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(daratumumab and hyaluronidase-fihj)

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DARZALEX FASPRO® (daratumumab and hyaluronidase-fihj)

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Use of DARZALEX FASPRO in Underweight or Obese Patients

Last Updated: 04/17/2025

Click on the following links to related sections within the document: COLUMBA and ANDROMEDA.
Abbreviations: AE, adverse event; AL, immunoglobulin light chain; C, cyclophosphamide; CI, confidence interval; CR, complete response; d, dexamethasone; DARA SC, daratumumab and hyaluronidase; DARA IV, daratumumab; IRR, infusion-related reaction; IV, intravenous; NR, not reached ORR, overall response rate; OS, overall survival; PK, pharmacokinetics; RRMM, relapsed or refractory multiple myeloma; SC, subcutaneous; TEAE, treatment-emergent adverse event; V, bortezomib.
aData on file (2025).1 bMateos (2020).2 cUsmani (2022).3 dUsmani (2022 suppl).4 eKastritis (2021).5 fComenzo (2021).6 gData on file (2020).7

PRODUCT LABELING

CLINICAL DATA

DARZALEX vs DARZALEX FASPRO Non-Inferiority Study in Patients with RRMM

COLUMBA (MMY3012; NCT03277105) is an ongoing, phase 3, randomized, open-label, multicenter, non-inferiority study evaluating the efficacy, PK, and IRRs of DARZALEX vs DARZALEX FASPRO in patients with RRMM.2,3 Mateos et al (2020)2 reported primary analysis of efficacy and safety results of the COLUMBA study after a median follow-up of 7.5 months. Usmani et al (2022)3 reported final analysis of efficacy and safety results of the COLUMBA study after a median follow-up of 29.3 months.

Study Design/Methods

  • The trial enrolled 522 patients from 19 countries, including the United States.
  • Patients will be randomized to receive either DARZALEX (n=259) or DARZALEX FASPRO (n=263) over 4-week treatment cycles:
    • DARZALEX: daratumumab 16 mg/kg IV infusion weekly for cycles 1 and 2, every 2 weeks for cycles 3-6, and every 4 weeks thereafter, or
    • DARZALEX FASPRO: daratumumab 1800 mg (flat dose) in combination with recombinant human hyaluronidase PH20 (rHuPH20) 2000 units/mL administered by manual push (15 mL) over 3-5 minutes at alternating left/right abdominal sites, weekly for cycles 1 and 2, every 2 weeks for cycles 3-6, and every 4 weeks thereafter.
  • Treatment will continue until disease progression or unacceptable toxicity.
  • Pre-infusion medications to be administered are acetaminophen 650-1000 mg, diphenhydramine 25-50 mg, methylprednisolone 60-100 mg, and montelukast 10 mg (optional).
  • Post-infusion medications to be administered are methylprednisolone 20 mg, and diphenhydramine, short-acting β2 adrenergic receptor agonist, and control medications for lung disease recommended for patients with higher risk of respiratory complications.
  • Co-primary endpoints: ORR and maximum Ctrough (serum pre-dose daratumumab concentration on cycle 3 day 1)

Results


Key Baseline Demographics and Clinical Characteristics (Intention-to-Treat)a, 2
Characteristic
DARZALEX (n=259)
DARZALEX FASPRO (n=263)
Body weight, n (%)
Median (range), kg
73 (28.6-138)
72.4 (39-130)
≤65 kg
92 (36)
94 (36)
>65-85 kg
105 (41)
102 (39)
>85 kg
61 (24)
66 (25)
aIntention-to-treat population defined as all randomized patients.
Treatment Exposure and Patient Disposition
  • In patients who received ≥1 treatment dose, 90% in the DARZALEX FASPRO and 91.1% in the DARZALEX arm discontinued study treatment. Progressive disease (DARZALEX FASPRO, 75.4%; DARZALEX, 75.6%) was the most common reason for treatment discontinuation as present in Table: Treatment Exposure and Patient Disposition.
  • At the clinical cutoff for the final analysis, 26 (10%) vs 23 (8.9%) patients continued treatment in the DARZALEX FASPRO vs DARZALEX arms, respectively.

Treatment Exposure and Patient Disposition3
Characteristic
DARZALEX
(n=259)
DARZALEX FASPRO (n=263)
Median duration of treatment, months (range)
6.1 (0.03-33.4)
5.6 (0.03-34.6)
Patients who discontinued study treatment, n (%)
235 (91.1)
234 (90)
Median number of treatment cycles, range
7.5 (1-37)
7 (1-38)
Median RDI, % (range)
99.9 (1.3-106.2)
100 (25-100)
Reason for discontinuation, n (%)
   Progressive disease
195 (75.6)
196 (75.4)
Abbreviation: RDI, relative dose density.
Efficacy

Efficacy Endpoints by Baseline Body Weight Subgroupsa, 3,4
Characteristic
DARZALEX
(n=259)
DARZALEX FASPRO
(n=263)
≤65 kg (n=92)
>65-85 kg (n=105)
>85 kg (n=61)
≤65 kg (n=94)
>65-85 kg (n=102)
>85 kg (n=66)
ORR, n (%)
39 (42.4)
44 (41.9)
20 (32.8)
46 (48.9)
38 (37.3)
31 (47)
OS, median (95% CI), months
23.8
(20.5-NE)
NR (19.9-NE)
23.0 (16.9-NE)
NR
(18.5-NE)
28.1
(18.4-NE)
28.8 (22.8-NE)
Abbreviations: CI, confidence interval; NE, not estimable; NR, not reached; ORR, overall response rate; OS, overall survival.
Safety
  • With the longer follow-up, the rates of any grade and grade 3/4 TEAEs across all body weight subgroups (≤65 Kg, >65-85 kg, and >85 kg) were similar to the overall population. See Table: Most Common Grade 3/4 (≥5%) TEAEs Across Body Weight Subgroups.
    • In ≤65 kg subgroup, incidence of neutropenia was higher in the DARZALEX FASPRO vs DARZALEX arms for any grade TEAEs (25.8% vs 14.1%) and grade 3/4 TEAEs (20.4% vs 8.7%), respectively.
    • In the ≤65 kg subgroup, there was no increase in the incidence of infections for any grade TEAEs (DARZALEX FASPRO, 57.0%; DARZALEX, 57.6%), and grade 3/4 TEAEs (DARZALEX FASPRO, 10.8%; DARZALEX, 17.4%).
    • In the ≤65 kg subgroup, incidence of serious infections was 10.8% vs 18.5% in the DARZALEX FASPRO vs DARZALEX arms, respectively.

Most Common Grade 3/4 (≥5%) TEAEs Across Body Weight Subgroups3,4
TEAEs, n (%)
DARZALEX
DARZALEX FASPRO
≤65 kg (n=92)
>65-85 kg (n=105)
>85 kg (n=61)
≤65 kg (n=93)
>65-85 kg (n=102)
>85 kg (n=65)
Any event
52 (56.5)
54 (51.4)
30 (49.2)
49 (52.7)
51 (50.0)
32 (49.2)
Hematologic
   Anemia
15 (16.3)
16 (15.2)
8 (13.1)
14 (15.1)
15 (14.7)
7 (10.8)
   Thrombocytopenia
12 (13.0)
14 (13.3)
9 (14.8)
15 (16.1)
16 (15.7)
6 (9.2)
   Neutropenia
8 (8.7)
9 (8.6)
3 (4.9)
19 (20.4)
10 (9.8)
5 (7.7)
   Lymphopenia
6 (6.5)
7 (6.7)
3 (4.9)
9 (9.7)
3 (2.9)
2 (3.1)
Non-hematologic
   Pneumonia
7 (7.6)
3 (2.9)
3 (4.9)
5 (5.4)
1 (1.0)
7 (10.8)
   Hypertension
4 (4.3)
6 (5.7)
5 (8.2)
4 (4.3)
4 (3.9)
3 (4.6)
   Back pain
3 (3.3)
2 (1.9)
2 (3.3)
1 (1.1)
2 (2.0)
2 (3.1)
   Fatigue
1 (1.1)
2 (1.9)
0
1 (1.1)
2 (2.0)
0
   Nausea
1 (1.1)
1 (1.0)
0
0
0
0
   Diarrhea
1 (1.1)
0
0
2 (2.2)
0
0
   Upper respiratory  
   infection
0
2 (1.9)
0
0
0
0
   Pyrexia
0
1 (1.0)
1 (1.6)
1 (1.1)
0
1 (1.5)
   Arthralgia
0
0
0
0
1 (1.0)
0
   Nasopharyngitis
0
0
0
0
0
1 (1.5)
   Cough
0
0
0
1 (1.1)
1 (1.0)
0
   Chills
0
0
2 (3.3)
0
1 (1.0)
0
   Dyspnea
0
0
2 (3.3)
1 (1.1)
0
1 (1.5)
Abbreviation: TEAE, treatment-emergent adverse event.

DARZALEX FASPRO in Combination with Bortezomib, Cyclophosphamide, and Dexamethasone in Patients with Newly Diagnosed Systemic AL Amyloidosis

ANDROMEDA (AMY3001; NCT03201965) is an ongoing, prospective, randomized, active-controlled, multicenter, phase 3 study evaluating the efficacy and safety of D-VCd compared to VCd alone in newly diagnosed patients with systemic AL amyloidosis.5 Kastritis et al (2021)5 reported primary results of this study. Kastritis et al (2021)8  presented updated efficacy and safety results of the ANDROMEDA study, with a median follow-up of 20.3 months. Comenzo et al (2021)6 presented updated efficacy and safety results of the ANDROMEDA study, with a median follow-up of 25.8 months. Kastritis et al (2024)9 presented results of the final analysis of major organ deterioration (MOD) progression-free survival (PFS) and overall survival (OS) from the phase 3 ANDROMEDA study with a median follow-up of 61.4 months.

Study Design/Methods

ANDROMEDA Study Design5

Abbreviations: AEs, adverse events; AL, immunoglobin light chain; BMI, body mass index; CR, complete response; Dara, daratumumab; DM, diabetes mellitus; eGFR, estimated glomerular filtration rate; IV, intravenous; MOD-PFS, major organ deterioration progression-free survival; MM, multiple myeloma; OS, overall survival; PFS, progression-free survival; PO, orally; rHuPH20, recombinant human hyaluronidase enzyme PH20; SC, subcutaneous; QW, every week; Q2W, every 2 weeks; Q4W, every 4 weeks; VCd, bortezomib, cyclophosphamide, dexamethasone.
aEach cycle was 28 days each.
bDivided into 20 mg as premedication and 20 mg on the day after Dara dosing for patients in the VCd plus Dara and hyaluronidase SC arm.
cBMI <18.5 kg/m2.
dComposite of endpoints occurring from randomization to whichever occurs first: death, clinical manifestation of cardiac or renal failure, or hematologic progressive disease.

Results - Body Weight Subgroup Analysis

Efficacy
  • Complete hematologic response rates across body weight categories were consistent (≤65 kg, 54.8%; >65 kg to ≤85 kg, 52.1%; >85 kg, 54.1%) with the overall population (53.3%) of subjects in the D-VCd arm.7
  • There was considerable overlap in Ctrough values at PK sampling timepoints across body weight subgroups. However, as expected for a monoclonal antibody administered SC by flat dose, higher serum daratumumab concentrations were observed in subjects with lower body weight and lower serum daratumumab concentrations were observed in subjects with higher body weight at all PK sampling timepoints with measurable serum daratumumab concentrations.7
  • For the lowest body weight subgroup (≤65 kg), the mean maximum Ctrough of daratumumab at cycle 3 day 1 was approximately 15% higher compared with that of the total PK-evaluable analysis set.7
  • For the highest body weight subgroup (>85 kg), the mean maximum Ctrough of daratumumab at cycle 3 day 1 was approximately 17% lower compared with that of the total PK-evaluable analysis set.7
  • For the middle body weight subgroup (>65 to 85 kg), the mean concentration of daratumumab at cycle 3 day 1 was comparable to that of the total PK-evaluable analysis set.7
  • The inter-subject variability (%CV) for serum daratumumab concentrations in each body weight subgroup was within the range of variability observed for the total PK-evaluable analysis set following D-VCd treatment. Trough serum daratumumab concentrations at other timepoints with measurable serum daratumumab concentrations showed a similar pattern as for cycle 3 day 1. The flat-dose administration of DARZALEX FASPRO achieved adequate exposure for all body weight subgroups in the D-VCd arm.7
Safety

Summary of TEAEs Across Body Weight Subgroups-ANDROMEDA7
Characteristic, %
D-VCd, n (%)
VCd, n (%)
≤65 kg
<65-85 kg
≥85 kg
Total
≤65 kg
<65-85 kg
≥85 kg
Total
Analysis set: safety
62
95
36
193
72
71
45
188
Any TEAE
61 (98.4)
93 (97.9)
35 (97.2)
189 (97.9)
72 (100)
69 (97.2)
44 (97.8)
185 (98.4)
Maximum toxicity grade
  Grade 1
2 (3.2)
5 (5.3)
1 (2.8)
8 (4.1)
1 (1.4)
7 (9.9)
2 (4.4)
10 (5.3)
  Grade 2
27 (43.5)
26 (27.4)
9 (25.0)
62 (32.1)
26 (36.1)
20 (28.2)
15 (33.3)
61 (32.4)
  Grade 3
16 (25.8)
46 (48.4)
17 (47.2)
79 (40.9)
28 (38.9)
32 (45.1)
23 (51.1)
83 (44.1)
  Grade 4
7 (11.3)
7 (7.4)
4 (11.1)
18 (9.3)
9 (12.5)
6 (8.5)
1 (2.2)
16 (8.5)
  Grade 5
9 (14.5)
9 (9.5)
4 (11.1)
22 (11.4)
8 (11.1)
4 (5.6)
3 (6.7)
15 (8.0)
Any serious TEAE
25 (40.3)
44 (46.3)
14 (38.9)
83 (43.0)
31 (43.1)
22 (31.0)
15 (33.3)
68 (36.2)
TEAE leading to discontinuation of study
treatmentb
1 (1.6)
6 (6.3)
1 (2.8)
8 (4.1)
3 (4.2)
2 (2.8)
3 (6.7)
8 (4.3)
Abbreviations: D-VCd, DARZALEX FASPRO + cyclophosphamide + bortezomib + dexamethasone; TEAE, treatment-emergent adverse event; VCd, cyclophosphamide + bortezomib + dexamethasone.
aTEAEs related to at least 1 of the 4 components of study treatment: cyclophosphamide, bortezomib, dexamethasone, and daratumumab.
bThis table includes adverse events leading to discontinuation of all study treatment due to an adverse event on the end-of-treatment case report form page.
Note: Toxicity grade is defined according to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.03.

18-month Follow-up Update on Efficacy and Safety Results of ANDROMEDA

Comenzo et al (2021)6 presented updated efficacy and safety results of the ANDROMEDA study, with a median follow-up of 25.8 months.

Results - Body Weight Subgroup Analysis

Efficacy

Hematologic Complete Response by Baseline Weight6
Subgroup
D-VCd
n/N (%)
VCd
n/N (%)
Odds Ratio (95% CI)
Overall
116/195 (59.5)
37/193 (19.2)
6.0 (3.8-9.6)
Baseline weight
≤65 kg
41/62 (66.1)
10/74 (13.5)
12.5 (5.4-29.2)
>65-85 kg
54/96 (55.3)
14/74 (18.9)
5.5 (2.7-11.2)
>85 kg
21/37 (56.8)
13/45 (28.9)
3.2 (1.3-8.1)
Abbreviations: CI, confidence interval; D-VCd, DARZALEX FASPRO + cyclophosphamide + bortezomib + dexamethasone; VCd, bortezomib + cyclophosphamide + dexamethasone.
Safety
  • Safety results were not stratified by baseline weight.

Final Analysis of MOD-PFS and OS - Results from the ANDROMEDA Study

Kastritis et al (2024)9 presented results of the final analysis of MOD-PFS and OS from the phase 3 ANDROMEDA study with a median follow-up of 61.4 months.

Results – Body Weight Subgroup Analysis

Efficacy

MOD-PFSa in Results by Body Weight9
Subgroup
D-VCd
VCd
D-VCd
VCd
HR (95% CI)
MOD-PFS (n/N)
Median MOD-PFS, months
Baseline weight
   ≤65 kg
23/62
49/74
NE
20.40
0.35 (0.21-0.57)
   >65-85 kg
42/96
41/74
NE
23.66
0.58 (0.38-0.89)
   >85 kg
14/37
28/45
NE
38.21
0.47 (0.25-0.89)
Abbreviations: CI, confidence interval; D-VCd, DARZALEX FASPRO + bortezomib + cyclophosphamide + dexamethasone; HR, hazard ratio; MOD, major organ deterioration; NE, not estimated; PFS, progression-free survival; VCd, bortezomib + cyclophosphamide + dexamethasone.
aMOD-PFS is a composite endpoint defined as end-stage cardiac disease (requiring a cardiac transplant, left ventricular assist device, or intra-aortic balloon pump), end-stage renal disease (requiring hemodialysis or renal transplant), hematologic progression per consensus guidelines, or death.

OS Results by Body Weight9
Subgroups
D-VCd
VCd
D-VCd
VCd
HR (95% CI)
Death (n/N)
Median OS, months
Baseline weight
   ≤65 kg
13/62
32/74
NE
NE
0.39 (0.21-0.75)
   >65-85 kg
26/96
20/74
NE
NE
0.96 (0.54-1.72)
   >85 kg
7/37
14/45
NE
NE
0.57 (0.23-1.41)
Abbreviations: CI, confidence interval; D-VCd, DARZALEX FASPRO + bortezomib + cyclophosphamide + dexamethasone; HR, hazard ratio; NE, not estimated; OS, overall survival; VCd, bortezomib + cyclophosphamide + dexamethasone.
Safety
  • Safety results were not stratified by body weight.

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 15 April 2025.

 

References

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1 Data on File. Daratumumab SC Company Core Data Sheet (CCDS). Janssen Research & Development, LLC. EDMS-ERI-184804517; 2025.  
2 MV Mateos, H Nahi, W Legiec, et al. Subcutaneous versus intravenous daratumumab in patients with relapsed or refractory multiple myeloma (COLUMBA): a multicentre, open-label, non-inferiority, randomised, phase 3 trial. Lancet Haematol. 2020;7:e370-e380.  
3 Usmani S, Nahi H, Legiec W, et al. Final analysis of the phase 3 non-inferiority COLUMBA study of subcutaneous versus intravenous daratumumab in patients with relapsed or refractory multiple myeloma. Haematoligica. 2022;107:2408-2417.  
4 Usmani S, Nahi H, Legiec W, et al. Supplement to: Final analysis of the phase 3 non-inferiority COLUMBA study of subcutaneous versus intravenous daratumumab in patients with relapsed or refractory multiple myeloma. Haematoligica. 2022;107:2408-2417.  
5 Kastritis E, Palladini G, Minnema M, et al. Daratumumab-based treatment for immunoglobulin light-chain amyloidosis. N Engl J Med. 2021;385(1):46-58.  
6 Comenzo R, Palladini G, Kastritis E, et al. Subcutaneous daratumumab with bortezomib, cyclophosphamide, and dexamethasone in patients with newly diagnosed light chain (AL) amyloidosis: 18-month landmark analysis of the phase 3 ANDROMEDA study. 2021;(Oral presentation).  
7 Data on File. Clinical Study Report 54767414AMY3001. Janssen Research & Development, LLC. EDMS-ERI-196853318; 2020.  
8 Kastritis E, Sanchorawala V, Palladini G. Subcutaneous daratumumab ¬± bortezomib, cyclophosphamide, and dexamethasone in patients with newly diagnosed light chain amyloidosis: updated results from the phase 3 ANDROMEDA study. Oral Presentation presented at: The 57th Annual Meeting of the American Society of Clinical Oncology (ASCO); June 4-8, 2021; Virtual.  
9 Kastritis E, Palladini G, Minnema MC, et al. Subcutaneous daratumumab (DARA) + bortezomib, cyclophosphamide, and dexamethasone (VCd) in patients with newly diagnosed light chain (AL) amyloidosis: final analysis of the phase 3 ANDROMEDA study. Oral Presentation presented at: The 66th American Society of Hematology (ASH) Annual Meeting and Exposition; December 7-10, 2024; San Diego, CA.