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DARZALEX® (daratumumab)

Medical Information

DARZALEX FASPRO - APOLLO (MMY3013) Study

Last Updated: 05/22/2025

SUMMARY

  • APOLLO is an ongoing, phase 3, randomized, open-label, multicenter study evaluating the safety and efficacy of daratumumab + pomalidomide + dexamethasone (D-Pd) vs pomalidomide + dexamethasone (Pd) in patients with relapsed or refractory multiple myeloma (RRMM) who received ≥1 prior line of treatment (LOT) with both lenalidomide and a proteasome inhibitor (PI).1–3
    • Dimopoulos et al (2021)3 reported the primary analysis of this ongoing study with a median follow-up of 16.9 months. The D-Pd arm reached a median progression-free survival (PFS) of 12.4 months (95% confidence interval [CI], 8.3-19.3) vs Pd arm achieving a median PFS of 6.9 months (95% CI, 5.5-9.3); (hazard ratio [HR], 0.63; 95% CI, 0.47-0.85; P=0.0018). The most common serious treatment-related adverse events (TEAEs) were pneumonia (D-Pd, 9%; Pd, 1%), lower respiratory tract infection (D-Pd, 3%; Pd, 1%), and febrile neutropenia (D-Pd, 3%; Pd, 1%).
    • Dimopoulos et al (2023)4 reported the final overall survival (OS) results and updated safety analysis of the APOLLO study at a median follow-up of 39.6 months. Median OS in the intent-to-treat (ITT) population was 34.4 months (95% CI, 23.7-40.3) vs 23.7 months (95% CI, 19.629.4) in the D-Pd vs Pd arm, respectively (HR, 0.82; 95% CI, 0.61-1.11; P=0.20). The most common grade 3 TEAEs (>10%) in the D-Pd arm were neutropenia (25%), anemia (17%), and leukopenia (11%), while those in the Pd arm were neutropenia (32%), anemia (21%), and thrombocytopenia (13%). The most common serious TEAE was pneumonia (D-Pd, 15%; Pd, 9%).
  • He et al (2022)5 reported the results of indirect treatment comparisons using patient-level data to evaluate the improvement in PFS with D-Pd vs DARZALEX + bortezomib + dexamethasone (D-Vd) and D-Pd vs bortezomib + dexamethasone (Vd) in patients with RRMM with prior immunomodulatory drug (IMiD) and PI exposure. A significant benefit in PFS was observed in patients receiving D-Pd compared with DVd or Vd when assessed using both the stabilized inverse probability of treatment weighting (sIPTW) and the cardinality matching (CM) adjustment method.
  • Terpos et al (2022)6 compared the impact of D-Pd vs Pd on the healthrelated quality of life (HRQoL) of patients in the APOLLO study. No significant change in least squares (LS) mean global health status (GHS) scores from baseline was reported in either treatment arm. The point estimates for GHS generally favored the D-Pd arm.
  • Dosne et al (2022)7 evaluated the population pharmacokinetics (PK) and exposureresponse relationship of daratumumab when administered in combination with Pd to patients with RRMM. PK characteristics of daratumumab were similar when administered with Pd vs when administered alone. PFS was improved with increased model-predicted exposure in patients having an exposure higher than quartile 1 (Q1; ≤121 μg/mL). No significant increase in TEAE rates was observed with increasing model-predicted first peak or maximum peak exposure of daratumumab.
  • Chari et al (2021)8 presented naïve comparison (without adjustments) and matching-adjusted indirect comparisons (MAIC) of PFS for DARZALEX for intravenous (IV) use in combination with carfilzomib and dexamethasone (D-Kd) vs pomalidomide in combination with bortezomib and dexamethasone (PVd) vs D-Pd in patients with RRMM. After naïve comparison, PFS benefit were observed for D-Kd vs PVd (median: 25.9 months vs 11.5 months, respectively; HR, 0.629; 95% CI, 0.397-0.747) and D-Kd vs D-Pd (median: 25.9 months vs 12.8 months, respectively; HR, 0.629; 95% CI, 0.445-0.890). After MAIC, PFS benefit were observed for D-Kd vs PVd (median: 25.0 months vs 11.5 months, respectively; HR, 0.539; 95% CI, 0.395-0.736) and D-Kd vs D-Pd (median: 25.0 months vs 12.8 months, respectively; HR, 0.677; 95% CI, 0.474-0.966).

PRODUCT LABELING

CLINICAL DATA

APOLLO (MMY3013; clinicaltrials.gov identifier: NCT03180736) is an ongoing phase 3, randomized, open-label, multicenter study evaluating the safety and efficacy of D-Pd vs Pd in patients with RRMM who received ≥1 prior treatment with both lenalidomide and a PI (N=304).1–3 Dimopoulos et al (2021)3 reported the primary analysis of this ongoing study with a median follow-up of 16.9 months. Sonneveld et al (2021)9 presented updated efficacy and safety results at a median follow-up of 30.7 months. Dimopoulos et al (2023)4 reported the final OS and updated safety analysis of D-Pd vs Pd alone in patients with RRMM in the APOLLO study with a median follow-up of 39.6 months.

Study Design/Methods

APOLLO (MMY3013): Study Design1–4,10

Abbreviations: CR, complete response; CrCl, creatinine clearance; d, dexamethasone; D, daratumumab; D-Pd, daratumumab + pomalidomide + dexamethasone; ECOG PS, Eastern Cooperative Oncology Group performance status; HRQoL, health-related quality of life; Ig, immunoglobulin; IgA, immunoglobulin A; IgD, immunoglobulin D, IgE, immunoglobulin E, IgG, immunoglobulin G, IgM, immunoglobulin M; ISS, International Staging System; MM, multiple myeloma; MRD, minimal residual disease; ORR, overall response rate; OS, overall survival; P, pomalidomide; Pd, pomalidomide + dexamethasone; PD, progressive disease; PFS, progression-free survival; PI, proteasome inhibitor; PO, oral; QW, every week; Q2W, every 2 weeks; Q4W, every 4 weeks; RRMM, relapsed/refractory multiple myeloma; sCR, stringent complete response; VGPR, very good partial response.
aMeasurable disease was defined as: IgG MM, serum M-protein level ≥1.0 g/dL or urine M-protein level ≥200 mg/24 hours; IgA, IgD, IgE, IgM MM, serum M-protein level ≥0.5 g/dL or urine M-protein level ≥200 mg/24 hours; light chain MM for patients without measurable disease in the serum or urine, serum Ig free light chain ≥10 mg/dL and abnormal serum Ig kappa lambda free light chain ratio.
bPre-infusion medications to be administered are acetaminophen, dexamethasone, diphenhydramine, and a leukotriene inhibitor (optional). Patients with a higher risk of respiratory complications will receive post-infusion medications, including diphenhydramine, a short-acting β2 adrenergic receptor agonist, and lung disease control medications.
cPatients initially were given DARZALEX 16 mg/kg; following a protocol amendment, new patients in the D-Pd arm received DARZALEX FASPRO. Patients who had already received DARZALEX prior to this amendment may switch to DARZALEX FASPRO on day 1 of cycle 3+.
dPatients aged ≥75 years received 20 mg QW.
eFollow-up is for patients who discontinued treatment for reasons other than PD, death, loss to follow-up, or withdrawal of consent.
fMRD was assessed by next-generation sequencing using bone marrow aspirate samples obtained at screening; at the time of suspected CR or sCR; and at 6, 12, 18, 24, and Q12W after achieving CR or sCR until disease progression.
gDisease assessments were collected by a central laboratory every cycle for the first 14 months and every other month thereafter.

Results

Patient Characteristics
  • Baseline characteristics are summarized in Table: Demographics and Baseline Characteristics.
  • A total of 98% of patients in the D-Pd arm received DARZALEX FASPRO.
  • A total of 95% (n/N=142/149) of 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.
  • Median duration of study treatment was 11.5 months in the D-Pd arm vs 6.6 months in the Pd arm.
  • The most common reason for treatment discontinuation was progressive disease, as presented in Table: Treatment Disposition.

Demographics and Baseline Characteristicsa, 3
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 to <75
63 (42)
62 (41)
≥75
25 (17)
31 (20)
Race, n (%)
White
135 (89)
137 (90)
Non-white
16 (11)
16 (10)
Gender, n (%)
Male
79 (52)
82 (54)
Female
72 (48)
71 (46)
ECOG PS score,b n (%)
0
91 (60)
77 (50)
1
54 (36)
57 (37)
2
6 (4)
19 (12)
ISS disease stage,c n (%)
I
68 (45)
69 (45)
II
50 (33)
51 (33)
III
33 (22)
33 (22)
Type of MM,d n (%)
IgG
62 (41)
63 (41)
IgA
24 (16)
20 (13)
Othere
1 (1)
0
Detected in urine only
17 (11)
17 (11)
Detected as serum free light-chain only
24 (16)
25 (16)
Serum and urine
23 (15)
28 (18)
Cytogenetic profilef
N
103
108
Standard risk, n (%)
64 (62)
73 (68)
High risk, n (%)
39 (38)
35 (32)
Time since MM diagnosis, years
Median (range)
4.4 (0.5-20.0)
4.5 (0.6-19.0)
Creatinine clearance
≤60 mL/min
40 (26)
47 (31)
>60 mL/min
111 (74)
106 (69)
Hepatic function
Normal
136 (90)
127 (83)
Impaired
15 (10)
26 (17)
Prior LOT
Median (range)
2 (1-5)
2 (1-5)
Distribution, n (%)
1
16 (11)
18 (12)
2-3
114 (75)
113 (74)
≥4
21 (14)
22 (14)
Prior PI or IMiD
151 (100)
153 (100)
Prior ASCT, n (%)
90 (60)
81 (53)
Disease refractory to last LOT, n (%)
122 (81)
123 (80)
Disease refractory to, n (%)
IMiD
119 (79)
122 (80)
Lenalidomide
120 (79)
122 (80)
PI
71 (47)
75 (49)
PI + lenalidomide
64 (42)
65 (42)
Lenalidomide as last prior LOT
94 (62)
90 (59)
Abbreviations: ASCT, autologous stem cell transplant D-Pd, daratumumab + pomalidomide + dexamethasone; ECOG PS, Eastern Cooperative Oncology Group performance status; IgA, immunoglobulin A; IgG, immunoglobulin G; IMiD, immunomodulatory drug; ISS, International Staging System; LOT, line of therapy; MM, multiple myeloma; Pd, pomalidomide + dexamethasone; PI, proteasome inhibitor. aIntent-to-treat population (N=304). bECOG PS is scored on a scale from 0-5, with 0 indicating no symptoms and higher scores indicating increasing disability. cBased on the combination of serum β2-microglobulin and albumin at study entry. dDetermined by immunofixation. eIncludes IgD, IgE, IgM, and biclonal. fBased on fluorescence in situ hybridization; high risk was defined as del17p, t(4;14), or t(4;16).

Treatment Disposition3
D-Pd (n=151)
Pd (n=153)
Patients treated, n
149
150
Ongoing at clinical cutoff, n
60
33
Discontinued, n
89
117
Progressive disease
66
87
Death
10
7
Adverse event
3
4
Physician decision
4
7
Lost to follow-up
1
0
Noncompliance with study drug
5
12
Abbreviations: D-Pd, daratumumab + pomalidomide + dexamethasone; Pd, pomalidomide + dexamethasone.
Efficacy
  • After a median 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 generally observed in all prespecified subgroups (Table: PFS in Prespecified Subgroups).
  • Overall response rate (ORR; ITT population): 69% D-Pd vs 46% Pd (odds ratio [OR], 2.7; 95% CI, 1.7-4.4; P<0.0001). A summary of response rates and minimal residual disease (MRD) status is shown in table: Summary of Response Rates and MRD Status in the Intent-to-Treat Population.
  • Median time to 1st response was 1 month (95% CI, 1.0-1.1) in the D-Pd arm and 1.9 months (1.0-2.0) in the Pd arm.
  • Median duration of response was not reached (95% CI, 15.2-not reached) in the D-Pd arm and 5.9 months (8.3-24.8) in the Pd arm.
  • Median time to subsequent therapy was 23.2 months (95% CI, 13.8-not evaluable [NE]) vs 11.8 months (8.9-15.4).
  • The OS data at this time is immature; 32% (n=48) of patients died in the D-Pd arm and 33% (n=51) in the Pd arm. Long-term survival follow-up is ongoing.

Summary of Response Rates and MRD Status in the Intent-to-Treat Population3
n (%)
D-Pd (N=151)
Pd (N=153)
Odds ratio (95% CI)
P value
Overall response
104 (69; 95% CI 61-76)
71 (46; 95% CI 38-55)
2.7 (1.7-4.4)
<0.0001a
Best overall response
≥CR
37 (25)
6 (4)
8.2 (3.4-20.3)
<0.0001a
sCRb
14 (9)
2 (1)
-
-
Complete response
23 (15)
4 (3)
-
-
≥VGPR
77 (51)
30 (20)
4.3 (2.6-7.3)
<0.0001a
PR
27 (18)
41 (27)
-
-
Minimal response
11 (7)
15 (10)
-
-
Stable disease
26 (17)
49 (32)
-
-
Progressive disease
4 (3)
7 (5)
-
-
Response could not be evaluated
6 (4)
11 (7)
-
-
Negative status for MRDd
13 (9)
3 (2)
4.7 (1.3-16.9)
0.010e
Abbreviations: CI, confidence interval; ≥CR, complete response or better; D-Pd, daratumumab + pomalidomide + dexamethasone; IMWG, International Myeloma Working Group; MRD, minimal residual disease; ORR, overall response rate; Pd, pomalidomide + dexamethasone; PR, partial response; sCR, stringent complete response; ≥VGPR, very good partial response or better. Note: The following secondary endpoints were sequentially tested, each with a two-sided α value of 0.05, by using a hierarchical testing approach: ORR, ≥VGPR rate, ≥CR rate, rate of MRD negative. ap value was calculated using the Cochran-Mantel-Haenszel χ² test. bCriteria for a sCR include the criteria for a complete response plus a normal free light-chain ratio and absence of clonal plasma cells, as assessed by immunofluorescence or immunohistochemical analysis. dNegative status for MRD, using a sensitivity threshold of one tumor cell per 10⁵ white cells, is based on a post-randomization assessment of bone marrow samples using a validated next-generation sequencing assay (clonoSEQ Assay, version 2.0; Adaptive Biotechnologies) in accordance with the MRD assessment guidelines established by the IMWG.ep value (two-sided) was calculated using the Fisher’s exact test.

PFS in Prespecified Subgroups3
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)
Sex
Male
46/79
54/82
10.7 (7.4-19.3)
7.2 (4.9-10.6)
0.69 (0.47-1.03)
Female
38/72
52/71
15.0 (8.2-NE)
6.5 (4.7-9.3)
0.54 (0.35-0.82)
Age
<65 years
36/63
41/60
9.2 (4.6-21.0)
5.8 (3.7-12.6)
0.69 (0.44-1.09)
≥65 years
48/88
65/93
14.2 (9.9-NE)
7.0 (6.1-10.1)
0.55 (0.38-0.81)
Race
White
75/135
93/137
12.1 (8.2-17.2)
7.4 (5.8-9.6)
0.66 (0.48-0.89)
Non-white
9/16
13/16
16.2 (4.9-NE)
5.0 (2.6-6.5)
0.34 (0.14-0.82)
ISS disease staging
1
31/68
43/69
19.3 (9.9-NE)
9.5 (6.5-15.9)
0.62 (0.39-0.98)
2
32/50
36/51
12.3 (7.5-17.2)
6.1 (2.8-8.9)
0.54 (0.33-0.87)
3
21/33
27/33
6.1 (3.0-12.9)
5.0 (2.9-9.6)
0.75 (0.42-1.32)
Revised ISS disease staging
1
11/26
17/25
NE (9.9-NE)
10.4 (4.7-19.6)
0.51 (0.24-1.10)
2
45/74
64/88
12.3 (7.5-17.2)
6.5 (4.0-8.3)
0.58 (0.39-0.85)
3
15/19
11/14
2.8 (1.1-4.9)
3.4 (1.9-9.6)
1.38 (0.62-3.11)
Number of prior LOT
1
9/16
12/18
14.1 (6.5-NE)
12.6 (3.7-19.6)
0.70 (0.30-1.67)
2-3
65/114
79/113
10.7 (7.5-16.2)
6.5 (4.7-9.5)
0.66 (0.48-0.92)
≥4
10/21
15/22
19.3 (6.7-NE)
6.6 (2.9-10.2)
0.40 (0.18-0.90)
Baseline creatinine clearance
≤60 ml/min
23/40
36/47
12.1 (5.8-16.2)
6.1 (3.4-9.3)
0.59 (0.35-0.99)
>60 ml/min
61/111
70/106
12.7 (8.2-NE)
7.8 (5.8-10.2)
0.64 (0.45-0.90)
Type of multiple myeloma
IgG
43/76
52/79
11.4 (7.8-NE)
8.5 (4.7-11.2)
0.67 (0.45-1.01)
Non-IgG
20/34
25/32
13.1 (6.5-21.0)
6.9 (3.7-9.6)
0.44 (0.24-0.81)
Cytogenetic profile
High risk
28/39
26/35
5.8 (4.4-7.5)
4.0 (2.8-9.2)
0.85 (0.49-1.44)
Standard risk
30/64
50/73
21.0 (12.3-NE)
7.4 (6.0-13.1)
0.51 (0.32-0.81)
Baseline hepatic function
Normal
69/136
88/127
15.2 (10.3-NE)
6.9 (5.5-9.3)
0.56 (0.41-0.77)
Impaired
15/15
18/26
6.1 (2.8-8.4)
8.3 (3.4-13.9)
1.72 (0.84-3.50)
ECOG PS
0
49/91
53/77
12.7 (8.2-NE)
6.9 (4.7-9.3)
0.61 (0.41-0.90)
≥1
35/60
53/76
12.1 (6.5-15.2)
7.2 (4.7-10.1)
0.65 (0.42-1.00)
Refractory to lenalidomide
No
8/31
17/31
NE (NE-NE)
10.6 (5.8-NE)
0.36 (0.15-0.83)
Yes
76/120
89/122
9.9 (6.5-13.1)
6.5 (4.7-8.9)
0.66 (0.49-0.90)
Refractory to last LOT
No
9/29
16/20
NE (15.2-NE)
10.6 (5.5-NE)
0.45 (0.20-1.02)
Yes
72/122
90/123
10.3 (7.4-14.2)
6.5 (4.7-8.9)
0.64 (0.47-0.87)
Refractory to PI
No
38/80
52/78
21.0 (10.7-NE)
9.3 (5.5-12.6)
0.53 (0.35-0.80)
Yes
46/71
54/75
8.3 (4.9-12.9)
6.3 (3.8-7.8)
0.73 (0.49-1.08)
Refractory to PI and IMiDs
No
40/87
58/88
21.0 (10.7-NE)
9.3 (6.0-12.6)
0.52 (0.34-0.77)
Yes
44/64
48/65
7.7 (3.9-12.3)
7.7 (3.9-12.3)
0.74 (0.49-1.12)
Refractory to lenalidomide as last LOT
No
25/57
39/63
21.0 (12.9-NE)
7.8 (5.8-15.9)
0.52 (0.31-0.86)
Yes
59/94
67/90
8.3 (6.5-12.3)
6.1 (4.0-9.3)
0.67 (0.47-0.95)
Abbreviations: D-Pd, daratumumab + pomalidomide + dexamethasone; Pd, pomalidomide + dexamethasone; CI, confidence interval; ECOG PS, Eastern Cooperative Oncology Group performance status; HR, hazard ratio; IgG, immunoglobulin G; IMiD, immunomodulatory drug; ISS, International Staging System; LOT, line of therapy; PI, proteasome inhibitor; Pd, pomalidomide + dexamethasone; PFS, progression-free survival.
Safety
  • Infusion-related reactions (IRRs) were reported in 5% of D-Pd patients; all were grade 1 or 2.
  • Local injection-site reactions were reported in 2% of patients who received DARZALEX FASPRO; all were grade 1.
  • The most common serious adverse events (SAEs) were pneumonia (D-Pd, 15%; Pd, 8%) and lower respiratory tract infection (D-Pd, 12%; Pd, 9%).
  • TEAEs leading to treatment discontinuation and TEAEs leading to death were similar in both groups (D-Pd, 2% and 7%; Pd, 3% and 7%, respectively).
  • Incidence of second primary malignancy was 2% in each group.
  • Safety data from the primary analysis are presented in Table: Most Common Adverse Events (Safety Population).

Most Common Adverse Events (Safety Population)a, 3
Adverse Event, n (%)
D-Pd (n=149)
Pd (n=150)
Grade 1/2
Grade 3
Grade 4
Grade 1/2
Grade 3
Grade 4
Hematologic adverse events
Neutropenia
4 (3)
37 (25)
64 (43)
4 (3)
49 (33)
27 (18)
Anemia
30 (20)
24 (16)
1 (1)
34 (23)
31 (21)
1 (1)
Thrombocytopenia
22 (15)
13 (9)
13 (9)
23 (15)
19 (13)
8 (5)
Leukopenia
14 (9)
16 (11)
9 (6)
11 (7)
6 (4)
1 (1)
Lymphopenia
4 (3)
10 (7)
8 (5)
7 (5)
3 (2)
2 (1)
Febrile neutropenia
0
10 (7)
3 (2)
0
3 (2)
1 (1)
Non-hematologic adverse events
Infections
61 (41)
32 (21)
4 (3)
48 (32)
29 (19)
1 (1)
Upper respiratory tract infection
34 (23)
0
0
21 (14)
3 (2)
0
Pneumonia
10 (7)
14 (9)
3 (2)
8 (5)
8 (5)
1 (1)
Lower respiratory tract infection
12 (8)
14 (9)
2 (1)
10 (7)
11 (7)
2 (1)
Fatigue
26 (17)
12 (8)
0
31 (21)
7 (5)
0
Asthenia
25(17)
7 (5)
1 (1)
23 (15)
1 (1)
0
Diarrhea
25(17)
8 (5)
0
20 (13)
1 (1)
0
Pyrexia
29 (20)
0
0
21 (14)
0
0
Hyperglycemia
7 (5)
7 (5)
1 (1)
12 (8)
7 (5)
0
Secondary primary malignancy
3 (2)
NA
NA
3 (2)
NA
NA
Any infusion-related reaction
8 (5%)
0
0
NA
NA
NA
Abbreviations: D-Pd, daratumumab + pomalidomide + dexamethasone; Pd, pomalidomide + dexamethasone.aAdverse events of any grade that were reported in at least 15% of patients in either treatment arm or grade 3/4 adverse events that were reported in at least 5% of patients in either treatment arm are listed.

Updated Analysis of the APOLLO Study

Dimopoulos et al (2023)4 reported the final OS and updated safety analysis of D-Pd vs Pd alone in patients with RRMM in the APOLLO study with a median follow-up of 39.6 months.

Study Design/Methods

  • OS was defined as the number of months from the date of randomization to the date of death from any cause). Patients were censored at the last date of contact.
  • Patients in the safety population were included if they received ≥1 administration of any study treatment.

Results

Patient Disposition and Treatment Characteristics
  • A total of 304 patients were randomized to receive either D-Pd (n=151) or Pd (n=153) and constituted the ITT population.
  • Patients included in this study were refractory to lenalidomide (D-Pd, 79% [n=120]; Pd, 80% [n=122]), a PI (D-Pd, 47% [n=71]; Pd, 49% [n=75]), or both (DPd, 42% [n=64]; Pd, 42% [n=65]).
  • Median duration of exposure to study treatment was 11.5 (interquartile range [IQR], 4.6-36.1) months vs 6.6 (IQR, 3.2-15.0) months in the D-Pd vs Pd arm, respectively.
  • The median duration of follow-up was 39.6 (IQR, 37.1-43.7) months.
  • In the safety population (D-Pd, n=149; Pd, n=150), the median relative dose intensity of DARZALEX and DARZALEX FASPRO was 86% (IQR, 80-94) and 95% (IQR, 86-100), respectively. In the D-Pd vs Pd arm, the median relative dose intensity of pomalidomide and dexamethasone was 74% (IQR, 55‑94) vs 91% (IQR, 77‑98; P<0.0001) and 78% (IQR, 49-95) vs 87% (IQR, 64-97; P=0.0278), respectively.
Efficacy
  • Median PFS on the next line of therapy (PFS2) was 24.4 months (95% CI, 17.1-35.7) vs 17.6 months (95% CI, 13.622.0) in the D-Pd vs Pd arm, respectively (HR, 0.73; 95% CI, 0.55-0.98; P=0.034).
    • The 3-year PFS2 rate was 41.4% (95% CI, 33.1-49.4) vs 27% (95% CI, 19.834.8) in the D-Pd vs Pd arm, respectively.
  • Median OS was 34.4 months (95% CI, 23.7-40.3) vs 23.7 months (95% CI, 19.6-29.4) in the D-Pd vs Pd arm, respectively (HR, 0.82; 95% CI, 0.61-1.11; P=0.20).
  • Median time to subsequent therapy was 20.0 months (95% CI, 13.8-27.1) vs 11.8 months (95% CI, 8.9-15.4) in the D-Pd vs Pd arm, respectively (HR, 0.61; 95% CI, 0.45-0.82; P=0.0008).
  • In the safety population, a total of 48% (n=72) of patients in the D-Pd arm and 68% (n=102) of patients in the Pd arm received subsequent therapy in any line as presented in Table: Most Common (>10%) subsequent antimyeloma therapies.

Most Common (>10%) Subsequent Antimyeloma Therapiesa, 4
Total receiving subsequent therapy, n (%)
Any Subsequent LOT
Next Subsequent LOT
D-Pdb
(n=72)
Pd
(n=102)
D-Pdb
(n=72)
Pd
(n=102)
Dexamethasone
57 (79)
83 (81)
51 (71)
72 (71)
Carfilzomib
31 (43)
34 (33)
24 (33)
24 (24)
Cyclophosphamide
26 (36)
36 (35)
13 (18)
19 (19)
Bortezomib
20 (28)
37 (36)
10 (14)
26 (25)
Pomalidomide
14 (19)
23 (23)
7 (10)
14 (14)
Lenalidomide
11 (15)
19 (19)
10 (14)
11 (11)
Selinexor
11 (15)
2 (2)
5 (7)
0
Thalidomide
8 (11)
3 (3)
4 (6)
1 (1)
DARZALEX
5 (7)
66 (65)
4 (6)
47 (46)
Abbreviations: D-Pd, daratumumab + pomalidomide + dexamethasone; LOT, line of therapy; Pd, pomalidomide + dexamethasone.aSubsequent systemic antimyeloma therapy was reported based on therapeutic class, pharmacological class, and preferred term.bD-Pd arm included all patients who received DARZALEX, regardless of the route of administration, with Pd.Note: Percentages have been rounded and therefore might not add up to 100%.

Safety

  • No new safety concerns were reported with longer follow-up.
  • The most common any grade and grade 3/4 TEAEs are presented in Table: Summary of Most Common TEAEs in the Safety Population.
  • Serious TEAEs were reported in 54% (n=80) vs 40% (n=60) of patients in the D-Pd vs Pd arm, respectively.
    • The most common serious TEAE was pneumonia (D-Pd, 15% [n=23]; Pd, 9% [n=13]).
  • Treatment modification occurred in 87% (n=130) vs 75% (n=112) of patients in the DPd vs Pd arm, respectively.
  • Treatment discontinuation due to TEAEs was low among both treatment arms (D-Pd, 2% [n=3]; Pd, 4% [n=6]).
    • Treatment discontinuation due to infection was reported in 1 (1%) patient each in both arms (D-Pd, meningoencephalitis bacterial infection; Pd, Coronavirus Disease 2019 [COVID-19]).
  • A total of 55% (n=83) vs 59% (n=91) of patients in the D-Pd vs Pd arm, respectively, died primarily due to disease progression, adverse events (AEs) unrelated to the study treatment, or COVID-19.
  • Second primary malignancies (cutaneous, invasive, and hematological) were reported in 3% (n=4) vs 4% (n=6) of patients in the D-Pd vs Pd arm, respectively.
    • In the D-Pd arm, cholangiocarcinoma, malignant melanoma, and squamous cell carcinoma were each reported in 1% (n=1) of patients.
    • In the Pd arm, malignant melanoma, acute myeloid leukemia, metastatic renal cell carcinoma, and thyroid neoplasm were each reported in 1% (n=1) of patients.
  • TEAEs leading to death were reported in 9% (n=13) of patients each in both arms.
    • The most common TEAEs leading to death were pneumonia (D-Pd, 2% [n=3]; Pd, 1% [n=2]) and COVID-19 (D-Pd, 1% [n=2]; Pd, 1% [n=1]).

Summary of Most Common TEAEs in the Safety Populationa, 4
TEAE, n (%)
D-Pd (n=149)
Pd (n=150)
Grade 1/2
Grade 3
Grade 4
Grade 5
Total
Grade 1/2
Grade 3
Grade
4
Grade 5
Total
Any AEs
12 (8)
45 (30)
75 (50)
13 (9)
145 (97)
23 (15)
79 (53)
31 (21)
13 (9)
146 (97)
Hematologic
Anemia
30 (20)
26 (17)
1 (1)
0
57 (38)
35 (23)
31 (21)
1 (1)
0
67 (45)
Thrombocytopenia
23 (15)
14 (9)
13 (9)
0
50 (34)
23 (15)
20 (13)
8 (5)
0
51 (34)
Leukopenia
14 (9)
16 (11)
9 (6)
0
39 (26)
11 (7)
6 (4)
1 (1)
0
18 (12)
Neutropenia
4 (3)
37 (25)
66 (44)
0
107 (72)
4 (3)
48 (32)
28 (19)
0
80 (53)
Lymphopenia
3 (2)
11 (7)
8 (5)
0
22 (15)
7 (5)
3 (2)
2 (1)
0
12 (8)
Bone marrow failure
0
0
0
1 (1)
1 (1)
0
0
0
0
0
Febrile neutropenia
0
10 (7)
3 (2)
0
13 (9)
0
4 (3)
1 (1)
0
5 (3)
Non-hematologic
Upper respiratory tract infection
37 (25)
0
0
0
37 (25)
21 (14)
3 (2)
0
0
24 (16)
Pyrexia
31 (21)
0
0
0
31 (21)
26 (17)
0
0
0
26 (17)
Diarrhea
28 (19)
8 (5)
0
0
36 (24)
22 (15)
1 (1)
0
0
23 (15)
Fatigue
28 (19)
15 (10)
0
0
43 (29)
31 (21)
7 (5)
0
0
38 (25)
Asthenia
25 (17)
7 (5)
1 (1)
0
33 (22)
23 (15)
2 (1)
0
0
25 (17)
Peripheral edema
25 (17)
0
0
0
25 (17)
14 (9)
0
0
0
14 (9)
Bronchitis
22 (15)
0
0
0
22 (15)
15 (10)
3 (2)
0
0
18 (12)
Dyspnea
12 (8)
3 (2)
1 (1)
1 (1)
17 (11)
12 (8)
1 (1)
0
0
13 (9)
Lower respiratory tract infection
12 (8)
14 (9)
2 (1)
1 (1)
29 (19)
10 (7)
11 (7)
2 (1)
1 (1)
24 (16)
COVID-19
10 (7)
5 (3)
1 (1)
2 (1)
18 (12)
2 (1)
0
0
1 (1)
3 (2)
Hyperglycemia
9 (6)
8 (5)
1 (1)
0
18 (12)
13 (9)
7 (5)
0
0
20 (13)
Muscular weakness
9 (6)
0
1 (1)
0
10 (7)
5 (3)
0
0
0
5 (3)
Pneumonia
9 (6)
14 (9)
4 (3)
3 (2)
30 (20)
9 (6)
9 (6)
1 (1)
2 (1)
21 (14)
Hypokalemia
6 (4)
6 (4)
1 (1)
0
13 (9)
8 (5)
1 (1)
0
0
9 (6)
Hyperuricemia
3 (2)
1 (1)
1 (1)
0
5 (3)
3 (2)
0
1 (1)
0
4 (3)
Myocardial ischemia
2 (1)
0
0
0
2 (1)
0
0
1 (1)
0
1 (1)
Acute myocardial infarction
1 (1)
1 (1)
0
0
2 (1)
0
0
0
1 (1)
1 (1)
General physical health deterioration
1 (1)
1 (1)
0
0
2 (1)
0
2 (1)
0
2 (1)
4 (3)
Hyperbilirubinemia
1 (1)
0
1 (1)
0
2 (1)
1 (1)
0
0
0
1 (1)
Lumbar vertebral fracture
1 (1)
0
1 (1)
0
2 (1)
0
2 (1)
0
0
2 (1)
Acute pulmonary edema
0
0
1 (1)
0
1 (1)
0
0
0
0
0
Campylobacter infection
0
0
0
1 (1)
1 (1)
0
0
0
0
0
Cardiac arrest
0
0
0
0
0
0
0
0
1 (1)
1 (1)
Cerebral hemorrhage
0
0
0
0
0
0
0
0
1 (1)
1 (1)
Embolism
0
0
1 (1)
0
1 (1)
0
0
0
0
0
Hypertensive hydrocephalus
0
0
0
0
0
0
0
0
1 (1)
1 (1)
Liver disorder
0
0
0
1 (1)
1 (1)
0
0
0
0
0
Pneumonia aspiration
0
0
0
1 (1)
1 (1)
0
0
0
1 (1)
1 (1)
Respiratory failure
0
1 (1)
0
1 (1)
2 (1)
1 (1)
1 (1)
1 (1)
0
3 (2)
Sepsis
0
1 (1)
0
1 (1)
2 (1)
0
0
1 (1)
0
1 (1)
Septic shock
0
0
0
1 (1)
1 (1)
0
0
0
2 (1)
2 (1)
Sudden death
0
0
0
1 (1)
1 (1)
0
0
0
0
0
Systemic candida
0
0
0
1 (1)
1 (1)
0
0
0
0
0
Viral pneumonia
0
0
1 (1)
0
1 (1)
0
0
0
0
0
Abbreviations: AE, adverse event; COVID-19, Coronavirus Disease 2019; D-Pd, daratumumab + pomalidomide + dexamethasone; MedDRA, Medical Dictionary for Regulatory Activities; NCI-CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Events; Pd, pomalidomide + dexamethasone; TEAE, treatment-emergent adverse event.aTEAEs are listed for all grade 4 or 5 events and any grade 3 event occurring in ≥15% of patients in either treatment group (corresponding grade 1 or 2 events are listed). Each patient could have >1 event, and multiple occurrences of each event but were only counted once for each row.

Indirect Treatment Comparisons of D-Pd vs D-Vd or Vd in Patients with RRMM

He et al (2022)5 reported the results of indirect treatment comparisons using patient-level data to evaluate the improvement in PFS with D-Pd vs D-Vd and D-Pd vs Vd in patients with RRMM with prior IMiD and PI exposure.

Study Design/Methods

  • Data for the D-Pd cohort were sourced from the APOLLO and EQUULEUS studies, and data for the D-Vd and Vd cohorts were sourced from the CASTOR study. The study designs are briefly described below:
    • APOLLO: The study design has been described above in the Study Design/Methods section of the main analysis.
    • EQUULEUS: Non-randomized, open-label, phase 1b study in patients with RRMM previously treated with ≥1 prior LOT.
      • Patients in the D-Pd arm received DARZALEX 16 mg/kg IV every week (QW) during cycles 1 and 2, then every 2 weeks (Q2W) during cycles 3-6, and every 4 weeks (Q4W) thereafter, along with pomalidomide 40 mg oral (PO) QD on days 1-21 of each cycle and dexamethasone 40 mg PO QW.
    • CASTOR: Randomized, open-label, phase 3 study in patients with RRMM previously treated with ≥1 prior LOT.
      • Patients in the D-Vd arm received DARZALEX 16 mg/kg IV QW during cycles 1 and 2, Q2W during cycles 3-6, and Q4W thereafter, along with bortezomib 1.3 mg/m2 subcutaneously (SC) on days 1, 4, 8, and 11 of cycles 18, and dexamethasone 20 mg PO or IV on days 1, 2, 4, 5, 8, 9, 11, and 12 of each cycle.
      • Patients in the Vd arm received bortezomib and dexamethasone at the same dosage and schedule as the D-Vd arm.
  • The following harmonized eligibility criteria were applied prior to weighting/matching:
    • Received ≥1 prior LOT, including an IMiD and a PI
    • No prior pomalidomide
  • Imbalances in baseline characteristics were adjusted using sIPTW, propensity score matching (PSM), and CM. Propensity scores were calculated using logistic regression for sIPTW and PSM.
    • A sensitivity study was conducted to evaluate the potential impact of not including International Staging System (ISS) stage and multiple myeloma (MM) type covariates in the CM analysis since these data were not available in the EQUULEUS dataset.

Results

Patient Characteristics

Baseline Characteristics for D-Pd and D-Vd Cohorts Before and After Adjustment5
Characteristic
Unadjusted Postharmonization
sIPTW
PSM
CM
D-Pd
(n=253)
D-Vd
(n=104)
D-Pd
(ESS=219)
D-Vd
(ESS=42)
D-Pd
(ESS=253)
D-Vd
(ESS=9)
D-Pd
(ESS=79)
D-Vd
(ESS=79)
Age, %
<65 years
45.5
50.0
46.0
46.0
45.5
32.4
40.5
44.3
65 to 74 years
41.5
38.5
41.5
40.5
41.5
53.8
49.4
45.6
≥75 years
13.0
11.5
12.5
13.6
13.0
13.8
10.1
10.1
Male, %
53.4
55.8
54.4
54.5
53.4
56.9
57.0
54.4
ECOG PS score, %
0
47.0
42.3
46.4
43.5
47.0
48.6
46.8
44.3
1
45.8
53.8
47.2
53.1
45.8
47.8
46.8
50.6
2
7.1
3.8
6.4
3.5
7.1
3.6
6.3
5.1
Cytogenetic risk, %
High risk
23.7
13.5
21.0
11.7
23.7
4.3
16.5
15.2
Standard risk
51.0
67.3
54.0
60.1
51.0
53.4
58.2
62.0
Missing
25.3
19.2
25.0
28.3
25.3
42.3
25.3
22.8
Prior LOTs, %
1
7.1
27.9
9.0
12.8
7.1
5.5
10.1
12.7
2-3
63.6
59.6
65.8
75.1
63.6
86.2
74.7
70.9
≥4
29.2
12.5
25.3
12.2
29.2
8.3
15.2
16.5
Refractory to lenalidomide, %
Yes
83.4
47.1
77.7
73.4
83.4
86.6
65.8
62.0
No/NA
16.6
52.9
22.3
26.6
16.6
13.4
34.2
38.0
Refractory status, %
IMiD only
29.6
51.0
36.0
44.8
19.6
26.5
57.0
60.8
PI only
6.3
0
4.7
0
6.3
0
1.3
0
Both IMiD + PI
54.2
5.8
42.3
32.2
54.2
60.1
10.1
7.6
None/NA
9.9
43.3
17.0
23.0
9.9
13.4
31.6
31.6
Years since diagnosis, median (IQR)
4.7
(2.72-7.19)
4.5
(2.92-6.61)
4.6
(2.74-7.06)
4.7
(3.14-6.31)
4.6
(2.71-7.16)
4.4
(3.17-5.48)
4.9
(2.84-7.19)
4.9
(3.17-7.39)
Prior ASCT, %
64.8
76.0
67.8
65.5
64.8
47.8
72.2
74.7
Abbreviations: ASCT, autologous stem cell transplant; CM, cardinality matching; D-Pd, daratumumab + pomalidomide + dexamethasone; D-Vd, DARZALEX + bortezomib + dexamethasone; ECOG PS, Eastern Cooperative Oncology Group performance status; ESS, effective sample size; IMiD, immunomodulatory drug; IQR, interquartile range; LOT, line of therapy; NA, not applicable; PI, proteasome inhibitor; PSM, propensity score matching; sIPTW, stabilized inverse probability of treatment weighting.

Baseline Characteristics for D-Pd and Vd Cohorts Before and After Adjustment5
Characteristic
Unadjusted Postharmonization
sIPTW
PSM
CM
D-Pd
(n=253)
Vd
(n=122)
D-Pd
(ESS=206)
Vd
(ESS=55)
D-Pd
(ESS=253)
Vd
(ESS=13)
D-Pd
(ESS=93)
Vd
(ESS=93)
Age, %
<65 years
45.5
59.0
49.3
51.1
45.5
45.1
50.5
52.7
65 to 74 years
41.5
28.7
37.9
35.6
41.5
42.3
37.6
33.3
≥75 years
13.0
12.3
12.7
13.3
13.0
12.6
11.8
14.0
Male, %
53.4
59.8
54.2
55.0
53.4
49.8
55.9
59.1
ECOG PS score, %
0
47.0
54.1
47.5
40.1
47.0
22.1
51.6
52.7
1
45.8
40.2
45.1
53.8
45.8
71.9
40.9
41.9
2
7.1
5.7
7.4
6.1
7.1
5.9
7.5
5.4
Cytogenetic risk, %
High risk
23.7
17.2
22.0
28.0
23.7
36.0
19.4
17.2
Standard risk
51.0
52.5
50.1
47.0
51.0
45.5
47.3
50.5
Missing
25.3
30.3
27.8
24.9
25.3
18.6
33.3
32.3
Prior LOTs, %
1
7.1
27.0
9.6
13.8
7.1
8.7
10.8
14.0
2-3
63.6
59.0
65.7
72.2
63.6
84.2
71.0
67.7
≥4
29.2
13.9
24.7
14.0
29.2
7.1
18.3
18.3
Refractory to lenalidomide, %
Yes
83.4
48.4
75.3
68.1
83.4
85.0
67.7
63.4
No/NA
16.6
51.6
24.7
31.9
16.6
15.0
32.3
36.6
Refractory status, %
IMiD only
29.6
49.2
36.2
44.0
29.6
28.9
59.1
60.2
PI only
6.3
2.5
5.2
5.0
6.3
4.3
4.3
3.2
Both IMiD + PI
54.2
4.9
39.4
25.9
54.2
55.3
9.7
6.5
None/NA
9.9
43.4
19.2
25.1
9.9
11.5
26.9
30.1
Years since diagnosis, median (IQR)
4.7
(2.72-7.19)
4.0
(2.45-6.22)
4.4
(2.72-6.95)
4.6
(2.91-6.95)
4.6
(2.71-7.16)
4.6
(3.11-7.49)
5.0
(2.74-7.05)
4.6
(2.83-6.95)
Prior ASCT, %
64.8
69.7
66.2
63.0
64.8
47.4
68.8
68.8
Abbreviations: ASCT, autologous stem cell transplant; CM, cardinality matching; D-Pd, daratumumab + pomalidomide + dexamethasone; ECOG PS, Eastern Cooperative Oncology Group performance status; ESS, effective sample size; IMiD, immunomodulatory drug; IQR, interquartile range; LOT, line of therapy; NA, not applicable; PI, proteasome inhibitor; PSM, propensity score matching; sIPTW, stabilized inverse probability of treatment weighting; Vd, bortezomib + dexamethasone.
Efficacy
  • HRs for PFS favored the D-Pd over the D-Vd and Vd regimens and were statistically significant for both the sIPTW and the CM method. See Table: Comparison of PFS in Patients Receiving D-Pd vs D-Vd and D-Pd vs Vd.
  • A sensitivity analysis conducted without data from the EQUULEUS study revealed that the CMadjusted PFS was improved with D-Pd vs D-Vd (HR, 0.58; 95% CI, 0.38-0.87) and with D-Pd vs Vd (HR, 0.24; 95% CI, 0.16-0.35).

Comparison of PFS in Patients Receiving D-Pd vs D-Vd and D-Pd vs Vd5
Parameter
D-Pd vs D-Vd
D-Pd vs Vd
PFS HRa (95% CI)
Before harmonization criteria
1.26 (0.99-1.60)
0.49 (0.39-0.61)
After harmonization criteria
0.83 (0.63-1.10)
0.42 (0.32-0.55)
P value
0.20
<0.01
sIPTW-adjusted PFS
HRa (95% CI)
0.66 (0.45-0.96)
0.33 (0.25-0.43)
P value
0.03
<0.01
CM-adjusted PFS
HRa (95% CI)
0.55 (0.36-0.82)
0.28 (0.19-0.41)
P value
<0.01
<0.01
Abbreviations: CI, confidence interval; CM, cardinality matching; D-Pd, daratumumab + pomalidomide + dexamethasone; D-Vd, DARZALEX + bortezomib + dexamethasone; HR, hazard ratio; PFS, progression-free survival; sIPTW, stabilized inverse probability of treatment weighting; Vd, bortezomib + dexamethasone.
aHR values <1 indicate an advantage for D-Pd.

Analysis of PROs and HRQoL

Terpos et al (2022)6 compared the impact of D-Pd vs Pd on the HRQoL of patients in the APOLLO study.

Study Design/Methods

  • Patient-reported outcomes (PROs) were assessed at day 1 of each treatment cycle before receiving treatment, using the following scales:
    • European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item (EORTC QLQ-C30)
    • European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Multiple Myeloma Module 20-item (EORTC QLQ-MY20)
    • EuroQol-5 Dimensions-5 Levels (EQ-5D-5L)

Results

Patient Characteristics
  • Overall, 304 patients were included (D-Pd, n=151; Pd, n=153).
  • The median duration of treatment was 11.5 months in the D-Pd arm and 6.6 months in the Pd arm.
  • The mean baseline HRQoL scores are presented in Table: Baseline HRQoL Characteristics in the ITT Population.
  • The PRO compliance rates were >95% at baseline and >93% through cycle 16 for both arms.

Baseline HRQoL Characteristics in the ITT Population6
Characteristic
D-Pd
(n=151)
Pd
(n=153)
EORTC QLQ-C30 scorea, mean (SD)
GHS
60.9 (22.9)
60.5 (20.3)
Functional scales
Physical functioning
71.2 (25.1)
69.3 (24.7)
Role functioning
68.0 (31.8)
66.9 (30.5)
Emotional functioning
80.7 (17.5)
78.1 (19.8)
Cognitive functioning
85.8 (19.5)
84.9 (19.5)
Social functioning
73.1 (28.3)
76.6 (26.8)
Symptom scales
Pain
30.8 (30.9)
34.9 (27.6)
Fatigue
35.5 (27.1)
38.1 (25.5)
Nausea/vomiting
4.7 (13.7)
3.9 (10.7)
EORTC QLQ-MY20 scorea, mean (SD)
Future perspective
62.3 (26.2)
61.8 (26.8)
Body image
83.2 (27.7)
80.0 (27.4)
Disease symptom
23.6 (23.0)
25.8 (22.4)
Adverse effects of treatment
15.6 (14.9)
17.7 (15.4)
EQ-5D-5L scores, mean (SD)
VASb
64.7 (20.1)
65.7 (19.3)
Abbreviations: D-Pd, daratumumab + pomalidomide + dexamethasone; EORTC QLQ-C30, European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item; EORTC QLQ-MY20, European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Multiple Myeloma Module 20-item; EQ-5D-5L, EuroQol-5 Dimensions-5 Levels; GHS, global health status; ITT, intent-to-treat; Pd, pomalidomide + dexamethasone; SD, standard deviation; VAS, visual analog scale.
aScores range from 0 to 100; higher scores represent better health status, better physical functioning, and more (worse) symptoms.bScores range from 0 to 100; higher scores represent better self-evaluated health status.
Efficacy
  • No significant change in LS mean GHS scores from baseline was reported in either treatment arm. The point estimates generally favored the D-Pd arm. The difference in LS mean change from baseline between arms was greatest at cycle 10 (D-Pd, 3.1 [95% CI, -1.0 to 7.2]; Pd, -1.9 [95% CI, -6.4 to 2.6]; P=0.0836).
  • Physical and emotional functioning remained unchanged from baseline in the D-Pd arm and worsened in the Pd arm. The maximum worsening was observed at cycle 15 (7.2 points) for physical functioning and at cycle 14 (9.1 points) for emotional functioning.
  • The between-group differences were more favorable in the D-Pd arm at all timepoints, with significant differences between arms (nominal P<0.05) at cycles 10, 11, and 15 for physical functioning and at cycles 5, 6, 8-11, 13, and 14 for emotional functioning.
  • The point estimates for pain scores favored the D-Pd vs Pd arm at all timepoints. Maximum LS mean improvement from baseline was reported in the D-Pd arm at cycle 12 (6.8 points, between-group P=0.0443). Maximum LS mean worsening from baseline was reported in the Pd arm at cycle 4 (2.7 points, between-group P=0.0286).
  • In the D-Pd vs Pd arm, the LS mean change in fatigue scores was -4.0 (95% CI, -8.7 to -0.6) vs 2.8 (95% CI, -2.4 to 7.9) at cycle 11 (P=0.0372) and -5.4 (95% CI, 10.4 to 0.4) vs 3.6 (95% CI, -2.2 to 9.4) at cycle 13 (P=0.0152).
  • Significant differences (nominal P<0.05) favoring the D-Pd vs Pd arm were observed in role-functioning, cognitive and social functioning scores, symptom scores of nausea/vomiting, and single-item scores (including dyspnea, insomnia, appetite loss, constipation, diarrhea, financial difficulties) at varying timepoints.
  • Disease symptoms and TEAEs were unchanged in the D-Pd arm and AEs were worsened in the Pd arm (maximum LS mean worsening at cycle 9 [4.0 points]).
  • LS mean changes from baseline in EORTC QLQ-C30 GHS, pain, fatigue, physical, and emotional functioning were similar to the overall population in subgroups based on age (<65/≥65 years) and number of prior LOT (1, 2-3, >4).
    • PROs were improved in the D-Pd vs Pd arm in patients from both age groups.
    • The greatest differences favoring D-Pd vs Pd in LS mean change from baseline in GHS (maximum difference, -9.7 points at cycle 16), pain (maximum difference, 11.8 points at cycle 15), physical functioning (maximum difference, -9.1 points at cycle 4), and emotional functioning (maximum difference, -12.1 points at cycle 16) scores were reported in the ≥65-years age group.
    • Differences favoring D-Pd vs Pd were more distinct with increasing numbers of prior LOT, with the most pronounced differences with ≥4 prior LOT.
  • In the D-Pd vs Pd arm, the proportion of patients with meaningful improvement from baseline was 55% vs 49% for disease symptoms, 43% vs 35.3% for physical functioning, and 41.7% vs 31.4% for emotional functioning.
  • Across arms, favorable clinical outcomes were correlated with improvements in EORTC QLQ-C30 GHS, pain, and fatigue subscales.
  • Across all measurement scales, the median time to improvement of PROs ranged between ~4 and 21 months and the median time to worsening of PROs ranged between ~3 and 6 months, except for nausea/vomiting (range, ~7-13 months), disease symptoms (range, ~8-10 months), and future perspective score (range, ~1421 months). See Table: Time to Improvement or Worsening in PROs Through Cycle 16.
  • The median times to improvement or worsening of EORTC QLQ-C30 GHS, fatigue, pain, and physical and emotional scores were similar and comparable to the overall population in all subgroups based on age and number of prior LOT.

Time to Improvement or Worsening in PROs Through Cycle 16a, 6
Score
Median Time to
Improvement (Range), Months
Median Time to
Worsening (Range), Months
D-Pd
Pd
HR
(95% CI)
D-Pd
Pd
HR
(95% CI)
EORTC QLQ-C30
GHS
5.62
(3.22-17.48)
3.81
(2.79-5.82)
0.88
(0.64-1.21)
4.01
(2.20-7.59)
3.84
(3.02-5.91)
0.90
(0.67-1.21)
Physical functioning
12.22
(6.47-NE)
20.73
(6.47-NE)
1.10
(0.76-1.59)
3.78
(2.86-5.62)
3.75
(2.86-6.01)
0.99
(0.74-1.32)
Role functioning
6.28
(3.35-NE)
9.30
(3.75-NE)
1.01
(0.72-1.41)
2.83
(2.00-4.76)
3.22
(2.79-5.55)
1.05
(0.79-1.40)
Emotional functioning
13.44
(7.00-NE)
20.11
(16.56-NE)
1.12
(0.76-1.63)
5.82
(4.40-9.26)
3.88
(2.86-6.14)
0.84
(0.62-1.13)
Cognitive functioning
NE
(11.40-NE)
NE
(NE-NE)
1.16
(0.77-1.73)
4.17
(2.86-6.05)
4.70
(2.76-5.62)
0.95
(0.72-1.27)
Social functioning
5.59
(3.98-NE)
NE
(8.35-NE)
1.35
(0.94-1.94)
3.81
(2.23-5.59)
2.76
(2.00-3.94)
0.88
(0.66-1.18)
Pain
4.63
(2.83-15.74)
4.14
(2.23-7.49)
0.92
(0.66-1.27)
4.01
(2.89-7.43)
3.71
(2.83-5.13)
0.89
(0.66-1.20)
Fatigue
14.06
(6.80-27.70)
NE
(11.43-NE)
1.17
(0.80-1.70)
5.59
(3.78-8.84)
4.63
(2.96-7.66)
0.99
(0.73-1.34)
Nausea/vomiting
NE
(NE-N E)
NE
(NE-NE)
1.09
(0.56-2.13)
12.91
(6.05-16.79)
7.43
(4.83-10.18)
0.86
(0.62-1.19)
EORTC QLQ-MY20
Future perspective
9.30
(4.63-NE)
6.51
(3.22-11.14)
0.83
(0.59-1.16)
21.49
(10.81-NE)
14.09
(6.87-NE)
0.94
(0.64-1.37)
Body image
NE
(NE-NE)
NE
(NE-NE)
0.78
(0.50-1.21)
4.73
(4.01-6.77)
7.39
(4.86-20.96)
1.27
(0.92-1.76)
Disease symptoms
NE
(3.55-NE)
8.87
(3.02-NE)
0.87
(0.62-1.24)
10.41
(5.78-NE)
8.67
(4.90-21.45)
0.90
(0.64-1.27)
Adverse effects of treatment
NE
(NE-NE)
NE
(NE-NE)
1.06
(0.69-1.65)
4.01
(2.86-5.78)
3.94
(2.83-5.55)
0.99
(0.73-1.34)
EQ-5D-5L
VAS
3.81
(2.10-10.25)
5.55
(3.75-NE)
1.15
(0.83-1.59)
3.78
(2.83-6.54)
2.86
(1.94-3.71)
0.82
(0.62-1.10)
Abbreviations: CI, confidence interval; D-Pd, daratumumab + pomalidomide + dexamethasone; EORTC QLQ-C30, European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item; EORTC QLQ-MY20, European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Multiple Myeloma Module 20-item; EQ-5D-5L, EuroQol-5 Dimensions-5 Levels; GHS, global health status; HR, hazard ratio; NE, not evaluable; Pd, pomalidomide + dexamethasone; PRO, patient-reported outcome; VAS, visual analog scale.
aAll between-group differences were statistically insignificant (nominal P value >0.05).

Population PK and Exposure-Response Analyses

Dosne et al (2022)7 evaluated the population PK and exposure-response relationship of daratumumab when administered in combination with Pd to patients with RRMM.

Study Design/Methods

  • Population PK analyses were conducted using data from the D-Pd cohorts of the APOLLO and the EQUULEUS studies.
  • Exposure-response relationships for key efficacy and safety endpoints were analyzed using data from the D-Pd and Pd cohorts of the APOLLO study.
  • The treatment regimen used in the APOLLO study has been described above in the Study Design/Methods section of the main analysis.
  • The following treatment regimen was used for patients in the D-Pd cohort of the EQUULEUS study (28 days/cycle):
    • DARZALEX: 16 mg/kg IV QW during cycles 1 and 2, then Q2W during cycles 3-6, and Q4W thereafter
    • Pomalidomide: 4 mg PO QD on days 1-21 of each cycle
    • Dexamethasone: 40 mg (20 mg for patients aged ≥75 years) PO QD on days 1, 8, 15, and 22 of each cycle (split IV/PO when co-administered with DARZALEX)

Results

Patient Characteristics
  • Overall, PK data of daratumumab from 1146 samples (SC, n=473; IV, n=673) from 239 PK-evaluable patients (APOLLO D-Pd cohort, n=140; EQUULEUS D-Pd cohort, n=99) were analyzed.
    • In APOLLO, 133 patients received DARZALEX FASPRO 1800 mg SC, 4 patients switched from 16 mg/kg IV to 1800 mg SC, and 3 patients received DARZALEX 16 mg/kg IV only.
    • In EQUULEUS, all patients received DARZALEX 16 mg/kg IV.
  • The exposure-response set, used for evaluating the exposure-response relationships for both efficacy and safety, included 290 patients from APOLLO (D-Pd, n=140; Pd, n=150).
Population PK Modeling
  • The serum concentration-time profiles of daratumumab following D-Pd combination therapy were similar in ranges across both the studies and across both SC and IV administration routes.
  • Body weight, albumin concentration, and type of MM (immunoglobulin [Ig]G vs non-IgG) were identified as statistically significant covariates on linear clearance. Body weight and sex were identified as statistically significant covariates on volume of distribution of the central compartment.
  • The first-order absorption rate of daratumumab SC was 0.012 h-1 (0.288 day-1), the estimated clearance was 0.00432 L/h (0.104 L/day), and the volume of distribution of the central compartment was 4.36 L. The clearance and the volume of distribution of the central compartment were related to body weight.
Comparison of PK in D-Pd Combination Therapy vs Historical Daratumumab Monotherapy
  • The median simulated plasma trough concentration (Ctrough) of daratumumab at cycle 3 day 1 was 23% higher with D-Pd than with monotherapy, with significant overlap in the concentration ranges.
  • The model-derived geometric mean half-life of daratumumab associated with linear elimination was 19.7 days (coefficient of variation [CV], 15.3%) for D-Pd and 20.4 days (CV, 22.4%) for monotherapy.
  • The PK of daratumumab was not affected when administered in combination with Pd.
Model-Predicted PK Profile, Target Saturation Profile, and Clearance Profile Under the Approved Dosing Regimen
  • The simulated PK profile of daratumumab administered per the approved regimen was similar between IV and SC administration routes.
  • Stable simulated daratumumab plasma concentrations were observed during the Q2W dosing period, starting week 16 and continuing until a change in dosage frequency to Q4W at week 24.
    • Steady state was reached approximately 5 months into the Q4W dosage schedule.
  • The model-predicted SC dose of daratumumab resulted in lower peak-to-trough fluctuations, lower maximum plasma concentration (Cmax), and higher Ctrough throughout the approved dose schedule, compared with the IV dose.
    • The median peak-to-trough ratio during the last week of QW dosing (week 8) of daratumumab SC was 1.07 (90% prediction interval, 1.01-1.26).
  • The model-predicted target saturation was maintained over 95% at all phases (QW, Q2W, and Q4W) of the approved schedules for all PK-evaluable patients, regardless of body weight.
  • The model-predicted clearance profile after administration was generally similar between daratumumab SC and IV, with a difference observed only during the first administration. The total clearance rate decreased over time and approached the clearance rate for nonspecific IgG approximately after 16 weeks.
  • After the first administration via the SC route, the model-predicted plasma concentration of daratumumab increased gradually due to slower absorption into systemic circulation, leading to slow receptor saturation and higher clearance rate than via the IV route.
Comparison of Model-Predicted Daratumumab Exposure in Subpopulations
  • The simulated Ctrough of daratumumab at cycle 3 day 1 (prior to the first dose of the Q2W dosage schedule) was generally consistent across subgroups. The largest differences in Ctrough at cycle 3 day 1 were reported in subgroups related to body weight, albumin concentration, and type of myeloma, compared with their respective reference groups, with a maximum geometric mean change of <20%.
Exposure-Response Analysis for Efficacy
  • A marked effect of daratumumab was observed on PFS in 75% of patients with modelpredicted exposures greater than Q1 (≤121 μg/mL), regardless of the exposure metric (first peak, first trough, or maximum trough) investigated.
  • No improvement in PFS was reported with D-Pd vs Pd in patients with a model-predicted exposure of Q1.
    • The lower daratumumab exposure in the Q1 group was not related to body weight. The mean body weight was 79.7 kg (standard deviation [SD], 15.7) in the Q1 group and 81.4 kg (SD, 12.6) in the quartile 2 (Q2; >121 to ≤151 μg/mL) group.
  • Improved PFS HR was observed with increased median first peak (HR, 0.48; 95% CI, 0.35-0.64), first trough (HR, 0.65; 95% CI, 0.52-0.81), and maximum trough (HR, 0.53; 95% CI, 0.42-0.67) exposure of daratumumab.
  • A case-matched exposure-response analysis revealed no correlation between an imbalance in covariates and a lack of improvement in PFS in patients receiving D-Pd with Q1 daratumumab exposure.
Exposure-Response Analysis for Safety
  • No significant increase in TEAE rates for all-grade or grade ≥3 IRRs, thrombocytopenia, anemia, neutropenia, and infections was observed with increasing model-predicted first peak or maximum peak exposure of daratumumab. See Table: Comparison of TEAE Rates Across Daratumumab Exposure Subgroups for D-Pd Combination Therapy in APOLLO.
  • A trend of inverse relationship between the rates of neutropenia, anemia, and thrombocytopenia and the maximum peak exposure was observed, possibly due to patients with TEAEs having treatment interruptions or delays, leading to lower exposure of daratumumab.
  • No increase in TEAE rates was identified in patients in the lower body weight (<65 kg) subgroup, except for anemia.
    • The higher rate of anemia in patients with low body weight was not related with the increased exposure of daratumumab. Increased exposure was associated with decreased anemia rates.

Comparison of TEAE Rates Across Daratumumab Exposure Subgroups for D-Pd Combination Therapy in APOLLO7
TEAE
Pd, % (95% CI)
(n=150)
D-Pd exposure quartilesa, % (95% CI)
Q1
(n=35)
Q2
(n=35)
Q3
(n=35)
Q4
(n=35)
Neutropenia
Any grade
53.3
(45.3-61.2)
82.9
(68.3-92.8)
77.1
(61.6-88.8)
71.4
(55.3-84.5)
71.4
(55.3-84.5)
Grade ≥3
50.7
(42.7-58.6)
74.3
(58.4-86.7)
74.3
(58.4-86.7)
71.4
(55.3-84.5)
71.4
(55.3-84.5)
Infections
Any grade
55.3
(47.3-63.1)
74.3
(58.4-86.7)
74.3
(58.4-86.7)
71.4
(55.3-84.5)
71.4
(55.3-84.5)
Grade ≥3
23.3
(17.1-30.5)
42.9
(27.4-59.3)
31.4
(17.7-47.7)
25.7
(13.3-41.6)
20.0
(9.1-35.1)
Anemia
Any grade
44.7
(36.9-52.7)
48.6
(32.6-64.8)
42.9
(27.4-59.3)
28.6
(15.5-44.7)
25.7
(13.3-41.6)
Grade ≥3
21.3
(15.3-28.3)
34.3
(20.1-50.7)
17.1
(7.2-31.7)
5.7
(1.0-16.6)
8.6
(2.2-20.7)
Thrombocytopenia
Any grade
33.3
(26.1-41.1)
42.9
(27.4-59.3)
37.1
(22.5-53.6)
22.9
(11.2-38.4)
20.0
(9.1-35.1)
Grade ≥3
18.0
(12.4-24.7)
31.4
(17.7-47.7)
25.7
(13.3-41.6)
5.7
(1.0-16.6)
8.6
(2.2-20.7)
IRRsb
Any grade
0
8.6
(2.2-20.7)
5.7
(1.0-16.6)
2.9
(0.2-12.0)
5.7
(1.0-16.6)
Grade ≥3
0
0
0
0
0
Abbreviations: CI, confidence interval; D-Pd, daratumumab + pomalidomide + dexamethasone; IRR, infusion-related reaction; Pd, pomalidomide + dexamethasone; Q, quartiles; TEAE, treatment-emergent adverse event.
aThe quartiles for maximum peak exposure were: Q1 (≤491 μg/mL), Q2 (>491 to ≤651 μg/mL), Q3 (>651 to ≤839 μg/mL), and Q4 (>839 to ≤1440 μg/mL). The quartiles for first peak exposure were: Q1 (≤121 μg/mL), Q2 (>121 to ≤151 μg/mL), Q3 (>151 to ≤185 μg/mL), and Q4 (>185 to ≤374 μg/mL).
bMaximum peak exposure was used as the exposure metric for analyses on all TEAEs except IRRs, where first peak exposure was used.

Literature Search

A literature search of MEDLINE®, Embase®, BIOSIS Previews®, and Derwent Drug File databases (and/or other resources, including internal/external databases) was conducted on 20 November 2024.

 

References

Show
1 1. Sonneveld P, Terpos E, Dimopoulos M, et al. Pomalidomide and dexamethasone (Pom-Dex) with or without daratumumab (DARA) in patients (pts) with relapsed or refractory multiple myeloma (RRMM): a multicenter, randomized, phase 3 study (APOLLO). Poster presented at: The Annual Meeting of the American Society of Clinical Oncology (ASCO); June 1-5, 2018; Chicago, IL.  
2 Dimopoulos M, Terpos E, Boccadoro M, et al. APOLLO: phase 3 randomized study of subcutaenous daratumumab plus pomalidomide and dexamethasone (D-Pd) versus pomalidomide and dexamethasone (Pd) alone in patients (pts) with relapsed/refractory multiple myeloma (RRMM). Poster presented at: 62nd American Society of Hematology (ASH) Annual Meeting & Exposition; December 5-8, 2020; Virtual.  
3 Dimopoulos MA, 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.  
4 Dimopoulos MA, Terpos E, Boccadoro M, et al. Subcutaneous daratumumab plus pomalidomide and dexamethasone versus pomalidomide and dexamethasone in patients with relapsed or refractory multiple myeloma (APOLLO): extended follow up of an open-label, randomised, multicentre, phase 3 trial. Lancet Haematol. 2023;10(10):e813-e824.  
5 He J, Berringer H, Heeg B, et al. Indirect treatment comparison of daratumumab, pomalidomide, and dexamethasone versus standard of care in patients with difficult-to-treat relapsed/refractory multiple myeloma. Adv Ther. 2022;39(9):4230-4249.  
6 Terpos E, Dimopoulos MA, Boccadoro M, et al. Health‐related quality of life in patients with relapsed/refractory multiple myeloma treated with pomalidomide and dexamethasone ± subcutaneous daratumumab: Patient‐reported outcomes from the APOLLO trial. Am J Hematol. 2022;97(4):481-490.  
7 Dosne A, Li X, Luo M, et al. Population pharmacokinetics and exposure-response analyses of daratumumab plus pomalidomide/dexamethasone in relapsed or refractory multiple myeloma. doi:10.1111/bcp.15628.  
8 Chari A, Dimopoulos M, Beksac M, et al. Comparison of efficacy outcomes for Carfilzomib plus Dexamethasone and Daratumumab (KdD) versus Pomalidomide plus Bortezomib and Dexamethasone (PVd) and D-Pd in relapsed or refractory Multiple Myeloma. Poster presented at: 18th International Myeloma Workshop (IMW); September 8-11, 2021; Vienna, Austria.  
9 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.  
10 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.