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(daratumumab and hyaluronidase-fihj)

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DARZALEX FASPRO® (daratumumab and hyaluronidase-fihj)

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DARZALEX + DARZALEX FASPRO- Use in Older Patients With Multiple Myeloma

Last Updated: 01/09/2025

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
  • An efficacy and safety analysis of elderly patients aged <75 and ≥75 years with RRMM who were treated in the CANDOR (DARZALEX + carfilzomib + dexamethasone [D-Kd] compared to carfilzomib + dexamethasone [Kd]) study was published by Dimopoulos et al (2020). 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%).3
    • 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%).
  • An efficacy and safety analysis evaluating the impact of age (≥75 years vs <75 years) in patients with NDMM ineligible for high-dose chemotherapy and ASCT who were treated in the MAIA5,6 (DARZALEX + lenalidomide + dexamethasone [D-Rd] compared to lenalidomide + dexamethasone [Rd]) study was presented at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting.6
    • Kumar et al (2022)7 presented (at the 64th American Society of Hematology [ASH] Annual Meeting and Exposition) the results of the updated efficacy and safety analysis of the MAIA study. At a median duration of follow-up of 64.5 months, PFS improved with D-Rd vs Rd treatment. At a median duration of follow-up of 73.6 months, a 35% reduction in the risk of death was observed with D-Rd vs Rd arm. In the subgroup of patients aged ≥75 years, median OS was 73.5 months in the D-Rd arm vs 54.8 months in the Rd arm (HR, 0.67; 95% CI 0.50-0.90). The most common grade 3/4 TEAEs (≥20%) in any arm were neutropenia (D-Rd, 54.1%; Rd, 37.0%) and anemia (D-Rd, 17.0%; Rd, 21.6%). The most common serious TEAE in both arms was pneumonia (D-Rd, 18.7%; Rd, 10.7%).
    • Facon et al (2022)8 presented (at the 64th ASH Annual Meeting and Exposition) the efficacy results of the MAIA study according to age group (<70 years, ≥70 to <75 years, and <75 years) at a median duration of follow-up of 64.5 months. All evaluated survival and response endpoints (including PFS, OS, overall response rate (ORR), complete response (CR) or better, stringent complete response (sCR), very good partial response (VGPR) or better (≥VGPR), and minimal residual disease
      (MRD)-negativity (10-5) were more favorable in the D-Rd arm than the Rd arm in patients aged <75 years, with the most pronounced PFS and OS benefit observed in patients aged <70 years.
    • Moreau et al (2022)9 presented (at the 64th ASH Annual Meeting and Exposition) 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.
  • An efficacy and safety analysis of elderly patients aged <75 and ≥75 years with NDMM ineligible for ASCT who were treated in the ALCYONE (DARZALEX + bortezomib + melphalan + prednisone [D-VMP] compared to bortezomib + melphalan + prednisone [VMP] alone) study was presented at the 2018 ASCO Annual Meeting.10 The median PFS for patients aged ≥75 years was not reported (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 (2022)11 presented (at the 64th ASH Annual Meeting and Exposition) an updated efficacy and safety analysis of the ALCYONE study (median duration of follow-up, 78.8 months). In the D-VMP arm, the median OS for patients aged
      ≥75 years was 59.1 months and 85.5 months in the patients aged <75 years.
      Grade 3 or 4 TEAEs in the D-VMP vs VMP arm were reported in 82.9% vs 77.4% of patients. The most common serious TEAE in both treatment arms was pneumonia (D-VMP, 14.7%; VMP, 3.7%).
  • Mateos et al (2019)12 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)13 presented (at the 19th International Myeloma Society [IMS] Annual Meeting) 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.
  • Baz et al (2024)14 presented (at the 66th ASH Annual Meeting) 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.
  • An efficacy and safety analysis evaluated the impact of age (<65 years vs ≥65 years) in patients with RRMM who were treated in the APOLLO (daratumumab + pomalidomide + dexamethasone [D-Pd] compared to pomalidomide + dexamethasone [Pd]) study and was published by Dimopoulos et al (2021). 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%).15
    • Sonneveld et al (2021)16 presented (at the 63rd ASH Annual Meeting & Exposition) 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%).
    • Dimopoulos et al (2022)17 presented (at the 64th ASH Annual Meeting and Exposition) updated efficacy and safety results of the APOLLO study with a median duration of follow-up of 39.6 months. The updated analysis did not discuss age specific data and the citation is listed in the references below.
  • Foster et al (2024)18 presented (at the 66th ASH Annual Meeting) 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 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.
  • Rodriguez-Otero et al (2024)19 presented (at the 21st IMS Annual Meeting) results from a post hoc analysis of the PERSEUS and GRIFFIN studies that evaluated the efficacy and safety of DARZALEX FASPRO in combination with bortezomib, lenalidomide, and dexamethasone (D-VRd) vs VRd in patients aged ≥65 years. Patients treated with D-VRd showed a 44% reduction in the risk of disease progression or death vs VRd (HR, 0.56; 95% CI, 0.31-1.01; P=0.05). 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. A higher overall MRD-negativity rate (10-5) of 66.4% vs 41.7% and a sustained MRD-negativity rate (≥12 months) of 52.5% vs 26.1% was observed in the D-VRd vs VRd groups, respectively. There were no new safety concerns observed, and the overall safety profile of patients aged ≥65 years was comparable to the pooled patient population irrespective of age. A higher incidence of grade 3/4 infections was observed in the D-VRd vs VRd group, with slightly higher rates in patients aged ≥65 years (36.3% vs 24.8%) than in all patients (29.5% vs 22.5%). The frequency of TEAEs that resulted in discontinuation of ≥1 study drug was similar between treatment groups in patients aged ≥65 years and in all patients.
  • Usmani et al (2019)20 presented efficacy results for patients aged ≥75 years treated in the COLUMBA study (DARZALEX FASPRO vs DARZALEX) in patients with RRMM. Safety results for this subgroup were NR separately. 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%).
    • Usmani et al (2022)21 reported final analysis of efficacy and safety results of the COLUMBA study after a median duration of follow-up of 29.3 months. The updated analysis did not discuss age specific data and the citation is listed in the references below.
  • Sanchez et al (2024)22,23 presented (at the 66th ASH Annual Meeting) 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%).

PRODUCT LABELING

Clinical Data - DARZALEX PHASE 3 STUDIES

Efficacy and Safety Analysis of Elderly Patients Aged <75 and ≥75 Years With RRMM in the CANDOR Study

CANDOR (clinicaltrials.gov identifier: NCT03158688) is a randomized, open-label, multicenter, phase 3 study evaluating the efficacy and safety of D-Kd vs Kd in patients with RRMM.3 Dimopoulos et al (2020)3 reported the primary results of CANDOR at a median duration of follow-up of approximately 17 months. Usmani et al (2023)4 reported the updated efficacy and safety results after a median duration of follow-up of approximately
50 months. Data specific to older patients from the final analysis are reported below.

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.
  • 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%.
  • Primary endpoint: PFS.
  • Key secondary endpoints: ORR, MRD (10-5), safety, rate of ≥CR and OS.

Results

Patient Characteristics

Key Demographics and Baseline Characteristics (CANDOR)4
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

OS in Prespecified Age Subgroups (CANDOR)4
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.
  • AEs are summarized in the Table: Most Common (≥10%) TEAEs (CANDOR).

Fatal TEAEsa, 24
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.
aExcludes fatal TEAE of plasma cell myeloma.

Most Common (≥10%) TEAEs (CANDOR)4
Adverse Events, n (%)
D-Kd (n=308)
Kd (n=153)
Any Gradea
Grade ≥3b
Any Gradea
Grade ≥3b
All TEAEs
306 (99.4)
273 (88.6)
149 (97.4)
120 (78.4)
Hematologic
   Thrombocytopenia
119 (38.6)
76 (24.7)
46 (30.1)
25 (16.3)
   Anemia
114 (37.0)
54 (17.5)
52 (34.0)
25 (16.3)
   Neutropenia
49 (15.9)
31 (10.1)
15 (9.8)
10 (6.5)
   Lymphopenia
29 (9.4)
22 (7.1)
13 (8.5)
11 (7.2)
Nonhematologic
   Diarrhea
118 (38.3)
18 (5.8)
28 (18.3)
1 (0.7)
   Hypertension
115 (37.3)
72 (23.4)
49 (32.0)
27 (17.6)
   Upper respiratory tract infection
105 (34.1)
12 (3.9)
37 (24.2)
2 (1.3)
   Fatigue
81 (26.3)
25 (8.1)
29 (19.0)
7 (4.6)
   Pneumonia
79 (25.6)
57 (18.5)
24 (15.7)
14 (9.2)
   Dyspnea
70 (22.7)
16 (5.2)
35 (22.9)
4 (2.6)
   Pyrexia
66 (21.4)
6 (1.9)
27 (17.6)
2 (1.3)
   Insomnia
64 (20.8)
16 (5.2)
19 (12.4)
3 (2.0)
   Back pain
63 (20.5)
7 (2.3)
21 (13.7)
2 (1.3)
   Nausea
62 (20.1)
0
22 (14.4)
1 (0.7)
   Hyperglycemia
31 (10.1)
16 (5.2)
13 (8.5)
5 (3.3)
   Cataract
34 (11.0)
15 (4.9)
13 (8.5)
8 (5.2)
Abbreviations: D-Kd, DARZALEX + carfilzomib + dexamethasone; Kd, carfilzomib + dexamethasone; TEAE, treatment-emergent adverse event.aAny grade TEAEs occurring in ≥20% of patients.bGrade ≥3 TEAEs occurring in ≥5% of patients.

Impact of Age on Efficacy and Safety in the MAIA Study

MAIA (MMY3008; clinicaltrials.gov identifier: NCT02252172) is an international, phase 3, randomized, open-label, active-controlled, multicenter study in patients with NDMM not eligible for high-dose chemotherapy and ASCT (N=737).5 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.

Study Design/Methods

  • 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 progressive disease (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.
  • Primary endpoint: PFS
  • Key secondary endpoints: ≥CR rate, ≥VGPR rate, duration of response (DOR),
    MRD-negativity rate at 10-5 sensitivity via next-generation sequencing, ORR, OS, PFS on subsequent line of therapy, stringent complete response, time to next (second-line) treatment, time to response (TTR), time to progression (TTP), and safety.

Results

Patient Characteristics

Demographics and Baseline Characteristics of the ITT Population (N=737)a by Age Group (MAIA)6
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, n (%)
   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, n (%)
   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).

Response Rate of ITT Populationa by Age Group (MAIA)6
Response rates, n (%)
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.
  • Infusion-related reactions (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).

Most Common (≥30%) All-Grade TEAEs and Incidence of Infections (MAIA)a, 6
TEAEs, n (%)
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)
Non-hematologic
   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.

Most Common (≥10% of Patients) Grade 3/4 TEAEs and Incidence of Infections (MAIA)a, 6
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

Kumar et al (2022)7 presented the results of the updated efficacy and safety analysis (median duration of follow-up, 64.5 months), including updated OS results (median duration of follow-up, 73.6 months), of the MAIA study in patients with NDMM who were ineligible for high-dose chemotherapy and ASCT.

Results

Patient Characteristics
  • A total of 737 patients were randomized (D-Rd, n=368; Rd, n=369).
  • The median duration of follow-up was 64.5 months overall and 73.6 months for OS.
Efficacy
  • At a median duration of follow-up of 64.5 months, the median PFS in the D-Rd vs Rd arm was 61.9 vs 34.4 months (HR, 0.55; 95% CI, 0.45-0.67; P<0.0001).
    • The 60-month PFS rate in the D-Rd vs Rd arm was 52.1% vs 29.6%.
  • At a median duration of follow-up of 73.6 months, the median OS in the D-Rd vs Rd arm was NR vs 64.1 months (HR, 0.65; 95% CI, 0.52-0.80; P<0.0001).
    • The 60-month OS rate in the D-Rd vs Rd arm was 66.7% vs 53.7%.
    • OS benefit with D-Rd vs Rd treatment was generally consistent across the prespecified age patient subgroups, see Table: OS in Prespecified Age Subgroups (MAIA).

OS in Prespecified Age Subgroups (MAIA)7
Subgroup
D-Rda
Rda
HR (95% CI)a, b
n/N
Median OS, Months
n/N
Median OS, Months
Age
   <75 years
71/208
NE
101/208
77.6
0.64 (0.47-0.86)
   ≥75 years
79/160
73.5
101/161
54.8
0.67 (0.50-0.90)
Abbreviations: CI, confidence interval; D-Rd, daratumumab + lenalidomide + dexamethasone; HR, hazard ratio; NE, not estimable; OS, overall survival; Rd, lenalidomide + dexamethasone.aData are based on a median duration of follow-up of 73.6 months.bHR and 95% CI from a Cox proportional hazards model with treatment as the sole explanatory variable. An HR <1 indicates an advantage for D-Rd.

Safety


Summary of Any Grade (≥30%) and Grade 3/4 (≥20%) TEAEs in the Safety Population (MAIA)7
Event, n (%)
D-Rd (n=364)a
Rd (n=365)a
Any Grade
Grade 3/4
Any Grade
Grade 3/4
Hematologic
   Neutropenia
224 (61.5)
197 (54.1)
166 (45.5)
135 (37.0)
   Anemia
154 (42.3)
62 (17.0)
150 (41.1)
79 (21.6)
Nonhematologic
   Diarrhea
240 (65.9)
33 (9.1)
188 (51.5)
22 (6.0)
   Fatigue
164 (45.1)
33 (9.1)
114 (31.2)
17 (4.7)
   Constipation
157 (43.1)
6 (1.6)
137 (37.5)
2 (0.5)
   Peripheral edema
155 (42.6)
10 (2.7)
117 (32.1)
3 (0.8)
   Back pain
155 (42.6)
14 (3.8)
109 (29.9)
14 (3.8)
   Asthenia
136 (37.4)
19 (5.2)
101 (27.7)
18 (4.9)
   Nausea
133 (36.5)
7 (1.9)
88 (24.1)
2 (0.5)
   Insomnia
125 (34.3)
11 (3.0)
116 (31.8)
14 (3.8)
   Bronchitis
124 (34.1)
12 (3.3)
87 (23.8)
7 (1.9)
   Pneumonia
113 (31.0)
71 (19.5)
66 (18.1)
39 (10.7)
   Cough
123 (33.8)
2 (0.5)
65 (17.8)
0 (0.0)
   Dyspnea
119 (32.7)
12 (3.3)
63 (17.3)
4 (1.1)
   Weight decreased
112 (30.8)
10 (2.7)
69 (18.9)
11 (3.0)
   Muscle spasms
111 (30.5)
2 (0.5)
86 (23.6)
5 (1.4)
   Peripheral sensory neuropathy
111 (30.5)
9 (2.5)
66 (18.1)
2 (0.5)
Abbreviations: D-Rd, daratumumab + lenalidomide + dexamethasone; Rd, lenalidomide + dexamethasone.aData are based on a median duration of follow-up of 64.5 months.

Subgroup Analysis of MAIA According to Age

Facon et al (2022)8 presented the efficacy results of the MAIA study according to age group.

Results

Patient Characteristics

Patient Disposition and Treatment Discontinuations According to Age Group in the ITT Population (MAIA)8
Parameter
Age <70 Years
Age ≥70 to
<75 Years
Age <75 Years
D-Rd (n=78)
Rd (n=77)
D-Rd (n=130)
Rd (n=131)
D-Rd (n=208)
Rd (n=208)
Patients treated, n (%)a
78 (100)
76 (98.7)
129 (99.2)
130 (99.2)
207 (99.5)
206 (99.0)
Patients who discontinued treatment, n (%)b
37 (47.4)
64 (84.2)
79 (61.2)
106 (81.5)
116 (56.0)
170 (82.5)
   Reasons for discontinuation, n (%)
      PD
17 (21.8)
34 (44.7)
42 (32.6)
47 (36.2)
59 (28.5)
81 (39.3)
      AE
9 (11.5)
12 (15.8)
20 (15.5)
33 (25.4)
29 (14.0)
45 (21.8)
      Noncompliance with study drug
5 (6.4)
5 (6.6)
7 (5.4)
7 (5.4)
12 (5.8)
12 (5.8)
      Death
5 (6.4)
2 (2.6)
5 (3.9)
7 (5.4)
10 (4.8)
9 (4.4)
      Physician’s decision
1 (1.3)
9 (11.8)
3 (2.3)
7 (5.4)
4 (1.9)
16 (7.8)
      Patient withdrawal
0
2 (2.6)
1 (0.8)
3 (2.3)
1 (0.5)
5 (2.4)
      Other
0
0
1 (0.8)
2 (1.5)
1 (0.5)
2 (1.0)
Abbreviations: AE, adverse event; D-Rd, DARZALEX + lenalidomide + dexamethasone; ITT, intent-to-treat; 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

Survival Outcomes According to Age Group in the ITT Population (MAIA)8
Parameter
Age <70 Years
Age ≥70 to
<75 Years
Age <75 Years
D-Rd
(n=78)
Rd
(n=77)
D-Rd
(n=130)
Rd
(n=131)
D-Rd
(n=208)
Rd
(n=208)
Median PFS, months
NR
39.2
61.9
37.5
NR
37.5
Median PFS HR (95% CI)
0.35 (0.21-0.56)
0.64 (0.45-0.89)
0.52 (0.39-0.68)
   P value
<0.0001
0.0079
<0.0001
60-month PFS, %
67.2
28.7
51.6
36.6
57.4
33.6
OS HR (95% CI)
0.50 (0.27-0.90)
0.64 (0.43-0.96)
0.59 (0.43-0.83)
   P value
0.0179
0.0274
0.0017
60-month OS, %
79.9
61.7
70.3
57.0
73.9
58.8
Abbreviations: D-Rd, DARZALEX + lenalidomide + dexamethasone; HR, hazard ratio; ITT, intent-to-treat; NR, not reported; OS, overall survival; PFS, progression-free survival; Rd, lenalidomide + dexamethasone.

Response Outcomes According to Age Group in the ITT Population (MAIA)8
Parameter, n (%)
Age <70 Years
Age ≥70 to
<75 Years
Age <75 Years
D-Rd
(n=78)
Rd
(n=77)
P
Value
D-Rd
(n=130)
Rd
(n=131)
P
Value
D-Rd
(n=208)
Rd
(n=208)
P
Value
ORR
73
(93.6)
62
(80.5)
0.0156
125
(96.2)
108
(82.4)
0.0004
198
(95.2)
170
(81.7)
<0.0001
   ≥CR
44
(56.4)
24
(31.2)
0.0016
73
(56.2)
41
(31.3)
<0.0001
117
(56.3)
65
(31.3)
<0.0001
      sCR
31
(39.7)
11
(14.3)
0.0004
50
(38.5)
23
(17.6)
0.0002
81
(38.9)
34
(16.3)
<0.0001
      CR
13
(16.7)
13
(16.9)
-
23
(17.7)
18
(13.7)
-
36
(17.3)
31
(14.9)
-
   ≥VGPR
64
(82.1)
45
(58.4)
0.0013
111
(85.4)
76
(58.0)
<0.0001
175
(84.1)
121
(58.2)
<0.0001
      VGPR
20
(25.6)
21
(27.3)
-
38
(29.2)
35
(26.7)
-
58
(27.9)
56
(26.9)
-
   PR
9
(11.5)
17
(22.1)
-
14
(10.8)
32
(24.4)
-
23
(11.1)
49
(23.6)
-
SD
1
(1.3)
14
(18.2)
-
3
(2.3)
20
(15.3)
-
4
(1.9)
34
(16.3)
-
PD
0
0
-
0
0
-
0
0
-
NE
4
(5.1)
1
(1.3)
-
2
(1.5)
3
(2.3)
-
6
(2.9)
4
(1.9)
-
MRD-negative (10-5)
28
(35.9)
9
(11.7)
0.0006
47
(36.2)
16
(12.2)
<0.0001
75
(36.1)
25
(12.0)
<0.0001
Abbreviations: CR, complete response; D-Rd, DARZALEX + lenalidomide + dexamethasone; ITT, intent-to-treat; MRD, minimal residual disease; 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.

Analysis of Clinically Important Subgroups of MAIA

Moreau et al (2022)9 presented the efficacy and safety results in clinically important subgroups of patients from the MAIA study.

Study Design/Methods

  • Efficacy outcomes (PFS, ORR, and MRD-negativity) were analyzed in Age subgroup based on the following patient characteristics:
    • Age ≥75 years.

Results

Patient Characteristics
  • Overall, 737 patients (D-Rd, 368; Rd, 369) were included in the ITT population.
  • The median duration of follow-up was 64.5 months.
Efficacy

Subgroup Analysis of PFS According to Age Group in the ITT Population of MAIA9
Subgroup
D-Rd
Rd
HR (95% CI)a
n/N
Median PFS, Month
n/N
Median PFS, Month
ITT (overall)
176/368
61.9
228/369
34.4
0.55 (0.45-0.67)
Baseline characteristic
   Age ≥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; ITT, intent-to-treat; PFS, progression-free survival; Rd, lenalidomide + dexamethasone.
aHR <1 indicates an advantage for D-Rd.

Subgroup Analysis of ORR According to Age Group in the ITT Population of MAIA9
Subgroup
D-Rd
n/N (%)
Rd
n/N (%)
OR (95% CI)a
ITT (overall)
342/368 (92.9)
301/369 (81.6)
2.97 (1.84-4.79)
Baseline characteristic
   Age ≥75 years
144/160 (90.0)
131/161 (81.4)
2.06 (1.07-3.95)
Abbreviations: CI, confidence interval; D-Rd, DARZALEX + lenalidomide + dexamethasone; ITT, intent-to-treat; OR, odds ratio; Rd, lenalidomide + dexamethasone.
aOR >1 indicates an advantage for D-Rd.

Subgroup Analysis of MRD-Negativity (10-5) Rates According to Age Group in the ITT Population of MAIA9
Subgroup
D-Rd
n/N (%)
Rd
n/N (%)
OR (95% CI)a
ITT (overall)
118/368 (32.1)
41/369 (11.1)
3.78 (2.55-5.59)
Baseline characteristic
   Age ≥75 years
43/160 (26.9)
16/161 (9.9)
3.33 (1.79-6.21)
Abbreviations: CI, confidence interval; D-Rd, DARZALEX + lenalidomide + dexamethasone; ITT, intent-to-treat; OR, odds ratio; Rd, lenalidomide + dexamethasone.
aOR >1 indicates an advantage for D-Rd.

Subgroup Analysis of Sustained MRD-Negativity (10-5) Rates According to Age Group Lasting ≥12 Months in the ITT Population9
Subgroup
D-Rd
n/N (%)
Rd
n/N (%)
OR (95% CI)a
ITT (overall)
69/368 (18.8)
15/369 (4.1)
5.45 (3.05-9.72)
Baseline characteristic
   Age ≥75 years
22/160 (13.8)
5/161 (3.1)
4.97 (1.83-13.49)
Abbreviations: CI, confidence interval; D-Rd, DARZALEX + lenalidomide + dexamethasone; ITT, intent-to-treat; OR, odds ratio; Rd, lenalidomide + dexamethasone.
aOR >1 indicates an advantage for D-Rd.
Safety (Patients Aged ≥75 Years)
  • 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 (D-Rd, 20.4%; Rd, 25.2%), and pneumonia (D-Rd, 20.4%; Rd, 14.5%).
  • Serious TEAEs were reported in 80.9% vs 79.2% of patients in the D-Rd vs Rd arm, the most common of which was pneumonia (D-Rd, 19.7%; Rd, 12.6%).
  • TEAEs led to treatment discontinuation in 15.3% vs 27.7% of patients in the D-Rd vs Rd arm.
  • TEAEs resulting in death were reported in 11.5% vs 13.2% of patients in the D-Rd vs Rd arm.

Efficacy and Safety Analysis of Elderly (≥75 Years) and Non-Elderly (<75 Years) Patients with NDMM in the ALCYONE Study

Cavo et al (2018)10 analyzed the efficacy and safety data of elderly patients aged <75 and ≥75 years treated in the ALCYONE study reported by Mateos et al (2018).25

Study Design/Methods
  • ALCYONE (MMY3007; clinicaltrials.gov identifier: NCT02195479) was a multicenter, randomized (1:1), open-label, active-controlled, phase 3 study of patients with NDMM who were ineligible for ASCT.
  • Patients in the ALCYONE study received 42-day cycles of VMP or D-VMP for up to 9 cycles.
    • Bortezomib 1.3 mg/m2 was administered SC twice weekly on weeks 1, 2, 4, and 5 of cycle 1 and once weekly on weeks 1, 2, 4, and 5, of cycles 2-9.
    • Melphalan 9 mg/m2 was administered PO once daily on days 1-4 of each cycle.
    • Prednisone 60 mg/m2 was administered PO once daily on days 1-4 of each cycle.
    • DARZALEX 16 mg/kg IV was administered once weekly in cycle 1, once every 3 weeks in cycles 2-9, and once every 4 weeks thereafter until disease progression.
  • Primary endpoint: PFS.
  • Secondary endpoints: ≥CR rate, ≥VGPR rate, MRD-negativity (10-5), ORR, and median OS.
Results
  • The median duration of follow-up was 16.5 months.
  • Baseline characteristics are summarized in Table: Demographics and Baseline Clinical Characteristics (ALCYONE).
  • Among patients aged ≥75 years:
    • Median duration of study treatment: 14.5 months D-VMP vs 12.0 months VMP.
    • Median cumulative dose of bortezomib: 43.1 mg/m2 D-VMP vs 34.1 mg/m2 VMP.
    • During cycles 1-9, 28% treated with D-VMP and 43% treated with VMP discontinued treatment.
    • During cycles 10+: 8% treated with D-VMP discontinued treatment.
  • Among patients aged <75 years:
    • Median duration of study treatment: 15.0 months D-VMP vs 12.0 months VMP.
    • Median cumulative dose of bortezomib: 48.6 mg/m2 D-VMP vs 46.2 mg/m2 VMP.
    • During cycles 1-9, 16% treated with D-VMP and 29% treated with VMP discontinued treatment.
    • During cycles 10+, 10% of patients treated with D-VMP discontinued treatment.

Demographics and Baseline Clinical Characteristics (ALCYONE)10
Characteristic
Aged <75 years
Aged ≥75 years
D-VMP (n=246)
VMP (n=249)
D-VMP (n=104)
VMP (n=107)
Age, years
   Median (range)
69 (40-74)
69 (50-74)
78 (75-93)
77 (75-91)
Male, %
47
47
43
47
Baseline ECOG scorea, %
   0/1/2
19/55/27
27/50/23
31/46/23
30/46/24
Baseline ISS stageb, %
   I/II/III
22/37/40
21/44/35
14/45/41
14/48/38
Cytogenetic profilec
   N
221
212
93
90
   High risk, %
15
16
20
12
Abbreviations: ECOG, Eastern Cooperative Oncology Group; ISS, International Staging System; D-VMP, DARZALEX + bortezomib + melphalan + prednisone; VMP, bortezomib + melphalan + prednisone.
aECOG performance status is scored on a scale from 0 to 5, with 0 indicating no symptoms and higher scored indicating increasing disability.
bBased on the combination of serum β2-microglobulin and albumin.
cBased on fluorescence in situ hybridization/karyotype testing performed at local sites; t(4;14), t(14;16), and del17p were classified as high-risk.
Efficacy
  • Median PFS:
    • ITT population: NR D-VMP vs 18.1 months VMP (HR, 0.50; 95% CI, 0.38-0.65; P<0.001).
    • ≥75 years: NR D-VMP vs 20.4 months VMP (HR, 0.53; 95% CI, 0.32-0.85).
    • <75 years: NR D-VMP vs 17.9 months VMP (HR, 0.49; 95% CI, 0.36-0.68).
  • 18-month PFS:
    • ≥75 years: 71% D-VMP vs 51% VMP.
    • <75 years: 72% D-VMP vs 50% VMP.
  • MRD-negativity rates (10-5 sensitivity threshold):
    • Overall population: 22% D-VMP vs 6% VMP (P<0.0001).
    • ≥75 years: 24% D-VMP vs 8% VMP (P=0.0011).
    • <75 years: 22% D-VMP vs 6% VMP (P<0.0001).
  • The response rates and characteristics are summarized in Table: Response Rates and Characteristics (ALCYONE).

Response Rates and Characteristics (ALCYONE)10
Response characteristic
ITT
Aged <75 years
Aged ≥75 years
D-VMP (n=350)
VMP (n=356)
D-VMP (n=246)
VMP (n=249)
D-VMP (n=104)
VMP (n=107)
ORR, %
90.9
73.9
92.3
75.5
87.5
70.1
sCR, %
18.0
7.0
17.5
7.2
19.2
6.5
≥CR, %
42.6
24.4
43.1
24.5
41.3
24.3
≥VGPR, %
71.1
49.7
72.4
50.2
68.3
48.6
Median (range) time to first responsea, months
0.79
(0.4-15.5)
0.82
(0.7-12.6)
0.79
(0.4-15.3)
0.85
(0.7-12.6)
0.82
(0.7-15.5)
0.82
(0.7-6.3)
Median (range) time to ≥CRa, months
8.31
(1.9-21.0)
7.46
(0.7-20.5)
8.41
(1.9-18.3)
7.10
(1.4-20.5)
6.93
(2.6-21.0)
9.00
(0.7-14.0)
Abbreviations: CR, complete response; D-VMP, DARZALEX + bortezomib + melphalan + prednisone; ITT, intent-to-treat; ORR, overall response rate; sCR, stringent complete response; VGPR, very good partial response; VMP, bortezomib + melphalan + prednisone.
aResponse of partial response or better in response-evaluable population (ie, patients who have a confirmed diagnosis of multiple myeloma and measurable disease at baseline and must have received ≥1 component of study treatment and have adequate post-baseline disease assessments).
Safety

Most Common All-grade (≥25%) TEAEs and TEAEs of Interest Among Elderly Patients (ALCYONE)10
Events, %
Overall Populationa
Aged <75 years
Aged ≥75 years
D-VMP (n=346)
VMP (n=354)
D-VMP (n=244)
VMP (n=248)
D-VMP (n=102)
VMP (n=106)
Most common all-grade TEAEs
   Neutropenia
50
53
45
52
62
55
   Thrombocytopenia
49
54
42
51
65
59
   Anemia
28
38
25
36
36
42
   URTI
26
14
26
13
28
15
   Diarrhea
24
25
21
21
30
33
   Pyrexia
23
21
20
21
31
20
   Nausea
21
22
19
18
26
30
TEAEs of interest
   Peripheral sensory
   neuropathy
28
34
30
32
24
40
   Infectionsb
67
48
64
46
73
52
Abbreviations: D-VMP, DARZALEX + bortezomib + melphalan + prednisone; MedDRA, Medical Dictionary for Regulatory Activities; TEAE, treatment-emergent adverse event; URTI, upper respiratory tract infection; VMP, bortezomib + melphalan + prednisone.
aIncludes all patients who received ≥1 dose of study treatment.
bMedDRA system organ class.

Most Common Grade 3/4 (≥10%) TEAEs and Grade 3/4 TEAEs of Interest Among Elderly Patients (ALCYONE)10
TEAEs, %
Overall Populationa
Aged <75 years
Aged ≥75 years
D-VMP (n=346)
VMP (n=354)
D-VMP (n=244)
VMP (n=248)
D-VMP (n=102)
VMP (n=106)
Patients with grade 3/4 TEAEs
78
77
73
74
89
85
Most common TEAEs
   Neutropenia
40
39
35
38
52
42
   Thrombocytopenia
34
38
28
35
51
43
   Anemia
16
20
13
19
24
23
   Leukopenia
8
9
6
9
13
9
   Lymphopenia
8
6
7
4
10
10
   Pneumonia
11
4
9
2
18
9
TEAEs of interest
   Peripheral sensory
   neuropathy
1
4
2
3
0
6
   Infectionsb
23
15
21
13
28
20
Abbreviations: D-VMP, DARZALEX + bortezomib + melphalan + prednisone; MedDRA, Medical Dictionary for Regulatory Activities; TEAE, treatment-emergent adverse event; VMP, bortezomib + melphalan + prednisone.
aIncludes all patients who received ≥1 dose of study treatment.
bMedDRA system organ class.

Updated Analysis of the ALCYONE Study

Mateos et al (2022)11 presented an updated analysis of the ALCYONE study that evaluated the efficacy and safety of D-VMP vs VMP in patients with NDMM who were ineligible for
high-dose chemotherapy and ASCT.

Study Design/Methods

  • Eligible patients were randomized 1:1 to receive either D-VMP or VMP until PD.

Results

Patient Disposition
  • A total of 706 patients were randomized (D-VMP, n=350; VMP, n=356) in the ALCYONE study.
  • The median duration of follow-up was 78.8 months.
  • At data cutoff, all patients had either discontinued or completed 9 cycles of VMP therapy.
Efficacy
  • In the D-VMP vs VMP arm, the median PFS was 37.3 vs 19.7 months (HR, 0.43; 95% CI, 0.36-0.52; P<0.0001) and the 72-month PFS rate was 31.9% vs 7.0%.
  • In the D-VMP vs VMP arm, the median OS was 82.7 vs 53.6 months (HR, 0.64; 95% CI, 0.52-0.79; P<0.0001) and the 72-month OS rate was 55.7% vs 39.7%.

OS in Prespecified Age Subgroups (ALCYONE)11
Subgroup
D-VMP
VMP
HR (95% CI)a
n/N
Median OS (months)
n/N
Median OS (months)
Age
   <75 years
105/246
85.5
137/249
56.6
0.62 (0.48-0.80)
   ≥75 years
55/104
59.1
70/107
49.7
0.71 (0.50-1.01)
Abbreviations: CI, confidence interval; D-VMP, daratumumab + bortezomib + melphalan + prednisone; HR, hazard ratio; OS, overall survival; VMP, bortezomib + melphalan + prednisoneaHR and 95% CI from a Cox proportional hazards model with treatment as the sole explanatory variable. An HR <1 indicates an advantage for D-VMP.

Safety

  • The most common TEAEs are summarized in the Table: Summary of Any Grade (≥15%) and Grade 3/4 (≥5%) TEAEs in the Safety Population (ALCYONE).
  • In the D-VMP vs VMP arm, grade 3/4 TEAEs were reported in 82.9% vs 77.4% of patients, and grade 3/4 infections were reported in 30.3% vs 15.0% of patients.
  • The most common serious TEAE in both treatment arms was pneumonia (D-VMP, 14.7%; VMP, 3.7%).
  • The rate of treatment discontinuation due to TEAEs in the D-VMP vs VMP arm was 9.0% vs 9.3%.

Summary of Any Grade (≥15%) and Grade 3/4 (≥5%) TEAEs in the Safety Population (ALCYONE)11
Event, n (%)
D-VMP (n=346)
VMP (n=354)
Any Grade
Grade 3/4
Any Grade
Grade 3/4
Hematologic
   Neutropenia
175 (50.6)
140 (40.5)
186 (52.5)
138 (39.0)
   Thrombocytopenia
173 (50.0)
120 (34.7)
190 (53.7)
134 (37.9)
   Anemia
112 (32.4)
63 (18.2)
131 (37.0)
70 (19.8)
   Leukopenia
47 (13.6)
28 (8.1)
53 (15.0)
30 (8.5)
   Lymphopenia
39 (11.3)
27 (7.8)
36 (10.2)
22 (6.2)
Nonhematologic
   Upper respiratory tract infection
107 (30.9)
8 (2.3)
50 (14.1)
6 (1.7)
   Diarrhea
101 (29.2)
9 (2.6)
87 (24.6)
11 (3.1)
   Peripheral sensory neuropathy
100 (28.9)
5 (1.4)
122 (34.5)
14 (4.0)
   Pyrexia
89 (25.7)
2 (0.6)
74 (20.9)
2 (0.6)
   Bronchitis
76 (22.0)
11 (3.2)
27 (7.6)
3 (0.8)
   Nausea
75 (21.7)
3 (0.9)
76 (21.5)
4 (1.1)
   Pneumonia
74 (21.4)
56 (16.2)
19 (5.4)
16 (4.5)
   Back pain
71 (20.5)
8 (2.3)
42 (11.9)
4 (1.1)
   Cough
71 (20.5)
1 (0.3)
27 (7.6)
1 (0.3)
   Constipation
64 (18.5)
3 (0.9)
65 (18.4)
1 (0.3)
   Peripheral edema
68 (19.7)
3 (0.9)
39 (11.0)
1 (0.3)
   Vomiting
62 (17.9)
5 (1.4)
55 (15.5)
6 (1.7)
   Fatigue
61 (17.6)
12 (3.5)
51 (14.4)
9 (2.5)
   Hypertension
52 (15.0)
23 (6.6)
11 (3.1)
6 (1.7)
Abbreviations: D-VMP, daratumumab + bortezomib + melphalan + prednisone; VMP, bortezomib + melphalan + prednisone

CASTOR and POLLUX Studies

Mateos et al (2019)12 analyzed the efficacy and safety data of patients aged 65-74 and ≥75 years treated in the POLLUX study reported by Dimopoulos et al (2016)26 and the CASTOR study reported by Palumbo et al (2016).27 Results of this analysis are summarized.

POLLUX

Study Design/Methods

  • POLLUX (MMY3003; clinicaltrials.gov identifier: NCT02076009) was a multicenter, randomized (1:1), open-label, active controlled phase 3 study of patients with RRMM.
  • Patients in the POLLUX study received 28-day cycles of Rd or D-Rd until PD, unacceptable toxicity, or withdrawal of consent.
    • Lenalidomide 25 mg PO was administered on days 1 to 21 of each cycle.
    • Dexamethasone 40 mg was administered weekly for patients aged <75 years and 20 mg weekly for patients aged ≥75 years.
      • Patients aged <75 years received a split dose of dexamethasone 20 mg PO or IV on the day of the infusion and dexamethasone 20 mg PO the day after DARZALEX infusion.
      • Patients aged ≥75 years received a full dose of dexamethasone 20 mg prior to the infusion.
    • DARZALEX 16 mg/kg IV was administered weekly for 8 weeks in cycles 1 and 2, every 2 weeks for 16 weeks in cycles 3 to 6, and every 4 weeks thereafter.
  • Primary endpoint: PFS.
  • Secondary endpoints: TTP, ORR, ≥VGPR, ≥CR, OS, DOR, MRD, and safety assessments.

Results

  • Among patients aged ≥75 years, 9 (31%) treated with D-Rd discontinued treatment vs 24 (68.6%) treated with Rd.
  • Among patients aged 65-74 years, 51 (41.5%) treated with D-Rd discontinued treatment vs 76 (70.4%) treated with Rd.
  • Patient demographic and baseline characteristics are summarized in Table: Patient Demographic and Baseline Clinical Characteristics (POLLUX).

Patient Demographic and Baseline Clinical Characteristics (POLLUX)12
Characteristic
Aged 65-74 years
Aged ≥75 years
D-Rd (n=124)
Rd (n=108)
D-Rd (n=29)
Rd (n=35)
Age, years
   Median (range)
69 (65-74)
69 (65-74)
77 (75-89)
78 (75-87)
   Male, %
83 (66.9)
62 (57.4)
14 (48.3)
21 (60)
Baseline ECOG score, %
   0/1/2
48.4/48.4/3.2
50/42.6/7.4
34.5/51.7/13.8
31.4/60/8.6
Abbreviations: D-Rd, DARZALEX + lenalidomide + dexamethasone; ECOG, Eastern Cooperative Oncology Group; Rd, lenalidomide + dexamethasone.
Efficacy
  • D-Rd significantly prolonged PFS vs Rd 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).
  • 18-month PFS rate in patients aged ≥75 years: 86.2% D-Rd vs 36.9% Rd.
  • 18-month PFS rate in patients aged 65-74 years: 72% D-Rd vs 48.7% Rd.
  • ORR in patients aged ≥75 years: 93.1% D-Rd vs 76.5% Rd (P<0.0001).
    • ≥VGPR: 75.9% D-Rd vs 41.2% Rd (P=0.0740).
    • ≥CR: 55.2% D-Rd vs 8.8% Rd (P<0.0001).
  • ORR in patients aged 65-74 years: 92.6% D-Rd vs 80.2% Rd (P=0.0057).
    • ≥VGPR: 76.2% D-Rd vs 49.1% Rd (P<0.0001).
    • ≥CR: 50% D-Rd vs 22.6% Rd (P<0.0001).
  • Rates of MRD-negative status (10-5 sensitivity): 23.4% D-Rd vs 8.3% Rd (P=0.001520) in patients aged 65-74 years; 27.6% D-Rd vs 5.7% Rd (P=0.014464) in patients aged ≥75 years.
Safety
  • Grade 3/4 TEAEs occurred in 25 (86.2%) and 27 (77.1%) patients aged ≥75 years in the D-Rd and Rd arms, respectively.
  • The most common grade 3/4 TEAEs are presented in Table: Most Common Grade 3/4 TEAEs (≥10%) Among Elderly Patients (POLLUX).
  • Any-grade IRRs were reported by 12 (41.4%) patients aged ≥75 years and 57 (46.3%) patients aged 65-74 years; no patients discontinued treatment due to an IRR.
    • Grade 3/4 IRRs were reported by 4 (13.8%) patients aged ≥75 years and included dyspnea, chills, feeling cold, and wheezing (1 [3.4%] each).
    • Grade 3/4 IRRs were reported by 6 (4.9%) patients aged 65-74 years and included dyspnea, wheezing, and vomiting (1 [0.8%] each).

Most Common Grade 3/4 TEAEs (≥10%) Among Elderly Patients (POLLUX)12
TEAE, n (%)
Aged 65-74 years
Aged ≥75 years
D-Rd (n=123)
Rd (n=108)
D-Rd (n=29)
Rd (n=35)
Patients with grade 3/4 TEAE
113 (91.9)
89 (82.4)
25 (86.2)
27 (77.1)
Hematologic
   Neutropenia
68 (55.3)
43 (39.8)
13 (44.8)
11 (31.4)
   Anemia
23 (18.7)
24 (22.2)
3 (10.3)
7 (20)
   Thrombocytopenia
19 (15.4)
16 (14.8)
3 (10.3)
5 (14.3)
Non-hematologic
   Dyspnea
7 (5.7)
0
3 (10.3)
0
   Pneumonia
19 (15.4)
7 (6.5)
5 (17.2)
4 (11.4)
   Hypokalemia
5 (4.1)
5 (4.6)
4 (13.8)
1 (2.9)
   Pulmonary embolism
4 (3.3)
2 (1.9)
1 (3.4)
4 (11.4)
Abbreviations: D-Rd, DARZALEX + lenalidomide + dexamethasone; Rd, lenalidomide + dexamethasone; TEAE, treatment-emergent adverse event.

CASTOR

Study Design/Methods

  • CASTOR (MMY3004; clinicaltrials.gov identifier: NCT02136134) was a multicenter, randomized (1:1), open-label, active controlled phase 3 study of patients with RRMM.
  • Patients received 21-day cycles of Vd or D-Vd for up to 8 cycles.
    • Bortezomib 1.3 mg/m2 was administered SC on days 1,4,8, and 11 of cycles 1 to 8.
    • Patients aged <75 received dexamethasone 20 mg PO or IV on days 1, 2, 4, 5, 8, 9, 11 and 12 for a total of 160 mg per cycle during cycles 1 to 8.
    • Patients aged ≥75 received dexamethasone 20 mg weekly.
    • DARZALEX 16 mg/kg IV was administered weekly (days 1,8, and 15) during cycles 1 to 3, every 3 weeks (day 1) during cycles 4 to 8 and every 4 weeks thereafter until withdrawal of consent, PD, or unacceptable toxicity.
  • Primary endpoint: PFS.
  • Secondary endpoints: time to disease progression, overall response, DOR, TTR, ≥VGPR, OS, and MRD.

Results

  • Among patients aged ≥75 years, 11 (55%) treated with D-Vd discontinued treatment vs 15 (42.9%) treated with Vd.
  • Among patients aged 65-74 years, 56 (59.6%) treated with D-Vd discontinued treatment vs 44 (51.2%) treated with Vd.
  • Patient demographic and baseline characteristics are summarized in Table: Patient Demographic and Baseline Clinical Characteristics (CASTOR).

Patient Demographic and Baseline Clinical Characteristics (CASTOR)12
Characteristic
Aged 65-74 years
Aged ≥75 years
D-Vd (n=96)
Vd (n=87)
D-Vd (n=23)
Vd (n=35)
Age, years
   Median (range)
69 (65-74)
69 (65-74)
78 (75-88)
78 (75-85)
   Male, %
53 (55.2)
53 (60.9)
13 (56.5)
20 (57.1)
Baseline ECOG score, %
   0/1/2
40.6/53.1/6.3
43.7/44.8/11.5
26.1/73.9/0
45.7/48.6/5.7
Abbreviations: D-Vd, DARZALEX + bortezomib + dexamethasone; ECOG, Eastern Cooperative Oncology Group; Vd, bortezomib + dexamethasone.
Efficacy
  • D-Vd significantly prolonged PFS vs Vd 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).
  • 18-month PFS rate in patients aged ≥75 years: 45.8% D-Vd vs 0% Vd.
  • ORR in patients aged ≥75 years: 95% D-Vd vs 78.8% Vd (P=0.1134).
    • ≥VGPR: 70% D-Vd vs 18.2% Vd (P=0.0002).
    • ≥CR: 25% D-Vd vs 3% Vd (P=0.0154).
  • ORR in patients aged 65-74 years: 82.8% D-Vd vs 62.4% Vd (P=0.0022).
    • ≥VGPR: 64.5% D-Vd vs 27.1% Vd (P<0.0001).
    • ≥CR: 33.3% D-Vd vs 10.6% Vd (P=0.0003).
  • Rates of MRD-negative status (10-5 sensitivity): 15.6% D-Vd vs 2.3% Vd (P=0.000959) in patients aged 65-74 years.
  • Among patients aged ≥75 years, 1 (4.3%) patient treated with D-Vd achieved
    MRD-negative status (10-5 sensitivity) compared with no patients in the Vd treatment arm.
Safety
  • Grade 3/4 TEAEs occurred in 18 (90%) and 26 (74.3%) patients aged ≥75 years in the D-Vd and Vd arms, respectively.
  • The most common grade 3/4 TEAEs are presented in Table: Most Common Grade 3/4 (≥10%) TEAEs Among Elderly Patients (CASTOR).
  • Any-grade IRRs were reported by 13 (65%) patients aged ≥75 years and 43 (45.7%) patients aged 65-74 years; no patients discontinued treatment due to an IRR.
    • Grade 3/4 IRRs were reported by 2 (10%) patients aged ≥75 years and included bronchospasm (1 [5%]).
    • Grade 3/4 IRRs were reported by 8 (8.5%) patients aged 65-74 years and included hypertension (5 [5.3%]), dyspnea (4 [4.3%]), and bronchospasm (1 [1.1%]).

Most Common Grade 3/4 (≥10%) TEAEs Among Elderly Patients (CASTOR)12
TEAE, n (%)
Aged 65-74 years
Aged ≥75 years
D-Vd (n=94)
Vd (n=86)
D-Vd (n=20)
Vd (n=35)
Patients with grade 3/4 TEAE
77 (81.9)
60 (69.8)
18 (90)
26 (74.3)
Hematologic
   Thrombocytopenia
49 (52.1)
28 (32.6)
9 (45)
13 (37.1)
   Neutropenia
15 (16)
3 (3.5)
0
1 (2.9)
   Anemia
14 (14.9)
15 (17.4)
2 (10)
4 (11.4)
   Lymphopenia
12 (12.8)
5 (5.8)
1 (5)
0
Non-hematologic
   Pneumonia
12 (12.8)
6 (7)
3 (15)
6 (17.1)
   Fatigue
6 (6.4)
1 (1.2)
3 (15)
4 (11.4)
   Peripheral sensory neuropathy
3 (3.2)
9 (10.5)
2 (10)
2 (5.7)
   Bronchitis
3 (3.2)
3 (3.5)
2 (10)
0
   Diarrhea
2 (2.1)
1 (1.2)
2 (10)
0
Abbreviations: D-Vd, DARZALEX + bortezomib + dexamethasone; TEAE, treatment-emergent adverse event; Vd, bortezomib + dexamethasone.

Post Hoc Analyses of CASTOR and POLLUX in Clinically Relevant Subgroups

Mateos et al (2022)13 presented a post hoc analysis of the phase 3 CASTOR and POLLUX studies to evaluate the efficacy of D-Vd vs Vd and D-Rd vs Rd in subgroups of patients with RRMM. Results from the subgroup of patients with ≥75 years of age are summarized below.

Results


PFS and OS in the Pooled ITT Population According to Age Group from CASTOR and POLLUX13
Subgroup
PFS
OS
DARZALEX Arm
Control Arm
HR
(95% CI)
DARZALEX Arm
Control Arm
HR
(95% CI)
n/N
Median, Mos
n/N
Median, Mos
n/N
Median, Mos
n/N
Median, Mos
Age ≥75 years
40/52
28.9
60/70
9.4
0.41
(0.27-0.63)
37/52
52.7
50/70
35.1
0.87
(0.57-1.33)
Abbreviations: CI, confidence interval; HR, hazard ratio; ITT, intent-to-treat; Mos, months; OS, overall survival; PFS, progression-free survival.

PFS According to Age Group in the ITT Population of CASTOR13
Subgroup
D-Vd
Vd
HR
(95% CI)
n/N
Median, Months
n/N
Median, Months
Age ≥75 years
18/23
17.9
32/35
8.1
0.22 (0.10-0.47)
Abbreviations: CI, confidence interval; D-Vd, DARZALEX + bortezomib + dexamethasone; HR, hazard ratio; ITT, intent-to-treat; PFS, progression-free survival; Vd, bortezomib + dexamethasone.

PFS According to Age Group in the ITT Population of POLLUX13
Subgroup
D-Rd
Rd
HR
(95% CI)
n/N
Median, Months
n/N
Median, Months
Age ≥75 years
22/29
36.4
28/35
11.4
0.48 (0.27-0.85)
Abbreviations: CI, confidence interval; D-Rd, DARZALEX + lenalidomide + dexamethasone; HR, hazard ratio; ITT, intent-to-treat; PFS, progression-free survival; Rd, lenalidomide + dexamethasone.

ORR and MRD-Negativity (10-5) Rates According to Age Group in CASTOR13
Subgroup
ORRa
MRD-negativity Rateb
D-Vd
(n/N [%])
Vd
(n/N [%])
OR
(95% CI)
P value
D-Vd
(n/N [%])
Vd
(n/N [%])
OR
(95% CI)
P value
Age ≥75 years
19/20 (95.0)
26/33 (78.8)
5.12
(0.58-45.13)
0.1134
1/23
(4.3)
0/35
NE
(NE-NE)
0.3966
Abbreviations: CI, confidence interval; D-Vd, DARZALEX + bortezomib + dexamethasone; MRD, minimal residual disease; NE, not estimable; OR, odds ratio; ORR, overall response rate; Vd, bortezomib + dexamethasone.

ORR and MRD-Negativity (10-5) Rates According to Age Group in POLLUX13
Subgroup
ORRa
MRD-negativity Rateb
D-Rd
(n/N [%])
Rd
(n/N [%])
OR
(95% CI)
P value
D-Rd
(n/N [%])
Rd
(n/N [%])
OR
(95% CI)
P value
Age ≥75 years
27/29 (93.1)
26/34 (76.5)
4.15
(0.81-21.42)
0.0740
8/29 (27.6)
1/35
(2.9)
12.95
(1.51-111.07)
0.0084
Abbreviations: CI, confidence interval; D-Rd, DARZALEX + lenalidomide + dexamethasone; MRD, minimal residual disease; NE, not estimable; OR, odds ratio; ORR, overall response rate; Rd, lenalidomide + dexamethasone.

CLINICAL DATA - DARZALEX PHASE 2 STUDIES

DARZALEX-Based Response-Adapted Therapy for Older Adults With NDMM - Final Results of a Phase 2 Study

Baz et al (2024)14 presented (at the 66th ASH Annual Meeting) the final results of a phase 2 study of DARZALEX-based response-adapted therapy for older adults with NDMM.

Study Design/Methods

  • A total of 32 patients with NDMM (>65 years of age) who were not considered for transplant received 2 cycles of DARZALEX and dexamethasone therapy between day 0 and day 60.14
    • If patients experienced a PR or better, DARZALEX and dexamethasone therapy was continued per the usual dose and schedule (group A; n=13) until relapse or unacceptable toxicity.
    • If patients experienced less than PR, frailty-adjusted dosing of lenalidomide (group B; n=12) or bortezomib (group C; n=7) was added to the DARZALEX and dexamethasone therapy until relapse or unacceptable toxicity.
  • Primary endpoint: Best response per International Myeloma Working Group (IMWG) criteria.14
  • Secondary endpoints: PFS and ORR (after 2 cycles of DARZALEX and dexamethasone).14

Results

Baseline Characteristics

Baseline Characteristics (Phase 2 Study)14
Characteristic
All Enrolled
(N=32)
Group Aa
(n=13)
Group Ba
(n=12)
Group Ca
(n=7)
Median age (range), years
77.5 (66-88)
78 (66-87)
80 (71-86)
74 (71-88)
   Age >75 years, n (%)
20 (62.5)
9 (69.2)
10 (83.3)
1 (14.3)
   Age >80 years, n (%)
11 (34.4)
4 (30.8)
6 (50)
1 (14.3)
Female, n (%)
15 (46.9)
4 (30.8)
8 (66.7)
3 (42.9)
Race, n (%)
   White
26 (81.3)
11 (84.6) 
 10 (83.3)
5 (71.4)
   African American
5 (15.6)
2 (15.4)
1 (8.3)
2 (28.6)
   Asian
1 (3.1)
-
1 (8.3)
-
Hispanic ethnicity, n (%)
3 (9.4)
0 (0.0)
2 (16.7)
1 (14.3)
ECOG PS, n (%)
   0
18 (56.2)
7 (53.8)
8 (66.7)
3 (42.9)
   1
10 (31.3)
2 (15.4)
4 (33.3)
4 (57.1)
   2
4 (12.5)
4 (30.8)
-
-
IMWG frailty score, n (%)
   0 (fit)
 6 (18.8)
 3 (23.1)
 0 (0.0)
 3 (42.9)
   1 (unfit)
12 (37.5)
5 (38.5)
4 (33.3)
3 (42.9)
   2+ (frail)
14 (43.8)
5 (38.5)
8 (66.7)
1 (14.3)
Timed up and go, sec
9.27 (5.46-17.5)
8.81 (6.08-12)
9.7 (5.46-13.16)
9.4 (6.2-17.5)
   >10
7 (21.9)
1 (7.7)
3 (25)
3 (42.9)
Heavy chain, n (%)
   IgG
 23 (71.9)
 10 (76.9)
 9 (75)
4 (57.1)
   IgA
6 (18.8)
1 (7.7)
3 (25)
2 (28.6)
   Light-chain, kappa
20 (62.5)
10 (76.9)
7 (58.3)
3 (42.9)
R-ISS, n (%)
   1
5 (15.6)
 3 (23.1)
2 (16.7)
 -
   2
21 (65.6)
7 (53.8)
8 (66.6)
6 (85.7)
   3
6 (18.8)
3 (23.1)
2 (16.7)
1 (14.3)
High-risk cytogenetics, n (%)b
5 (15.6)
3 (23.1)
1 (8.3)
1 (14.3)
   Gain/Amp 1q
13 (40.6)
6 (46.2)
3 (25)
4 (57.1)
   Del1p
10 (31.3)
6 (46.2)
2 (16.7)
2 (28.6)
Baseline laboratory test
   B2M, median (range), mg/L
3.9 (2-15.9)
3.5 (2.0-7.1)
4.7 (2.2-9.5)
4.0 (3.6-15.9)
   Albumin
3.7 (2.6-4.4)
3.7 (3.3-4.4)
3.6 (2.6-4.4)
3.8 (2.7-4.2)
   LDH
207.5 (107-497)
229 (140-497)
195.5 (107-265)
185 (149-329)
   Hemoglobin
11.1 (7.9-15)
12 (8.2-15)
11.4 (7.9-13.2)
8.9 (8-9.5)
   D-dimer
1199.5
(347-19,811)
1206
(347-19,811)
1217
(434-2433)
1193
(501-1529)
   C-reactive protein
0.3 (0.03-9.3)
0.3 (0.04-9.3)
0.3 (0.03-0.5)
0.2 (0.05-0.9)
Abbreviations: B2M, beta 2 microglobulin; ECOG PS, Eastern Cooperative Oncology Group performance status; Ig, immunoglobulin; IMWG, International Myeloma Working Group; LDH, lactate dehydrogenase; R-ISS, Revised International Staging System.aGroup A, DARZALEX + dexamethasone; group B, DARZALEX + lenalidomide + dexamethasone; group C, DARZALEX + bortezomib + dexamethasone.bHigh risk was defined as presence of 1 of the following: del17p, t(4;14), t(14;16).
Efficacy
  • The adapted therapy achieved an ORR of 97% and a median PFS of 42 months among a predominantly frail NDMM population. Notably, 37% of these patients were treated primarily with DARZALEX and dexamethasone.14
  • The summary of response rates is presented in Table: Summary of Response Rates (Phase 2 Study).

Summary of Response Rates (Phase 2 Study)14
Patients, n (%)a
All Enrolled
(N=32)
C2D22
(N=32)
Group Ab
(n=12)
Group Bb
(n=12)
Group Cb
(n=7)
sCR
2 (6.3)
-
1 (8.3)
1 (8.3)
-
CR
2 (6.3)
-
1 (8.3)
1 (8.3)
-
VGPR
21 (65.6)
3 (9.4)
7 (58.3)
9 (75)
5 (71.4)
PR
5 (15.6)
9 (28.1)
3 (25)
1 (8.3)
1 (14.3)
MR
-
13 (40.6)
-
-
-
SD
1 (3.1)
5 (15.6)
-
-
1 (14.3)
PD
-
1 (3.1)
-
-
-
NE
1 (3.1)
1 (3.1)
-
-
-
PR or better
30 (96.8)
12 (37.5)
12 (100)
12 (100)
6 (85.7)
Abbreviations: C2D22, response on cycle 2 day 22 after 2 cycles of DARZALEX + dexamethasone; CR, complete response; MR, minimal response; NE, not evaluable; PD, progressive disease; PR, partial response; sCR, stringent complete response; SD, stable disease; VGPR, very good partial response. aA patient discontinued the protocol therapy after receiving 1 dose due to disseminated tuberculosis. This patient was considered as NE according to the protocol.bGroup A, DARZALEX + dexamethasone; group B, DARZALEX + lenalidomide + dexamethasone; group C, DARZALEX + bortezomib + dexamethasone.
Safety
  • Notably, 37% of patients were treated primarily with a combination of DARZALEX and dexamethasone, which had a very tolerable side effect profile.14
  • The AEs of interest included peripheral neuropathy (n=4; all events occurred in group C), injection site reactions (9% of patients [grade 2; n=1]), and pneumonia (n=1).14
  • The AEs at least possibly related to therapy occurring in ≥10% of patients or grade ≥3 are summarized in Table: Any-Grade (≥10%) or Grade ≥3 AEs (Phase 2 Study).

Any-Grade (≥10%) or Grade ≥3 AEs (Phase 2 Study)14
AEs, n (%)
Any Grade
Grade ≥3
Anemia
3 (9)
1 (3)
Sinus tachycardia
1 (3)
1 (3)
Adrenal insufficiency
1 (3)
1 (3)
Constipation
4 (13)
1 (3)
Diarrhea
12 (38)
2 (6)a
Fatigue
11 (34)
0 (0)
Edema limbs
8 (25)
0 (0)
Aspartate aminotransferase increased
6 (19)
1 (3)
Lymphocyte count decreased
11 (34)
2 (6)
Neutrophil count decreased
8 (25)
1 (3)
Platelet count decreased
4 (13)
0 (0)
Hyperglycemia
22 (69)
1 (3)
Hypokalemia
7 (22)
0 (0)
Peripheral sensory neuropathy
4 (13)
0 (0)
Tremor
4 (13)
0 (0)
Agitation
6 (19)
1 (3)
Insomnia
11 (34)
0 (0)
Pruritus
6 (19)
0 (0)
Rash maculo-papular
5 (16)
1 (3)
Abbreviations: AE, adverse event.aPatients from group B (DARZALEX + lenalidomide + dexamethasone).

CLINICAL DATA - DARZALEX FASPRO PHASE 3 STUDIES

Efficacy and Safety Analysis of Elderly Patients Aged <65 and ≥65 Years with RRMM in the APOLLO Study

APOLLO (MMY3013; clinicaltrials.gov identifier: NCT03180736) is an ongoing, phase 3, randomized, open-label, multicenter study evaluating the efficacy and safety of D-Pd vs Pd in patients with RRMM who received ≥1 prior treatment with both lenalidomide and a proteasome inhibitor (N=304). Dimopoulos et al (2021)15 reported the primary analysis of this ongoing study. Sonneveld et al (2021)16 presented updated efficacy and safety results at a median duration of follow-up of 30.7 months.

Study Design/Methods

  • Patients were randomized 1:1 to D-Pd (n=151) or Pd (n=153), stratified by number of previous lines to treatment and ISS disease stage. These patients received 28-day cycles of:
    • In the D-Pd arm, patients received:
      • Daratumumab:
        • Before a protocol amendment, patients were administered DARZALEX 16 mg/kg IV once weekly for cycles 1 and 2, every 2 weeks for cycles 3-6, and every 4 weeks for cycles ≥7. These patients could switch to DARZALEX FASPRO starting on day 1 of cycle 3 or later.
        • Subsequent to the protocol amendment, all new patients will receive DARZALEX FASPRO (1800 mg daratumumab co-formulated with recombinant human hyaluronidase PH20 [rHuPH20]) as listed above.
      • Pd: pomalidomide 4 mg PO daily on days 1-21 every cycle and dexamethasone 40 mg PO (20 mg for patients aged ≥75 years of age) weekly every cycle.
    • In the Pd arm, patients received pomalidomide 4 mg PO daily on days 1-21 every cycle and dexamethasone 40 mg PO (20 mg for patients aged ≥75 years of age) weekly every cycle.
  • Primary endpoint: PFS.
  • Secondary endpoints: ORR, ≥VGPR rate, ≥CR rate, MRD-negativity rate, OS, TTR, DOR, time to next therapy, safety, HRQoL, PK analysis of daratumumab, and daratumumab immunogenicity.

Results

Patient Characteristics
  • Median duration of study treatment was 11.5 months in the D-Pd arm vs 6.6 months in the Pd arm.
  • A total of 98% of patients in the D-Pd arm received DARZALEX FASPRO.
  • A total of 142 of 149 (95%) patients in the D-Pd arm started treatment with DARZALEX FASPRO.
  • Seven of 149 patients started treatment with DARZALEX. Among these patients, 4 switched to DARZALEX FASPRO and 3 progressed on DARZALEX before switching was permitted per the protocol amendment.
  • The demographics and baseline characteristics were well balanced between both arms as shown in Table: Key Baseline Characteristics and Demographics (APOLLO).

Key Baseline Characteristics and Demographics (APOLLO)a, 15

D-Pd (n=151)
Pd (n=153)
Age, years
   Median (range)
67 (42-86)
68 (35-90)
   Distribution, n (%)
      <65
63 (42)
60 (39)
      65-<75
63 (42)
62 (41)
      ≥75
25 (17)
31 (20)
Abbreviations: D-Pd, daratumumab + pomalidomide + dexamethasone; Pd, pomalidomide + dexamethasone.
aIntent-to-treat population (N=304).
Efficacy
  • After a median duration of follow-up of 16.9 months, median PFS was 12.4 months with D-Pd vs 6.9 months with Pd (HR, 0.63; 95% CI, 0.47-0.85; P=0.0018).
    • Median PFS among patients refractory to lenalidomide was 9.9 months with D-Pd vs 6.5 months with Pd.
  • The estimated 12-month PFS rate was 52% with D-Pd vs 35% with Pd.
  • A PFS benefit of D-Pd vs Pd was observed in all prespecified subgroups which included age as presented in Table: PFS in Prespecified Age Subgroup (APOLLO).
  • ORR (ITT population): 69% D-Pd vs 46% Pd (odds ratio [OR], 2.7; 95% CI, 1.7-4.4; P<0.0001).
  • Median time to 1st response was 1 month (95% CI, 1.0-1.1) in the D-Pd arm and 1.9 months (range, 1.0-2.0) in the Pd arm.
  • Median DOR was NR (95% CI 15.2 to NR) in the D-Pd arm and 5.9 months (range, 8.3-24.8) in the Pd arm.
  • Median time to subsequent therapy was 23.2 months (95% CI, 13.8-NE) vs 11.8 months (range, 8.9-15.4).
  • OS data at this time are immature. Death was reported in 48 (32%) patients in the D-Pd arm and 51 (33%) patients in the Pd arm. Long-term survival follow-up is ongoing.

PFS in Prespecified Age Subgroup (APOLLO)15
Events/patients
Median (95% CI) PFS, months
HR (95% CI)
D-Pd
Pd
D-Pd
Pd
Overall
84/151
106/153
12.4 (8.3-19.3)
6.9 (5.5-9.3)
0.63 (0.47-0.85)
Age, years
   <65
36/63
41/60
9.2 (4.6-21.0)
5.8 (3.7-12.6)
0.69 (0.44-1.09)
   ≥65
48/88
65/93
14.2 (9.9-NE)
7.0 (6.1-10.1)
0.55 (0.38-0.81)
Abbreviations: CI, confidence interval; D-Pd, daratumumab + pomalidomide + dexamethasone; HR, hazard ratio; Pd, pomalidomide + dexamethasone; PFS, progression-free survival.
Safety

TEAEs in the Safety Population Stratified by Age (APOLLO)28
Event, n (%)
D-Pd (n=149)
Pd (n=150)
Aged <65 years (n=61)
Aged ≥65 years (n=88)
Aged <65 years (n=58)
Aged ≥65 years (n=92)
Any TEAE
57 (93.4)
88 (100.0)
57 (98.3)
89 (96.7)
Any serious TEAE
25 (41.0)
50 (56.8)
19 (32.8)
40 (43.5)
TEAEs leading to discontinuation
0
3 (3.4%)
1 (1.7%)
3 (3.3%)
Grade ≥3 TEAE
52 (85.2)
79 (89.8)
46 (79.3)
77 (83.7)
Abbreviations: D-Pd, daratumumab + pomalidomide + dexamethasone; Pd, pomalidomide + dexamethasone; TEAE, treatment-emergent adverse event.

Most Common Any Grade (≥15%) and Grade 3/4 (≥5%) TEAEs in the Safety Population Stratified by Age (APOLLO)28
TEAEsa, n (%)
D-Pd (n=149)
Pd (n=150)
Aged <65 years (n=61)
Aged ≥65 years (n=88)
Aged <65 years (n=58)
Aged ≥65 years (n=92)
Any grade
Grade 3/4
Any grade
Grade 3/4
Any Grade
Grade 3/4
Any grade
Grade 3/4
Hematologic
   Neutropenia
39 (63.9)
37 (60.7)
66 (75.0)
64 (72.7)
25 (43.1)
25 (43.1)
55 (59.8)
51 (55.4)
  Thrombocytopenia
21 (34.4)
12 (19.7)
27 (30.7)
14 (15.9)
19 (32.8)
11 (19.0)
31 (33.7)
16 (17.4)
   Anemia
20 (32.8)
7 (11.5)
35 (39.8)
18 (20.5)
32 (55.2)
16 (27.6)
34 (37.0)
16 (17.4)
   Leukopenia
11 (18.0)
5 (8.2)
28 (31.8)
20 (22.7)
6 (10.3)
2 (3.4)
12 (13.0)
5 (5.4)
   Lymphopenia
7 (11.5)
7 (11.5)
15 (17.0)
11 (12.5)
5 (8.6)
2 (3.4)
7 (7.6)
3 (3.3)
   Febrile
   neutropenia
4 (6.6)
4 (6.6)
9 (10.2)
9 (10.2)
2 (3.4)
2 (3.4)
2 (2.2)
2 (2.2)
Non-hematologic
   Infections
42 (68.9)
15 (24.6)
63 (71.6)
27 (30.7)
34 (58.6)
14 (24.1)
49 (53.3)
20 (21.7)
      Upper RTI
17 (27.9)
0
17 (19.3)
0
14 (24.1)
0
10 (10.9)
3 (3.3)
      Pneumonia
14 (23.0)
7 (11.5)
16 (18.2)
13 (14.8)
11 (19.0)
6 (10.3)
8 (8.7)
4 (4.3)
      Lower RTI
9 (14.8)
7 (11.5)
20 (22.7)
10 (11.4)
11 (19.0)
7 (12.1)
13 (14.1)
7 (7.6)
   Fatigue
10 (16.4)
2 (3.3)
28 (31.8)
10 (11.4)
14 (24.1)
2 (3.4)
24 (26.1)
5 (5.4)
   Diarrhea
9 (14.8)
3 (4.9)
24 (27.3)
5 (5.7)
8 (13.8)
0
13 (14.1)
1 (1.1)
   Asthenia
9 (14.8)
3 (4.9)
24 (27.3)
5 (5.7)
9 (15.5)
0
15 (16.3)
1 (1.1)
   Pyrexia
8 (13.1)
0
21 (23.9)
0
8 (13.8)
0
13 (14.1)
0
   Insomnia
6 (9.8)
5 (8.2)
6 (6.8)
2 (2.3)
7 (12.1)
3 (5.2)
11 (12.0)
2 (2.2)
   Constipation
5 (8.2)
1 (1.6)
16 (18.2)
0
5 (8.6)
0
17 (18.5)
1 (1.1)
   Bone pain
5 (8.2)
1 (1.6)
9 (10.2)
0
9 (15.5)
1 (1.7)
10 (10.9)
1 (1.1)
   Cough
3 (4.9)
0
14 (15.9)
0
3 (5.2)
0
7 (7.6)
0
   Hyperglycemia
3 (4.9)
1 (1.6)
12 (13.6)
7 (8.0)
11 (19.0)
4 (6.9)
8 (8.7)
3 (3.3)
   Peripheral edema
3 (4.9)
0
19 (21.6)
0
3 (5.2)
0
8 (8.7)
0
   Dyspnea
2 (3.3)
0
14 (15.9)
4 (4.5)
4 (6.9)
0
7 (7.6)
1 (1.1)
Abbreviations: D-Pd, daratumumab + pomalidomide + dexamethasone; Pd, pomalidomide + dexamethasone; RTI, respiratory tract infection; TEAE, treatment-emergent adverse event.
aAdverse events are shown for any grade occurring in ≥15% of patients and grade 3 or 4 occurring in ≥5% of patients. Events are grouped by MedDRA system organ class/preferred term.

Approximately 3-Year Update on Efficacy and Safety Outcomes

Sonneveld et al (2021)16 evaluated the efficacy and safety of D-Pd vs Pd alone in patients with RRMM from the APOLLO study, with an additional 13.8 months of follow-up since the primary analysis.

Results

Patient Characteristics
  • A total of 304 patients were randomized (D-Pd, n=151; Pd, n=153).
  • A total of 120 (79.5%) patients in the D-Pd arm and 122 (79.7%) patients in the Pd arm were refractory to lenalidomide at randomization.
  • Treatment discontinuation was reported in 106 (71.1%) patients in the D-Pd arm and 134 (89.3%) patients in the Pd arm.
Efficacy
  • At a median duration of follow-up of 30.7 months, PFS favored D-Pd vs Pd (median 12.1 months vs 7.0 months, respectively; HR, 0.63; 95% CI, 0.48-0.83; P=0.0007).
  • Among patients who were refractory to lenalidomide, median PFS was 9.9 months vs 6.5 months in D-Pd- vs Pd-treated patients, respectively (HR, 0.64; 95% CI, 0.48-0.86).
  • Among those who were refractory to lenalidomide and received a last lenalidomide dose of 5 to 10 mg, median PFS was 10.3 months vs 8.5 months in D-Pd- vs Pd-treated patients, respectively (HR, 0.83; 95% CI, 0.47-1.45; P=0.5030).
    • Estimated PFS rates at 18 months were 27.6% and 24.1%, respectively.
  • Among those who were refractory to lenalidomide and received a last lenalidomide dose of 15 to 25 mg, median PFS was 10.7 months vs 6.5 months in D-Pd- vs Pd-treated patients, respectively (HR, 0.56; 95% CI, 0.39-0.80; P=0.0011).
    • Estimated PFS rates at 18 months were 39.5% and 22.0%, respectively.
  • The PFS benefit associated with D-Pd vs Pd was consistent across age subgroups as summarized in Table: Age Subgroup Analysis of PFS in the ITT Population (APOLLO).

Age Subgroup Analysis of PFS in the ITT Population (APOLLO)16
Events/Patients
Median PFS, Months
HR (95% CI)a
D-Pd
Pd
D-Pd
Pd
Overall
100/151
120/153
12.09
7.03
0.63 (0.48-0.83)
Age
   <65 years
41/63
49/60
8.34
6.54
0.63 (0.41-0.96)
   ≥65 years
59/88
71/93
13.11
7.23
0.60 (0.42-0.85)
Abbreviations: CI, confidence interval; D-Pd, DARZALEX FASPRO + pomalidomide + dexamethasone; HR, hazard ratio; ITT, intent-to-treat; Pd, pomalidomide + dexamethasone; PFS, progression-free survival; ULN, upper limit of normal.
aHRs and 95% CIs were calculated from a Cox proportional hazards model with treatment as the sole explanatory variable. An HR <1 indicates an advantage for D-Pd.
  • D-Pd was associated with improvement in the following efficacy outcomes vs Pd:
    • ORR: 68.9% vs 47.1%, respectively (OR, 2.61; 95% CI, 1.61-4.23; P<0.0001).
    • ≥VGPR rate: 51.0% vs 20.9%, respectively.
    • ≥CR rate: 27.2% vs 5.9%, respectively.
  • Among those who were refractory to lenalidomide, ORR was 65.0% with D-Pd vs 41.0% with Pd (OR, 2.67; 95% CI, 1.59-4.50).
Safety
  • The overall safety profile of D-Pd at the updated analysis (30.7 months) was consistent with that observed at the primary analysis (16.9 months). No new safety concerns were reported with longer follow-up.
  • The most common any-grade and grade 3/4 TEAEs are presented in the Table: Most Common Any-Grade (≥15%) and Grade 3/4 (≥5%) TEAEs in the Safety Population (APOLLO).
  • Grade ≥3 TEAEs were reported in 133 (89.3%) patients in the D-Pd arm vs 123 (82.0%) patients in the Pd arm.

Most Common Any-Grade (≥15%) and Grade 3/4 (≥5%) TEAEs in the Safety Population (APOLLO)16
Event, n (%)
D-Pd
(n=149)
Pd
(n=150)
Any Grade
Grade 3/4
Any Grade
Grade 3/4
Hematologic
   Neutropenia
107 (71.8)
103 (69.1)
80 (53.3)
76 (50.7)
   Anemia
57 (38.3)
27 (18.1)
67 (44.7)
32 (21.3)
   Thrombocytopenia
50 (33.6)
27 (18.1)
51 (34.0)
28 (18.7)
   Leukopenia
39 (26.2)
25 (16.8)
18 (12.0)
7 (4.7)
   Lymphopenia
22 (14.8)
18 (12.1)
12 (8.0)
5 (3.3)
   Febrile neutropenia
13 (8.7)
13 (8.7)
5 (3.3)
5 (3.3)
Non-hematologic
   Infections
106 (71.1)
47 (31.5)
89 (59.3)
35 (23.3)
      Upper respiratory tract infection
35 (23.5)
3 (2.0)
24 (16.0)
0
      Pneumonia
30 (20.1)
21 (14.1)
20 (13.3)
11 (7.3)
      Lower respiratory tract infection
29 (19.5)
17 (11.4)
24 (16.0)
14 (9.3)
   Fatigue
43 (28.9)
15 (10.1)
38 (25.3)
7 (4.7)
   Diarrhea
35 (23.5)
8 (5.4)
23 (15.3)
1 (0.7)
   Asthenia
33 (22.1)
8 (5.4)
25 (16.7)
1 (0.7)
   Pyrexia
30 (20.1)
0
25 (16.7)
0
   Peripheral edema
23 (15.4)
0
13 (8.7)
0
   Hyperglycemia
17 (11.4)
8 (5.4)
20 (13.3)
7 (4.7)
Abbreviations: D-Pd, DARZALEX FASPRO + pomalidomide + dexamethasone; Pd, pomalidomide + dexamethasone; TEAE, treatment-emergent adverse event.
  • Serious TEAEs were reported in 76 (51.0%) vs 61 (40.7%) patients in the D-Pd vs Pd arms.
    • The most common serious TEAEs were pneumonia (D-Pd, 15.4%; Pd, 8.7%) and lower respiratory tract infection (D-Pd, 12.1%; Pd, 9.3%).
  • Treatment discontinuation due to TEAEs was low among both treatment arms (D-Pd, 2.0%; Pd, 4.0%).
  • Second primary malignancy was reported in 2.7% vs 3.3% patients in the D-Pd vs Pd arms.

Clinically Relevant Subgroup Analysis - Phase 3 AURIGA Study

Foster et al (2024)18 presented (at the 66th ASH Annual Meeting) 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 ISS disease staging; and patients with a high cytogenetic risk per standard, revised, and IMS 2024 high-risk criteria.

Results

Demographics and Disease Characteristics

Demographics and Disease Characteristics of the ITT Population18 
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

Subgroup Analysis of MRD-negativity (10-5 Sensitivity) Conversion Ratea from Baseline to 12 Months of Maintenance Treatment18 
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.18
    • 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.18

Safety Results for Patients With ≥1 TEAE Based on Age18 
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.

Post hoc Analysis of Patients Aged ≥65 Years From the PERSEUS and GRIFFIN Studies

Rodriguez-Otero et al (2024)19 presented (at the 21st IMS Annual Meeting) results from a post hoc analysis of the PERSEUS and GRIFFIN studies that evaluated the efficacy and safety of D-VRd vs VRd in 237 patients aged ≥65 years.

Results

Patient Characteristics
  • Patients aged ≥65 years represented 25.5% of patients from the PERSEUS study (D-VRd, 94 of 355 patients vs VRd, 87 of 354 patients) and 27.1% of patients from the GRIFFIN study (D-VRd, 28 of 104 patients vs VRd, 28 of 103 patients). 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 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 relative dose intensities were comparable between the D-VRd vs VRd groups for bortezomib (92.9% vs 93.5%) and dexamethasone (95.5% vs 100%) but were relatively lower in the D-VRd group for lenalidomide (75.5% vs 87.7%). The median relative dose intensity for DARZALEX FASPRO in the D-VRd group was 99.7%.
  • Treatment discontinuation rates were comparable between the D-VRd vs VRd groups for bortezomib (12.5% vs 12.3%) and dexamethasone (3.3% vs 3.5%) but were higher in the D-VRd group for lenalidomide (23.3% vs 17.5%).

Baseline Demographic and Disease Characteristics in Patients Aged ≥65 Years in the Pooled PERSEUS/GRIFFIN ITT Populationa,19
Characteristic
D-VRd
(n=122)
VRd
(n=115)
Median age (range), years
67 (65-70)
67 (65-70)
Male, n (%)
76 (62.3)
67 (58.3)
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)
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)
   Missing
28 (23.0)
28 (24.3)
Cytogenetic riskc, 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 + bortezomib, lenalidomide, and dexamethasone; ECOG PS, Eastern Cooperative Oncology Group performance status; ISS, International Staging System; ITT, intent-to-treat; VRd, bortezomib, lenalidomide, and dexamethasone.aPooled ITT population included all patients aged ≥65 years who were randomized in PERSEUS or GRIFFIN.bISS staging was derived based on the combination of serum β2-microglobulin and albumin.cHigh 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
  • Majority of patients aged ≥65 years who received ≥1 dose of the study treatment (D-VRd, n=120 vs VRd, n=114) underwent stem cell mobilization (93.3% vs 84.2%).
    • The median number of CD34+ cells collected was sufficient for ASCT 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 proportions of patients who proceeded to ASCT was comparable between the treatment groups (D-VRd, 86.7% vs VRd, 82.5%).
    • The median time to engraftment was comparable between the treatment groups (D-VRd, 14 days vs VRd, 13 days).
  • The stem cell mobilization and ASCT outcomes are summarized in Table: Stem Cell Mobilization and ASCT Outcomes in Patients Aged ≥65 Years in the Pooled PERSEUS/GRIFFIN Safety Population

Stem Cell Mobilization and ASCT Outcomes in Patients Aged ≥65 Years in the Pooled PERSEUS/GRIFFIN Safety Populationa,19
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 (%)
   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 CD34+ stem cells collected, median (range), ×106/kg
4.22 (1.80-13.50)
5.76 (1.12-49.50)
Patients who completed melphalan conditioning therapy, n
104
94
Total dose of melphalan conditioning therapy, median
   (range), mg/m2
193 (59-385)
192 (52-371)
Patients who proceeded to ASCT, n (%)
104 (86.7)
94 (82.5)
Patients with hematopoietic reconstitution, n
103
93
Time to achieve ANC ≥0.5×109/L,c median (range), days
13 (0-28)
12 (0-34)
Time to achieve platelets ≥20×109/L without transfusion,c median (range), days
13 (0-33)
12 (1-48)
Time to engraftment,c,d 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 + 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 ASCT date, excluding patients whose counts did not reach nadir below the set threshold.dThe date of engraftment post-ASCT 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 in the PERSEUS and GRIFFIN groups, respectively.
  • Patients treated with D-VRd showed 44% reduction in the risk of disease progression or death vs VRd (HR, 0.56; 95% CI, 0.31-1.01; P = 0.05).
  • The estimated 48-month PFS rates were 79.1% and 71.6% for the D-VRd vs VRd groups, 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 groups, respectively, and is presented in Table: Summary of Response Rates and MRD-negativity Rates in Patients Aged ≥65 Years in the Pooled PERSEUS/GRIFFIN ITT Population.

Summary of Response Rates and MRD-negativity Rates in Patients Aged ≥65 Years in the Pooled PERSEUS/GRIFFIN ITT Populationa,19
Patients, %
D-VRd
(n=122)
VRd
(n=115)
OR (95% CI)b
P Valuec
sCR
59.0
49.6
1.49 (0.88-2.53)
0.14
≥CR
82.8
67.0
2.37 (1.28-4.39)
0.005
CR
23.8
17.4
-
-
VGPR
10.7
19.1
-
-
PR
1.6
9.6
-
-
SD/PD/NE
4.9
4.3
-
-
Overall MRD-negativity (10-5)d
66.4
41.7
2.75 (1.61-4.71)
0.0002
Sustained MRD-negativity (10-5) (≥12 months)e
52.5
26.1
3.2 (1.83-5.58)
<0.0001
Abbreviations: CI, confidence interval; CR, complete response; D-VRd, DARZALEX FASPRO + bortezomib + lenalidomide + dexamethasone; ISS, International Staging System; ITT, intent-to-treat; MRD, minimal residual disease; NE, not evaluable; OR, odds ratio; 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.dMRD-negativity rates were for patients who also achieved ≥CR. MRD was assessed using bone marrow aspirate and evaluated by next-generation sequencing (clonoSEQ assay version 2.0; Adaptive Biotechnologies). eSustained MRD-negativity was defined as 2 consecutive MRD measurements ≥12 months apart without an MRD-positive measurement in between.
Safety
  • There were no new safety concerns observed, and the overall safety profile of patients aged ≥65 years was comparable to the pooled patient population irrespective of age.
  • A higher incidence of grade 3/4 infections was observed in the D-VRd vs VRd group, with slightly higher rates in patients ≥65 years (36.3% vs 24.8%) than in all patients (29.5% vs 22.5%).
  • The frequency of TEAEs that resulted in discontinuation of ≥1 study drug was similar between treatment groups in patients aged ≥65 years and all patients. The summary of TEAEs is presented in Table: Summary of TEAEs in Patients Aged ≥65 Years and All Patients Irrespective of Age in the Pooled PERSEUS/GRIFFIN Safety Population.

Summary of TEAEs in Patients Aged ≥65 Years and All Patients Irrespective of Age in the Pooled PERSEUS/GRIFFIN Safety Populationa,19
Patients, n (%)
Age (≥65 Years)
All Patients
D-VRd
(n=120)
VRd
(n=114)
D-VRd
(n=450)
VRd
(n=449)
Grade 3/4 TEAEs
113 (94.2)
99 (86.8)
406 (90.2)
378 (84.2)
   Most commonb
      Neutropenia/febrile neutropenia
71 (59.2)
49 (43.0)
282 (62.7)
214 (47.7)
      Thrombocytopenia
46 (38.3)
22 (19.3)
118 (26.2)
69 (15.4)
      Diarrhea
17 (14.2)
12 (10.5)
44 (9.8)
32 (7.1)
      Pneumonia
13 (10.8)
7 (6.1)
49 (10.9)
35 (7.8)
Serious TEAEs
81 (67.5)
60 (52.6)
246 (54.7)
224 (49.9)
   Most commonc
      Pneumonia
15 (12.5)
9 (7.9)
55 (12.2)
35 (7.8)
      Febrile neutropenia
8 (6.7)
5 (4.4)
19 (4.2)
17 (3.8)
      Pyrexia
8 (6.7)
2 (1.8)
24 (5.3)
26 (5.8)
      Diarrhea
7 (5.8)
4 (3.5)
11 (2.4)
11 (2.4)
      Sepsis
6 (5.0)
3 (2.6)
9 (2.0)
10 (2.2)
Fatal TEAEsd
6 (5.0)
4 (3.5)
14 (3.1)
17 (3.8)
Discontinuation of ≥1 study drug due to TEAEs
49 (40.8)
52 (45.6)
149 (33.1)
136 (30.3)
Abbreviations: D-VRd, DARZALEX FASPRO + bortezomib + lenalidomide + dexamethasone; TEAE, treatment-emergent adverse event; VRd, bortezomib + lenalidomide + dexamethasone. aPooled safety population included all patients who were randomized in PERSEUS or GRIFFIN and received ≥1 dose of study treatment.bGrade 3/4 TEAEs that occurred in ≥10% of patients aged ≥65 years in either treatment group.cSerious TEAEs that occurred in ≥5% of patients aged ≥65 years in either treatment group.dFatal TEAEs were considered related to daratumumab in 1 patient aged ≥65 years (squamous cell carcinoma) and in 1 patient aged <65 years (sepsis).

COLUMBA

Usmani et al (2019)20 presented updated efficacy results at a median duration of
follow-up of 13.7 months for patients aged ≥75 years treated in the COLUMBA study, an ongoing phase 3 randomized, open-label, multicenter, non-inferiority study (MMY3012; clinicaltrials.gov identifier: NCT03277105) evaluating the efficacy, PK, and IRRs of DARZALEX FASPRO vs DARZALEX in adults patients with heavily pre-treated RRMM.

Study Design/Methods

  • Patients were randomized to receive either DARZALEX FASPRO (n=263) or DARZALEX (n=259) over 4-week treatment cycles (treatment continued until PD or unacceptable toxicity):
    • DARZALEX FASPRO: daratumumab 1800 mg (flat dose) in combination with recombinant human hyaluronidase PH20 (rHuPH20) 2000 Units/mL administered by manual push (15 mL) over 3-5 minutes at alternating left/right abdominal sites, weekly for cycles 1 and 2, every 2 weeks for cycles 3-6, and every 4 weeks thereafter, or
    • DARZALEX: daratumumab 16 mg/kg IV infusion weekly for cycles 1 and 2, every 2 weeks for cycles 3-6, and every 4 weeks thereafter.
  • Pre-dose and/or post-dose medications were administered to prevent IRRs.

Results

Patient Characteristics
  • Of the 263 and 259 patients randomized to the DARZALEX FASPRO and DARZALEX arms, respectively, 47 (18%) and 59 (23%) were aged ≥75 years and 95 (36%) and 100 (39%) were aged 65-74 years.
Efficacy
  • The ORR in patients aged ≥75 years was 44.7% in the DARZALEX FASPRO arm vs 45.8% in the DARZALEX arm (RR, 0.98; 95% CI, 0.63-1.48).
  • The ORR in patients aged <75 years was 43.1% in the DARZALEX FASPRO arm vs 37.5% in the DARZALEX arm (RR, 1.15; 95% CI, 0.91-1.46).
Safety
  • Safety results for patients aged ≥75 years were NR separately.
  • Overall, after a median duration of follow-up of 13.7 months, 76% of patients in the DARZALEX FASPRO arm and 77% in the DARZALEX arm discontinued study treatment.
  • Most common TEAEs are summarized in Table: Most Common Any Grade (>10%) and Grade 3/4 (>5%) TEAEs (COLUMBA).
  • Rates of IRRs were 12.7% in the DARZALEX FASPRO arm vs 34.5% in the DARZALEX arm (OR, 0.28; 95% CI, 0.18-0.44; P<0.0001).
  • Injection-site reactions occurred in 6.9% of patients in the DARZALEX FASPRO arm; all were of grade 1/2 severity.
  • Rates of grade 3/4 TEAEs were 49% in the DARZALEX FASPRO arm and 52% in the DARZALEX arm; rates of grade 5 TEAEs were 6% and 7%, respectively.
  • Rates of TEAEs that led to treatment discontinuation were 7% in the DARZALEX FASPRO arm and 9% in the DARZALEX arm.

Most Common Any Grade (>10%) and Grade 3/4 (>5%) TEAEs (COLUMBA)20
TEAEs, n (%)
DARZALEX FASPRO (n=260)
DARZALEX (n=258)
Any Grade
Grade 3/4
Any Grade
Grade 3/4
Hematologic
   Anemia
27
14
25
15
   Thrombocytopenia
20
14
19
14
   Neutropenia
20
13
14
8
   Lymphopenia
8
5
7
6
Non-hematologic
   Upper RTI
16
0
11
1
   Diarrhea
15
1
12
<1
   Pyrexia
14
<1
14
1
   Fatigue
12
1
11
1
   Back pain
11
2
14
3
   Arthralgia
11
<1
7
0
   Cough
10
1
14
0
   Nausea
9
0
12
1
   Chills
6
<1
12
1
   Hypertension
6
4
9
6
   Dyspnea
5
1
11
1
Abbreviations: RTI, respiratory tract infection; TEAEs, treatment-emergent adverse events.

CLINICAL DATA - DARZALEX FASPRO PHASE 2 STUDIES

Phase 2 Study of DARZALEX FASPRO in Combination With Dose-Attenuated VRd in Transplant-Ineligible Older Adults With NDMM

Sanchez et al (2024)22,23 presented (at the 66th ASH Annual Meeting) interim analysis results from an ongoing, single-center, phase 2 study (clinicaltrials.gov identifier: NCT04052880) of DARZALEX FASPRO combined with dose-attenuated VRd in older adults (aged ≥70 years) with NDMM who were ineligible for SCT; the median follow-up was 43.5 months.

Study Design/Methods

  • Patients received twelve 28-day cycles of initial DARZALEX-VRd therapy as follows23:
    • DARZALEX FASPRO 1800 mg SC once weekly for cycles 1 to 2, every 2 weeks for cycles 3 to 6, and every 4 weeks thereafter.
    • Bortezomib 1.3 mg/m2 SC on day 1, day 8, and day 15.
    • Lenalidomide 15 mg PO on day 1 to day 21 (for patients with a CrCl of 30-60 mL/min and 15-30 mL/min, lenalidomide was reduced to 10 mg and 5 mg, respectively).
    • Dexamethasone 20 mg once weekly.
  • After 12 cycles of initial therapy, patients received maintenance therapy with 28-day cycles of D-R or DARZALEX + ixazomib (only patients with t[4;14]).23
  • Therapy was continued until PD or unacceptable toxicity.23
  • Maintenance DARZALEX FASPRO was discontinued after 2 years. However, if it was determined that a patient would continue to clinically benefit from DARZALEX FASPRO, the patient could be taken off the study to receive a combination of standard-of-care therapy and DARZALEX FASPRO maintenance therapy.23
  • The primary endpoint was the ≥VGPR rate.23
  • Key secondary endpoints were the ≥CR rate, MRD-negativity rate (at the 10-5 or 10-6 sensitivity threshold by flow cytometry/next-generation sequencing), PFS, OS, and predictive value of frailty assessments for outcomes.23
  • AEs were graded using National Cancer Institute Common Terminology Criteria for Adverse Events v5.0.23

Results

Patient Characteristics
  • As of July 30, 2024, 15 patients were enrolled; the median age was 77.3 years (range, 70.4-87.3).23
    • Among these, 53.3% of patients were male, 60% had an ECOG performance status of 1, and 60% were White. Additionally, 57.1% of patients had Revised International Staging System (R-ISS) stage II, and 28.5% of patients had high-risk cytogenetics as determined by fluorescence in situ hybridization (FISH; defined by presence of t[4;14], t[14;16], or del17p).
    • Overall, 71.4% of patients had an IMWG frailty score of ≥2. Furthermore, 57.1% of patients had a gait speed of <1 m/s, with 26.7% having a gait speed of <0.8 m/s.
Efficacy
  • Of 14 patients who were evaluable for response, 85.7% (12/14) achieved ≥VGPR, with 50% achieving ≥CR.23
    • The median time to best response was 6.2 months (range, 2.3-14.7). Among 7 patients who achieved ≥CR, 4 achieved an MRD-negative status.
  • The median time on study was 32.2 months (range, 1.1-37.7); median PFS and DOR were not yet reached.23
    • The 24-month PFS (95% CI) and DOR probability (95% CI) were 0.89 (0.71-1.00) and 0.86 (0.63-1.00), respectively.
    • Eight patients completed the 12 initial cycles and underwent 2 years of maintenance; they then continued DARZALEX FASPRO-based maintenance therapy off study thereafter. The median PFS in these patients has not been reached, with the 48-month PFS probability being 0.71 (0.43-1.00).
  • The median OS was not reached (36-month OS probability [95% CI], 0.91 [0.75-1.00]).23
Safety
  • The most common (occurring in ≥15% of patients) grade 3/4 TEAEs were lymphopenia (42.8%) and neutropenia (28.5%).23
    • Grade 3 infections (pneumonia and upper respiratory tract infection), grade 1/2 infections, and grade 1 infections occurred in 14%, 35.7%, and 35.7% of patients, respectively.
    • Grade 2 peripheral neuropathy was observed in 14.2% of patients, and grade 2 deep vein thrombosis was observed in 14% of patients.
  • Overall, 64% (9/14) of patients had a dose reduction in ≥1 drug due to AE; the doses of lenalidomide, dexamethasone, and bortezomib were reduced in 6, 5, and 1 patients, respectively.23
  • Two patients discontinued lenalidomide due to AEs.23
  • No patients discontinued the study due to AEs, and there were no deaths.23
  • Among 10 patients with a frailty score of ≥2, 70% had dose reduction; however, none of the 3 patients with a frailty score of <2 had dose reduction (P=0.0699).23
  • The probability of achieving CR within 12 months of therapy was 13% for patients with a gait speed of <1 m/s vs 60% for patients with a gait speed of >1 m/s (log rank P=0.1293).23
  • The 12-month CR rate was 25% in frail patients (frailty score ≥2) vs 67% in nonfrail patients (frailty score <2).23
  • Overall, the time to achieving CR was significantly shorter in nonfrail patients vs frail patients (log rank P=0.0348).23

LITERATURE SEARCH

A literature search of MEDLINE®, Embase®, BIOSIS Previews®, and Derwent Drug File (and/or other resources, including internal/external databases) was conducted on 07 January 2025.

References

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1 Data on File. Daratumumab Intravenous Formulation Company Core Data Sheet (CCDS). Janssen Research & Development, LLC. EDMS-ERI-78724630; 2024.  
2 Data on File. Daratumumab SC CCDS. Janssen Research & Development, LLC. EDMS-ERI-184804517; 2024.  
3 Dimopoulos M, Quach H, Mateos MV, et al. Carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone for patients with relapsed or refractory multiple myeloma (CANDOR): results from a randomised, multicentre, open-label, phase 3 study. Lancet. 2020;396(10245):186-197.  
4 Usmani SZ, Quach H, Mateos MV, et al. Final analysis of carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone in the CANDOR Study. Blood Adv. 2023;7(14):3739-3748.  
5 Facon T, Kumar S, Plesner T, et al. Daratumumab plus lenalidomide and dexamethasone for untreated myeloma. N Engl J Med. 2019;380:2104-2115.  
6 Usmani SZ, Facon T, Kumar S, et al. Impact of age on efficacy and safety of daratumumab in combination with lenalidomide and dexamethasone (D-Rd) in patients with transplant-ineligible newly diagnosed multiple myeloma (NDMM): MAIA. presented at: The Annual Meeting of the American Society of Clinical Oncology (ASCO); May 31-June 4, 2019; Chicago, Illinois.  
7 Kumar SK, Moreau P, Bahlis N, et al. Daratumumab plus lenalidomide and dexamethasone (D-Rd) versus lenalidomide and dexamethasone (Rd) alone in transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM): updated analysis of the phase 3 MAIA study. Poster presented at: The 64th American Society of Hematology (ASH) Annual Meeting & Exposition; December 10-13, 2022; New Orleans, LA.  
8 Facon T, Kumar S, Weisel K, et al. Daratumumab plus lenalidomide and dexamethasone in patients with transplant-ineligible newly diagnosed multiple myeloma: MAIA age subgroup analysis. presented at: 64th American Society of Hematology (ASH) Annual Meeting and Exposition; December 10-13, 2022; New Orleans, LA/Virtual meeting.  
9 Moreau P, Facon T, Usmani S, et al. Daratumumab plus lenalidomide and dexamethasone (D-Rd) versus lenalidomide and dexamethasone (Rd) in transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM): clinical assessment of key subgroups of the phase 3 MAIA study. 2022;(Poster).  
10 Cavo M, Iida S, Blade J, et al. Daratumumab plus bortezomib-melphalan-prednisone (VMP) in elderly ( ≥75 y) patients (pts)  with newly diagnosed multiple myeloma (NDMM) ineligible for transplantation (ALCYONE). Poster presented at: The Annual Meeting of the American Society of Clinical Oncology (ASCO); June 1-5, 2018; Chicago, IL.  
11 Mateos M, San-Miguel J, Cavo M, et al. Daratumumab plus bortezomib, melphalan, and prednisone (D-VMP) versus bortezomib, melphalan, and prednisone (VMP) alone in transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM): updated analysis of the phase 3 ALCYONE study. Poster presented at: The 64th American Society of Hematology (ASH) Annual Meeting & Exposition; December 10-13, 2022; New Orleans, LA.  
12 Mateos M, Spencer A, Nooka A, et al. Daratumumab-based regimens are highly effective and well tolerated in relapsed or refractory multiple myeloma regardless of patient age: subgroup analysis of the phase 3 CASTOR and POLLUX studies. Haematologica. 2020;105:468-477.  
13 Mateos M, Richardson P, Weisel K, et al. Daratumumab (DARA) plus bortezomib and dexamethasone (D-Vd) or lenalidomide and dexamethasone (D-Rd) in relapsed or refractory multiple myeloma (RRMM): subgroup analyses of CASTOR and POLLUX. Poster presented at: 19th International Myeloma Society (IMS) Annual Meeting; August 25-27, 2022; Los Angeles, CA.  
14 Baz R, Meads MB, Kim J, et al. Daratumumab based response adapted therapy for older adults with newly diagnosed multiple myeloma: final results of a phase II study. Poster presented at: The 66th American Society of Hematology (ASH) Annual Meeting and Exposition; December 7-10, 2024; San Diego, CA.  
15 Dimopoulos M, Terpos E, Boccadoro M, et al. Daratumumab plus pomalidomide and dexamethasone versus pomalidomide and dexamethasone alone in previously treated multiple myeloma (APOLLO): an open-label, randomised, phase 3 trial. Lancet Oncol. 2021;22(6):801-812.  
16 Sonneveld P, Terpos E, Boccadoro M, et al. Pomalidomide and dexamethasone with or without subcutaneous daratumumab in patients with relapsed or refractory multiple myeloma: updated analysis of the phase 3 APOLLO study. Poster presented at: 63rd American Society of Hematology (ASH) Annual Meeting & Exposition; December 11-14, 2021; Atlanta, GA/Virtual.  
17 Dimopoulos M, Terpos E, Boccadoro M, et al. Subcutaneous daratumumab plus pomalidomide and dexamethasone (D-Pd) versus pomalidomide and dexamethasone (Pd) alone in patients with relapsed or refractory multiple myeloma (RRMM): overall survival results from the phase 3 APOLLO study. Poster presented at: 64th American Society of Hematology (ASH) Annual Meeting and Exposition; December 10-13, 2022; New Orleans, LA.  
18 Foster L, Anderson LD Jr, Chung A, et al. Daratumumab plus lenalidomide (D-R) versus lenalidomide (R) alone as maintenance therapy in newly diagnosed multiple myeloma (NDMM) after transplant: analysis of the phase 3 AURIGA study among clinically relevant subgroups. Oral Presentation presented at: The 66th American Society of Hematology (ASH) Annual Meeting and Exposition; December 7-10, 2024; San Diego, CA.  
19 Rodriguez-Otero P, Voorhees PM, Boccadoro M, et al. Daratumumab plus bortezomib, lenalidomide, and dexamethasone in transplant-eligible patients with multiple myeloma: a pooled analysis of patients aged ≥65 years from both PERSEUS and GRIFFIN studies. Poster presented at: The 21st International Myeloma Society (IMS) Annual Meeting; September 25-28, 2024; Rio de Janeiro, Brazil.  
20 Usmani SZ, Mateos MV, Nahi H, et al. Randomized, open-label, non-inferiority, phase 3 study of subcutaneous (SC) versus intravenous (IV) daratumumab (DARA) administration in patients with relapsed or refractory multiple myeloma: COLUMBA update. Poster presented at: 61st American Society of Hematology (ASH) Annual Meeting and Exposition; December 7-10, 2019; Orlando, FL.  
21 Usmani SZ, Nahi H, Legiec W, et al. Final analysis of the phase III non-inferiority COLUMBA study of subcutaneous versus intravenous daratumumab in patients with relapsed or refractory multiple myeloma. Haematologica. 2022;107(10):2408-2417.  
22 Janssen Research & Development, LLC. Study of subq dara with dose-attenuated bortezomib, lenalidomide, dexamethasone in elderly NDMM. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [cited 2025 January 7]. Available from: https://clinicaltrials.gov/study/NCT04052880 NLM Identifier: NCT04052880.  
23 Sanchez LJ, Moshier E, Lieberman-Cribbin A, et al. A phase 2 study of daratumumab in combination with dose-attenuated bortezomib, lenalidomide, and dexamethasone in transplant ineligible older adults with newly diagnosed multiple myeloma. Abstract presented at: The 66th American Society of Hematology (ASH) Annual Meeting and Exposition; December 7-10, 2024; San Diego, CA.  
24 Usmani S, Quach H, Mateos M, et al. Supplement to: Final analysis of carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone in the CANDOR Study. Blood Adv. 2023;7(14):3739-3748.  
25 Mateos MV, Dimopoulos MA, Cavo M, et al. Daratumumab plus bortezomib, melphalan, and prednisone for untreated myeloma. N Engl J Med. 2018;378(6):518-528.  
26 Dimopoulos M, Oriol A, Nahi H, et al. Daratumumab, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2016;375:1319-1331.  
27 Palumbo A, Chanan-Khan A, Weisel K, et al. Daratumumab, bortezomib, and dexamethasone for multiple myeloma. N Engl J Med. 2016;375:754-766.  
28 Dimopoulos M, Terpos E, Boccadoro M, et al. Supplement to: Daratumumab plus pomalidomide and dexamethasone versus pomalidomide and dexamethasone alone in previously treated multiple myeloma (APOLLO): an open-label, randomised, phase 3 trial. Lancet Oncol. 2021;22(6):801-812.