at 10-5 sensitivity (53.2% [50/94] vs 31.0% [27/87]; OR, 2.53; 95% CI, 1.37-4.64) and 10-6 sensitivity (39.4% [37/94] vs 21.8% [19/87]; OR, 2.32; 95% CI, 1.21-4.48). - Moreau et al (2025)22
presented findings from the phase 3 PERSEUS study, highlighting the impact of sustained MRD-negativity on PFS and the incidence of functionally high-risk disease. For patients ≥65 years, the sustained MRD-negativity rates were higher in the D-VRd vs VRd group at ≥12 months (53.2% [50/94] vs 31.0% [27/87]; OR, 2.53; CI, 1.37-4.64) and ≥24 months (43.6% [41/94] vs 23.0% [20/87]; OR, 2.59; CI, 1.36-4.94), respectively.
- Rodriguez-Otero et al (2025)23
reported results from a post hoc, pooled analysis of data from the PERSEUS and GRIFFIN studies. These studies evaluated the efficacy and safety of DARZALEX FASPRO and DARZALEX in combination with bortezomib, lenalidomide, and dexamethasone (D-VRd) vs VRd in patients aged ≥65 years. At a median follow-up of 47.5 months and 49.6 months, the median PFS was not reached in the PERSEUS and GRIFFIN groups, respectively. The PFS HR favored D-VRd vs VRd group (HR, 0.56; 95% CI, 0.31-1.01; P=0.05). The overall MRD-negativity rate (10-5) and sustained MRD-negativity rate (10-5) (≥12 months) in the D-VRd vs VRd group was 66.4% vs 41.7% and of 52.5% vs 26.1%, respectively. A higher incidence of grade 3/4 infections was observed in the D-VRd vs VRd group in patients aged ≥65 years (36.3% vs 24.8%, respectively). The percentage of TEAEs that resulted in the discontinuation of ≥1 study drug was similar between the D-VRd and VRd groups (40.8% and 45.6%, respectively) in patients aged ≥65 years. - Baz et al (2024)24
presented the final results of a phase 2 study of DARZALEX-based response-adapted therapy for older adults with NDMM. The adapted therapy achieved an ORR of 97% and a median PFS of 42 months among a predominantly frail NDMM population. Notably, 37% of patients were treated primarily with DARZALEX and dexamethasone, which had a very tolerable side effect profile. - Sanchez et al (2024)25
,26 presented interim efficacy and safety results of an ongoing, single-center, phase 2 study of DARZALEX FASPRO + dose-attenuated VRd in stem cell transplant (SCT)-ineligible older adults (aged ≥70 years) with NDMM. Of 14 patients who were evaluable for treatment response, 85.7% achieved ≥VGPR, with 50% achieving ≥CR. The most common (occurring in ≥15% of patients) grade 3/4 TEAEs were lymphopenia (42.8%) and neutropenia (28.5%). - Other relevant literature has been identified in addition to the data summarized above and is listed in the References section for your information.27
,28
DARZALEX (daratumumab) [Prescribing Information]. Horsham, PA: Janssen Biotech, http://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/DARZALEX-pi.pdf - DARZALEX FASPRO (daratumumab and hyaluronidase-fihj) [Prescribing Information]. Horsham, PA: Janssen Biotech, Inc.; http://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/DARZALEX+Faspro-pi.pdf
Clinical Data - DARZALEX PHASE 3 STUDIES
Study Design/Methods
- Patients were randomized 2:1 to receive either of the following as 28-day cycles until disease progression:
- D-Kd:
- 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 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).s
- Dexamethasone 40 mg orally (PO) or IV weekly (or 20 mg if ≥75 years starting on the second week).
- Kd: Carfilzomib and dexamethasone as above.
- D-Kd:
- Key eligibility criteria: RRMM; 1-3 prior therapies with ≥ partial response (PR) to ≥ 1 prior therapy; Eastern Cooperative Oncology Group (ECOG) performance status of 0-2; creatinine clearance (CrCl) ≥20 mL/min; left ventricular ejection fraction ≥40%.
Results
Patient Characteristics
- Key demographics and baseline characteristics are summarized in the Table: Key Demographics and Baseline Characteristics (CANDOR).
| Characteristic | D-Kd (n=312) | Kd (n=154) |
|---|---|---|
| Median age (range), years | 64.0 (57-70) | 64.5 (59-71) |
| ≤64, n (%) | 163 (52) | 77 (50) |
| 65-74, n (%) | 121 (39) | 55 (38) |
| ≥75, n (%) | 28 (9) | 22 (14) |
| Abbreviations: D-Kd, DARZALEX + carfilzomib + dexamethasone; Kd, carfilzomib + dexamethasone. | ||
Efficacy
- The HR for median OS favored the D-Kd arm across prespecified age subgroups as summarized in the Table: OS in Prespecified Age Subgroups (CANDOR).
| Age at Baseline, Years | D-Kd (n=312) | Kd (n=154) | Hazard Ratio (95% CI) | ||
|---|---|---|---|---|---|
| Events/ Participants | Median OS (95% CI), Months | Events/ Participants | Median OS (95% CI), Months | ||
| <65 | 75/163 | NE (43.2-NE) | 44/77 | 41.5 (32.6-NE) | 0.714 (0.487-1.045) |
| ≥65 | 73/149 | 48.8 (42.4-NE) | 36/77 | 50.3 (30.8-NE) | 0.912 (0.603-1.381) |
| Abbreviations: CI, confidence interval; D-Kd, DARZALEX, carfilzomib, and dexamethasone; Kd, carfilzomib and dexamethasone; NE, not estimable; OS, overall survival. | |||||
Safety
- Updated safety data was consistent with previously reported results, and no new safety signals were identified with the longer follow-up. In the D-Kd vs Kd arms:
- Grade ≥3 TEAEs occurred in 273 (88.6%) vs 120 (78.4%) patients.
- Serious TEAEs occurred in 211 (68.5%) vs 80 (52.3%) patients.
- Adverse events (AEs) leading to treatment discontinuation occurred in 105 (34.1%) vs 41 (26.8%) patients.
- Fatal TEAEs in patients ≥65 years and <65 years are summarized in Table: Fatal TEAEs.
| Parameter | D-Kd | Kd |
|---|---|---|
| Fatal TEAEs, n (%) | 35 (11.4) | 9 (5.9) |
| Age ≥65 years | 25 (17.4) | 3 (3.9) |
| Age <65 years | 10 (6.3) | 6 (8.0) |
| Abbreviations: D-Kd, DARZALEX + carfilzomib + dexamethasone; Kd, carfilzomib + dexamethasone; TEAE, treatment-emergent adverse event. a | ||
- Patients were randomized 1:1 to receive either of the following (28-day cycles):
- D-Rd (n=368):
- DARZALEX: 16 mg/kg IV every week on cycles 1-2, every 2 weeks on cycles 3-6, and every 4 weeks thereafter until PD.
- Lenalidomide: 25 mg PO daily on days 1-21 until PD (10 mg daily if CrCl between 30-50 mL/min).
- Dexamethasone: 40 mg PO weekly until PD (20 mg weekly in patients >75 years of age or with a body mass index [BMI] <18.5).
- Rd (n=369): lenalidomide and dexamethasone as above.
- D-Rd (n=368):
Results
Patient Characteristics
- The median duration of follow-up was 28.0 months.
- The demographics and baseline characteristics are summarized in the Table: Demographics and Baseline Characteristics of the ITT Population (N=737) by Age Group (MAIA).
| Characteristic | Aged ≥75 years | Aged <75 years | ||
|---|---|---|---|---|
| D-Rd (n=160) | Rd (n=161) | D-Rd (n=208) | Rd (n=208) | |
| Median Age (range), years | 78 (75-90) | 79 (75-89) | 70 (50-74) | 71 (45-74) |
| Male, n (%) | 94 (59) | 88 (55) | 95 (46) | 107 (51) |
| ECOG PS scoreb | ||||
| 0 | 51 (32) | 47 (29) | 76 (37) | 76 (37) |
| 1 | 78 (49) | 83 (52) | 100 (48) | 104 (50) |
| ≥2 | 31 (19) | 31 (19) | 32 (15) | 28 (14) |
| ISS stagec | ||||
| I | 33 (21) | 37 (23) | 65 (31) | 66 (32) |
| II | 75 (47) | 70 (44) | 88 (42) | 86 (41) |
| III | 52 (33) | 54 (34) | 55 (26) | 56 (27) |
| Cytogenetic profiled | ||||
| N | 141 | 138 | 178 | 185 |
| Standard risk, n (%) | 117 (83) | 118 (86) | 154 (87) | 161 (87) |
| High risk, n (%) | 24 (17) | 20 (15) | 24 (14) | 24 (13) |
| Abbreviations: D-Rd, DARZALEX + lenalidomide + dexamethasone; ECOG PS, Eastern Cooperative Oncology Group performance status; ISS, International Staging System; ITT, intent-to-treat; Rd, lenalidomide + dexamethasone. aThe ITT population included all randomized patients. bECOG PS is scored on a scale from 0 to 5, with 0 indicating no symptoms and higher scores indicating increasing disability. cBased on the combination of serum ß2-microglobulin and albumin. dBased on fluorescence in situ hybridization/karyotype testing performed at local sites; t(4;14), t(14;16), and del17p were classified as high risk. Note: percentages may not add up to 100% due to rounding. | ||||
Efficacy
- A lower median relative dose intensity (RDI) of lenalidomide in the D-Rd arm vs the Rd arm was administered regardless of age.
- In the D-Rd arm, 30.8% of patients received a lower starting dose of lenalidomide vs 22.7% in the Rd arm.
- A higher rate of lenalidomide dose modification in the D-Rd arm was observed vs the Rd arm in both age groups due to TEAEs.
- A lower median RDI of dexamethasone was observed in the D-Rd arm vs the Rd arm in patients <75 years old.
- In the ITT population, median PFS was prolonged for D-Rd vs Rd in both age groups.
- For patients aged ≥75 years, PFS was NR with D-Rd vs 31.9 months with Rd (HR, 0.63; 95% CI, 0.44-0.92; P=0.0146).
- For patients aged <75 years, PFS was NR in the D-Rd arm vs 33.7 months with Rd (HR, 0.50; 95% CI, 0.35-0.71; P<0.0001).
- The reduction of risk of PD or death was 37% in the ≥75 years age group and 50% in the <75 years age group in the D-Rd arm.
- In the phase 3 MAIA study, the combination of D-Rd more than tripled MRD-negativity rates, as well as decreased the risk of death or disease progression by 44% vs Rd in patients with transplant-ineligible NDMM.
- The MRD-negativity rate (10-5 sensitivity threshold) was increased with D-Rd vs Rd in both age groups:
- For patients aged ≥75 years, 19.4% in the D-Rd arm vs 7.5% in the Rd arm (P=0.0018).
- For patients aged <75 years, 27.9% in the D-Rd arm vs 7.2% in the Rd arm (P<0.0001).
- The response rates are summarized in the Table: Response Rate of ITT Population by Age Group (MAIA).
| Aged ≥75 Years | Aged <75 Years | |||||
|---|---|---|---|---|---|---|
| D-Rd (n=160) | Rd (n=161) | P Valueb | D-Rd (n=208) | Rd (n=208) | P Valueb | |
| ORR | 144 (90) | 130 (81) | 0.0192 | 198 (95) | 170 (82) | <0.0001 |
| ≥CR | 66 (41) | 40 (25) | 0.0018 | 109 (52) | 52 (25) | <0.0001 |
| sCR | 40 (25) | 19 (12) | 0.0023 | 72 (35) | 27 (13) | <0.0001 |
| ≥VGPR | 123 (77) | 85 (53) | <0.0001 | 169 (81) | 111 (53) | <0.0001 |
| VGPR | 57 (36) | 45 (28) | - | 60 (29) | 59 (28) | - |
| PR | 21 (13) | 45 (28) | - | 29 (14) | 59 (28) | - |
| SD | 7 (4) | 22(14) | - | 4 (2) | 34 (16) | - |
| PD | 1 (1) | 0 | - | 0 | 0 | - |
| NE | 8 (5) | 9 (6) | - | 6 (3) | 4 (2) | - |
| Abbreviations: ≥CR, complete response or better; D-Rd, DARZALEX + lenalidomide + dexamethasone; ITT, intent-to-treat; NE, not evaluable; ORR, overall response rate; PD, progressive disease; PR, partial response; Rd, lenalidomide + dexamethasone; sCR, stringent complete response; SD, stable disease; ≥VGPR, very good partial response or better. aThe ITT population included all randomized patients. bCochran-Mantel-Haenszel chi-square test. | ||||||
Safety
- For patients aged ≥75 years, serious TEAEs were reported in 65.6% and 70.4% in the D-Rd arm vs the Rd arm, respectively.
- For patients aged <75 years, serious TEAEs were reported in 60.9% and 56.8% in the D-Rd arm vs the Rd arm, respectively.
- The rates of treatment discontinuation due to TEAEs:
- Aged ≥75 years: 10.2% and 20.8% receiving D-Rd and Rd, respectively.
- Aged <75 years: 4.8% and 2.1% receiving D-Rd and Rd, respectively.
- IRRs in the D-Rd arm occurred in 35.7% of patients in the ≥75 years old group vs 44.9% in the <75 years old group.
- No new safety concerns were observed, and grade 3/4 infection rates were consistent with the overall population.
- The most common all-grade TEAEs and incidence of infection are summarized in the Table: Most Common (≥30%) All-Grade TEAEs and Incidence of Infections (MAIA).
- The most common grade 3/4 TEAEs and incidence of infection are summarized in the Table: Most Common (≥10% of Patients) Grade 3/4 TEAEs and Incidence of Infections (MAIA).
| Aged ≥75 Years | Aged <75 Years | |||
|---|---|---|---|---|
| D-Rd (n=157) | Rd (n=159) | D-Rd (n=207) | Rd (n=206) | |
| Hematologic | ||||
| Neutropenia | 103 (66) | 76 (48) | 104 (50) | 78 (38) |
| Anemia | 61 (39) | 69 (43) | 65 (31) | 69 (34) |
| Nonhematologic | ||||
| Diarrhea | 84 (54) | 74 (47) | 123 (59) | 94 (46) |
| Constipation | 70 (45) | 60 (38) | 79 (38) | 70 (34) |
| Peripheral edema | 70 (45) | 51 (32) | 70 (34) | 56 (27) |
| Fatigue | 67 (43) | 43 (27) | 80 (39) | 61 (30) |
| Back pain | 53 (34) | 46 (29) | 70 (34) | 50 (24) |
| Asthenia | 49 (31) | 39 (25) | 68 (33) | 51 (25) |
| Weight decreased | 47 (30) | 26 (16) | 54 (26) | 37 (18) |
| Nausea | 42 (27) | 38 (24) | 73 (35) | 46 (22) |
| Muscle spasms | 41 (26) | 32 (20) | 66 (32) | 47 (23) |
| Insomnia | 39 (25) | 38 (24) | 70 (34) | 69 (34) |
| Cough | 39 (25) | 23 (15) | 61 (30) | 36 (18) |
| Dyspnea | 36 (23) | 29 (18) | 65 (31) | 27 (13) |
| Infectionsb | 133 (85) | 112 (70) | 181 (87) | 156 (76) |
| Bronchitis | 43 (27) | 28 (18) | 63 (30) | 46 (22) |
| Abbreviations: D-Rd, DARZALEX + lenalidomide + dexamethasone; MedDRA, Medical Dictionary for Regulatory Activities; Rd, lenalidomide + dexamethasone; TEAE, treatment-emergent adverse event. aIncludes all patients who received ≥1 dose of study treatment. bMedDRA system organ class. | ||||
| TEAEs, n (%) | Aged ≥75 Years | Aged <75 Years | ||
|---|---|---|---|---|
| D-Rd (n=157) | Rd (n=159) | D-Rd (n=207) | Rd (n=206) | |
| Patients with grade 3/4 TEAEs | 148 (94) | 141 (89) | 179 (87) | 160 (78) |
| Neutropenia | 94 (60) | 65 (41) | 88 (43) | 64 (31) |
| Lymphopenia | 30 (19) | 19 (12) | 25 (12) | 20 (10) |
| Anemia | 25 (16) | 35 (22) | 18 (9) | 37 (18) |
| Leukopenia | 19 (12) | 9 (6) | 21 (10) | 9 (4) |
| Infectionsb | 51 (33) | 38 (24) | 66 (32) | 47 (23) |
| Pneumonia | 24 (15) | 16 (10) | 26 (13) | 13 (6) |
| Abbreviations: D-Rd, DARZALEX + lenalidomide + dexamethasone; MedDRA, Medical Dictionary for Regulatory Activities; Rd, lenalidomide + dexamethasone; TEAE, treatment-emergent adverse event. aIncludes all patients who received ≥1 dose of study treatment. bMedDRA system organ class. | ||||
Updated Analysis of the MAIA Study
Results
Patient Characteristics
- A total of 737 (D-Rd, n=368; Rd, n=369) patients were randomized in this study.7
- The median follow-up was 64.5 months (range, 0-77.6).7
- Baseline characteristics based on age subgroups are summarized in Table: Demographic and Baseline Disease Characteristics Based on Age Subgroups.
- The median treatment duration was 47.5 months (range, 0.1-77.3) vs 22.6 months (range, 0.03-77.5) in the D-Rd vs Rd arm, respectively.30
- As of the clinical cutoff date of October 21, 2021, 233 (64.0%) vs 311 (85.2%) patients from the D-Rd vs Rd arm, respectively, discontinued treatment; the main reasons for discontinuation were PD (D-Rd, 29.4%; Rd, 35.9%) and AEs (D-Rd, 15.7%; Rd, 24.4%).7 The proportion of patients who discontinued treatment across the arms is summarized in Table: Patient Disposition and Treatment Discontinuation According to Age Group (MAIA - Long-term Follow-up).
| Characteristic | <70 Years | ≥70 to <75 Years | ≥75 Years | ≥80 Years | ||||
|---|---|---|---|---|---|---|---|---|
| D-Rd (n=78) | Rd (n=77) | D-Rd (n=130) | Rd (n=131) | D-Rd (n=160) | Rd (n=161) | D-Rd (n=66) | Rd (n=71) | |
| Age | ||||||||
| Median (range), years | 68 (50-69) | 68 (45-69) | 72 (70-74) | 72 (70-74) | 78 (75-90) | 79 (75-89) | 82 (79-90) | 82 (80-89) |
| Abbreviations: D-Rd, DARZALEX + lenalidomide + dexamethasone; Rd, lenalidomide/dexamethasone. | ||||||||
| Parameter | <70 Years | ≥70 to <75 Years | ≥75 Years | ≥80 Years | ||||
|---|---|---|---|---|---|---|---|---|
| D-Rd (n=78) | Rd (n=77) | D-Rd (n=130) | Rd (n=131) | D-Rd (n=160) | Rd (n=161) | D-Rd (n=66) | Rd (n=71) | |
| Patients treateda, n (%) | 78 (100) | 76 (98.7) | 129 (99.2) | 130 (99.2) | 157 (98.1) | 159 (98.8) | 65 (98.5) | 70 (98.6) |
| Patients who discontinued treatmentb, n (%) | 37 (47.4) | 64 (84.2) | 79 (61.2) | 106 (81.5) | 117 (74.5) | 141 (88.7) | 44 (67.7) | 64 (91.4) |
| Reasons for discontinuation, n (%) | ||||||||
| PD | 17 (21.8) | 34 (44.7) | 42 (32.6) | 47 (36.2) | 48 (30.6) | 50 (31.4) | 20 (30.8) | 22 (31.4) |
| AE | 9 (11.5) | 12 (15.8) | 20 (15.5) | 33 (25.4) | 28 (17.8) | 44 (27.7) | 6 (9.2) | 21 (30.0) |
| Noncompliance with study drug | 5 (6.4) | 5 (6.6) | 7 (5.4) | 7 (5.4) | 9 (5.7) | 18 (11.3) | 5 (7.7) | 7 (10.0) |
| Death | 5 (6.4) | 2 (2.6) | 5 (3.9) | 7 (5.4) | 14 (8.9) | 16 (10.1) | 6 (9.2) | 6 (8.6) |
| Physician’s decision | 1 (1.3) | 9 (11.8) | 3 (2.3) | 7 (5.4) | 12 (7.6) | 8 (5.0) | 3 (4.6) | 6 (8.6) |
| Patient withdrawal | 0 (0) | 2 (2.6) | 1 (0.8) | 3 (2.3) | 1 (0.6) | 3 (1.9) | 0 (0) | 0 (0) |
| Lost to follow-up | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 1 (0.6) | 2 (1.3) | 1 (1.5) | 2 (2.9) |
| Other | 0 (0) | 0 (0) | 1 (0.8) | 2 (1.5) | 4 (2.5) | 0 (0) | 3 (4.6) | 0 (0) |
| Abbreviations: AE, adverse event; D-Rd, DARZALEX + lenalidomide + dexamethasone; PD, progressive disease; Rd, lenalidomide + dexamethasone. aPercentages are based on the number of patients randomized. bPercentages are based on the number of patients treated. | ||||||||
Efficacy
- PFS improved with D-Rd vs Rd across subgroups of patients based on age as summarized in Table: PFS and OS Based on Age Subgroups.
- The PFS benefit with D-Rd vs Rd was consistent across prespecified subgroups based on baseline characteristics as presented in Table: Analysis of PFS in Prespecified Patient Subgroups.
- OS improved with D-Rd vs Rd across subgroups of patients based on age as summarized in Table: PFS and OS Based on Age Subgroups:
- The OS benefit with D-Rd vs Rd was consistent across prespecified patient subgroups based on baseline characteristics as presented in Table: Analysis of OS in Prespecified Patient Subgroups.
- The ORR, ≥CR rate, and ≥VGPR rate were higher for the D-Rd vs Rd arm across all age subgroups and are summarized in Table: Response Rates Based on Age Subgroups.
- The D-Rd vs Rd arm was associated with an increased MRD-negativity rate across all age subgroups as summarized in Table: Response Rates Based on Age Subgroups.
| Parameter | Age <70 Years | Age ≥70 to <75 Years | Age ≥75 Years | Age ≥80 Years | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| D-Rd (n=78) | Rd (n=77) | HR (95% CI) | P Value | D-Rd (n=130) | Rd (n=131) | HR (95% CI) | P Value | D-Rd (n=160) | Rd (n=161) | HR (95% CI) | P Value | D-Rd (n=66) | Rd (n=71) | HR (95% CI) | P Value | |
| PFS | ||||||||||||||||
| Median, months | NR | 39.2 | 0.35 (0.21-0.56) | <0.0001 | 61.9 | 37.5 | 0.64 (0.45-0.89) | 0.0079 | 54.3 | 31.4 | 0.59 (0.44-0.79) | 0.0003 | 52.2 | 30.4 | 0.48 (0.31-0.76) | 0.0011 |
| OS | ||||||||||||||||
| Median, months | - | - | 0.50 (0.27-0.90) | 0.0179 | - | - | 0.64 (0.43-0.96) | 0.0274 | - | - | 0.75 (0.55-1.02) | 0.0671 | - | - | 0.71 (0.44-1.14) | 0.1574 |
| Abbreviations: CI, confidence interval; D-Rd, DARZALEX + lenalidomide + dexamethasone; HR, hazard ratio; NR, not reachable; OS, overall survival; Rd, lenalidomide + dexamethasone. | ||||||||||||||||
| Subgroup | D-Rd | Rd | HR (95% CI)b | ||
|---|---|---|---|---|---|
| n/N | Median PFS, Months | n/N | Median PFS, Months | ||
| Age | |||||
| <75 years | 89/208 | NE | 122/208 | 37.5 | 0.52 (0.39-0.68) |
| ≥75 years | 87/160 | 54.3 | 106/161 | 31.4 | 0.59 (0.44-0.79) |
| Abbreviations: CI, confidence interval; D-Rd, DARZALEX + lenalidomide + dexamethasone; HR, hazard ratio; NE, not estimable; PFS, progression-free survival; Rd, lenalidomide + dexamethasone. aAnalysis of PFS in subgroups of the ITT population, which were defined according to baseline characteristics. bHRs and 95% CIs from a Cox proportional hazards model with treatment as the sole explanatory variable. HR <1 indicates an advantage for D-Rd. | |||||
| Subgroup | D-Rd | Rd | HR (95% CI)b | ||
|---|---|---|---|---|---|
| n/N | Median OS, Months | n/N | Median OS, Months | ||
| Age | |||||
| <75 years | 59/208 | NE | 90/208 | NE | 0.59 (0.43-0.83) |
| ≥75 years | 73/160 | 73.7 | 86/161 | 54.8 | 0.75 (0.55-1.02) |
| Abbreviations: CI, confidence interval; D-Rd, DARZALEX + lenalidomide + dexamethasone; HR, hazard ratio; NE, not estimable; OS, overall survival; Rd, lenalidomide + dexamethasone. aAnalysis of OS in subgroups of the ITT population, which were defined according to baseline characteristics. bHRs and 95% CIs from a Cox proportional hazards model with treatment as the sole explanatory variable. HR <1 indicates an advantage for D-Rd. | |||||
| Response, n (%) | Age <70 Years | Age ≥70 to <75 Years | Age ≥75 Years | Age ≥80 Years | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| D-Rd (n=78) | Rd (n=77) | P Value | D-Rd (n=130) | Rd (n=131) | P Value | D-Rd (n=160) | Rd (n=161) | P Value | D-Rd (n=66) | Rd (n=71) | P Value | |
| ORR | 73 (93.6) | 62 (80.5) | 0.0156a | 125 (96.2) | 108 (82.4) | 0.0004a | 144 (90.0) | 131 (81.4) | 0.0275a | 59 (89.4) | 55 (77.5) | 0.0629a |
| ≥CR | 44 (56.4) | 24 (31.2) | 0.0016a | 73 (56.2) | 41 (31.3) | <0.0001a | 71 (44.4) | 46 (28.6) | 0.0033a | 29 (43.9) | 15 (21.1) | 0.0044a |
| sCR | 31 (39.7) | 11 (14.3) | 0.0004a | 50 (38.5) | 23 (17.6) | 0.0002a | 50 (31.3) | 24 (14.9) | 0.0005 | 23 (34.8) | 8 (11.3) | 0.0010a |
| CR | 13 (16.7) | 13 (16.9) | - | 23 (17.7) | 18 (13.7) | - | 21 (13.1) | 22 (13.7) | - | 6 (9.1) | 7 (9.9) | - |
| ≥VGPR | 64 (82.1) | 45 (58.4) | 0.0013a | 111 (85.4) | 76 (58.0) | <0.0001a | 125 (78.1) | 89 (55.3) | <0.0001a | 50 (75.8) | 31 (43.7) | 0.0001a |
| VGPR | 20 (25.6) | 21 (27.3) | - | 38 (29.2) | 35 (26.7) | - | 54 (33.8) | 43 (26.7) | - | 21 (31.8) | 16 (22.5) | - |
| PR | 9 (11.5) | 17 (22.1) | - | 14 (10.8) | 32 (24.4) | - | 19 (11.9) | 42 (26.1) | - | 9 (13.6) | 24 (33.8) | - |
| SD | 1 (1.3) | 14 (18.2) | - | 3 (2.3) | 20 (15.3) | - | 7 (4.4) | 21 (13.0) | - | 3 (4.5) | 11 (15.5) | - |
| PD | 0 (0) | 0 (0) | - | 0 (0) | 0 (0) | - | 1 (0.6) | 0 (0) | - | 0 (0) | 0 (0) | - |
| NE | 4 (5.1) | 1 (1.3) | - | 2 (1.5) | 3 (2.3) | - | 8 (5.0) | 9 (5.6) | - | 4 (6.1) | 5 (7.0) | - |
| MRD-negativity response rate, n (%) | 28 (35.9) | 9 (11.7) | 0.0006 | 47 (36.2) | 16 (12.2) | 0.0001 | 43 (26.9) | 16 (9.9) | 0.0001 | 17 (25.8) | 4 (5.6) | 0.0016 |
| Abbreviations: CR, complete response; D-Rd, DARZALEX + lenalidomide + dexamethasone; MRD, minimal residual disease; NE, not estimable; ORR, overall response rate; PD, progressive disease; PR, partial response; Rd, lenalidomide + dexamethasone; sCR, stringent complete response; SD, stable disease; VGPR, very good partial response. aP value was calculated using the Cochran-Mantel-Haenszel chi-square test. | ||||||||||||
Safety
- No new safety concerns were observed with a longer follow-up.7
- Grade 3/4 TEAEs occurred in 95.9% vs 88.8% of patients from the D-Rd vs Rd arm, respectively.
- Among patients aged ≥75 years, grade 3/4 TEAEs occurred in 95.5% vs 95.0% of patients from the D-Rd vs Rd arm, respectively.
- Among patients aged ≥80 years, grade 3/4 TEAEs occurred in 92.3% vs 95.7% of patients from the D-Rd vs Rd arm, respectively.
- The rates of common grade 3/4 TEAEs in patients aged ≥75 years and those aged ≥80 years were similar to those in the overall study population.
- The most common (≥20%) grade 3/4 TEAEs with D-Rd vs Rd were neutropenia (54.1% vs 37.0%, respectively) and anemia (17.0% vs 21.6%, respectively). A summary of the most common TEAEs is presented in Table: Most Common Any-Grade or Grade 3/4 TEAEs Among Patients Aged ≥75 Years and ≥80 Years in the Safety Population.
- Grade 3/4 infections occurred in 42.6% vs 29.6% of patients from the D-Rd vs Rd arm, respectively.
- Serious TEAEs occurred in 78.8% vs 71.0% of patients from the D-Rd vs Rd arm, respectively, with pneumonia being the most common serious TEAE (18.7% vs 10.7%, respectively).
- Among patients aged ≥75 years, serious TEAEs occurred in 80.9% vs 79.2% of patients from the D-Rd vs Rd arm, respectively, with pneumonia being the most common serious TEAE (19.7% vs 12.6%, respectively).
- Among patients aged ≥80 years, serious TEAEs occurred in 81.5% vs 82.9% of patients from the D-Rd vs Rd arm, respectively, with pneumonia being the most common serious TEAE (24.6% vs 8.6%, respectively).
- The overall discontinuation rate due to TEAEs was lower in the D-Rd vs Rd arm (14.6% vs 23.8%).
- Among patients aged ≥75 years, treatment discontinuation due to TEAEs was reported in 15.3% vs 27.7% of patients from the D-Rd vs Rd arm, respectively.
- Among patients aged ≥80 years, treatment discontinuation due to TEAEs was reported in 6.2% vs 20.0% of patients from the D-Rd vs Rd arm, respectively.
- TEAEs leading to death were reported in 9.9% vs 9.3% of patients from the D-Rd vs Rd arm, respectively.
- Among patients aged ≥75 years, TEAEs leading to death were reported in 11.5% vs 13.2% of patients from the D-Rd vs Rd arm, respectively.
- Among patients aged ≥80 years, TEAEs leading to death were reported in 12.3% vs 11.4% of patients from the D-Rd vs Rd arm, respectively.
- Grade 3/4 TEAEs occurred in 95.9% vs 88.8% of patients from the D-Rd vs Rd arm, respectively.
| TEAE, n (%) | Patients Aged ≥75 Years | Patients Aged ≥80 Years | ||||||
|---|---|---|---|---|---|---|---|---|
| D-Rd (n=157) | Rd (n=159) | D-Rd (n=65) | Rd (n=70) | |||||
| Any Grade | Grade 3/4 | Any Grade | Grade 3/4 | Any Grade | Grade 3/4 | Any Grade | Grade 3/4 | |
| Hematologic | ||||||||
| Neutropenia | 109 (69.4) | 98 (62.4) | 81 (50.9) | 66 (41.5) | 45 (69.2) | 37 (56.9) | 34 (48.6) | 26 (37.1) |
| Anemia | 71 (45.2) | 32 (20.4) | 73 (45.9) | 40 (25.2) | 31 (47.7) | 12 (18.5) | 35 (50.0) | 19 (27.1) |
| Thrombocytopenia | 39 (24.8) | 16 (10.2) | 43 (27.0) | 19 (11.9) | 21 (32.3) | 7 (10.8) | 20 (28.6) | 8 (11.4) |
| Lymphopenia | 37 (23.6) | 33 (21.0) | 25 (15.7) | 20 (12.6) | 10 (15.4) | 8 (12.3) | 13 (18.6) | 10 (14.3) |
| Nonhematologic | ||||||||
| Diarrhea | 98 (62.4) | 16 (10.2) | 80 (50.3) | 8 (5.0) | 37 (56.9) | 5 (7.7) | 35 (50.0) | 3 (4.3) |
| Peripheral edema | 76 (48.4) | 6 (3.8) | 53 (33.3) | 2 (1.3) | 31 (47.7) | 0 (0.0) | 24 (34.3) | 2 (2.9) |
| Constipation | 75 (47.8) | 2 (1.3) | 61 (38.4) | 1 (0.6) | 27 (41.5) | 0 (0.0) | 27 (38.6) | 1 (1.4) |
| Fatigue | 73 (46.5) | 15 (9.6) | 48 (30.2) | 8 (5.0) | 26 (40.0) | 7 (10.8) | 19 (27.1) | 3 (4.3) |
| Back pain | 65 (41.4) | 7 (4.5) | 53 (33.3) | 6 (3.8) | 24 (36.9) | 2 (3.1) | 21 (30.0) | 2 (2.9) |
| Asthenia | 58 (36.9) | 8 (5.1) | 43 (27.0) | 10 (6.3) | 25 (38.5) | 3 (4.6) | 26 (37.1) | 8 (11.4) |
| Weight decreased | 49 (31.2) | 6 (3.8) | 31 (19.5) | 5 (3.1) | 19 (29.2) | 2 (3.1) | 16 (22.9) | 2 (2.9) |
| Bronchitis | 48 (30.6) | 7 (4.5) | 31 (19.5) | 4 (2.5) | 18 (27.7) | 2 (3.1) | 15 (21.4) | 1 (1.4) |
| Nausea | 48 (30.6) | 2 (1.3) | 40 (25.2) | 0 (0.0) | 21 (32.3) | 1 (1.5) | 20 (28.6) | 0 (0.0) |
| Pneumonia | 44 (28.0) | 32 (20.4) | 33 (20.8) | 23 (14.5) | 22 (33.8) | 17 (26.2) | 13 (18.6) | 8 (11.4) |
| Pyrexia | 44 (28.0) | 6 (3.8) | 22 (13.8) | 3 (1.9) | 20 (30.8) | 4 (6.2) | 7 (10.0) | 0 (0.0) |
| Abbreviations: D-Rd, DARZALEX + lenalidomide + dexamethasone; Rd, lenalidomide + dexamethasone; TEAE, treatment-emergent adverse event. aAny-grade TEAEs that are listed are those that occurred in ≥30% of patients in either group. | ||||||||
Study Design/Methods
- Eligible patients were randomized 1:1 to receive D-MVP (n=350) or VMP (n=356).
- Randomization was stratified by the ISS disease stage (I, II, and III); higher stages indicate poor prognosis.
- Staging was based on the central laboratory results of albumin and β2-microglobulin levels at screening, geographical region (Europe vs other), and age (<75 years vs ≥75 years).
- In both treatment groups, patients received up to nine 6-week cycles of subcutaneous bortezomib (1.3 mg/m2 of body surface area, twice per week on weeks 1, 2, 4, and 5 of cycle 1 and once weekly on weeks 1, 2, 4, and 5 of cycles 2-9), oral melphalan (9 mg/m², once daily on days 1-4 of each cycle), and prednisone (60 mg/m², once daily on days 1-4 of each cycle).
- In the D-VMP group, patients received DARZALEX at a dose of 16 mg/kg IV once weekly during cycle 1; once every 3 weeks during cycles 2-9; and once every 4 weeks thereafter until disease progression, unacceptably toxicity, or the end of study.
Results
Patient Characteristics and Disposition
- Baseline characteristics were balanced between the D-VMP and VMP treatment groups and are summarized in Table: Baseline Demographics and Patient Characteristics in the ITT Population.32
Baseline Demographics and Patient Characteristics in the ITT Population
| Characteristic | D-VMP (n=350) | VMP (n=356) | Total (N=706) |
|---|---|---|---|
| Age | |||
| Median (range), years | 71 (40-93) | 71 (50-91) | 71 (40-93) |
| Distribution, n (%) | |||
| <65 years | 36 (10) | 24 (7) | 60 (8) |
| 65-74 years | 210 (60) | 225 (63) | 435 (62) |
| ≥75 years | 104 (30) | 107 (30) | 211 (30) |
| Sexb, n (%) | |||
| Male | 160 (46) | 167 (47) | 327 (46) |
| Female | 190 (54) | 189 (53) | 379 (54) |
| Raceb, n (%) | |||
| White | 297 (85) | 304 (85) | 601 (85) |
| Asian | 47 (13) | 45 (13) | 92 (13) |
| Black or African American | 3 (1) | 3 (1) | 6 (1) |
| Otherc | 1 (<1) | 3 (1) | 4 (1) |
| Unknown/not reported | 2 (1) | 1 (<1) | 3 (<1) |
| Ethnicity, n (%) | |||
| Hispanic or Latino | 24 (7) | 16 (4) | 40 (6) |
| Not Hispanic or Latino | 320 (91) | 332 (93) | 652 (92) |
| Unknown/not reported | 6 (2) | 8 (2) | 14 (2) |
| ECOG performance statusd, n (%) | |||
| 0 | 78 (22) | 99 (28) | 177 (25) |
| 1 | 182 (52) | 173 (49) | 355 (50) |
| 2 | 90 (26) | 84 (24) | 174 (25) |
| ISS disease stagee | |||
| I | 69 (20) | 67 (19) | 136 (19) |
| II | 139 (40) | 160 (45) | 299 (42) |
| III | 142 (41) | 129 (36) | 271 (38) |
| Cytogenetic risk profilef | |||
| Standard risk | 261/314 (83) | 257/302 (85) | 518/616 (84) |
| High risk | 53/314 (17) | 45/302 (15) | 98/616 (16) |
| Median time since diagnosis of multiple myeloma (range), months | 0.76 (0.1-11.4) | 0.82 (0.1-25.3) | 0.79 (0.1-25.3) |
| Abbreviations: D-VMP, DARZALEX + bortezomib + melphalan + prednisone; ECOG, Eastern Cooperative Oncology Group; ISS, International Staging System; ITT, intention-to-treat; VMP, bortezomib + melphalan + prednisone. aThe ITT population was defined as all patients who were randomized. bSex and race were self-reported by patients. cPatients reporting multiple races. dThe ECOG performance status is scored on a scale from 0 to 5, with 0 indicating no symptoms and higher scores indicating increasing disability. eThe ISS disease stage is based on the combination of serum β2-microglobulin and albumin levels. Higher stages indicate more advanced disease. fCytogenetic risk was assessed using fluorescence in situ hybridization or karyotype testing; high risk was defined as the presence of t(4;14), t(14;16), or del(17p). | |||
- At final analysis clinical cutoff date of May 31, 2023, the median duration of treatment in the D-VMP vs VMP groups was 33.0 months (IQR, 14.5-77.3) vs 12.0 months (IQR, 7.2-12.0), respectively.10
- Patient disposition in the ITT population is summarized in Table: Summary of Patient Disposition.10,32
| Parameter | D-VMP (n=350) | VMP (n=356) |
|---|---|---|
| Patients treated, n (%) | 346 (99) | 354 (99) |
| Patients still on treatment, n (%) | 76 (22) | 0 (0) |
| Patients who discontinued treatment, n (%)b | 270 (78) | 118 (33) |
| Reason for discontinuation | ||
| Progressive disease, n (%) | 167 (48) | 47 (13) |
| Adverse event, n | 32 | 34 |
| Death, n | 28 | 8 |
| Noncompliance with study drug, n | 16 | 15 |
| Patient withdrawal, n | 15 | 6 |
| Physician decision, n | 4 | 7 |
| Lost to follow-up, n | 2 | 0 |
| Other, n | 6 | 1 |
| Abbreviations: D-VMP, DARZALEX + bortezomib + melphalan + prednisone; VMP, bortezomib + melphalan + prednisone. | ||
Efficacy
- At a median follow-up of 86.7 months (IQR, 28.5-85.2), the median OS in the D-VMP vs VMP group was 83.0 months (95% CI, 72.5-not estimable) vs 53.6 months (95% CI, 46.3-60.9), respectively (HR, 0.65; 95% CI, 0.53-0.80; P<0.0001).10
- Details regarding patients censored for OS are summarized in Table: Summary of Reasons for Censoring for OS in the ITT Population.32
- A prespecified subgroup analysis of OS indicated a nonsignificant trend favoring D-VMP group vs the VMP in patients ≥75 years of age and other subgroups with poor prognosis, such as those with renal impairment or ISS stage III disease. Results of prespecified subgroup analyses for OS in the DVMP and VMP groups are presented in Table: OS in Prespecified Subgroups in the ITT Population.10
| Parameter, n (%) | D-VMP (n=350) | VMP (n=356) |
|---|---|---|
| Patients censored | 178 (51) | 139 (39) |
| Reason for censoring | ||
| Other | 134 (38) | 90 (25) |
| End of data collection | 130 (37) | 87 (24) |
| Withdrawal by patient | 29 (8) | 30 (8) |
| Lost to follow-up | 15 (4) | 18 (5) |
| Physician decision | 0 | 1 (<1) |
| Abbreviations: D-VMP, DARZALEX + bortezomib + melphalan + prednisone; ITT, intention-to-treat; OS, overall survival; VMP, bortezomib + melphalan + prednisone. | ||
| Subgroup | D-VMP | VMP | HR (95% CI) | ||
|---|---|---|---|---|---|
| Events/Patients n/N | Median (95% CI), Months | Events/Patients sn/N | Median (95% CI), Months | ||
| All patients | 172/350 | 83.0 (72.5-NE) | 217/356 | 53.6 (46.3-60.9) | 0.65 (0.53-0.80) |
| Sex | |||||
| Male | 84/160 | 72.7 (60.3-89.1) | 99/167 | 50.7 (42.3-68.5) | 0.71 (0.53-0.95) |
| Female | 88/190 | 89.2 (74.1-NE) | 118/189 | 55.1 (46.9-64.8) | 0.60 (0.46-0.79) |
| Age | |||||
| <75 years | 112/246 | 89.2 (78.7-NE) | 144/249 | 56.6 (47.7-69.4) | 0.62 (0.48-0.79) |
| ≥75 years | 60/104 | 59.1 (50.7-82.7) | 73/107 | 49.7 (39.2-57.5) | 0.74 (0.53-1.04) |
| Race | |||||
| White | 154/297 | 80.1 (63.6-89.1) | 191/304 | 52.9 (45.7-58.8) | 0.67 (0.54-0.83) |
| Other | 18/53 | NE (72.7-NE) | 26/52 | 78.1 (39.6-NE) | 0.54 (0.29-0.98) |
| Region | |||||
| Europe | 149/289 | 81.0 (63.8-89.1) | 187/295 | 53.6 (45.7-58.9) | 0.67 (0.54-0.83) |
| Other | 23/61 | NE (69.7-NE) | 30/61 | 57.9 (39.6-NE) | 0.57 (0.33-0.99) |
| Baseline renal function (CrCl) | |||||
| >60 mL/min | 99/200 | 85.9 (64.5-NE) | 119/211 | 57.9 (47.9-72.6) | 0.72 (0.55-0.94) |
| ≤60 mL/min | 73/150 | 80.1 (63.6-NE) | 98/145 | 48.1 (38.0-56.0) | 0.56 (0.41-0.76) |
| Baseline hepatic functiona | |||||
| Normal | 151/304 | 82.7 (69.7-NE) | 181/304 | 55.7 (48.1-66.4) | 0.68 (0.55-0.85) |
| Impaired | 21/46 | 85.9 (44.6-NE) | 36/52 | 40.7 (26.5-56.0) | 0.49 (0.28-0.84) |
| ISS disease stageb | |||||
| I | 19/69 | 94.4 (94.4-NE) | 27/67 | NE (67.0-NE) | 0.53 (0.29-0.95) |
| II | 68/139 | 83.0 (59.5-NE) | 96/160 | 61.3 (50.7-78.1) | 0.70 (0.51-0.96) |
| III | 85/142 | 63.6 (52.9-79.2) | 94/129 | 42.3 (36.0-46.9) | 0.60 (0.45-0.81) |
| Type of MM | |||||
| IgG | 105/207 | 81.0 (62.9-NE) | 133/218 | 58.2 (46.9-69.4) | 0.70 (0.54-0.90) |
| Non-IgG | 48/82 | 72.5 (54.4-85.9) | 52/83 | 46.2 (42.7-56.6) | 0.73 (0.49-1.08) |
| Cytogenetic risk at study entryc | |||||
| High risk | 35/53 | 46.2 (26.7-72.5) | 31/45 | 39.5 (31.6-54.1) | 0.91 (0.56-1.47) |
| Standard risk | 122/261 | 85.9 (78.7-NE) | 156/257 | 55.1 (48.1-66.4) | 0.59 (0.47-0.75) |
| ECOG PS | |||||
| 0 | 26/78 | NE (83.0-NE) | 58/99 | 53.7 (43.9-75.7) | 0.40 (0.25-0.63) |
| 1-2 | 146/272 | 72.5 (59.2-85.9) | 159/257 | 52.9 (45.2-58.9) | 0.72 (0.58-0.90) |
| Abbreviations: CI, confidence interval; CrCl, creatinine clearance; D-VMP, DARZALEX + bortezomib + melphalan + prednisone; ECOG PS, Eastern Cooperative Oncology Group performance status; HR, hazard ratio; IgG, immunoglobulin G; ISS, International Staging System; ITT, intention-to-treat; MM, multiple myeloma; NE, not estimable; OS, overall survival; ULN, upper limit of normal; VMP, bortezomib + melphalan + prednisone. aImpaired baseline hepatic function includes mild (total bilirubin ≤ULN and aspartate aminotransferase >ULN or total bilirubin >ULN but ≤1.5× ULN), moderate (total bilirubin >1.5× ULN but ≤3× ULN), and severe (total bilirubin >3× ULN). bThe ISS disease stage is derived based on the combination of serum β2-microglobulin and albumin concentrations. cHigh-risk cytogenetics are defined either by fluorescence in situ hybridization testing: t(4;14), t(14;16), or del(17p); or by karyotype testing: t(4;14) or del(17p). | |||||
- The MRD-negativity rate (at the 10-5 and 10-6 sensitivity levels) was higher in the D-VMP group than in the VMP group. Compared with the VMP group, the D-VMP group had a higher durable MRD-negativity rate (10-5 sensitivity level) for ≥6 and ≥12 months. The MRD status of the DVMP and VMP groups is summarized in Table: Summary of MRD-Negativity Rates and Durable MRD-Negativity Rates in the ITT Population.10
- In the D-VMP and VMP groups, a longer OS was observed in patients who were MRD-negative (HR, 0.60; 95% CI, 0.31-1.14) than that in patients who were not MRD-negative (HR, 0.77; 95% CI, 0.62-0.95).10
| Parameter | DVMP (n=350) | VMP (n=356) | OR (95% CI)a,b | P Valuec |
|---|---|---|---|---|
| MRD-negativity, n (%) | ||||
| 10-5 | 99 (28) | 25 (7) | 5.23 (3.27-8.36) | <0.0001 |
| 10-6 | 33 (9) | 3 (1) | 12.96 (3.85-43.57) | <0.0001 |
| Durable MRD-negativity (10-5)d, n (%) | ||||
| ≥6 months | 56 (16) | 16 (4) | 4.05 (2.27-7.21) | <0.0001 |
| ≥12 months | 49 (14) | 10 (3) | 5.63 (2.80-11.31) | <0.0001 |
| Abbreviations: CI, confidence interval; DVMP, DARZALEX + bortezomib + melphalan + prednisone; ISS, International Staging System; ITT, intention-to-treat; MRD, minimal residual disease; OR, odds ratio; VMP, bortezomib + melphalan + prednisone. aAMantel-Haenszel estimate of the common OR for stratified tables was used for the MRD status. The stratification factors were as follows: ISS disease stage (I, II, or III), region (Europe vs other), and age (<75 years vs ≥75 years) as randomized. An OR of greater than 1 indicates an advantage for D-VMP. bA Mantel-Haenszel estimate of the common OR without stratification was used for the durable MRD status. An OR greater than 1 indicates an advantage for D-VMP. cP values were derived from a Fisher’s exact test. dDurable MRD-negativity was defined as the absence of MRD confirmed at least 6 or 12 months apart without any instances of MRD-positivity in between the assessments. | ||||
- In the ITT population, 46% vs 72% of patients in the D-VMP vs VMP group were initiated on subsequent antimyeloma therapy or died from progressive disease without subsequent treatment.10
- The median time-to-subsequent antimyeloma therapy in the DVMP vs VMP group was 66.8 months (95% CI, 47.9-not estimable) vs 25.9 months (95% CI, 23.4-28.6), respectively (HR, 0.37; 95% CI, 0.30-0.46; P<0.0001).10
- A total of 12 (3%) of 346 patients in the D-VMP group and 93 (26%) of 354 patients in the VMP group received daratumumab as a subsequent antimyeloma therapy.10
- Details pertaining to subsequent antimyeloma therapies are summarized in Table: Summary of the Most Common Subsequent Antimyeloma Therapies in the Safety Population.32
| Parameter, n (%) | D---VMP (n=346) | VMP (n=354) | Total (N=700) |
|---|---|---|---|
| Patients receiving ≥1 subsequent antimyeloma therapy | 150 (43) | 243 (69) | 393 (56) |
| Most common first subsequent therapy regimens | |||
| Lenalidomide/dexamethasone | 47 (14) | 77 (22) | 124 (18) |
| Carfilzomib/lenalidomide/dexamethasone | 18 (5) | 15 (4) | 33 (5) |
| Lenalidomide/dexamethasone/ixazomib | 16 (5) | 8 (2) | 24 (3) |
| Bortezomib/dexamethasone | 7 (2) | 3 (1) | 10 (1) |
| Thalidomide/cyclophosphamide/dexamethasone | 6 (2) | 17 (5) | 23 (3) |
| Bortezomib/cyclophosphamide/dexamethasone | 5 (1) | 9 (3) | 14 (2) |
| Lenalidomide/dexamethasone/elotuzumab | 2 (1) | 8 (2) | 10 (1) |
| DARZALEX/lenalidomide/dexamethasone | 1 (<1) | 25 (7) | 26 (4) |
| DARZALEX/bortezomib/dexamethasone | 0 | 11 (3) | 11 (2) |
| Abbreviations: D-VMP, DARZALEX + bortezomib + melphalan + prednisone; VMP, bortezomib + melphalan + prednisone. aMost common defined as ≥2% of patients in either treatment group. | |||
- PFS events on the subsequent line of therapy were reported in 53% vs 67% of patients in the D-VMP vs VMP group, respectively.10
- The median PFS on the next line of therapy in the D-VMP vs VMP group was 66.7 months (95% CI, 58.6-80.1) vs 42.4 months (95% CI, 37.3-47.1), respectively (HR, 0.56; 95% CI, 0.46-0.68; P<0.0001).10
Safety
- No new safety concerns were identified with a longer follow-up.10
- TEAEs were experienced by 98% of patients in the D-VMP group and 97% of patients in the VMP group. The most common TEAEs are summarized in Table: Summary of the Most Common TEAEs.10
- Grade 3 or 4 TEAEs occurred in 83% of patients receiving D-VMP and 77% of patients receiving VMP.10
- The most common grade 3 or 4 infection in both treatment groups was pneumonia (D-VMP, 16%; VMP, 5%).10
- IRRs of any grade were reported in 29% of patients in the D-VMP group, including a grade 3 reaction in 4% and a grade 4 reaction in 1% of patients.10
- The D-VMP group experienced a higher rate of serious TEAEs compared with the VMP group (21% vs 16%). The most common serious TEAE observed in D-VMP vs VMP group was pneumonia (5% vs 2%, respectively).10
- The rate of treatment discontinuation due to TEAEs was 9% in both the D-VMP and VMP groups and are detailed in Table: Summary of Treatment Discontinuation Due to TEAEs.10,32
| Event, n (%) | D-VMP (n=346) | VMP (n=354) | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Any Gradea | Grade 1-2 | Grade 3 | Grade 4 | Grade 5 | Any Gradea | Grade 1-2 | Grade 3 | Grade 4 | Grade 5 | |
| Any TEAEs | 338 (98) | 47 (14) | 184 (53) | 77 (22) | 30 (9) | 342 (97) | 65 (18) | 180 (51) | 77 (22) | 20 (6) |
| Hematologic AE | ||||||||||
| Neutropenia | 175 (51) | 35 (10) | 107 (31) | 33 (10) | 0 | 186 (53) | 48 (14) | 103 (29) | 35 (10) | 0 |
| Thrombocytopenia | 173 (50) | 53 (15) | 83 (24) | 37 (11) | 0 | 190 (54) | 56 (16) | 83 (23) | 51 (14) | 0 |
| Anemia | 112 (32) | 49 (14) | 61 (18) | 2 (1) | 0 | 131 (37) | 61 (17) | 68 (19) | 2 (1) | 0 |
| Nonhematologic AE | ||||||||||
| Peripheral sensory neuropathy | 100 (29) | 95 (27) | 4 (1) | 1 (<1) | 0 | 122 (34) | 108 (31) | 14 (4) | 0 | 0 |
| Diarrhea | 101 (29) | 92 (27) | 9 (3) | 0 | 0 | 87 (25) | 76 (21) | 11 (3) | 0 | 0 |
| Pyrexia | 89 (26) | 87 (25) | 2 (1) | 0 | 0 | 74 (21) | 72 (20) | 2 (1) | 0 | 0 |
| Nausea | 76 (22) | 73 (21) | 3 (1) | 0 | 0 | 76 (21) | 72 (20) | 4 (1) | 0 | 0 |
| Back pain | 73 (21) | 65 (19) | 8 (2) | 0 | 0 | 42 (12) | 38 (11) | 4 (1) | 0 | 0 |
| Cough | 71 (21) | 70 (20) | 1 (<1) | 0 | 0 | 27 (8) | 26 (7) | 1 (<1) | 0 | 0 |
| Upper respiratory tract infection | 107 (31) | 99 (29) | 7 (2) | 0 | 1 (<1) | 50 (14) | 44 (12) | 6 (2) | 0 | 0 |
| Bronchitis | 77 (22) | 66 (19) | 11 (3) | 0 | 0 | 27 (8) | 24 (7) | 3 (1) | 0 | 0 |
| Pneumonia | 78 (23) | 19 (5) | 53 (15) | 4 (1) | 2 (1) | 19 (5) | 3 (1) | 15 (4) | 1 (<1) | 0 |
| Abbreviations: AE, adverse event; D-VMP, DARZALEX + bortezomib + melphalan + prednisone; TEAE, treatment-emergent adverse event; VMP, bortezomib + melphalan + prednisone. aPreferred terms for any grade of TEAEs with an occurrence of ≥20% are reported. | ||||||||||
| TEAEs | D-VMP (n=346) | VMP (n=354) |
|---|---|---|
| Patients with TEAEs leading to treatment discontinuation, n (%) | 31 (9) | 33 (9) |
| TEAEs leading to treatment discontinuationa, n (%) | ||
| Pneumonia | 4 (1) | 1 (<1) |
| Upper respiratory tract infection | 2 (1) | 0 |
| Acute respiratory failure | 2 (1) | 0 |
| Fatigue | 1 (<1) | 2 (1) |
| Peripheral sensory neuropathy | 0 | 6 (2) |
| Neuralgia | 0 | 2 (1) |
| Abbreviations: D-VMP, DARZALEX + bortezomib + melphalan + prednisone; VMP, bortezomib + melphalan + prednisone; TEAE, treatment-related adverse event. aTEAEs leading to treatment discontinuation in at least 2 patients in either treatment group are reported. | ||
- The incidence of second primary malignancies in the D-VMP vs VMP group was 8% vs 6%, respectively.10
- Death due to adverse events was reported in 10% vs 6% of patients in the D-VMP vs VMP group, respectively.10
- Deaths due to an adverse event considered related to at least 1 of the 4 study treatment components occurred in 5 (1%) of 346 patients receiving D-VMP (due to pneumonia, acute myocardial infarction, neuroendocrine tumor, tumor lysis syndrome, and acute respiratory failure [one each]) and in 3 (1%) of 354 patients receiving VMP (due to acute myeloid leukemia, pulmonary embolism, and bacterial pneumonia [one each]).10
European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-Item Assessment (EORTC QLQ-C30)
- In the D-VMP vs VMP group, respectively, the mean European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-Item (EORTC QLQ-C30) score in the ITT Population was as follows:10
- Global health status (GHS): 50.7 (21.0) vs 52.4 (22.6).
- Pain: 46.3 (33.1) vs 43.1 (31.4).
- Physical functioning: 59.9 (27.0) vs 63.6 (25.6).
- The least-squares (LS) mean change in EORTC QLQ-C30 scores from baseline at 3 months in the ITT population is presented in Table: LS Mean Change in EORTC QLQ-C30 Scores From Baseline at 3 Months in the ITT Population.10
- Mean (standard deviation) EORTC QLQ-C30 scores in the ITT population with bone lesions at baseline in the D-VMP vs VMP group:10
- GHS: 49.9 (21.2) vs 51.2 (22.6).
- Pain: 50.8 (31.3) vs 46.8 (31.7).
- Physical functioning: 58.1 (26.9) vs 61.4 (26.2).
- Both D-VMP and VMP groups showed a decrease in the pain score in addition to bone lesion and improvement in physical functioning score. LS mean changes in EORTC QLQ-C30 scores from baseline at 3 months in the ITT population with bone lesion and pain symptom score in addition to bone lesion are presented in Table: LS Mean Change in EORTC QLQ-C30 Scores From Baseline at 3 Months in the ITT Population With Bone Lesion and Pain Symptom Score in Addition to Bone Lesions.10
- The completion rate of EORTC QLQ-30 at baseline and at each timepoint is provided in Table: Compliance With EORTC QLQ-C30 Assessments Over Time in the ITT Population.32
| LSa Mean Change (95% CI) | |||
|---|---|---|---|
| D-VMP (n=350) | VMP (n=356) | PValue | |
| Global health status score | 7.5 (5.2-9.7) | 4.0 (1.7-6.3) | 0.0233 |
| Pain score | -13.7 (-16.5 to -10.9) | -10.4 (-13.3 to -7.5) | ≥0.05 |
| Physical functioning score | 5.4 (3.1-7.7) | 4.3 (2.0-6.7). | ≥0.05 |
| Abbreviations: CI, confidence interval; DVMP, DARZALEX + bortezomib + melphalan + prednisone; EORTC QLQ-C30, European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-Item; ISS, International Staging System; ITT, intention-to-treat; LS, least-squares; VMP, bortezomib + melphalan + prednisone. aLS means are derived based on the mixed effects model with repeated measures in which the dependent variable is change from baseline in score and independent variables are baseline, visit, treatment, visit by treatment interaction, and randomization stratification factors (ISS disease stage [I, II, III], region [Europe vs other], and age [<75 years vs ≥75 years]) as fixed effects and individual patient as random effect. | |||
| Parameter | LSa Mean Change (95% CI) | ||
|---|---|---|---|
| D-VMP | VMP | PValue | |
| Patients with bone lesion, n | 279 | 273 | - |
| Global health status score | 10.4 (8.1-12.7) | 7.0 (4.6-9.4) | 0.0443 |
| Patients with pain symptom score in addition to bone lesion, n | 251 | 253 | - |
| Pain score | -19.4 (-22.3 to -16.6) | -15.0 (-18.0 to -12.0). | 0.0376 |
| Physical functioning score | 9.9 (7.5-12.2) | 8.1 (5.6-10.5) | ≥0.05 |
| Abbreviations: CI, confidence interval; DVMP, DARZALEX + bortezomib + melphalan + prednisone; EORTC QLQ-C30, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item; ISS, International Staging System; ITT, intention-to-treat; LS, least-squares; VMP, bortezomib + melphalan + prednisone. aLS means are derived based on the mixed-effects model with repeated measures in which the dependent variable is change from baseline in score and independent variables are baseline, visit, treatment, visit by treatment interaction, and randomization stratification factors (ISS disease stage [I, II, III], region [Europe vs other], and age [<75 years vs ≥75 years]) as fixed effects and individual patient as random effect. | |||
| Time points | D-VMP (n=350) | VMP (n=356) | ||
|---|---|---|---|---|
| Expecteda | Received, n (%) | Expecteda | Received, n (%) | |
| Baseline | 350 | 317 (90.6) | 356 | 327 (91.9) |
| Month 3 | 326 | 281 (86.2) | 324 | 260 (80.2) |
| Month 6 | 317 | 251 (79.2) | 286 | 221 (77.3) |
| Month 9 | 300 | 241 (80.3) | 258 | 192 (74.4) |
| Month 12 | 288 | 231 (80.2) | 243 | 186 (76.5) |
| Month 18 | 253 | 206 (81.4) | 178 | 127 (71.3) |
| Month 24 | 210 | 160 (76.2) | 122 | 76 (62.3) |
| Month 30 | 190 | 165 (86.8) | 84 | 64 (76.2) |
| Month 36 | 168 | 146 (86.9) | 64 | 44 (68.8) |
| Month 42 | 150 | 126 (84.0) | 41 | 28 (68.3) |
| Month 48 | 132 | 104 (78.8) | 34 | 20 (58.8) |
| Abbreviations: D-VMP, DARZALEX + bortezomib + melphalan + prednisone; EORTC QLQ-C30, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item; ITT, Intention-to-treat; VMP, bortezomib + melphalan + prednisone. aFor the D-VMP group, EORTC QLQ-C30 assessments were expected from all patients who were still on study treatment by the month indicated. For the VMP group, EORTC QLQ-C30 assessments were expected through month 12 from all patients who were still on study treatment by the month indicated and for month 18 and beyond from all patients who were on study and had not progressed or received subsequent antimyeloma therapy by the month indicated. Data are shown through month 48 due to the low number of expected assessments in the VMP group after this time. | ||||
CLINICAL DATA - DARZALEX FASPRO AND DARZALEX PHASE 3 STUDIES
Study Design/Methods
- The trial enrolled 200 patients from the United States and Canada.16
- Patients underwent 1:1 randomization to receive D-R (n=99) or R alone (n=101) across 28-day cycles.16,18
- D-R: DARZALEX FASPRO 1800 mg SC QW in cycles 1-2, Q2W in cycles 3-6, Q4W in cycles 7+.
- R: Lenalidomide 10 mg PO once a dayon days 1-28.
- The treatment regimen continued until unacceptable toxicity, disease progression, consent withdrawal, or for a maximum of 36 cycles.16
Results
Demographics and Disease Characteristics
- A total of 200 patients were randomized into the D-R maintenance (n=99) vs lenalidomide alone maintenance (n=101) group.19
- The median follow-up was 32.3 months
.19 - Demographics and disease characteristics of the ITT population are presented in Table: Demographics and Disease Characteristics of the ITT Population.
| D-R (n=99) | R (n=101) | |
|---|---|---|
| Age, n (%) | ||
| <65 years | 61 (61.6) | 61 (60.4) |
| ≥65 years | 38 (38.4) | 40 (39.6) |
| Abbreviations: D-R, DARZALEX FASPRO + lenalidomide; ITT, intention-to-treat; R, lenalidomide. | ||
Efficacy
- A subgroup analysis of MRD-negativity (10-5 sensitivity) conversion rates by 12 months of maintenance showed improvement for D-R vs R regardless of age.19 The results are summarized in Table: Subgroup Analysis of MRD-negativity (10-5 Sensitivity) Conversion Ratea from Baseline to 12 Months of Maintenance Treatment.
| Subgroup, n/N (%) | D-R | R | ORb (95% CI) |
|---|---|---|---|
| ITTc | 50/99 (50.5) | 19/101 (18.8) | 4.51 (2.37-8.57) |
| Age | |||
| <65 years | 30/61 (49.2) | 12/61 (19.7) | 3.95 (1.76-8.85) |
| ≥65 years | 20/38 (52.6) | 7/40 (17.5) | 5.24 (1.86-14.74) |
| Abbreviations: CI, confidence interval; D-R, DARZALEX FASPRO + lenalidomide; IMWG, International Myeloma Working Group; ITT, intention-to-treat; MRD, minimal residual disease; NGS, nextgeneration sequencing; OR, odds ratio; R, lenalidomide. aDefined as the proportion of patients who achieved MRD-negative status (at 10-5) by NGS by 12 months after maintenance treatment and prior to progressive disease or subsequent antimyeloma therapy. bMantel-Haenszel estimate of the common OR for stratified tables is used for ITT; Mantel-Haenszel estimate of the common OR for unstratified tables is used for subgroups. An OR >1 indicates an advantage for D-R.cITT analysis set is defined as all patients who were randomized to treatment. | |||
Safety
- No unexpected safety concerns were observed in patients aged ≥65 years.19
- The median duration of therapy was 25.0 months (D-R, 30.5 months; lenalidomide, 23.5 months) for patients aged <65 years and 24.4 months (D-R, 32.7 months; lenalidomide, 19.2 months) for patients aged ≥65 years. Safety results based on age for patients with ≥1 TEAE are summarized in Table: Safety Results for Patients With ≥1 TEAE Based on Age.
- D-R maintenance did not increase grade 3/4 infection or cytopenia rates in patients ≥65 years of age.19
| Patients With ≥1 TEAE, n (%) | D-R | R | ||
|---|---|---|---|---|
| <65 Years (n=59) | ≥65 Years (n=37) | <65 Years (n=58) | ≥65 Years (n=40) | |
| Grade 3/4 TEAEs | 45 (76.3) | 26 (70.3) | 37 (63.8) | 29 (72.5) |
| Most commona | ||||
| Neutropeniab | 26 (44.1) | 19 (51.4) | 25 (43.1) | 16 (40.0) |
| Lymphopenia | 7 (11.9) | 3 (8.1) | 3 (5.2) | 2 (5.0) |
| Hypertension | 6 (10.2) | 1 (2.7) | 3 (5.2) | 1 (2.5) |
| Leukopenia | 6 (10.2) | 3 (8.1) | 2 (3.4) | 4 (10.0) |
| Hypokalemia | 4 (6.8) | 3 (8.1) | 2 (3.4) | 4 (10.0) |
| Pneumonia | 1 (1.7) | 4 (10.8) | 1 (1.7) | 3 (7.5) |
| Grade 3/4 cytopenias | 31 (52.5) | 21 (56.8) | 27 (46.6) | 19 (47.5) |
| Grade 3/4 infections | 11 (18.6) | 7 (18.9) | 6 (10.3) | 7 (17.5) |
| Serious TEAEs | 14 (23.7) | 15 (40.5) | 7 (12.1) | 15 (37.5) |
| COVID-19 events | ||||
| Any grade | 19 (32.2) | 9 (24.3) | 22 (37.9) | 7 (17.5) |
| Grade 3/4 | 1 (1.7) | 0 (0.0) | 3 (5.2) | 0 (0.0) |
| TEAEs leading to discontinuation of any treatment componentc | 7 (11.9) | 7 (18.9) | 4 (6.9) | 4 (10.0) |
| Death due to TEAEs | 0 (0.0) | 2 (5.4) | 0 (0.0) | 1 (2.5) |
| Abbreviations: AE, adverse event; COVID-19, coronavirus disease 2019; D-R, DARZALEX FASPRO + lenalidomide; R, lenalidomide; TEAE, treatment-emergent adverse event. aOccurring in ≥10% of patients in either treatment group in either age category. bPreferred term grouping. cIncludes those who had AEs with action taken as drug withdrawn to ≥1 component of study treatment on the “AE” complete report form page. | ||||
Results
Patient Characteristics
- Patients aged ≥65 years represented 25.5% of patients in the PERSEUS study (D-VRd, 94 of 355 patients vs VRd, 87 of 354 patients) and 27.1% of patients in the GRIFFIN study (D-VRd, 28 of 104 patients vs VRd, 28 of 103 patients).23 The baseline demographic and disease characteristics are summarized in Table: Baseline Demographic and Disease Characteristics in Patients Aged ≥65 Years in the Pooled PERSEUS/GRIFFIN ITT Population.
- The median duration of treatment for patients aged ≥65 years was 37.4 months (range, 0.5-52.5) and 32.6 months (range, 0.1-53.0) in the D-VRd and VRd groups, respectively.
- The median number of treatment cycles received in the D-VRd vs VRd group were 33.5 vs 31.0 cycles.
- The median relative dose intensities were similar between the D-VRd vs VRd group for bortezomib (92.9% vs 93.5%, respectively) and dexamethasone (95.5% vs 100%, respectively) but were slightly lower in the D-VRd group for lenalidomide (75.5% vs 87.7%, respectively). The median relative dose intensity for DARZALEX FASPRO/DARZALEX in the D-VRd group was 99.7%.
- Cycle delays were reported in the D-VRd vs VRd group for 82.5% vs 75.4% of patients, respectively.
- Treatment discontinuation rates in the D-VRd vs VRd group were higher for lenalidomide (23.3% vs 17.5%, respectively) but were comparable between the D-VRd vs VRd group for bortezomib (12.5% vs 12.3%, respectively) and dexamethasone (3.3% vs 3.5%, respectively).
- The discontinuation rate of DARZALEX FASPRO/DARZALEX in the D-VRd group was 2.5%.
| Characteristic | D-VRd (n=122) | VRd (n=115) |
|---|---|---|
| Median age (range), years | 67 (65-70) | 67 (65-70) |
| Sex | ||
| Female, n (%) | 46 (37.7) | 48 (41.7) |
| Male, n (%) | 76 (62.3) | 67 (58.3) |
| Race, n (%) | ||
| White | 110 (90.2) | 106 (92.2) |
| Asian | 4 (3.3) | 1 (0.9) |
| Black | 2 (1.6) | 3 (2.6) |
| American Indian/Alaska Native | 1 (0.8) | 0 |
| Native Hawaiian/Pacific Islander | 1 (0.8) | 0 |
| Multiple/unknown/not reported | 4 (3.3) | 5 (4.3) |
| ECOG PS score, n/N (%) | ||
| 0 | 66/122 (54.1) | 66/114 (57.9) |
| 1 | 47/122 (38.5) | 40/114 (35.1) |
| 2 | 9/122 (7.4) | 8/114 (7.0) |
| 3 | 0 | 0 |
| ISS disease stageb, n (%) | ||
| I | 51 (41.8) | 39 (33.9) |
| II | 32 (26.2) | 33 (28.7) |
| III | 11 (9.0) | 15 (13.0) |
| Type of measurable diseasec, n (%) | ||
| Serum | 96 (78.7) | 100 (87.0) |
| IgG | 67 (54.9) | 65 (56.5) |
| IgA | 24 (19.7) | 28 (24.3) |
| Otherd | 5 (4.1) | 7 (6.1) |
| Urine only | 13 (10.7) | 9 (7.8) |
| Serum FLC only | 12 (9.8) | 6 (5.2) |
| Not evaluablee | 1 (0.8) | 0 |
| Cytogenetic riskf, n/N (%) | ||
| Standard risk | 88/119 (73.9) | 91/114 (79.8) |
| High risk | 27/119 (22.7) | 22/114 (19.3) |
| del(17p) | 17/119 (14.3) | 12/114 (10.5) |
| t(4;14) | 10/119 (8.4) | 7/114 (6.1) |
| t(14;16) | 2/119 (1.7) | 5/114 (4.4) |
| Indeterminate | 4/119 (3.4) | 1/114 (0.9) |
| Abbreviations: D-VRd, DARZALEX FASPRO/DARZALEX + bortezomib, lenalidomide, and dexamethasone; ECOG PS, Eastern Cooperative Oncology Group performance status; FLC, free-light chain; IgA/IgD/IgE/IgG/IgM, immunoglobulin A/D/E/G/M; ISS, International Staging System; ITT, intent-to-treat; VRd, bortezomib, lenalidomide, and dexamethasone.aThe pooled ITT population included all patients aged ≥65 years who were randomized in PERSEUS or GRIFFIN. bISS staging is derived based on the combination of serum β2-microglobulin and albumin. cIncludes patients without measurable disease in serum and urine. dIncludes patients with IgD, IgM, IgE, and biclonal disease.eOne patient with no evaluable measurable disease. fHigh risk was defined as ≥1 of the following cytogenetic abnormalities: del(17p), t(4;14), and/or t(14;16) by fluorescence in situ hybridization. Standard risk was defined by the absence of these cytogenetic abnormalities. | ||
Transplant Characteristics
- Among patients aged ≥65 years who received ≥1 dose of the study treatment, 93.3% (112/120) vs 84.2% (96/114) patients in the D-VRd vs VRd group, proceeded for stem cell mobilization.23
- The median number of CD34+
cells collected was sufficient for transplant in both the treatment groups. - Two patients from the D-VRd group vs 1 patient from the VRd group had <2×106/kg CD34+ stem cells collected.
- The median number of CD34+
- The proportions of patients who proceeded to transplant were comparable between the treatment groups (D-VRd, 86.7% vs VRd, 82.5%).23
- The median time to engraftment was 14 (range, 0-33) days vs 13 (range, 1-48) days in the D-VRd vs VRD groups, respectively.
- The stem cell mobilization and transplant outcomes are summarized in Table: Stem Cell Mobilization and Transplant Outcomes in Patients Aged ≥65 Years in the Pooled PERSEUS/GRIFFIN Safety Population
| Characteristic | D-VRd (n=120) | VRd (n=114) |
|---|---|---|
| Patients proceeded to stem cell mobilization, n (%) | 112 (93.3) | 96 (84.2) |
| Mobilization medication/therapy used, n (%) | ||
| N | 112 | 96 |
| G-CSFb | 110 (98.2) | 91 (94.8) |
| Cyclophosphamide | 71 (63.4) | 51 (53.1) |
| Plerixafor | 59 (52.7) | 32 (33.3) |
| Chemotherapy | 2 (1.8) | 0 (0) |
| Other | 1 (0.9) | 2 (2.1) |
| Patients with stem cells collected, n (%) | 108 (90.0) | 95 (83.3) |
| Total number of CD34+ stem cells collected | ||
| Median (range),×106/kg | 4.22 (1.80-13.50) | 5.76 (1.12-49.50) |
| <2×106/kg, n (%) | 2 (1.9) | 1 (1.1) |
| 2 to <5×106/kg, n (%) | 68 (63.0) | 35 (36.8) |
| ≥5×106/kg, n (%) | 38 (35.2) | 59 (62.1) |
| Patients who completed stem cell conditioning therapy, n (%) | 104 (86.7) | 94 (82.5) |
| Total dose of melphalan conditioning therapy | ||
| N | 102 | 94 |
| Median (range), mg/m2 | 193 (59-385) | 192 (52-371) |
| Patients who proceeded to ASCT, n (%) | 104 (86.7) | 94 (82.5) |
| Time to achieve ANC ≥0.5×109/L, post-transplant | ||
| N | 103 | 93 |
| Median (range), days | 13 (0-28) | 12 (0-34) |
| Time to achieve platelets ≥20×109/L post-transplant without transfusionc | ||
| N | 103 | 93 |
| Median (range), days | 13 (0-33) | 12 (1-48) |
| Time to engraftmentc,d | ||
| N | 103 | 93 |
| Median (range), days | 14 (0-33) | 13 (1-48) |
| Abbreviations: ANC, absolute neutrophil count; ASCT, autologous stem cell transplant; CD, cluster of differentiation; D-VRd, DARZALEX FASPRO/DARZALEX + bortezomib, lenalidomide, and dexamethasone; G-CSF, granulocyte colony-stimulating factor; VRd, bortezomib, lenalidomide, and dexamethasone. aPooled safety population included all patients aged ≥65 years who were randomized in PERSEUS or GRIFFIN and received ≥1 dose of study treatment. bIncluded standardized medications of filgrastim, lenograstim, and G-CSF. cNumber of days from the transplant date, excluding patients whose counts did not reach nadir below the set threshold.dThe date of engraftment after transplant was defined as the latest date of ANC ≥0.5×109/L and platelet count ≥20×109/L. Patients with hematopoietic reconstitution were included. | ||
Efficacy
- At a median follow-up of 47.5 and 49.6 months, the median PFS was not reached for patients aged ≥65 years in the PERSEUS and GRIFFIN groups, respectively.23
- The PFS HR favored D-VRd vs VRd (HR, 0.56; 95% CI, 0.31-1.01; P=0.05).
- At 48 months, PFS rates for D-VRd vs VRd group were 79.1% vs 71.6%, respectively.
- Higher response rates, overall MRD-negativity rates (10-5), and sustained negativity rates (10-5; ≥12 months) were observed in the D-VRd vs VRd group and are detailed in Table: Response Rates, Overall and Sustained MRD-Negativity Rates in Patients Aged ≥65 Years in the Pooled PERSEUS/GRIFFIN ITT Population.
| Parameter | D-VRd (n=122) | VRd (n=115) | OR (95% CI)b | P Valuec | ||
|---|---|---|---|---|---|---|
| n (%) | 95% CI | n (%) | 95% CI | |||
| ≥CR | 101 (82.8) | 74.9-89.0 | 77 (67.0) | 57.6-75.4 | 2.37 (1.28-4.39) | 0.005 |
| ≥VGPR | 114 (93.4) | 87.5-97.1 | 99 (86.1) | 78.4-91.8 | 2.47 (1.03-5.92) | 0.04 |
| ORRd | 116 (95.1) | 89.6-98.2 | 110 (95.7) | 90.1-98.6 | 0.86 (0.25-2.96) | 0.81 |
| Best response | ||||||
| sCR | 72 (59.0) | 49.7-67.8 | 57 (49.6) | 40.1-59.0 | 1.49 (0.88-2.53) | 0.14 |
| CR | 29 (23.8) | 16.5-32.3 | 20 (17.4) | 11.0-25.6 | - | - |
| VGPR | 13 (10.7) | 5.8-17.5 | 22 (19.1) | 12.4-27.5 | - | - |
| PR | 2 (1.6) | 0.2-5.8 | 11 (9.6) | 4.9-16.5 | - | - |
| SD | 3 (2.5) | 0.5-7.0 | 2 (1.7) | 0.2-6.1 | - | - |
| PD | 0 | NE-NE | 0 | NE-NE | - | |
| NE | 3 (2.5) | 0.5-7.0 | 3 (2.6) | 0.5-7.4 | - | |
| Overall MRD-negativity (10-5), % | 81 (66.4) | - | 48 (41.7) | - | 2.75 (1.61-4.71) | 0.0002 |
| MRD-negativity (10-5) at the end of consolidation, % | 60 (49.2) | - | 34 (29.6) | - | 2.23 (1.31-3.80) | 0.003 |
| Sustained MRD-negativity (10-5) (≥12 months), % | 64 (52.5) | - | 30 (26.1) | - | 3.2 (1.83-5.58) | <0.0001 |
| Abbreviations: CI, confidence interval; CR, complete response; D-VRd, DARZALEX FASPRO/DARZALEX + bortezomib + lenalidomide + dexamethasone; ISS, International Staging System; ITT, intent-to-treat; MRD, minimal residual disease; NE, not evaluable; 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. aPooled ITT population included all patients aged ≥65 years who were randomized in PERSEUS or GRIFFIN.bMantel-Haenszel estimates of the common ORs for stratified tables were used. The stratification factors were ISS disease stage (I vs II vs III) and cytogenetic risk (high risk vs standard/unknown risk).cP value from the stratified Cochran-Mantel-Haenszel chi-square test. dORR was defined as sCR + CR + VGPR + PR. | ||||||
Safety
- The incidence of grade 3/4 TEAEs in the D-VRd vs VRd group among patients aged ≥65 years was 94.2% vs 86.8%, respectively.23
- The incidence of serious TEAEs in the D-VRd vs VRd group among patients aged ≥65 years was 67.5% vs 52.6%, respectively.
- A higher incidence of grade 3/4 infections of 36.3% vs 24.8% was observed in patients aged ≥65 years in the D-VRd vs VRd group, respectively.23
- The percentage of patients with TEAEs that resulted in the discontinuation of ≥1 study drug in the D-VRd vs VRd group was 40.8% vs 45.6%, respectively, in patients aged ≥65 years. The summary of the most common TEAEs is presented in Table: Most Common TEAEs in Patients Aged ≥65 Years in the Pooled PERSEUS/GRIFFIN Safety Population.
- Treatment discontinuation was mostly due to peripheral sensory neuropathy: D-VRd, 12.5%; VRd, 13.2%.23
| TEAEs, n (%) | D-VRd (n=120) | VRd (n=114) | ||
|---|---|---|---|---|
| Any Grade | Grade 3/4 | Any Grade | Grade 3/4 | |
| Hematologic TEAEs | ||||
| Neutropeniac | 80 (66.7) | 71 (59.2) | 61 (53.5) | 49 (43.0) |
| Thrombocytopenia | 66 (55.0) | 46 (38.3) | 44 (38.6) | 22 (19.3) |
| Anemia | 33 (27.5) | 8 (6.7) | 29 (25.4) | 7 (6.1) |
| Nonhematologic TEAEs | ||||
| Diarrhea | 71 (59.2) | 17 (14.2) | 66 (57.9) | 12 (10.5) |
| Peripheral sensory neuropathy | 69 (57.5) | 7 (5.8) | 55 (48.2) | 7 (6.1) |
| Constipation | 58 (48.3) | 3 (2.5) | 47 (41.2) | 1 (0.9) |
| Pyrexia | 45 (37.5) | 3 (2.5) | 37 (32.5) | 2 (1.8) |
| Fatigue | 44 (36.7) | 6 (5.0) | 39 (34.2) | 7 (6.1) |
| Upper respiratory tract infection | 43 (35.8) | 1 (0.8) | 40 (35.1) | 2 (1.8) |
| Edema peripheral | 43 (35.8) | 4 (3.3) | 35 (30.7) | 3 (2.6) |
| Cough | 43 (35.8) | 1 (0.8) | 22 (19.3) | 0 (0.0) |
| Back pain | 39 (32.5) | 1 (0.8) | 22 (19.3) | 0 (0.0) |
| Nausea | 38 (31.7) | 2 (1.7) | 26 (22.8) | 1 (0.9) |
| Rash | 33 (27.5) | 4 (3.3) | 24 (21.1) | 8 (7.0) |
| Arthralgia | 30 (25.0) | 0 (0.0) | 25 (21.9) | 1 (0.9) |
| Insomnia | 30 (25.0) | 4 (3.3) | 21 (18.4) | 3 (2.6) |
| Asthenia | 26 (21.7) | 2 (1.7) | 31 (27.2) | 2 (1.8) |
| COVID-19 | 26 (21.7) | 1 (0.8) | 17 (14.9) | 0 (0.0) |
| Muscle spasms | 24 (20.0) | 2 (1.7) | 27 (23.7) | 2 (1.8) |
| Bronchitis | 24 (20.0) | 2 (1.7) | 13 (11.4) | 1 (0.9) |
| Pneumonia | 23 (19.2) | 13 (10.8) | 17 (14.9) | 7 (6.1) |
| Hypokalemia | 23 (19.2) | 5 (4.2) | 26 (22.8) | 7 (6.1) |
| Abbreviations: D-VRd, DARZALEX FASPRO/DARZALEX + bortezomib + lenalidomide + dexamethasone; TEAE, treatment-emergent adverse event; VRd, bortezomib + lenalidomide + dexamethasone. aTEAEs of any grade that occurred in ≥20% of patients aged ≥65 years in either treatment group, or grade 3/4 TEAEs that occurred in ≥10% of patients aged ≥65 years in either treatment group. bThe pooled safety population includes all patients who were randomized in GRIFFIN or PERSEUS and received ≥1 dose of study treatment. cNeutropenia as a grouped term that included the preferred terms neutropenia and febrile neutropenia. | ||||
A literature search of MEDLINE®
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