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DARZALEX FASPRO® (daratumumab and hyaluronidase-fihj)

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Use of DARZALEX FASPRO in High-Risk Multiple Myeloma in Clinical Trials

Last Updated: 05/02/2025

SUMMARY

  • Janssen does not recommend the use of DARZALEX FASPRO in a manner that is inconsistent with the approved labeling.
  • This response includes information on high-risk subgroups from studies that include patients with newly diagnosed multiple myeloma (NDMM) and relapsed/refractory multiple myeloma (RRMM).

Newly Diagnosed Multiple Myeloma

  • PERSEUS is an ongoing, phase 3 study evaluating the efficacy and safety of DARZALEX FASPRO in combination with bortezomib, lenalidomide, and dexamethasone (D-VRd) vs VRd induction and consolidation followed by maintenance with lenalidomide and daratumumab (D-R) in DVRd group or lenalidomide (R) in VRd group in patients with NDMM eligible for autologous stem cell transplant (ASCT).1
    • Dimopoulos et al (2024)2 presented an expanded sub-group analysis of PERSEUS clinical outcomes (progression-free survival [PFS], overall minimal residual disease [MRD] negativity, and sustained MRD negativity) based on the presence of high-risk cytogenetic abnormalities (HRCAs), including gain(1q21) and amp(1q21). At a median follow-up of 47.5 months, hazard ratio (HR) point estimates for PFS favored D-VRd vs VRd for revised standard (HR, 0.29; 95% confidence interval [CI], 0.15-0.56; P=0.0001) and revised high cytogenetic risk (HR, 0.53; 95% CI, 0.35-0.81; P=0.0027).
    • Dimopoulos et al (2024)3 presented an expanded subgroup analysis of PERSEUS clinical outcomes (PFS, overall MRD-negativity, and sustained MRD-negativity) based on the second revised International Staging System (R2-ISS) and the presence of HRCAs, including gain(1q21) and amp(1q21). At a median follow-up of 47.5 months, HR point estimates for PFS favored D-VRd vs VRd for revised standard risk (HR, 0.29; 95% CI, 0.15-0.56; P=0.0001) and revised high risk (HR, 0.53; 95% CI, 0.35-0.81; P=0.0027). D-VRd increased PFS irrespective of the R2-ISS disease stage with a pronounced effect for R2-ISS stages II (HR, 0.29; 95% CI, 0.14-0.57) and III (HR, 0.46; 95% CI, 0.29-0.75). The overall and sustained (≥12 months) MRD-negativity (at 10-5 and 10-6 threshold) with ≥CR rates based on the R2-ISS disease stage favored D-VRd followed by D-R maintenance over VRd followed by R maintenance.
    • Bertamini et al (2024)4 presented results from the PERSEUS study that highlighted the significance of circulating tumor cells (CTCs) as a biomarker in transplant-eligible NDMM patients. D-VRd vs VRd improved PFS in patients with high cytogenetic risk and low CTC levels. However, there was no improvement in outcomes for patients with high cytogenetic risk combined with high CTC levels.
  • CEPHEUS is a phase 3 study evaluating the efficacy and safety of DARZALEX FASPRO in combination with bortezomib, lenalidomide, and dexamethasone (D-VRd) or VRd in patients with NDMM who are transplant ineligible (TIE) or for whom transplant is not planned as initial therapy (transplant deferred). The trial has enrolled 395 patients in 13 countries.5-7
  • AURIGA is an ongoing, open-label, active-controlled, multicenter, randomized phase 3 study evaluating the conversion rate to MRD-negativity after maintenance treatment with DARZALEX FASPRO in combination with lenalidomide (D-R) vs R alone in patients with NDMM who are anti-cluster of differentiation (CD) 38 naïve, have a very good partial response or better (≥VGPR), and are MRD-positive following ASCT after standard-of-care induction/consolidation. A total of 200 patients were randomized (D-R, n=99; R, n=101).8-10
    • Badros et al (2024)8,9,11 reported primary results from the phase 3 AURIGA study. Efficacy data by key subgroups is noted in Table: Subgroup Analysis (ISS Staging, Cytogenetic Risk, and Revised Cytogenetic Risk at Diagnosis) of MRD-Negativity (10- 5) Conversion Rate From Baseline to 12 Months of Maintenance Treatment in the ITT Population.8
    • Foster et al (2024)12 presented a post hoc analysis of the phase 3 AURIGA study that evaluated clinically relevant subgroups at a median follow-up of 32.3 months. The clinically relevant subgroups included elderly and Black patients; patients with high-risk disease per the International Staging System (ISS) disease staging; and patients with high cytogenetic risk per standard, revised, and IMS 2024 high-risk criteria. The subgroup analysis of MRD-negativity (10-5 sensitivity) conversion rates by 12 months of maintenance appeared to consistently favor D-R vs lenalidomide (R) maintenance alone, regardless of age, race, ISS disease stage, or response upon study entry. D-R vs R maintenance improved MRD-negativity (10-5 sensitivity) conversion rates by 12 months in patients with ultra high-risk disease, standard-risk disease, and patients with modified IMS 2024 high-risk disease. D-R vs R maintenance showed a PFS benefit across various definitions of high cytogenetic risk, in addition to patients with standard-risk disease and regardless of the number of HRCAs. D-R vs R maintenance improved PFS among patients with gain/amp(1q21), irrespective of other HRCAs (HR, 0.46; 95% CI, 0.13-1.59).

Relapsed/Refractory Multiple Myeloma

  • APOLLO is a phase 2 study evaluating the safety of pomalidomide + lenalidomide (Pd) vs DARZALEX FASPRO + Pd (D-Pd) in patients with RRMM who received ≥1 prior treatment with both lenalidomide and a proteasome inhibitor (PI).13,14
    • Sonneveld et al (2021)15 presented updated efficacy and safety data at a median follow-up of 30.7 months. PFS favored D-Pd vs Pd across subgroups, including ISS stage and cytogenetic risk status and is presented in the Table: PFS in the ISS Staging and Cytogenetic Profile Subgroups (APOLLO).
    • Dimopoulos et al (2022)16 presented final OS results and updated safety data at a median follow-up of 39.6 months. The updated analysis did not discuss cytogenetic risk status and the citation is listed in the reference below.

PRODUCT LABELING

CLINICAL studies – newly Diagnosed Multiple Myeloma

DARZALEX FASPRO in Combination With Bortezomib, Lenalidomide, and Dexamethasone

PERSEUS (MMY3014; NCT03710603) is an ongoing, open-label, multicenter, phase 3 study evaluating the efficacy and safety of D-VRd vs VRd induction and consolidation followed by maintenance with D-R in DVRd group or lenalidomide in VRd arm in patients with NDMM eligible for ASCT. Sonneveld et al (2023)1 reported efficacy and safety results from the PERSEUS study evaluating D-VRd vs VRd in patients with NDMM eligible for ASCT. Dimopoulos et al (2024)2 presented an expanded analysis of PERSEUS clinical outcomes (PFS, overall MRD negativity, and sustained MRD negativity) based on the presence of HRCAs, including gain(1q21) and amp(1q21). The results of the expanded analysis are presented below. Dimopoulos et al (2024)3 presented (at the 21st IMS Annual Meeting) an expanded subgroup analysis of PERSEUS clinical outcomes (PFS, overall MRD-negativity, and sustained MRD-negativity) based on R2-ISS and the presence of HRCAs, including gain(1q21) and amp(1q21).

Study Design/Methods

  • A total of 709 patients were randomized 1:1 to into D-VRd (n=355) vs VRd (n=354) arm.1
    • Stratification was done based on the ISS disease stage (I, II, or III) and standard or high cytogenetic risk (defined as the absence or presence, respectively, of a del[17p], t[4;14], or t[14;16]).1
  • Primary endpoint: PFS.1
  • Key secondary endpoints: Overall ≥CR, overall MRD-negativity, and OS.1
  • Other secondary endpoints: ORR, ≥VGPR, stringent complete response (sCR), duration of MRD-negativity.1

Results

Patient Characteristics

Demographics and Baseline Clinical Characteristics of the High-Risk ITT Populationa,2,3
D-VRd
(n=355)
VRd
(n=354)
Cytogenetic abnormalities, n (%)
   del(17p)
36 (10.1)
34 (9.6)
   t(4;14)
33 (9.3)
38 (10.7)
   t(14;16)
11 (3.1)
14 (4)
   Gain(1q21)b
59 (16.6)
71 (20.1)
   Amp(1q21)c
28 (7.9)
36 (10.2)
Cytogenetic risk profiled, n (%)
   Standard risk
264 (74.4)
266 (75.1)
   High risk
76 (21.4)
78 (22)
      del(17p)
36 (10.1)
34 (9.6)
      t(4;14)
33 (9.3)
38 (10.7)
      t(14;16)
11 (3.1)
14 (4)
   Indeterminate
15 (4.2)
10 (2.8)
Revised cytogenetic riske, n (%)
   Revised standard risk
174 (49)
167 (47.2)
   Revised high risk
130 (36.6)
148 (41.8)
   Indeterminate
51 (14.4)
39 (11)
ISS disease stage, n/N (%)
   I
186/355 (52.4)
178/353 (50.4)
   II
114/355 (32.1)
125/353 (35.4)
   III
55/355 (15.5)
50/353 (14.2)
R2-ISS disease stage, n (%)
   Low (I)
116 (32.7)
114 (32.2)
   Low-intermediate (II)
111 (31.3)
106 (29.9)
   Intermediate-high (III)
108 (30.4)
115 (32.5)
   High (IV)
20 (5.6)
19 (5.4)
Abbreviations: D-VRd, DARZALEX FASPRO + bortezomib + lenalidomide + dexamethasone; FISH; fluorescence in situ hybridization; ISS, International Staging System; ITT, intent-to-treat; R2-ISS, second revised International Staging System; VRd, bortezomib + lenalidomide + dexamethasone.
aThe ITT population was defined as all patients who underwent randomization.
bGain(1q21) was defined as the presence of 3 copies of chromosome 1q21.cAmp(1q21) was defined as the presence of 4 or more copies of chromosome 1q21. dCytogenetic risk was based on FISH; high risk was defined as the presence of del(17p), t(4;14), or t(14;16).eRevised cytogenetic risk was defined as the presence of del(17p), t(4;14), t(14;16), gain(1q21), or amp(1q21).
  • Across all cytogenetic risk subgroups, PFS was favored for D-VRd followed by D-R maintenance vs VRd followed by R maintenance and is summarized in Table: Cytogenetic Risk Subgroup Analysis of PFS in the ITT Population.2
    • HR point estimates for PFS favored D-VRd vs VRd for revised standard (HR, 0.29; 95% CI, 0.15-0.56; P=0.0001) and revised high cytogenetic risk (HR, 0.53; 95% CI, 0.35-0.81; P=0.0027).2,3
    • Irrespective of other HRCAs, HR point estimates for PFS also favored D-VRd vs VRd in patients with the presence of gain(1q21), amp(1q21), and gain(1q21) or amp(1q21).2
  • D-VRd increased PFS irrespective of the R2-ISS disease stage with a pronounced effect for R2-ISS stages II and III and is summarized in Table: Subgroup Analysis of PFS Based on R2-ISS Disease Stage.3
  • Regardless of high-risk cytogenetic markers, a subgroup analysis of overall and sustained (≥12 months) MRD negativity (at 10-5 and 10-6) ≥CR rates based on cytogenetic risk markers favored treatment with D-VRd followed by D-R maintenance over VRd followed by R maintenance and is summarized in Table: Subgroup Analysis of MRD Negativity.

Cytogenetic Risk Subgroup Analysis of PFS in the ITT Population2
Subgroup
D-VRd
D-VRd
VRd
VRd
HR (95% CI)
P Value
n/N
Median PFS,
Months
n/N
Median PFS,
Months
Standard riska
25/264
NE
62/266
NE
0.35 (0.22-0.56)
<0.0001
High riskb
24/76
NE
38/78
44.1
0.59 (0.36-0.99)
0.0439
Revised standard riskc
12/174
NE
35/167
NE
0.29 (0.15-0.56)
0.0001
Revised high riskd
33/130
NE
62/148
NE
0.53 (0.35-0.81)
0.0027
gain(1q21)e
15/59
NE
26/71
NE
0.62 (0.33-1.18)
0.1400
amp(1q21)f
6/28
NE
17/36
46.7
0.37 (0.15-0.94)
0.0306
gain(1q21)/ amp(1q21)g
21/87
NE
43/107
NE
0.52 (0.31-0.88)
0.0133
Isolated gain(1q21)h
8/37
NE
15/47
NE
0.57 (0.24-1.36)
0.2004
Isolated amp(1q21)i
1/17
NE
9/23
NE
0.11 (0.01-0.87)
0.0115
1 revised HRCA
21/97
NE
43/110
NE
0.47 (0.28-0.79)
0.0035
≥2 revised HRCAs
12/33
NE
19/38
44.1
0.73 (0.35-1.50)
0.3878
Abbreviations: CI, confidence interval; D-VRd, DARZALEX FASPRO + bortezomib + lenalidomide + dexamethasone; HR, hazard ratio; HRCA, high-risk cytogenetic abnormality; ITT, intent-to-treat; NE, not estimable; PFS, progression-free survival; VRd, bortezomib + lenalidomide + dexamethasone.
aStandard risk (per protocol), defined as none of the following HRCAs: del(17p), t(4;14), t(14;16).
bHigh risk (per protocol), defined as 1 or more of the following HRCAs: del(17p), t(4;14), t(14;16).
cDefined as none of the following HRCAs: del(17p), t(4;14), t(14;16), gain(1q21), amp(1q21).
dDefined as 1 or more of the following HRCAs: del(17p), t(4;14), t(14;16), gain(1q21), amp(1q21).
eDefined as the presence of 3 copies of chromosome 1q21, with or without other HRCAs.
fDefined as the presence of 4 or more copies of chromosome 1q21, with or without other HRCAs.
gDefined as the presence of gain(1q21) or amp(1q21), with or without other HRCAs.
hDefined as the presence of 3 copies of chromosome 1q21, without any other HRCAs.
iDefined as the presence of 4 or more copies of chromosome 1q21, without any other HRCAs.

Subgroup Analysis of PFS Based on R2-ISS Disease Stage3
Subgroup
D-VRd
D-VRd
VRd
VRd
HR (95% CI)
n/N
Median PFS,
Months
n/N
Median PFS,
Months
Low (I)
6/116
NE
13/114
NE
0.42 (0.16-1.11)
Low-intermediate (II)
11/111
NE
30/106
NE
0.29 (0.14-0.57)
Intermediate-high (III)
25/108
NE
50/115
NE
0.46 (0.29-0.75)
High (IV)
8/20
NE
10/19
39.8
0.63 (0.25-1.61)
Abbreviations: CI, confidence interval; D-VRd, DARZALEX FASPRO + bortezomib + lenalidomide + dexamethasone; HR, hazard ratio; ITT, intent-to-treat; NE, not estimable; PFS, progression-free survival; VRd, bortezomib + lenalidomide + dexamethasone.

Subgroup Analysis of MRD Negativity2,3
Subgroup
D-VRd
VRd
OR (95% CI)
P Value
n/N (%)
n/N (%)
MRD negativity (10-5) with ≥CR
   Standard riska
204/264 (77.3)
128/266 (48.1)
3.67 (2.52-5.33)
<0.0001
   High riskb
52/76 (68.4)
37/78 (47.4)
2.40 (1.24-4.63)
0.0086
   Revised standard riskc
131/174 (75.3)
79/167 (47.3)
3.39 (2.14-5.37)
<0.0001
   Revised high riskd
95/130 (73.1)
73/148 (49.3)
2.79 (1.68-4.62)
<0.0001
   gain(1q21)e
41/59 (69.5)
33/71 (46.5)
2.62 (1.27-5.41)
0.0086
   amp(1q21)f
24/28 (85.7)
20/36 (55.6)
4.80 (1.38-16.69)
0.0104
   gain(1q21)/amp(1q21)g
65/87 (74.7)
53/107 (49.5)
3.01 (1.63-5.56)
0.0004
   Isolated gain(1q21)h
27/37 (73)
23/47 (48.9)
2.82 (1.12-7.10)
0.0268
   Isolated amp(1q21)i
16/17 (94.1)
13/23 (56.5)
12.31 (1.39-109.10)
0.0093
   1 revised HRCA
73/97 (75.3)
55/110 (50)
3.04 (1.68-5.51)
0.0002
   ≥2 revised HRCAs
22/33 (66.7)
18/38 (47.4)
2.22 (0.85-5.83)
0.1044
   Low (I)
92/116 (79.3)
55/114 (48.2)
4.11 (2.30-7.35)
-
   Low-intermediate (II)
84/111 (75.7)
49/106 (46.2)
3.62 (2.03-6.45)
-
   Intermediate-high (III)
79/108 (73.1)
55/115 (47.8)
2.97 (1.70-5.21)
-
   High (IV)
12/20 (60)
9/19 (47.4)
1.67 (0.47-5.93)
-
Sustained MRD negativity (10-5) lasting ≥12 months
   Standard riska
183/264 (69.3)
83/266 (31.2)
4.98 (3.45-7.20)
<0.0001
   High riskb
37/76 (48.7)
20/78 (25.6)
2.75 (1.40-5.42)
0.0032
   Revised standard riskc
115/174 (66.1)
53/167 (31.7)
4.19 (2.67-6.59)
<0.0001
   Revised high riskd
77/130 (59.2)
41/148 (27.7)
3.79 (2.30-6.26)
<0.0001
   gain(1q21)e
37/59 (62.7)
21/71 (29.6)
4 (1.92-8.34)
0.0002
   amp(1q21)f
20/28 (71.4)
10/36 (27.8)
6.50 (2.17-19.48)
0.0006
   gain(1q21)/amp(1q21)g
57/87 (65.5)
31/107 (29)
4.66 (2.54-8.56)
<0.0001
   Isolated gain(1q21)h
25/37 (67.6)
15/47 (31.9)
4.44 (1.77-11.17)
0.0012
   Isolated amp(1q21)i
15/17 (88.2)
6/23 (26.1)
21.25 (3.71-121.61)
0.0001
   1 revised HRCA
60/97 (61.9)
31/110 (28.2)
4.13 (2.31-7.41)
<0.0001
   ≥2 revised HRCAs
17/33 (51.5)
10/38 (26.3)
2.97 (1.10-8.04)
0.0303
   Low (I)
82/116 (70.7)
38/114 (33.3)
4.82 (2.76-8.43)
-
   Low-intermediate (II)
76/111 (68.5)
27/106 (25.5)
6.35 (3.51-11.49)
-
   Intermediate-high (III)
63/108 (58.3)
36/115 (31.3)
3.07 (1.77-5.32)
-
   High (IV)
9/20 (45)
4/19 (21.1)
3.07 (0.75-12.59)
-
MRD negativity (10-6) with ≥CR
   Standard riska
177/264 (67)
88/266 (33.1)
4.12 (2.87-5.91)
<0.0001
   High riskb
44/76 (57.9)
24/78 (30.8)
3.09 (1.60-6.00)
0.0007
   Revised standard riskc
115/174 (66.1)
56/167 (33.5)
3.86 (2.47-6.05)
<0.0001
   Revised high riskd
82/130 (63.1)
48/148 (32.4)
3.56 (2.17-5.84)
<0.0001
   gain(1q21)e
36/59 (61)
22/71 (31)
3.49 (1.69-7.20)
0.0006
   amp(1q21)f
21/28 (75)
15/36 (41.7)
4.20 (1.42-12.39)
0.0082
   gain(1q21)/amp(1q21)g
57/87 (65.5)
37/107 (34.6)
3.59 (1.98-6.52)
<0.0001
   Isolated gain(1q21)h
24/37 (64.9)
15/47 (31.9)
3.94 (1.58-9.80)
0.0028
   Isolated amp(1q21)i
14/17 (82.4)
9/23 (39.1)
7.26 (1.62-32.60)
0.0069
   1 revised HRCA
63/97 (64.9)
35/110 (31.8)
3.97 (2.23-7.08)
<0.0001
   ≥2 revised HRCAs
19/33 (57.6)
13/38 (34.2)
2.61 (1.00-6.83)
0.0500
   Low (I)
78/116 (67.2)
37/114 (32.5)
4.27 (2.46-7.41)
-
   Low-intermediate (II)
76/111 (68.5)
31/106 (29.2)
5.25 (2.94-9.38)
-
   Intermediate-high (III)
65/108 (60.2)
40/115 (34.8)
2.83 (1.65-4.88)
-
   High (IV)
12/20 (60)
6/19 (31.6)
3.25 (0.87-12.14)
-
Sustained MRD negativity (10-6) lasting ≥12 months
   Standard riska
137/264 (51.9)
54/266 (20.3)
4.24 (2.88-6.22)
<0.0001
   High riskb
23/76 (30.3)
11/78 (14.1)
2.64 (1.18-5.90)
0.0160
   Revised standard riskc
87/174 (50)
35/167 (21)
3.77 (2.34-6.07)
<0.0001
   Revised high riskd
55/130 (42.3)
23/148 (15.5)
3.99 (2.27-7.01)
<0.0001
   gain(1q21)e
25/59 (42.4)
11/71 (15.5)
4.01 (1.76-9.15)
0.0007
   amp(1q21)f
17/28 (60.7)
6/36 (16.7)
7.73 (2.42-24.63)
0.0003
   gain(1q21)/amp(1q21)g
42/87 (48.3)
17/107 (15.9)
4.94 (2.53-9.63)
<0.0001
   Isolated gain(1q21)h
19/37 (51.4)
9/47 (19.1)
4.46 (1.69-11.77)
0.0020
   Isolated amp(1q21)i
13/17 (76.5)
3/23 (13)
21.67 (4.15-113.02)
<0.0001
   1 revised HRCA
45/97 (46.4)
18/110 (16.4)
4.42 (2.32-8.42)
<0.0001
   ≥2 revised HRCAs
10/33 (30.3)
5/38 (13.2)
2.87 (0.87-9.51)
0.0797
   Low (I)
58/116 (50)
24/114 (21.1)
3.75 (2.10-6.69)
-
   Low-intermediate (II)
56/111 (50.5)
18/106 (17)
4.98 (2.65-9.34)
-
   Intermediate-high (III)
47/108 (43.5)
22/115 (19.1)
3.26 (1.79-5.94)
-
   High (IV)
7/20 (35)
2/19 (10.5)
4.58 (0.81-25.80)
-
Abbreviations: CI, confidence interval; ≥CR, complete response or better; D-VRd, DARZALEX FASPRO + bortezomib + lenalidomide + dexamethasone; HRCA, high-risk cytogenetic abnormality; MRD, minimal residual disease; OR, odds ratio; VRd, bortezomib + lenalidomide + dexamethasone.
aStandard risk (per protocol), defined as none of the following HRCAs: del(17p), t(4;14), t(14;16).
bHigh risk (per protocol), defined as 1 or more of the following HRCAs: del(17p), t(4;14), t(14;16).
cRevised standard risk, defined as none of the following HRCAs: del(17p), t(4;14), t(14;16), gain(1q21), amp(1q21).
dRevised high risk, defined as 1 or more of the following HRCAs: del(17p), t(4;14), t(14;16), gain(1q21), amp(1q21).
eDefined as the presence of 3 copies of chromosome 1q21, with or without other HRCAs.
fDefined as the presence of 4 or more copies of chromosome 1q21, with or without other HRCAs.
gDefined as the presence of gain(1q21) or amp(1q21), with or without other HRCAs.
hDefined as the presence of 3 copies of chromosome 1q21, without any other HRCAs.
iDefined as the presence of 4 or more copies of chromosome 1q21, without any other HRCAs.

Significance of CTC as a Biomarker in Transplant-Eligible NDMM Patients - Results From the PERSEUS Study

Bertamini et al (2024)4 presented results from the PERSEUS study that highlighted the significance of CTC as a biomarker in transplant-eligible NDMM patients.

Results

Patient Characteristics

Baseline Characteristics in Patients From the PERSEUS Study - CTC Subgroup4
Characteristic
D-VRd
(n=231)
VRd
(n=220)
P Value
ISS disease stage, %
   I
53.2
50.9
0.76
   II
31.6
35
0.76
   III
15.2
14.1
0.76
High LDH, n (%)
63 (27.3)
42 (19.1)
0.04
Cytogenetic high riska, n (%)
51 (22.1)
49 (22.3)
0.86
Abbreviations: CTC, circulating tumor cell; D-VRd, DARZALEX FASPRO + bortezomib + lenalidomide + dexamethasone; ISS, International Staging System; LDH, lactate dehydrogenase; VRd, bortezomib + lenalidomide + dexamethasone.aHigh-risk cytogenetics was defined by the presence of t(4;14), and/or t(14;16) and/or del17p by fluorescence in situ hybridization.
Efficacy
  • D-VRd vs VRd improved PFS in patients with high cytogenetic risk and low CTC levels. However, there was no improvement in the outcomes for patients with high cytogenetic risk combined with high CTC levels.4 The prognostic impact of CTC and other risk factors on PFS is presented in Table: Prognostic Impact of CTC and Other Risk Factors on PFS.
    • D-VRd vs VRd significantly improved PFS in patients with both high and low CTC levels (P<0.0001).4

Prognostic Impact of CTC and Other Risk Factors on PFS4
Risk Factor
HR (95% CI)
P Value
CTC (log10)
1.36 (1.15-1.6)
≤0.05
Cytogenetics high riska
2.71 (1.76-4.17)
≤0.05
ISS stage II
1.31 (0.81-2.12)
>0.05b
   ISS stage III
2.5 (1.45-4.32)
≤0.05
Elevated LDH
1.04 (0.65-1.68)
>0.05b
Abbreviations: CI, confidence interval; CTC, circulating tumor cell; HR, hazard ratio; ISS, International Staging System; LDH, lactate dehydrogenase; PFS, progression-free survival. aComparison with standard risk. High-risk cytogenetics is defined by the presence of t(4;14) and/or t(14;16) and/or del17p by fluorescence in situ hybridization. Absence of those is considered standard risk.bNot significant.

DARZALEX FASPRO in Combination with Bortezomib, Lenalidomide, and Dexamethasone

CEPHEUS (MMY3019; NCT03652064) is an ongoing, randomized, open-label, multicenter, phase 3 study evaluating the efficacy and safety of D-VRd vs VRd in patients with NDMM who are transplant ineligible (TIE) or for whom transplant is not planned as initial therapy (transplant deferred).5-7 Usmani et al (2025)7 reported results from the phase 3 CEPHEUS study.

Study Design/Methods

  • The trial has enrolled 395 patients from 13 different countries including the United States.5,6
  • Primary endpoint: Overall MRD-negativity (≥CR) rate at 10-5 sensitivity threshold.5,6
  • Key secondary endpoints: PFS, ORR, ≥VGPR, ≥CR, PFS2, OS, and sustained MRD-negativity (10-5) rate at ≥12 months.5,6

Results

Patient Characteristics

Baseline Demographics and Clinical Characteristics of the High-Risk ITT Population7
D-VRd (n=197)
VRd (n=198)
ISS disease stagea, n (%)
   I
68 (34.5)
68 (34.3)
   II
73 (37.1)
75 (37.9)
   III
56 (28.4)
55 (27.8)
Cytogenetic risk profileb, n (%)
   Standard risk
149 (75.6)
149 (75.3)
   High risk
25 (12.7)
27 (13.6)
   Indeterminatec
23 (11.7)
22 (11.1)
Abbreviations: D-VRd, DARZALEX FASPRO + bortezomib + lenalidomide + dexamethasone; ISS, International Staging System; ITT, intent-to-treat; VRd, bortezomib + lenalidomide + dexamethasone.
aBased on the combination of serum β2-microglobulin and albumin levels. Higher stages indicate more advanced disease. bAssessed by fluorescence in situ hybridization; high risk was defined as the presence of del(17p), t(4;14), and/or t(14;16). cIndeterminate includes patients with missing or unevaluable samples.
Efficacy

Prespecified Subgroup Analysis of Overall MRD-Negativity Rates (ISS Staging and Cytogenic Risk)7
Subgroup
D-VRd
VRd
OR (95% CI)
Number of Patients With MRD-Negativity/
Total Number of Patients (%)
ISS staging
   I
45/68 (66.2)
30/68 (44.1)
2.48 (1.24-4.96)
   II
47/73 (64.4)
29/75 (38.7)
2.87 (1.47-5.59)
   III
28/56 (50)
19/55 (34.5)
1.89 (0.88-4.07)
Cytogenetic risk
   High risk
12/25 (48)
15/27 (55.6)
0.74 (0.25-2.20)
   Standard risk
95/149 (63.8)
57/149 (38.3)
2.84 (1.78-4.54)
   Indeterminate
13/23 (56.5)
6/22 (27.3)
3.47 (0.99-12.09)
Abbreviations: CI, confidence interval; D-VRd, DARZALEX FASPRO + bortezomib + lenalidomide + dexamethasone; ISS, International Staging System; MRD, minimal residual disease; OR, odds ratio; VRd, bortezomib + lenalidomide + dexamethasone.

PFS in Prespecified Subgroups (ISS Staging and Cytogenic Risk)7
Subgroups
D-VRd
VRd
D-VRd
VRd
HR (95% CI)
Number of Disease Progression Events or Deaths/Total Number of Patients
Median PFS, months
ISS staging
   I
21/68
28/68
NE
60.6
0.66 (0.37-1.16)
   II
18/73
37/75
NE
45.6
0.36 (0.21-0.64)
   III
24/56
26/55
NE
49.2
0.84 (0.48-1.46)
Cytogenetic risk
   High risk
13/25
17/27
39.8
31.7
0.88 (0.42-1.84)
   Standard risk
43/149
60/149
NE
60.6
0.61 (0.41-0.91)
   Indeterminate
7/22
14/22
NE
47.9
0.33 (0.13-0.82)
Abbreviations: CI, confidence interval; D-VRd, DARZALEX FASPRO + bortezomib + lenalidomide + dexamethasone; HR, hazard ratio; ISS, International Staging System; NE, not estimated; PFS, progression-free survival; VRd, bortezomib + lenalidomide + dexamethasone.
Safety
  • The safety data were consistent with the established safety profile of each individual drug.7
    • Overall, deaths were reported in 51 vs 60 patients from the D-VRd vs VRd arm, respectively.
    • Grade 5 non-COVID-related TEAEs occurred in 10.7% vs 7.7% of patients from the D-VRd vs VRd arm, respectively.
    • Serious TEAEs occurred in 142 (72.1%) vs 131 (67.2%) of patients from the D-VRd vs VRd arm, respectively, with the most common serious TEAE being pneumonia (D-VRd, 13.7%; VRd, 12.8%).
    • Most grade 5 TEAEs occurred after the discontinuation of bortezomib (cycle 8) in both arms (D-VRd, 13%; VRd, 9%). When adjusted for treatment exposure, the rate of grade 5 TEAEs was similar between the two arms (D-VRd, 0.39 per 100 patient-months; VRd, 0.31 per 100 patient-months).

DARZALEX FASPRO in Combination with Lenalidomide

AURIGA (MMY3021; NCT03901963) is an ongoing, open-label, active-controlled, multicenter, randomized, phase 3 study evaluating the conversion rate to MRDnegativity after maintenance treatment with DR vs lenalidomide alone in patients with NDMM who are anti-CD 38 naïve, have ≥VGPR, and are MRD positive after ASCT.8-10 Badros et al (2024)8,9 reported primary results from the phase 3 AURIGA study.

Study Design/Methods

  • The trial enrolled 200 patients from the United States and Canada.8
  • Patients underwent 1:1 randomization to receive D-R (n=99) or R alone (n=101) across 28-day cycles.8,10
    • D-R: DARZALEX FASPRO 1800 mg SC QW in cycles 1-2, Q2W in cycles 3-6, Q4W in cycles 7+.
    • R: Lenalidomide 10 mg PO once a dayon days 1-28.
  • The treatment regimen continued until unacceptable toxicity, disease progression, consent withdrawal, or for a maximum of 36 cycles.8
  • Primary endpoint: MRD-negativity conversion rate from baseline by 12 months.8
    • MRD was assessed at 12, 18, 24, and 36 months.
    • If lenalidomide is well tolerated, the dose may be increased to 15 mg daily after cycle 3, at the investigator’s discretion.
  • Key secondary endpoints: Safety, PFS, overall MRD-negativity conversion rate, sustained MRD-negativity rate (≥6 months), response rates including CR/sCR as assessed by International Myeloma Working Group 2016 criteria, duration of ≥CR, OS, HRQoL changes based on patient reported outcomes.8

Results

Patient Characteristics
  • A total of 200 patients were randomized into the D-R maintenance (n=99) and R alone maintenance (n=101) arms.8
  • The median duration of treatment was 30.7 (range, 0.7-37.5) months vs 20.6
    (range, 0-37.7) months in the D-R vs R arm, respectively.8
  • The baseline demographics and disease characteristics of the ITT population are presented in Table: Baseline Demographics and Disease Characteristics of the High-Risk ITT Population.8
  • The median follow-up was 32.3 months.8
  • Patients in the D-R vs R arm received a median of 33 (range, 1-36) vs 21.5
    (range, 1-36) maintenance cycles, respectively.8
  • Overall, 85 of 96 (88.5%) vs 77 of 98 (78.6%) patients in the D-R vs R arm completed ≥12 maintenance cycles, respectively.8

Baseline Demographics and Disease Characteristics of the High-Risk ITT Population8
D-R (n=99)
R (n=101)
ISS disease stagea, n (%)
   I
40 (44)
38 (38.8)
   II
28 (30.8)
37 (37.8)
   III
23 (25.3)
23 (23.5)
Median induction cycles (range)b, n
5 (4-8)
5 (4-8)
Cytogenetic risk at diagnosisc, n (%)
   Standard risk
63 (68.5)
66 (74.2)
   High riskd
22 (23.9)
15 (16.9)
      del(17p)
13 (14.1)
3 (3.4)
      t(4;14)
10 (10.9)
12 (13.5)
      t(14;16)
6 (6.5)
7 (7.9)
   Unknown
7 (7.6)
8 (9)
Revised cytogenetic risk at diagnosise, n (%)
   Standard risk
52 (55.9)
53 (59.6)
   High riskf
32 (34.4)
30 (33.7)
      del(17p)
13 (14)
3 (3.4)
      t(4;14)
10 (10.8)
12 (13.5)
      t(14;16)
6 (6.5)
7 (7.9)
      t(14;20)
1 (1.1)
2 (2.2)
      gain/amp(1q21)
16 (17.2)
22 (24.7)
   Unknown
9 (9.7)
6 (6.7)
Abbreviations: D-R, DARZALEX FASPRO+lenalidomide; ISS, International Staging System; ITT, intent-to-treat; NR, not reported; R, lenalidomide.
aD-R vs R: n=91 vs n=98, respectively.
bD-R vs R: n=98 vs n=99, respectively.
cD-R vs R: n=92 vs n=89, respectively.
dHigh risk is defined as positive for any of del(17p), t(14;16), or t(4;14).
eD-R vs R: n=93 vs n=89, respectively.
fRevised high-risk cytogenetics is defined as ≥1 abnormality from del(17p), t(4;14), t(14;16), t(14;20), and gain/amp(1q21).
Efficacy

Subgroup Analysis of MRD-Negativity (10-5) Conversion Rate From Baseline to 12 Months of Maintenance Treatment in the High-Risk ITT Population8
Subgroup, n/N (%)
D-R (n=99)
R (n=101)
OR (95% CI)
ISS staging at diagnosis
   I
19/40 (47.5)
8/38 (21.1)
3.39 (1.25-9.19)
   II
13/28 (46.4)
7/37 (18.9)
3.71 (1.23-11.25)
   III
15/23 (65.2)
3/23 (13)
12.50 (2.83-55.25
Cytogenetic risk at diagnosis
   High riska
7/22 (31.8)
1/15 (6.7)
6.53 (0.71-60.05)
   Standard risk
35/63 (55.6)
14/66 (21.2)
4.64 (2.15-10.04)
Revised cytogenetic risk at diagnosis
   High riskb
14/32 (43.8)
4/30 (13.3)
5.06 (1.43-17.88)
   Standard risk
28/52 (53.8)
12/53 (22.6)
3.99 (1.72-9.26)
Abbreviations: CI, confidence interval; D-R, DARZALEX FASPRO+lenalidomide; ISS, International Staging System; ITT, intent-to-treat; MRD, minimal residual disease; OR, odds ratio; R, lenalidomide.
aHigh risk is defined as positive for any of the following abnormalities: del(17p), t(14;16), or t(4;14).
bRevised high-risk cytogenetics is defined as ≥1 abnormality from del(17p), t(4;14), t(14;16), t(14;20), and gain/amp(1q21).
Safety
  • Slightly higher occurrence rates of grade 3/4 cytopenias (54.2% vs 46.9%) and infections (18.8% vs 13.3%) were observed with D-R vs R.8
  • Serious AEs were reported in 30.2% vs 22.4% of patients in the D-R vs R arm, respectively.8
  • Any TEAEs occurred in 99% of patients in both the D-R and R arms.8
    • Grade 3/4 TEAEs occurred in 74% and 67.3% of patients in the D-R and R arms, respectively.
  • During the analysis, 32 of 96 (33.3%) vs 47 of 98 (48%) patients in the D-R vs R arm, respectively, discontinued ≥1 component of the study treatment.8

Clinically Relevant Subgroup Analysis - Phase 3 AURIGA Study

Foster et al (2024)12  presented (at the 66th ASH Annual Meeting) a post hoc analysis of the phase 3 AURIGA study that evaluated clinically relevant subgroups 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 high cytogenetic risk per standard, revised, and IMS 2024 high-risk criteria.

Results

Demographics and Disease Characteristics

Demographics and Disease Characteristics of the ITT Population12
D-R (n=99)
R (n=101)
ISS disease stage, n (%)
   n
91
98
   I
40 (44)
38 (38.8)
   II
28 (30.8)
37 (37.8)
   III
23 (25.3)
23 (23.5)
Cytogenetic risk at diagnosis per standard definitiona,b, n (%)
   n
92
89
   Standard-risk
63 (68.5)
66 (74.2)
   High-risk
22 (23.9)
15 (16.9)
   Unknown
7 (7.6)
8 (9)
Cytogenetic risk at diagnosis per revised definitionc, n (%)
   n
93
89
   Revised standard risk (0 HRCAs)
52 (55.9)
53 (59.6)
   Revised high-risk (≥1 HRCA)
32 (34.4)
30 (33.7)
      1 HRCA
21 (22.6)
20 (22.5)
      ≥2 HRCAs
11 (11.8)
10 (11.2)
      Gain/amp(1q21)
16 (17.2)
22 (24.7)
      Isolated gain/amp(1q21)
10 (10.8)
15 (16.9)
   Unknown
9 (9.7)
6 (6.7)
Cytogenetic risk per modified IMS 2024 criteriad, n (%)
   n
93
90
   Modified IMS 2024 standard-risk
67 (72)
68 (75.6)
   Modified IMS 2024 high-risk
17 (18.3)
8 (8.9)
      ≥20% del(17p)
10 (10.8)
2 (2.2)
      t(4;14)/(14;16)/(14;20) + gain/amp(1q21) and/or del(1p32)
5 (5.4)
6 (6.7)
      Del(1p32) + gain/amp(1q21)
4 (4.3)
0 (0)
   Unknown
9 (9.7)
14 (15.6)
Abbreviations: D-R, DARZALEX FASPRO + lenalidomide; HRCA, high-risk cytogenetic abnormalities; IMS, International Myeloma Society; IMWG, International Myeloma Working Group; ISS, International Staging System; ITT, intention-to-treat; R, lenalidomide.
aHigh-risk cytogenetics per the standard definition are defined as ≥1 abnormality including del(17p), t(4;14), or t(14;16). bThe imbalance in cytogenetic risk between arms, especially a higher number of patients with del(17p) for patients randomized to the D-R arm, was since some assessments were made on cytogenetic data at screening and some on cytogenetic data at the time of diagnosis.cRevised high-risk cytogenetics per the revised definition are defined as ≥1 abnormality including del(17p), t(4;14), t(14;16), t(14;20), or gain/amp(1q21).dHigh risk per the modified IMS 2024 criteria is defined as the presence of ≥20% del(17p); or the association of ≥2 of the following: t(4;14) or t(14;16) or t(14;20); gain/amp(1q21); or del(1p32) [in the AURIGA study, data were not available on TP53 mutations, baseline ß2M, and creatinine levels and differentiation between monoallelic versus biallelic del(1p32)].
Efficacy
  • A subgroup analysis of MRD-negativity (10-5 sensitivity) conversion rates by 12 months of maintenance showed improvement for D-R vs R regardless of age, race, ISS disease stage, or response upon study entry.12 The results are summarized in Table: Subgroup Analysis of MRD-negativity (10-5 Sensitivity) Conversion Ratea from Baseline to 12 Months of Maintenance Treatment.
  • D-R vs R improved MRD-negativity (10-5 sensitivity) conversion rates by 12 months of maintenance in patients with ultra-high-risk disease and standard-risk disease.12 The results are summarized in Table: Subgroup Analysis of MRD-negativity (10-5 Sensitivity) Conversion Ratea from Baseline to 12 Months of Maintenance Treatment by Risk Status.
  • D-R vs R improved MRD-negative (10-5 sensitivity) conversion rate by 12 months of maintenance, among patients with modified IMS 2024 high-risk disease.12 The results are summarized in Table: Subgroup Analysis of MRD-negativity (10-5 Sensitivity) Conversion Rate from Baseline to 12 Months of Maintenance Treatment by Modified IMS 2024 Criteria.
  • D-R vs R maintenance showed a PFS benefit across various definitions of high cytogenetic risk, in addition to patients with standard-risk disease. The HR and 95% CI values presented below are derived from a Cox proportional hazards model with treatment as the sole explanatory variable. A HR <1 indicates an advantage for D-R maintenance.12 
    • Standard criteria: High-risk cytogenetics was defined as ≥1 abnormality including del(17p), t(4;14), or t(14;16).
      • Standard-risk: HR, 0.59; 95% CI, 0.23-1.49.
      • High-risk: HR, 0.60; 95% CI, 0.21-1.70.
    • Revised criteria: Revised high-risk cytogenetics was defined as ≥1 abnormality including del(17p), t(4;14), t(14;16), t(14;20), or gain/amp(1q21).
      • Revised standard-risk: HR, 0.69; 95% CI, 0.24-1.95.
      • Revised high-risk: HR, 0.53; 95% CI, 0.21-1.31.
    • Modified IMS 2024 criteria: High risk per the modified IMS 2024 criteria was defined as the presence of ≥20% del(17p); or the association of ≥2 of the following: t(4;14) or t(14;16) or t(14;20); gain/amp(1q21); or del(1p32). In the AURIGA study, data were not available on TP53 mutations, baseline ß2M, and creatinine levels and differentiation between monoallelic versus biallelic del(1p32).
      • Modified IMS 2024 standard-risk: HR, 0.42; 95% CI, 0.16-1.07.
      • Modified IMS 2024 high-risk: HR, 0.45; 95% CI, 0.13-1.53.
  • D-R vs R maintenance demonstrated a PFS benefit regardless of the number of HRCAs. The HRCA numbers presented below were defined as number of abnormalities from del(17p), t(4;14), t(14;16), t(14;20), or gain/amp(1q21). Cytogenetic results at diagnosis (based on case report forms collected data from local laboratories) were used in the analysis. The HR and 95% CI were derived from a Cox proportional hazards model with treatment as the sole explanatory variable. A HR <1 indicates an advantage for D-R maintenance.12
    • 0 HRCAs: HR, 0.69; 95% CI, 0.24-1.95.
    • 1 HRCAs: HR, 0.36; 95% CI, 0.09-1.45.
    • ≥2 HRCAs: HR, 0.61; 95% CI, 0.17-2.25.
  • D-R vs R maintenance improved PFS among patients with gain/amp(1q21), irrespective of other HRCAs (HR, 0.46; 95% CI, 0.13-1.59).12

Subgroup Analysis of MRD-negativity (10-5 Sensitivity) Conversion Ratea from Baseline to 12 Months of Maintenance Treatment12
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)
Race
   White
31/67 (46.3)
14/68 (20.6)
3.32 (1.55-7.10)
   Black
12/20 (60)
4/24 (16.7)
7.50 (1.85-30.34)
ISS staging at diagnosis
   I
19/40 (47.5)
8/38 (21.1)
3.39 (1.25-9.19)
   II
13/28 (46.4)
7/37 (18.9)
3.71 (1.23-11.25)
   III
15/23 (65.2)
3/23 (13)
12.50 (2.83-55.25)
Baseline response statusd
   <CR
27/71 (38)
11/71 (15.5)
3.35 (1.50-7.46)
   ≥CR
23/28 (82.1)
8/30 (26.7)
12.65 (3.58-44.64)
Abbreviations: CI, confidence interval; CR, complete response; D-R, DARZALEX FASPRO + lenalidomide; IMWG, International Myeloma Working Group; ISS, International Staging System; 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.dResponse status upon entering the study as assessed by IMWG 2016 criteria.

Subgroup Analysis of MRD-negativity (10-5 Sensitivity) Conversion Ratea from Baseline to 12 Months of Maintenance Treatment by Risk Status12
Subgroup, n/N (%)
D-R
R
ORb (95% CI)
Cytogenetic risk at diagnosis
   Standard risk
35/63 (55.6)
14/66 (21.2)
4.64 (2.15-10.04)
   High riskc
7/22 (31.8)
1/15 (6.7)
6.53 (0.71-60.05)
Revised cytogenetic risk at diagnosis
   Revised standard risk (0 HRCAs)
28/52 (53.8)
12/53 (22.6)
3.99 (1.72-9.26)
   Revised high-risk (≥1 HRCA)d
14/32 (43.8)
4/30 (13.3)
5.06 (1.43-17.88)
   1 HRCA
8/21 (38.1)
4/20 (20)
2.46 (0.60-10.04)
   ≥2 HRCAs
6/11 (54.5)
0/10 (0)
NE (NE-NE)e
   Gain/amp(1q21)
10/16 (62.5)
3/22 (13.6)
10.56 (2.17-51.42)
   Isolated gain/amp(1q21)
7/10 (70)
3/15 (20)
9.33 (1.46-59.48)
Abbreviations: CI, confidence interval; D-R, DARZALEX FASPRO + lenalidomide; HRCA, high-risk cytogenetic abnormalities; MRD, minimal residual disease; NE, not estimable; 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 unstratified tables is used. An OR >1 indicates an advantage for D-R.cHigh-risk cytogenetics per the standard definition are defined as ≥1 abnormality including del(17p), t(4;14), or t(14;16). dRevised high-risk cytogenetics per the revised definition are defined as ≥1 abnormality including del(17p), t(4;14), t(14;16), t(14;20), or gain/amp(1q21). eNot evaluable because no patient in the R group had MRD-negative conversion.

Subgroup Analysis of MRD-negativity (10-5 Sensitivity) Conversion Rate from Baseline to 12 Months of Maintenance Treatment by Modified IMS 2024 Criteriaa,b,c,12
Subgroup, n/N (%)
D-R
R
Modified IMS 2024 standard-risk
34/67 (50.7)
16/68 (23.5)
Modified IMS 2024 high-risk
7/17 (41.2)
0/8 (0)
≥20% del(17p)
2/10 (20)
0/2 (0)
t(4;14)/(14;16)/(14;20) + gain/amp(1q21) and/or del(1p32)
2/5 (40)
0/6 (0)
Del(1p21) + gain/amp(1q21)
3/4 (75)
0/0 (0)
Abbreviations: D-R, DARZALEX FASPRO + lenalidomide; IMS, International Myeloma Society; MRD, minimal residual disease; R, lenalidomide.
aHigh risk per the modified IMS 2024 criteria is defined as the presence of ≥20% del(17p), or the association of ≥2 of the following: t(4;14) or t(14;16) or t(14;20); gain/amp(1q21); or del(1p32) [in the AURIGA study, data were not available on TP53 mutations, baseline ß2M, and creatinine levels and differentiation between monoallelic versus biallelic del(1p32)]. bDefined 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. cDefined as the proportion of patients who achieved MRD-negative status any time after the date of randomization.

CLINICAL STUDIES – RELAPSED/REFRACTORY MULTIPLE MYELOMA

Daratumumab in Combination with Pomalidomide and Dexamethasone

APOLLO (MMY3013; NCT03180736) is a randomized, open-label, multicenter, phase 3 study evaluating the safety and efficacy of D-Pd vs Pd with RRMM who received ≥1 prior treatment with both lenalidomide and a PI (N=304).13,14 Sonneveld et al (2021)15 presented updated efficacy and safety data at a median follow-up of 30.7 months. Results in the high-risk cytogenetic subgroup are summarized below.

Study Design/Methods

  • Primary endpoint: PFS
  • Secondary endpoints: ORR, ≥VGPR, ≥CR, MRD-negativity, OS, TTR, DOR, time to next therapy, safety, and health-related quality of life

Results


Key Baseline Characteristics in the ISS and Cytogenetic Profile Subgroups (APOLLO)15

D-Pd (n=151)
Pd (n=153)
ISS disease stagea, n (%)
   I
68 (45)
69 (45.1)
   II
50 (33.1)
51 (33.3)
   III
33 (21.9)
33 (21.6)
Cytogenetic profileb
   N
103
108
   Standard-risk, n (%)
64 (62.1)
73 (67.6)
   High-risk, n (%)
39 (37.9)
35 (32.4)
Abbreviations: D-Pd, DARZALEX FASPRO + pomalidomide + dexamethasone; ISS, International Staging System; Pd, pomalidomide + dexamethasone.
aBased on the combination of serum β2-microglobulin and albumin.
bBased on fluorescence in situ hybridization. Patients with high cytogenetic risk had a del17p, t(4;14), or t(14;16) abnormality. Patients with standard cytogenetic risk had an absence of high-risk cytogenetic abnormalities.
Efficacy

PFS in the ISS Staging and Cytogenetic Profile Subgroups (APOLLO)15
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)
ISS disease staging
   I
40/68
50/69
19.32
10.12
0.66 (0.43-1)
   II
36/50
41/51
12.25
6.08
0.52 (0.33-0.82)
   III
24/33
29/33
6.05
5.03
0.67 (0.39-1.17)
Revised ISS disease staging
   I
14/26
19/25
17.54
11.17
0.61 (0.30-1.22)
   II
54/74
72/88
12.25
6.47
0.58 (0.41-0.83)
   III
16/19
12/14
2.83
3.38
1.17 (0.55-2.51)
Cytogenetic risk at study entry
   High-risk
32/39
28/35
5.78
3.98
0.88 (0.53-1.46)
   Standard-risk
39/64
58/73
17.54
8.54
0.56 (0.37-0.84)
Abbreviations: CI, confidence interval; D-Pd, DARZALEX FASPRO + pomalidomide + dexamethasone; HR, hazard ratio; ISS, International Staging System; Pd, pomalidomide + dexamethasone; PFS, progression-free survival.
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.
Safety
  • Grade ≥3 TEAEs were reported in 133 (89.3%) D-Pd-treated patients vs 123 (82%) Pd-treated patients.
  • Grade 3/4 TEAEs occurring in ≥15% of patients in the D-Pd vs Pd arm were neutropenia (69.1% vs 50.7%), infections (31.5% vs 23.3%), anemia (18.1% vs 21.3%), thrombocytopenia (18.1% vs 18.7%), and leukopenia (16.8% vs 4.7%).
  • Treatment discontinuation due to TEAEs was low among both treatment groups (D-Pd, 2%; Pd, 4%).

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 17 April 2025.

 

References

Show
1 Sonneveld P, Dimopoulos MA, Boccadoro M, et al. Daratumumab, bortezomib, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2024;390(4)(4):301-313.  
2 Dimopoulos MA, Sonneveld P, Rodriguez-Otero P, et al. Daratumumab (DARA)/ bortezomib/lenalidomide/ dexamethasone (D-VRd) with D-R maintenance in transplant-eligible (TE) newly diagnosed multiple myeloma (NDMM): analysis of PERSEUS based on cytogenetic risk. Poster presented at: The European Hematology Association (EHA) Hybrid Congress; June 13-16, 2024; Madrid, Spain.  
3 Dimopoulos MA, Sonneveld P, Rodriguez-Otero P, et al. Daratumumab (DARA SC)/bortezomib/lenalidomide/dexamethasone (D-VRd) with D-R maintenance in transplant-eligible (TE) newly diagnosed myeloma (NDMM): PERSEUS cytogenetic risk analysis. Oral Presentation presented at: 21st International Myeloma Society (IMS) Annual Meeting; September 25-28, 2024; Rio de Janeiro, Brazil.  
4 Bertamini L, Fokkema C, Rodriguez-Otero P, et al. Circulating tumor cells as a biomarker to identify high-risk transplant-eligible myeloma patients treated with bortezomib, lenalidomide, and dexamethasone with or without daratumumab during induction/consolidation, and lenalidomide with or without daratumumab during maintenance: results from the PERSEUS study. Oral Presentation presented at: The 66th American Society of Hematology (ASH) Annual Meeting and Exposition; December 7-10, 2024; San Diego, CA.  
5 Zweegman S, Usmani S, Chastian K, et al. Bortezomib, lenalidomide, and dexamethasone (VRd) ± daratumumab in patients with newly diagnosed multiple myeloma for whom transplant is not planned as initial therapy: a multicenter, randomized, phase 3 study (CEPHEUS). Poster presented at: The Annual Meeting of the American Society of Clinical Oncology (ASCO). May 31-June 4, 2019; Chicago, IL.  
6 Janssen Research & Development, LLC. A study comparing daratumumab, velcade (bortezomib), lenalidomide, and dexamethasone (D-VRd) with velcade, lenalidomide, and dexamethasone (VRd) in participants with untreated multiple myeloma and for whom hematopoietic stem cell transplant is not planned as initial therapy. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [cited 2025 April 03]. Available from: https://clinicaltrials.gov/ct2/show/NCT03652064 NML Identifier: NCT03652064.  
7 Usmani SZ, Facon T, Hungria V. Daratumumab plus bortezomib, lenalidomide and dexamethasone for transplant-ineligible or transplant-deferred newly diagnosed multiple myeloma: the randomized phase 3 CEPHEUS study. doi.org/10.1038/s41591-024-03485-7. Nat Med. 2025.  
8 Badros A, Foster L, Anderson LD Jr, et al. Daratumumab with lenalidomide as maintenance after transplant in newly diagnosed multiple myeloma: the AURIGA study. Blood. 2025;145(3):300-310.  
9 Badros A, Foster L, Anderson LD Jr, et al. Subcutaneous daratumumab plus lenalidomide versus lenalidomide alone as maintenance therapy in newly diagnosed multiple myeloma after transplant: primary results from the phase 3 AURIGA study. Oral Presentation presented at: The 21st International Myeloma Society (IMS) Annual Meeting; September 25-28, 2024; Rio de Janeiro, Brazil.  
10 Janssen Research & Development, LLC. A study of daratumumab plus lenalidomide versus lenalidomide alone as maintenance treatment in participants with newly diagnosed multiple myeloma who are minimal residual disease positive after frontline autologous stem cell transplant (AURIGA). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [cited 2025 April 03]. Available from: https://www.clinicaltrials.gov/ct2/show/NCT03901963 NLM Identifier: NCT03901963.  
11 Badros A, Foster L, Anderson LD Jr, et al. Supplement to: Daratumumab with lenalidomide as maintenance after transplant in newly diagnosed multiple myeloma: the AURIGA study. Blood. 2025;145(3):300-310.  
12 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.  
13 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.  
14 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.  
15 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.  
16 Dimopoulos MA, Evangelos T, Delimpasi S, 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.