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DARZALEX FASPRO® (daratumumab and hyaluronidase-fihj)

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DARZALEX FASPRO - AMY3001 (ANDROMEDA) Study

Last Updated: 01/12/2025

SUMMARY

  • ANDROMEDA is a phase 3 study evaluating the efficacy and safety of DARZALEX FASPRO for subcutaneous (SC) use in combination with bortezomib, cyclophosphamide, and dexamethasone (D-VCd) compared to VCd alone in newly diagnosed patients with systemic immunoglobulin light-chain (AL) amyloidosis.1
    • Kastritis et al (2021)1 reported primary results of the study with a median follow-up of 11.4 months. The primary endpoint of hematologic complete response (CR) was achieved in 53.3% of the D-VCd arm vs 18.1% of the VCd arm, respectively (relative risk ratio, 2.9; 95% confidence interval [CI], 2.1 to 4.1; P<0.001). The most common all-grade treatment-emergent adverse events (TEAEs) occurring in >25% of patients in the D-VCd arm were diarrhea, peripheral edema, constipation, peripheral sensory neuropathy, fatigue, nausea, and upper respiratory tract infection.
    • Comenzo et al (2021)2 presented (at the 63rd American Society of Hematology [ASH] Annual Meeting & Exposition) updated efficacy and safety results of the ANDROMEDA study, with a median follow-up of 25.8 months. Hematologic CR rate was achieved by 60% of patients in the D-VCd arm vs 19% in the VCd arm (odds ratio [OR], 6; 95% CI, 3.8-9.6; P<0.0001). No new safety concerns were reported, except for 1 additional grade 3/4 TEAE (fatigue: D-VCd, 5%; VCd, 3%). The most common any grade TEAEs occurring in >20% of patients in the D-VCd arm were peripheral edema, diarrhea, constipation, fatigue, peripheral sensory neuropathy, nausea, insomnia, upper respiratory tract infection, anemia, and dyspnea. Deaths were reported in 17% (34/193) of patients vs 24% (45/188) of patients in the D-VCd arm vs VCd arm, respectively. There were no additional systemic ARRs reported.
    • Kastritis et al (2024)3 presented (at the 66th ASH Annual Meeting) 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. The final analysis confirmed that D-VCd substantially increased the rate of hematologic CR vs VCd alone (59.5% vs 19.2%; OR, 6.03; 95% CI, 3.80-9.58) and consistently resulted in a higher rate of hematologic response. D-VCd significantly improved MOD-PFS vs VCd alone. At a median follow-up of 61.4 months, the median MOD-PFS was not reached in the D-VCd arm and was 30.2 months in the VCd arm. MOD-PFS was observed in 79/195 vs 118/193 patients from the D-VCd vs VCd arm, respectively (hazard ratio [HR], 0.44; 95% CI, 0.31-0.63; P<0.0001). At a median follow-up of 61.4 months, D-VCd vs VCd significantly improved OS, despite crossover in >70% of VCd patients who received DARZALEX FASPRO as subsequent therapy (HR, 0.62; 95% CI, 0.42-0.90; P=0.0121). D-VCd vs VCd provided MOD-PFS and OS benefits across prespecified relevant subgroups. D-VCd was associated with 2 to 3 times higher cardiac and renal response rates vs VCd alone across study timepoints. Safety data were consistent with the known safety profiles of D-VCd and VCd.
    • Palladini et al (2020)4 reported safety run-in results of the ANDROMEDA study with a median follow-up of 17.6 months. Comenzo et al (2020)5 reported (at the 17th International Symposium of Amyloidosis [ISA]) updated safety run-in results with a median follow-up of 22.9 months (N=28). The primary endpoint of overall hematologic CR rate was achieved in 57% of patients and the overall response rate (ORR) was 96%. Administration-related reactions (ARRs) occurred in 7% (n=2) of patients, injection-site reactions (ISRs) occurred in 11% (n=3) of patients, and Grade 3/4 TEAEs occurred in 71% (n=20) of patients.
    • Palladini et al (2022)6 evaluated the results of the ANDROMEDA study as per the revised ISA criteria vs the original ANDROMEDA study criteria for CR with a median follow-up of 11.4 months. At month 3, the rate of hematologic CR was 31.3% vs 14% for ISA criteria and 38% vs 10.9% for ANDROMEDA criteria in the D-VCd vs VCd arm, respectively.
    • Other relevant literature has been identified in addition to the data summarized above.7-15

PRODUCT LABELING

CLINICAL DATA

Phase 3 Study in Newly Diagnosed Systemic AL Amyloidosis

ANDROMEDA (AMY3001; clinicaltrials.gov identifier: 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.1Kastritis et al (2021)1 reported primary results of this study. Kastritis et al (2021)16 presented updated efficacy and safety results of the ANDROMEDA study, with a median follow-up of 20.3 months. Comenzo et al (2021)2 presented updated efficacy and safety results of the ANDROMEDA study, with a median follow-up of 25.8 months. Kastritis et al (2024)3 presented (at the 66th ASH Annual Meeting) 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.

Study Design/Methods

ANDROMEDA Study Design1

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 daratumumab 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

Baseline Characteristics
  • Baseline patient demographics and disease characteristics were balanced between both arms from the primary results and are presented in Table: Baseline Characteristics in the Intent-to-Treat (ITT) Population.
  • Overall, 65.5% (n=254) of patients had ≥2 organs involved; 71.4% had cardiac involvement, 59% had kidney involvement.
  • Most patients (76.8%) were classified as having a cardiac stage of II or higher.

Baseline Characteristics in the ITT Population1
Characteristic
D-VCd (N=195)
VCd (N=193)
Age
Median age (range), years
62 (34-87)
64 (35-86)
   <65 years, n (%)
108 (55.4)
97 (50.3)
   ≥65 years, n (%)
87 (44.6)
96 (49.7)
Gender, n (%)
   Male
108 (55.4)
117 (60.6)
   Female
87 (44.6)
76 (39.4)
Race, n
   White
151
143
   Asian
30
34
   Other
14
16
ECOG performance statusa, n (%)
   0/1/2
90 (46.2) / 86 (44.1) /19 (9.7)
71 (36.8) / 106 (54.9) / 16 (8.3)
AL Isotypeb, n (%)
   Lambda/Kappa
158 (81) / 37 (19)
149 (77.2) / 44 (22.8)
Median time since diagnosis  (range), days
48 (8-1611)
43 (5-1102)
dFLC
   Median baseline dFLC (range),
   mg/L
200 (2-4749)
186 (1-9983)
   <50 mg/L, n (%)
23 (11.8)
13 (6.7)
   <20 mg/L, n (%)
10 (5.1)
5 (2.6)
Involved organs, n (%)
   Median (range)
2 (1-5)
2 (1-6)
   Heart/Kidney/Liver/Otherc
 140 (71.8) / 115 (59) / 15 (7.7)/ 127 (65.1)
137 (71.0) / 114 (59.1) / 16 (8.3) /124 (64.2)
Cardiac staged, n (%)
   I/ II/ IIIA/ IIIBe
47 (24.1) / 76 (39) /
70 (35.9) / 2 (1)
43 (22.3) / 80 (41.5) / 64 (33.2) / 6 (3.1)
Renal stagee, n (%)
n=193
n=193
   I/II/III
107 (55.4) / 67 (34.7) / 19 (9.8)
101 (52.3) / 74 (38.3) / 18 (9.3)
Creatinine clearance, n (%)
   <60 mL/min
69 (35.4)
62 (32.1)
   ≥60 mL/min
124 (64.6)
131 (67.9)
Median NT-proBNP level (range), ng/L
1388.6 (51-10,182)
1746 (51-12,950)
Median estimated GFR (range), mL/min/1.73 m2
77.8 (21-126)
76.2 (20-121)
Abbreviations: AL, immunoglobulin light chain; D-VCd, DARZALEX FASPRO + bortezomib + cyclophosphamide + dexamethasone; dFLC, difference between involved and uninvolved free light chain; ECOG, Eastern Cooperative Oncology Group; GFR, glomerular filtration rate; ITT, Intent-to-Treat;l; NT-proBNP, N-terminal pro-brain natriuretic peptide; VCd, bortezomib + cyclophosphamide + dexamethasone.
aECOG performance status is scored on a scale from 0-5, with 0 indicating no symptoms and higher scores indicating increasing disability.
bBased on immunofixation or light chain measurement.
cIncludes gastrointestinal tract, lung, peripheral nervous system, autonomic nervous system, and soft tissue.
dBased on the European Modification of the Mayo staging system. Cardiac stage was based on 2 biomarker risk factors: NT-proBNP and high-sensitivity cardiac troponin that was assessed at a central laboratory.
eAll the patients had a cardiac stage of I, II, or IIIA at screening. Some converted to stage IIIB at cycle 1, day 1 (results determined by the central laboratory were made available only after cycle 1, day1).
eRenal stage is based on the combination of estimated GFR and urinary protein excursion.
Treatment Exposure and Patient Disposition
  • Treatment exposure and patient disposition from the primary results are presented in Table: Treatment Exposure and Patient Disposition in Primary Analysis.
  • Median duration of follow-up was 11.4 months (range, 0.03-21.3+).
  • The percentage of patients who completed the protocol-defined treatment completion of 6 cycles was 82.4% (n=159) in the D-VCd arm and 64.4% in the VCd arm (n=121).  
  • At the time of analysis, 141 of 195 patients (72.3%) continued with DARZALEX FASPRO monotherapy.
  • In the first 60 days of treatment, each arm reported 13 deaths.  
  • A total of 56 deaths were reported (D-VCd, n=27; VCd, n=29); mostly due to amyloidosis-related cardiomyopathy.
  • The incidence of deaths related to adverse events (AEs) was 11.9% (n=23) in the D-VCd arm and 7.4% (n=14) in the VCd arm.
  • Disease progression was reported as a cause of death in 1% of patients in the D-VCd arm and 4.8% in the VCd arm.
  • Other reasons for death were reported in 1% of patients in the D-VCd arm and 2.7% in the VCd arm.

Treatment Exposure and Patient Disposition in Primary Analysis1
Parameter
D-VCd
VCd
Safety population (≥1 dose study treatment), n
193
188
Median duration of study treatment, months
9.6
5.3
Deaths, na
27
29
Intention-to-treat population, n
195
193
Discontinued treatment, n (%)
52 (26.9)
68 (36.2)
Subsequent therapyc
193
188
   Any, n (%)
19 (9.8)
79 (42)
   ASCT, n
13 (6.7)
20 (10.6)
   DARZALEX monotherapy or combo regimen, n
0
48
Abbreviations: ASCT, autologous stem cell transplant; D-VCd, DARZALEX FASPRO + bortezomib + cyclophosphamide + dexamethasone; VCd, bortezomib + cyclophosphamide + dexamethasone.
aOnepatient in the VCd arm died before receiving treatment.
bIncludesphysiciandecision and patient withdrawal.
cSubsequent non-cross resistant, antiplasma cell therapy.
Efficacy
  • At 6 months, 179 of the 195 patients in the D-VCd arm had any type of hematologic response and 148 of 193 patients in the VCd arm. Efficacy data from the primary analysis are presented in Table: Summary of Overall Hematologic Responses in Primary Analysis (ITT Population).
  • The primary endpoint of hematologic CR was achieved by 53.3% of patients in the D-VCd arm vs 18.1% in the VCd arm, respectively.
  • The hematologic CR rate at 6 months was consistent with the overall hematologic CR rate: 49.7% in the D-VCd arm vs 14% in the VCd arm (OR, 6.1; 95% CI, 3.7-10; P<0.001).
  • Median time to CR was 60 days vs 85 days in the D-VCd arm vs the VCd arm, respectively.
  • At 6 months, renal progression was reported in 4.3% of patients in the D-VCd arm and 11.5% in the VCd arm.
  • At 6 months, cardiac progression was reported in 2.5% of patients in the D-VCd arm and 7.7% in the VCd arm.
  • Improvement in hematologic CR with D-VCd was consistent across subgroups
  • At 11.4 months, MOD-PFS was significantly better in the D-VCd arm compared to VCd alone (HR, 0.58; 95% CI, 0.36-0.93; P=0.02).
  • Major organ deterioration event-free survival (MOD-EFS), hematologic progression, or subsequent treatment was better in the D-VCd arm compared to VCd alone (HR 0.39; 95% CI, 0.27-0.56).

Summary of Overall Hematologic Responses in Primary Analysis (ITT Population)1
Parameter
D-VCd (N=195)
VCd (N=193)
P Value
Any hematologic response, n
179
148
-
   % of patients (95% CI)
91.8 (87-95.2)
76.7 (70.1-82.5)
-
Complete responsea, n
104b
35b
<0.001
   % of patients (95% CI)
53.3 (46.1-60.5)
18.1 (13-24.3)
-
≥VGPR, n (%)
153 (78.5)
95 (49.2)
-
VGPR, n (%)
49 (25.1)
60 (31.1)
-
PR, n (%)
26 (13.3)
53 (27.5)
-
No response, n (%)
8 (4.1)
38 (19.7)
-
Progressive disease, n (%)
0
0
-
Response could not be evaluated, n (%)
8 (4.1)
7 (3.6)
-
Involved free light-chain ≤20 mg/Lc, n/total N (%)
136/193 (70.5)
39/193 (20.2)
-
dFLC <10 mg/Ld, n/total n, (%)
119/188 (63.3)
56/190 (29.5)
-
Abbreviations: CI, confidence interval; D, DARZALEX FASPRO + bortezomib + cyclophosphamide + dexamethasone; dFLC, difference between involved and uninvolved free light chain; ITT, intention-to-treat; PR, partial response; VCd, bortezomib + cyclophosphamide + dexamethasone; VGPR, very good partial response.
aBased on consensus criteria with clarifications as specified in the trial protocol that required confirmation by the independent review committee. Complete response was defined as negative immunofixation and normalization of the free light-chain ratio without confirmation, a reduction in the absolute involved free light-chain level to ≤20 mg/L, and a reduction in the dFLC to <10 mg/L.
bOf the 104 patients who had a hematologic complete response in the D-VCd arm, 4 patients died while in complete response and no patients with a complete response had a relapse. Of the 35 patients who had a hematologic complete response in the control arm, 2 patients died while in complete response and 2 patients had a relapse after a complete response.
cExcluded are 2 patients with an involved free light-chain level of ≤20 mg/L at baseline (both in the D-VCd arm).
dExcluded are 10 patients with a dFLC of less than 10 mg per liter at baseline (7 in the D-VCd arm and 3 in the VCd arm).

Cardiac and Renal Responses at 6 Months in Primary Analysis1
Parameter
D-VCd (N=195)
VCd (N=193)
Cardiac response
   Number of patients who could be evaluateda
118
117
   Percent with a response (95% CI)
41.5 (32.5-51)
22.2 (15.1-30.8)
Renal response
   Number of patients who could be evaluatedb
117
113
   Percent with a response (95% CI)
53 (43.3-62.3)
23.9 (16.4-32.8)
Abbreviations: CI, confidence interval; D-VCd, DARZALEX FASPRO + bortezomib + cyclophosphamide + dexamethasone; NYHA, New York Heart Association; VCd, bortezomib + cyclophosphamide + dexamethasone.
aPatients who could be evaluated for cardiac response were defined as those with a baseline NT-proBNP value of >650 ng/L or a baseline NYHA class of III or IV. Additionally, patients must have received at least 1 administration of trial treatment and have at least 1 postbaseline NT-proBNP measurement (if the baseline NT-proBNP was ≥650 ng/L) or NYHA function evaluation (if the baseline NYHA class was III or IV).
bPatients who could be evaluated for renal response were defined as those with a baseline urinary protein excretion of >0.5g/day. Additionally, patients must have received at least 1 administration of trial treatment and at least 1 postbaseline measurement of urinary protein excretion.

Summary of Overall Responses in Subgroups in the Primary Analysis1
n/N, (%)
D-VCd
VCd
Odds Ratio (95% CI)
Overall
104/195 (53)
35/193 (18)
5.13 (3.22-8.16)
Male
60/108 (56)
16/117 (14)
7.89 (4.12-15.11)
Age
   <65 years
61/108 (56)
20/97 (21)
5 (2.68-9.31)
   65 years
43/87 (49)
15/96 (16)
5.28 (2.64-10.55)
Weight at baseline
   ≤65 kg
34/62 (55)
8/74 (11)
10.02 (4.12-24.35)
   >65-85 kg
50/96 (52)
14/74 (19)
4.66 (2.30-9.44)
   >85 kg
20/37 (54)
13/45 (29)
2.90 (1.16-7.22)
Race
   White
80/151 (53)
28/143 (20)
4.63 (2.75-7.80)
   Asian
18/30 (60)
3/34 (9)
15.50 (3.85-62.36)
   Other
6/14 (43)
4/16 (25)
2.25 (0.48-10.60)
Cardiac stage at baseline
   I
21/47 (45)
12/43 (28)
2.09 (0.87-5.03)
   II
41/76 (54)
16/80 (20)
4.69 (2.30-9.53)
   IIIA or IIIB
42/72 (58)
7/70 (10)
12.60 (5.07-31.32)
Creatinine clearance at baseline
   ≥60 mL/min
69/126 (55)
25/131 (19)
5.13 (2.93-8.98)
   <60 mL/min
35/69 (51)
10/62 (16)
5.35 (2.35-12.22)
Cardiac involvement at baseline
   Yes
80/140 (57)
22/137 (16)
6.97 (3.96-12.27)
   No
24/55 (44)
13/56 (23)
2.56 (1.13-5.80)
Renal stage at baseline
   I
52/107 (49)
15/101 (15)
5.42 (2.78-10.56)
   II
45/67 (67)
15/74 (20)
8.05 (3.75-17.24)
   III
6/19 (32)
5/18 (28)
1.20 (0.29-4.94)
Alkaline phosphatase at baseline
   Abnormal
5/11 (45)
0/15
NE
   Normal
99/184 (54)
35/178 (20)
4.76 (2.98-7.61)
ECOG PS score at baseline
   0
45/90 (50)
14/71 (20)
4.07 (1.99-8.33)
   1 or 2
59/105 (56)
21/122 (17)
6.17 (3.36-11.33)
Cytogenetic risk at baseline
   High risk
8/17 (47)
0/19
NE
   Standard risk
74/138 (54)
31/147 (21)
4.33 (2.58-7.27)
Presence of t(11;14) mutation on FISH
   Yes
28/51 (55)
7/55 (13)
8.35 (3.18-21.93)
   No
23/44 (52)
13/52 (25)
3.29 (1.39-7.78)
Abbreviations: D-VCd, DARZALEX FASPRO + bortezomib + cyclophosphamide + dexamethasone; ECOG PS, Eastern Cooperative Oncology Group Performance Status; FISH, fluorescent in situ hybridization; NE, not estimable; VCd, bortezomib + cyclophosphamide + dexamethasone.
Safety
  • Safety data from the primary analysis are presented in Table: Most Common Any Grade (>25%) and Grade 3/4 (≥5%) Adverse Events (Safety Population).
  • Serious AEs occurred in 43% and 36.2% of the D-VCd and VCd arms, respectively, with the most common being pneumonia (D-VCd, 7.3%; VCd, 4.8%).
  • Grade 3/4 infections were reported in 16.6% and 10.1% of the D-VCd and VCd arms, respectively.
  • The rate of discontinuation due to AEs was 4.1 % in the D-VCd arm and 4.3% in the VCd arm.

Most Common Any Grade (>25%) and Grade 3/4 (≥5%) Adverse Events (Safety Population)a, 1
n, (%)
D-VCd (N=193)
VCd (N=188)
Any grade
Grade 3/4
Any grade
Grade 3/4
Diarrhea
69 (35.8)
11 (5.7)
57 (30.3)
7 (3.7)
Peripheral edema
69 (35.8)
6 (3.1)
68 (36.2)
11 (5.9)
Constipation
66 (34.2)
3 (1.6)
54 (28.7)
0
Peripheral sensory neuropathy
60 (31.1)
5 (2.6)
37 (19.7)
4 (2.1)
Fatigue
52 (26.9)
8 (4.1)
53 (28.2)
6 (3.2)
Nausea
52 (26.9)
3 (1.6)
52 (27.7)
0
Upper respiratory tract infection
50 (25.9)
1 (0.5)
21 (11.2)
1 (0.5)
Lymphopenia
36 (18.7)
25 (13)
28 (14.9)
19 (10.1)
Hypokalemia
24 (12.4)
3 (1.6)
28 (14.9)
10 (5.3)
Neutropenia
21 (10.9)
10 (5.2)
12 (6.4)
5 (2.7)
Pneumonia
21 (10.9)
15 (7.8)
12 (6.4)
8 (4.3)
Syncope
14 (7.3)
10 (5.2)
12 (6.4)
12 (6.4)
Cardiac failureb
18 (9.3)
12 (6.2)
14 (7.4)
9 (4.8)
Abbreviations: D-VCd, DARZALEX FASPRO + bortezomib + cyclophosphamide + dexamethasone; VCd, bortezomib + cyclophosphamide + dexamethasone.
aSafety population included patients who received at least 1 administration of treatment.
bIncludes overall and congestive heart failure.
Systemic ARRs and ISRs
  • Grade 1/2 systemic ARRs related to DARZALEX FASPRO occurred in 14 (7.3%) patients with a median time to onset of 1.3 hours (range, 0.2-7.3). Most ARRs (86%) occurred at first administration.
    • Systemic ARRs occurring in >1 patient in the D-VCd arm were chills (n=3), pyrexia (n=3), dizziness (n=2) and nausea (n=2).17
  • Local ISRs to any drug in the treatment regimen occurred in 28% and 23.9% of patients in the D-VCd and VCd arms, respectively.17
  • Local ISRs related to DARZALEX FASPRO occurred in 10.9% (n=21) patients in the D-VCd arm. All ISRs were reported as grade 1/2.17
  • DARZALEX FASPRO-related ISRs occurring in >1 patient were reported as injection-site erythema (n=10), injection-site pain (n=6), and infusion-site pain (n=2).17

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

Comenzo et al (2021)2 presented updated efficacy and safety results of the ANDROMEDA study, with a median follow-up of 25.8 months.

Results

Treatment Exposure and Patient Disposition
  • Median duration of treatment for the D-VCd and VCd arms at clinical cutoff was 21.3 months and 5.3 months, respectively.
  • Treatment exposure and patient disposition from the additional follow-up are presented in Table: Treatment Exposure and Patient Disposition in Updated Analysis.
  • At a median follow-up of 25.8 months, 149 (77.2%) patients within the D-VCd arm received DARZALEX FASPRO monotherapy following 6 cycles of D-VCd treatment; of these, 132 (88.6%) patients received 18 cycles and 17 (11.4%) patients were still receiving treatment.

Treatment Exposure and Patient Disposition in Updated Analysis2
Safety Population (≥1 dose of study treatment)
D-VCd
(n=193)
VCd
(n=188)
Median duration of study treatment (range), months
21.3 (0.03-25.8)
5.3 (0.03-7.3)
Median number of cycles / >3 cycles (range), %
24 (1-25) / 86
6 (1-6) / 80
DARZALEX FASPRO monotherapy maintenance (>6 cycles), %
77
-
DARZALEX FASPRO as subsequent therapy, %
3
34
Intention-to-treat population, n
193
188
   Discontinued treatment, %
36
36
      Death (on study treatment)
11
7
      Received ASCT
6
2
      Adverse event
6
4
      Subsequent therapy
3
12
      Othera
6
5
      Progressive disease
4
6
Abbreviations: ASCT, autologous stem cell transplant; D-VCd, DARZALEX FASPRO + bortezomib + cyclophosphamide + dexamethasone; VCd, bortezomib + cyclophosphamide + dexamethasone.
aIncludesphysiciandecision and patient withdrawal.
Efficacy
  • Hematologic CR rate was achieved by 60% of patients in the D-VCd arm vs 19% in the VCd arm (OR, 6; 95% CI, 3.8-9.6; P<0.0001).
    • Rate of very good partial response (VGPR) or more was 79% in the D-VCd arm.
  • Improvement in hematologic CR rates with D-VCd vs VCd was consistent across subgroups. See Table: Subgroup Analysis of Hematologic CR Rates in Updated Analysis.

Subgroup Analysis of Hematologic CR Rates in Updated Analysis2
Subgroup
D-VCd n/N (%)
VCd n/N (%)
OR (95% CI)
Overall
116/195 (59.5)
37/193 (19.2)
6 (3.8-9.6)
Age
   <65 years
68/108 (63)
20/97 (20.6)
6.6 (3.5-12.3)
   ≥65 years
48/87 (55.2)
17/96 (17.7)
5.7 (2.9-11.2)
Sex
   Male
65/108 (60.2)
17/117 (14.5)
8.9 (4.7-16.9)
   Female
51/87 (58.6)
20/76 (26.3)
4 (2-7.7)
Race
   White
89/151 (58.9)
28/143 (19.6)
5.9 (3.5-10.0)
   Asian
21/30 (70)
5/34 (14.7)
13.5 (4.0-46.3)
   Others
6/14 (42.9)
4/16 (25)
2.3 (0.5-10.6)
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)
Baseline cardiac stage
   I
24/47 (51.1)
13/43 (30.2)
2.4 (1-5.7)
   II
46/76 (61.8)
17/80 (21.3)
6 (3-12.2)
   IIIa
45/72 (62.5)
7/70 (10)
15 (6-37.5)
Cardiac involvement at baseline
   Yes
88/140 (62.9)
22/137 (16.1)
8.9 (5-15.7)
   No
28/55 (50.9)
15/56 (26.8)
2.8 (1.3-6.3)
Baseline renal stage
   I
21/39 (53.8)
6/36 (16.7)
5.8 (2-17.2)
   II
41/56 (73.2)
14/60 (23.3)
9 (3.9-20.8)
   III
11/19 (57.9)
5/18 (27.8)
3.6 (0.9-14.2)
Baseline ECOG PS score
   0
52/90 (57.8)
16/71 (22.5)
4.7 (2.3-9.4)
   1 or 2
64/105 (61)
21/122 (17.2)
7.5 (4.1-13.9)
FISH t(11;14)
   Present
31/51 (60.8)
7/55 (12.7)
10.6 (4-28.1)
Organ response rate at 6 months
   Cardiac response, %
42
22
2.4 (1.4-4.4), P=0.0029
   Renal response, %
54
27
3.7 (2.1-6.6), P<0.0001
Organ response rate at 18 months
   Cardiac response, %
53
24
3.3 (1.9-5.9), P<0.0001
   Renal response, %
58
26
4.4 (2.4-7.9), P<0.0001
Abbreviations: CI, confidence interval; D-VCd, DARZALEX FASPRO + bortezomib + cyclophosphamide + dexamethasone; ECOG PS, Eastern Cooperative Oncology Group performance status; FISH, fluorescence in situ hybridization; OR, odds ratio; VCd, bortezomib + cyclophosphamide + dexamethasone.
aCardiac stage III includes both IIIA patients and patients who were IIIA at randomization and progressed to IIIB at cycle 1 day 1.
Safety
  • No new safety concerns were reported, except for 1 additional grade 3/4 TEAE (fatigue: D-VCd, 5%; VCd, 3%).
  • There were 34 vs 45 deaths reported in the D-VCd vs VCd arms, respectively. See Table: Deaths and Cause of Death in Each Treatment Arm.
  • Serious TEAEs occurred in 47% vs 36% of patients in the D-VCd arm vs VCd arm, respectively, with the most common being pneumonia in both arms (D-VCd, 7%; VCd, 5%).
  • The rate of discontinuation due to TEAEs was 5% vs 4% in the D-VCd arm vs VCd arm, respectively.
  • There were no additional systemic ARRs reported.

Deaths and Cause of Death in Each Treatment Arm2
Safety Population (≥1 dose of study treatment)
D-VCd
(n=193)
VCd
(n=188)
Total number of deaths, n (%)a
   11.4 months of follow-up
27 (14)
29 (15)
   20.3 months of follow-up
31 (16)
40 (21)
   25.8 months of follow-up
34 (17)
45 (24)
Death on therapy, n/N (%)
22/34 (64)
14/45 (31)
Primary cause of death, n (%)
   AEs
26 (14)
15 (8)
      Related to study treatment
6 (3)
2 (1)
      Unrelated to study treatment
20 (10)
13 (7)
   Disease progression
4 (2)
13 (7)
   Other
4 (2)
17 (9)
Abbreviations: AEs, adverse events; D-VCd, DARZALEX FASPRO + bortezomib + cyclophosphamide + dexamethasone; VCd, bortezomib + cyclophosphamide + dexamethasone.
aOne patient in the VCd arm died before receiving treatment.

Most Common Any Grade (≥20%) and Grade 3/4 (≥5%) TEAEs2
Patients, %
D-VCd
(n=193)
VCd
(n=188)
≥1 Any grade TEAEs
98
98
   Peripheral edema
37
36
   Diarrhea
36
30
   Constipation
36
29
   Fatigue
29
28
   Peripheral sensory neuropathy
34
20
   Nausea
29
28
   Insomnia
25
25
   Upper respiratory tract infection
26
11
   Anemia
25
23
   Dyspnea
25
17
≥1 Grade 3/4 TEAEs
62
57
   Lymphopenia
13
10
   Pneumonia
8
4
   Fatigue
5
3
   Syncope
6
6
   Diarrhea
6
4
   Cardiac failure
6
3
   Neutropenia
5
3
   Peripheral edema
3
6
   Hypokalemia
2
5
Abbreviations: TEAEs, treatment-emergent adverse events.

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

Kastritis et al (2024)3 presented (at the 66th ASH Annual Meeting) 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

Baseline Demographics and Clinical Characteristics

Baseline Demographics and Clinical Characteristics3
Characteristic
D-VCd
(n=195)
VCd
(n=193)
Age
Median (range), years
62 (34-87)
64 (35-86)
   ≥65 years, n (%)
87 (44.6)
96 (49.7)
Male sex, n (%)
108 (55.4)
117 (60.6)
Race, n (%)a
   White
151 (77.4)
143 (74.1)
   Black or African American
6 (3.1)
7 (3.6)
   Not reported
7 (3.6)
5 (2.6)
ECOG performance status score, n (%)b
   0
90 (46.2)
71 (36.8)
   1
86 (44.1)
106 (54.9)
   2
19 (9.7)
16 (8.3)
AL isotype, n (%)c
   Lambda
158 (81)
149 (77.2)
   Kappa
37 (19)
44 (22.8)
Median time since amyloidosis diagnosis (range), days
48 (8-1611)
43 (5-1102)
Involved organs
   Median (range)
2 (1-5)
2 (1-6)
   Distribution, n (%)
      Heart
 140 (71.8)
137 (71)
      Kidney
115 (59)
114 (59.1)
      Liver
15 (7.7)
16 (8.3)
      Otherd
127 (65.1)
124 (64.2)
Cardiac stage, n (%)e
   I
47 (24.1)
43 (22.3)
   II
76 (39)
80 (41.5)
   IIIA
70 (35.9)
64 (33.2)
   IIIBf
2 (1)
6 (3.1)
Renal stage, n/total n (%)g
   I
107/193 (55.4)
101/193 (52.3)
   II
67/193 (34.7)
74/193 (38.3)
   III
19/193 (9.8)
18/193 (9.3)
Abbreviations: AL, light-chain; D-VCd, DARZALEX FASPRO + bortezomib + cyclophosphamide + dexamethasone; ECOG, Eastern Cooperative Oncology Group; GFR, glomerular filtration rate; NT-proBNP, N-terminal pro-B-type natriuretic peptide; VCd, bortezomib + cyclophosphamide + dexamethasone.
aRace was reported by the patient.
bECOG performance status was scored on a scale from 0 to 5, with 0 indicating no symptoms and higher scores indicating increasing disability.
cData are based on immunofixation and AL measurement.
dOther included the gastrointestinal tract, lungs, the peripheral nervous system, the autonomic nervous system, and soft tissues.
eCardiac stage was classified in accordance with the European modification of the staging system of Mayo Clinic. Cardiac stage was based on 2 biomarker risk factors—NT-proBNP and high-sensitivity cardiac troponin T—that were assessed at a central laboratory.
fAll patients had a cardiac stage of I, II, or IIIA at screening; however, some converted to stage IIIB at cycle 1, day 1 (results determined by the central laboratory were made available only after cycle 1, day 1).
gRenal stage was based on the combination of estimated GFR and urinary protein excretion.
Treatment Exposure and Subsequent Therapy
  • Treatment exposure and subsequent therapy details are presented in Table: Treatment Exposure and Subsequent Therapy.
    • A total of 25.9% vs 61.2% of patients from the D-VCd vs VCd arm, respectively, received subsequent therapy.3
    • A total of 71.3% (82/115) of patients from the VCd arm received subsequent DARZALEX FASPRO-based therapy.3
    • The most common reasons for DARZALEX FASPRO discontinuation included death (n=23), autologous stem cell transplant (n=12), and AEs (n=11).3
  • The median follow-up was 61.4 months.3

Treatment Exposure and Subsequent Therapy3
Parameter
D-VCd
(n=193)
VCd
(n=188)
Median duration of study treatment, months (range)
21.3 (0.03-26.7)
5.3 (0.03-7.3)
Median number of cycles received (range)
24 (1-25)
6.0 (1-6)
Received 6 cycles of treatment per protocol, n (%)a
159 (82.4)
121 (64.4)
Completed 2 years of DARZALEX FASPRO maintenance, n (%)a
124 (64.2)
-
Subsequent therapy, n (%)b
50 (25.9)
115 (61.2)
Abbreviations: D-VCd, DARZALEX FASPRO + bortezomib + cyclophosphamide + dexamethasone; VCd, bortezomib + cyclophosphamide + dexamethasone.
aPatients in the VCd arm received a maximum of 6 cycles of treatment, whereas the maximum treatment duration was 2 years for patients in the D-VCd arm.
bNon-cross-resistant subsequent therapy, which was defined as any antiplasma cell agent not included in the original protocol-assigned treatment.
Efficacy
  • Efficacy data from the final analysis are presented in Table: Summary of Overall Hematologic Responses in the Final Analysis.
    • The median time to a hematologic CR was 67.5 vs 85 days for the D-VCd vs VCd arm, respectively.3
    • The final analysis confirmed that D-VCd substantially increased hematologic CR vs VCd alone (59.5% vs 19.2%; OR, 6.03; 95% CI, 3.80-9.58) and consistently resulted in a higher rate of hematologic response.3
  • D-VCd significantly improved MOD-PFS vs VCd alone.3
    • At a median follow-up of 61.4 months, the median MOD-PFS was not reached in the D-VCd arm and was 30.2 months in the VCd arm.
    • The estimated 60-month MOD-PFS rate was 60.2% vs 33.2% in the D-VCd vs VCd arm, respectively.
    • MOD-PFS was observed in 79/195 vs 118/193 patients from the D-VCd vs VCd arm, respectively (HR, 0.44; 95% CI, 0.31-0.63; P<0.0001).
      • Hematologic progression occurred in 41 vs 63 patients, MOD occurred in 3 vs 11 patients, and death occurred in 35 vs 44 patients from the D-VCd vs VCd arm, respectively.
    • Analyses of MOD-PFS rates in prespecified subgroups appeared to consistently favor D-VCd over VCd across relevant subgroups; the results are summarized in Table: MOD-PFS in Prespecified Subgroups.
    • Attaining hematologic and cardiac CR was associated with improved MOD-PFS in both patients with hematologic/cardiac CR and those with nonhematologic/noncardiac CR.
      • D-VCd vs VCd hematologic CR: HR, 0.57; P=0.1799.
      • D-VCd vs VCd nonhematologic CR: HR, 0.39; P=0.0004.
      • D-VCd vs VCd cardiac CR: HR, 0.34; P=0.073.
      • D-VCd vs VCd noncardiac CR: HR, 0.50; P=0.004.
    • Attaining cardiac CR was associated with improved MOD-PFS (HR, 0.23; 95% CI, 0.12-0.43) and OS (HR, 0.05; 95% CI, 0.01-0.19) rates.
  • At a median follow-up of 61.4 months, D-VCd vs VCd significantly improved OS, despite crossover in >70% of VCd patients who received DARZALEX FASPRO as subsequent therapy (HR, 0.62; 95% CI, 0.42-0.90; P=0.0121).3
    • The estimated 60-month OS rate was 76.1% vs 64.7% in the D-VCd vs VCd arm, respectively.
    • D-VCd vs VCd provided an OS benefit across prespecified relevant subgroups; results are summarized in Table: OS in Prespecified Subgroups.
  • D-VCd was associated with 2 to 3 times higher cardiac and renal response rates vs VCd alone across study timepoints; results are summarized in Table: Cardiac and Renal Responses in the Final Analysis.

Summary of Overall Hematologic Responses in the Final Analysis3
Parameter, %
D-VCd
(n=195)
VCd
(n=193)
OR (95% CI)
P Value
Overall CR
59.5
19.2
6.03 (3.80-9.58)
<0.0001
Overall hematologic response
91.8
76.7
-
-
   CR
59.5
19.2
-
-
   ≥VGPR
79
50.3
3.74 (2.39-5.86)
<0.0001
   VGPR
19.5
31.1
-
-
   PR
12.8
26.4
-
-
Abbreviations: CI, confidence interval; CR, complete response; D-VCd, DARZALEX FASPRO + bortezomib + cyclophosphamide + dexamethasone; OR, odds ratio; PR, partial response; VCd, bortezomib + cyclophosphamide + dexamethasone; VGPR, very good partial response.

MOD-PFSa in Prespecified Subgroups3
Subgroup
D-VCd
VCd
D-VCd
VCd
HR (95% CI)
MOD-PFS (n/N)
Median MOD-PFS, months
Sex
   Male
45/108
76/117
NE
22.14
0.46 (0.32-0.66)
   Female
34/87
42/76
NE
33.61
0.49 (0.31-0.78)
Age
   <65 years
38/108
52/97
NE
31.11
0.44 (0.29-0.67)
   ≥65 years
41/87
66/96
59.66
20.86
0.51 (0.34-0.75)
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)
Race
   White
64/151
87/143
NE
31.11
 0.50 (0.36-0.69)
   Asian
7/30
21/34
NE
16.33
0.25 (0.11-0.59)
   Other
8/14
10/16
53.59
24.05
0.83 (0.32-2.12)
Baseline cardiac stage
   I
18/47
22/43
NE
48.59
0.56 (0.30-1.04)
   II
27/76
50/80
NE
24.64
0.39 (0.24-0.62)
   IIIa/IIIb
34/72
46/70
59.66
20.86
0.51 (0.33-0.80)
Residence in a country that typically offers transplantation for patients with AL amyloidosis
   Yes
58/147
90/146
NE
26.74
0.45 (0.32-0.63)
   No
21/48
28/47
NE
31.11
0.53 (0.30-0.94)
Baseline creatinine clearance
   ≥60 mL/min
49/126
74/131
NE
28.42
0.46 (0.32-0.67)
   <60 mL/min
30/69
44/62
NE
29.90
0.47 (0.29-0.74)
Baseline cardiac involvement
   Yes
57/140
87/137
NE
21.88
0.44 (0.31-0.61)
   No
22/55
31/56
NE
42.41
0.55 (0.32-0.96)
Baseline renal stage
   I
13/39
22/36
NE
20.57
0.30 (0.15-0.60)
   II
20/56
35/60
NE
33.02
0.40 (0.23-0.70)
   III
7/19
13/18
59.33
45.50
0.49 (0.19-1.24)
Baseline alkaline phosphatase
   Abnormal
4/11
12/15
NE
17.74
0.20 (0.06-0.66)
   Normal
75/184
106/178
NE
30.23
0.50 (0.37-0.67)
Baseline ECOG PS score
   0
34/90
40/71
NE
43.96
0.47 (0.30-0.75)
   1 or 2
45/105
78/122
NE
20.83
0.49 (0.34-0.70)
Cytogenetic risk at study entry
   High risk
6/17
15/19
NE
16.39
0.24 (0.09-0.62)
   Standard risk
55/138
90/147
NE
28.42
0.46 (0.33-0.65)
FISH t(11;14)
   Abnormal
18/51
30/55
NE
34.10
0.41 (0.23-0.75)
   Normal
13/44
32/52
NE
20.27
0.33 (0.17-0.63)
Abbreviations: AL, light-chain; CI, confidence interval; D-VCd, DARZALEX FASPRO + bortezomib + cyclophosphamide + dexamethasone; ECOG PS, Eastern Cooperative Oncology Group performance status; FISH, fluorescence in situ hybridization; 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 in Prespecified Subgroups3
Subgroups
D-VCd
VCd
D-VCd
VCd
HR (95% CI)
Death (n/N)
Median OS, months
Sex
   Male
25/108
43/117
NE
NE
0.59 (0.36-0.96)
   Female
21/87
23/76
NE
NE
0.71 (0.39-1.28)
Age
   <65 years
16/108
18/97
NE
NE
0.74 (0.38-1.46)
   ≥65 years
30/87
48/96
NE
60.25
0.63 (0.40-0.99)
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)
Race
   White
37/151
48/143
NE
NE
0.68 (0.44-1.04)
   Asian
4/30
14/34
NE
NE
0.25 (0.08-0.77)
   Other
5/14
4/16
NE
NE
1.71 (0.46-6.37)
Baseline cardiac stage
   I
3/47
7/43
NE
NE
0.34 (0.09-1.30)
   II
14/76
23/80
NE
NE
0.63 (0.32-1.22)
   IIIa/IIIb
29/72
36/70
NE
36.83
0.64 (0.39-1.05)
Residence in a country that typically offers transplantation for patients with AL amyloidosis
   Yes
36/147
53/146
NE
NE
0.61 (0.40-0.93)
   No
10/48
13/47
NE
NE
0.72 (0.31-1.64)
Baseline creatinine clearance
   ≥60 mL/min
26/126
34/131
NE
NE
0.72 (0.43-1.21)
   <60 mL/min
20/69
32/62
NE
49.61
0.50 (0.29-0.88)
Baseline cardiac involvement
   Yes
42/140
54/137
NE
NE
0.68 (0.45-1.02)
   No
4/55
12/56
NE
NE
0.31 (0.10-0.96)
Baseline renal stage
   I
7/39
10/36
NE
NE
0.49 (0.18-1.28)
   II
7/56
18/60
NE
NE
0.37 (0.16-0.90)
   III
5/19
8/18
NE
NE
0.66 (0.22-2.03)
Baseline alkaline phosphatase
   Abnormal
2/11
6/15
NE
49.61
0.34 (0.07-1.68)
   Normal
44/184
60/178
NE
NE
0.66 (0.44-0.97)
Baseline ECOG PS score
   0
10/90
18/71
NE
NE
0.39 (0.18-0.84)
   1 or 2
36/105
48/122
NE
NE
0.82 (0.53-1.26)
Cytogenetic risk at study entry
   High risk
3/17
9/19
NE
56.87
0.26 (0.07-0.96)
   Standard risk
31/138
51/147
NE
NE
0.59 (0.37-0.92)
FISH t(11;14)
   Abnormal
8/51
16/55
NE
NE
0.47 (0.20-1.11)
   Normal
7/44
20/52
NE
NE
0.34 (0.14-0.81)
Abbreviations: AL, light-chain; CI, confidence interval; D-VCd, DARZALEX FASPRO + bortezomib + cyclophosphamide + dexamethasone; ECOG PS, Eastern Cooperative Oncology Group performance status; FISH, fluorescence in situ hybridization; HR, hazard ratio; NE, not estimated; OS, overall survival; VCd, bortezomib + cyclophosphamide + dexamethasone.

Cardiac and Renal Responses in the Final Analysis3
Parameter
D-VCd
VCd
Cardiac response, n
118
117
   6 months, %
41.5
22.2
   12 months, %
56.8
28.2
   24 months, %
47.5
18.8
   36 months, %
39
12.8
   48 months, %
27.1
9.4
Cardiac CR, %
40.7
13.7
Cardiac ≥VGPR, %
64.4
31.6
Renal response, n
117
113
   6 months, %
53.8
27.4
   12 months, %
57.3
27.4
   24 months, %
51.3
22.1
   36 months, %
48.7
16.8
   48 months, %
40.2
15
Abbreviations: CR, complete response; D-VCd, DARZALEX FASPRO + bortezomib + cyclophosphamide + dexamethasone; VCd, bortezomib + cyclophosphamide + dexamethasone; VGPR, very good partial response.
Safety

Any-Grade (>25%) and Grade 3/4 (≥5%) AEs (Final Analysis)a,3
Event, n (%)
D-VCd (n=193)
VCd (n=188)
Any Gradeb
Grade 3/4b
Any Gradeb
Grade 3/4b
Peripheral edema
71 (36.8)
6 (3.1)
68 (36.2)
11 (5.9)
Diarrhea
70 (36.3)
11 (5.7)
57 (30.3)
7 (3.7)
Constipation
70 (36.3)
3 (1.6)
54 (28.7)
0
Peripheral sensory neuropathy
65 (33.7)
5 (2.6)
37 (19.7)
4 (2.1)
Fatigue
55 (28.5)
10 (5.2)
53 (28.2)
6 (3.2)
Nausea
55 (28.5)
3 (1.6)
52 (27.7)
0
Upper respiratory tract infection
50 (25.9)
1 (0.5)
21 (11.2)
1 (0.5)
Anemia
49 (25.4)
8 (4.1)
44 (23.4)
9 (4.8)
Insomnia
49 (25.4)
0
47 (25)
2 (1.1)
Dyspnea
49 (25.4)
5 (2.6)
32 (17)
6 (3.2)
Lymphopenia
37 (19.2)
25 (13)
28 (14.9)
19 (10.1)
Hypokalemia
26 (13.5)
4 (2.1)
28 (14.9)
10 (5.3)
Pneumonia
24 (12.4)
16 (8.3)
12 (6.4)
8 (4.3)
Neutropenia
21 (10.9)
10 (5.2)
12 (6.4)
5 (2.7)
Cardiac failure
18 (9.3)
12 (6.2)
10 (5.3)
5 (2.7)
Syncope
16 (8.3)
12 (6.2)
12 (6.4)
12 (6.4)
Abbreviations: AE, adverse event; D-VCd, DARZALEX FASPRO + bortezomib + cyclophosphamide + dexamethasone; VCd, bortezomib + cyclophosphamide + dexamethasone.
aThe safety population included patients who received at least 1 dose of the study treatment.
bAEs of any grade that were reported in >25% of patients in either treatment arm and grade 3/4 AEs that were reported in ≥5% of patients in either treatment arm are listed.

Safety Run-in Results of ANDROMEDA

Palladini et al (2020)4 reported safety run-in results of the ANDROMEDA study with a median follow-up of 17.6 months. Comenzo et al (2020)5 reported updated safety run-in results of ANDROMEDA with a median follow-up of 22.9 months.

Study Design/Methods

  • At least 10 patients were to be enrolled in the safety run-in cohort to determine the safety and tolerability of DARZALEX FASPRO in combination with VCd.
  • If no safety signal is observed after ≥1 cycle of treatment, particularly regarding volume overload, approximately 360 patients are expected to be randomized 1:1 to receive VCd with or without DARZALEX FASPRO.
  • Key inclusion criteria: histopathological diagnosis of AL amyloidosis and measurable disease without prior therapy, ≥1 organ involvement, difference between involved and uninvolved free light chain (dFLC) ≥50 mg/L or M-protein ≥0.5 g/dL, and cardiac stage I to IIIA (European Modification of Mayo 2004). and an Eastern Cooperative Oncology Group (ECOG) performance status ≤2.
  • Key exclusion criteria: prior therapy for AL amyloidosis or multiple myeloma including medications that target CD38, previous or current diagnosis of symptomatic multiple myeloma, grade 2 sensory or grade 1 painful peripheral neuropathy, New York Heart Association (NYHA) stage IIIB or IV heart failure, or any form of non-AL amyloidosis.
  • Patients received either DARZALEX FASPRO + VCd or VCd alone as presented in the Kastritis et al (2021)1 Study Design/Methods section.
  • Patients were stratified as follows:
    • Cardiac stage (I vs II vs IIIA)
    • Transplant typically offered in local country (yes vs no)
    • Creatinine clearance (>60 mL/min vs <60 mL/min)
  • Primary endpoint: overall hematologic CR rate
  • Secondary endpoints: MOD-PFS, PFS, organ response rate as assessed by biomarkers, OS, improvement in patient-reported fatigue.

Results

Baseline Characteristics

Baseline Characteristics of Patients4,5
Characteristic
Patients (N=28)
Median age (range), years / ≥65
68 (35-83) / 16 (57)
Male, n (%)
16 (57)
White, n (%)
25 (89)
Black/African American, n (%)
2 (7)
Unknown, n (%)
1 (4)
ECOG performance statusa, n (%)
   0/1/2
7 (25) / 18 (64) / 3 (11)
Median time since diagnosis (range), days
60 (15-501)
Median dFLC (range), mg/L
156.7 (5.4-6983.1)
Median NT-proBNP (range), pg/mL
1,120 (59-9,927)
Median baseline creatinine clearance (range), mL/min
82.4 (26.1-116.1)
Cardiac stageb,n (%)
   I/II/IIIa/IIIbc
6 (21) / 16 (57) / 5 (18) / 1 (4)
Involved organs
   Median (range)
2 (1-4)
   ≥2 organs, n (%)
19 (68)
   Kidney/heart/liver, n (%)
19 (68) /17 (61) / 4 (14)
   Otherd, n (%)
21 (75)
Median duration of follow-up (range),e months
22.9 (1.3-26)
Median duration of study treatment (range), months
20.7 (0.2-23.7)
Median number of cycles received (range)
21 (1-24)
Abbreviations: dFLC, difference between involved and uninvolved free light chain; ECOG, Eastern Cooperative Oncology Group; NT-proBNP, N-terminal pro-brain natriuretic peptide.
aECOG performance status is scored on a scale from 0 to 5, with 0 indicating no symptoms and higher scores indicating increasing disability.
bBased on the European Modification of the Mayo Staging system (Wechalekar et al. Blood 2013;121(17):3420-3427); cardiac stage was based on 2 biomarker risk factors: NT-proBNP and high sensitivity cardiac troponin.
cOne patient with values corresponding to IIIa during screening subsequently increased to IIIB on cycle 1, day 1.
dIncludes nerves, peripheral nerve system, autonomic nerve system, gastrointestinal tract, and soft tissue.
eBased on Kaplan-Meier estimate.
Characteristics
  • Median dose intensity of DARZALEX FASPRO (mg/cycle): 2580 (range, 2374-6000)
  • Median dose intensity of cyclophosphamide (mg/m2/cycle): 922 (range, 434-1182)
  • Median dose intensity of bortezomib (mg/m2/cycle): 5 (range, 3-5)
  • Median dose intensity of dexamethasone (mg/cycle): 110 (range, 20-160)
Efficacy

Hematologic Response Rates5
Response rate, %
Patients (N=28)
ORRa
96
CRb
57
VGPR
25
PR
14
Abbreviations: CR, complete response; ORR, overall response rate; PR, partial response; VGPR, very good partial response.
a1 (3.6%) patient had no response.
bCR per Comenzo criteria (Comenzo RL, et al. Leukemia. 2012;26(11):2317-2325. 2. Sidana S, et al. Leukemia. 2019;34(5):1472-1475) with 2 clarifications: abnormal FLC ratio did not preclude CR, CR required confirmation.
  • Median time to first response: 22 days (range, 7-339).
  • Median time to VGPR: 19 days (range, 7-339).
  • Median time to CR: 99 days (range, 29-589).
  • Median duration of hematologic CR has not been reached. Deep hematologic response rates were:
    • 19/28 (68%) patients had an absolute dFLC level <10 mg/L
    • 20/28 (71%) patients had an involved free light chain (iFLC) level ≤20 mg/L.
  • Responses occurred in 82% (14/17) of patients with cardiac involvement, in 79% (15/19) of patients with renal involvement, and in 50% (2/4) of patients with hepatic involvement.
    • Cardiac response was defined by a decrease in N-terminal pro-brain natriuretic peptide (NT-proBNP) of 30% and >300 ng/L from baseline or NYHA class response.
    • Renal response was defined by a ≥30% decrease in proteinuria or drop in proteinuria below 0.5 g in 24 hours without renal progression.
    • Liver response was defined by a ≥50% decrease in abnormal alkaline phosphatase value.
Safety
  • The most common (≥50%) any-grade TEAEs were diarrhea (n=19; 68%), fatigue (n=16; 57%), peripheral edema (n=14; 50%), and dizziness (n=14, 50%).
  • A total of 20 (71%) patients experienced grade 3/4 TEAEs and 12 (43%) patients experienced serious TEAEs.
  • Grade 3/4 (>5%) TEAEs are presented in Table: Grade 3/4 (>5%) TEAEs.

Grade 3/4 (>5%) TEAEsa, 5
n (%)
Patients (N=28)
Overall
20 (71)
Fatigue
6 (21)
Lymphopenia
5 (18)
Peripheral edema
4 (14)
Diarrhea
4 (14)
Anemia
4 (14)
Fall
3 (11)
Pneumonia
3 (11)
Thrombocytopenia
2 (7)
Cellulitis
2 (7)
Hypoalbuminemia
2 (7)
Hyponatremia
2 (7)
Syncope
2 (7)
Acute kidney injury
2 (7)
Abbreviations: TEAE, treatment-emergent adverse event.
aOccurring in ≥2 patients (>5%).
  • The most common grade 3/4 TEAEs were fatigue (n=6; 21%), lymphopenia (n=5; 18%), diarrhea, anemia, and peripheral edema (all n=4; 14%), fall and pneumonia (each n=3; 11%)
  • Serious TEAEs included fall and acute kidney injury (each n=3; 11%), cellulitis (not related to injection site) and pneumonia (each n=2; 7%).
  • Systemic ARRs occurred in 2 (7%) patients, which presented as chest discomfort (n=2, 7%), cough (n=1, 4%), hypotension (n=1, 4%), oropharyngeal pain (n=1, 4%), and sneezing (n=1, 4%). All presented as grade 1 and occurred on cycle 1 day 1 with the exception of hypotension which occurred on cycle 1 day 8. All ARRs were resolved.
  • ISRs (n=6) occurred in 3 (11%) patients (all grade 1); these included erythema, induration, and skin discoloration. None led to changes in treatment.
  • A total of 5 (18%) patients died (n=3 were transplant-related; n=1 due to progressive hepatic amyloidosis, peritonitis, and renal failure complications; n=1 due to progressive cardiac and liver amyloidosis).

Outcomes Across Response Criteria in the ANDROMEDA Study

Palladini et al (2022)6 evaluated the results of the ANDROMEDA study as per the revised ISA criteria of CR vs the original ANDROMEDA study CR criteria at 3 and 6 months, respectively.

Study Design/Methods

  • As per the revised ISA criteria, CR was defined as negative serum and urine immunofixation and normal free light chain ratio (FLCr); however, an abnormal FLCr was not considered to preclude the achievement of CR when the uninvolved free light chain (uFLC) concentration is greater than the iFLC concentration.18
  • As per the original ANDROMEDA study criteria, CR was defined as negative serum and urine immunofixation, normal FLCr, and normal iFLC levels (normal uFLC level and normal FLCr were not required if the iFLC level was <upper limit of normal).1
  • Hematologic response was assessed using both the revised ISA criteria and the ANDROMEDA study criteria at 3 months and 6 months, respectively.

Results

  • At a median follow-up of 11.4 months, hematologic responses at 3 months and 6 months were similar between the ISA criteria and the ANDROMEDA study criteria. See Table: Hematologic Response in the ITT Population.
    • Rates of hematologic CR and ≥VGPR were higher in the D-VCd arm vs the VCd arm regardless of the criteria for CR applied.
  • The Cohen’s Kappa coefficient for hematologic response was 0.91 (95% CI, 0.88-0.94) at 3 months and 0.89 (95% CI, 0.86-0.93) at 6 months, indicating a strong concordance between the two criteria.
  • MOD-PFS and -EFS by hematologic response at 3 months and 6 months are presented in Table: MOD-PFS and -EFS by Hematologic Response at 3 Months and 6 Months.

Hematologic Response in the ITT Population6
Parameter, %
ISA Criteria
ANDROMEDA Criteria
D-VCd (n=195)
VCd (n=193)
D-VCd (n=195)
VCd (n=193)
At 3 months
   CR
31.3
14
38
10.9
   VGPR
33.8
21.8
27.7
25.4
   PR
13.3
21.8
13.3
22.8
   NR
5.1
16.1
3.6
14.5
   PD
0.5
0.5
1
0.5
   NE
15.9
25.9
16.4
25.9
At 6 months
   CR
38.5
18.1
46.7
15
   VGPR
30.8
24.9
22.6
28
   PR
8.2
11.9
9.2
12.4
   NR
3.1
5.2
1.5
4.7
   PD
0
1
0.5
1
   NE
19.5
38.9
19.5
38.9
Abbreviations: CR, complete response; D-VCd, DARZALEX FASPRO + bortezomib + cyclophosphamide + dexamethasone; ISA, International Society of Amyloidosis; ITT, intention-to-treat; NE, not evaluable; NR, no response; PD, progressive disease; PR, partial response; VCd, bortezomib + cyclophosphamide + dexamethasone; VGPR, very good partial response.

MOD-PFS and -EFS by Hematologic Response at 3 Months and 6 Months6
Criteria Used
3 Months
6 Months
HR
(95% CI)
P Value
Harrell’s Concordance
HR
(95% CI)
P Value
Harrell’s Concordance
MOD-PFS by hematologic response (<CR vs CR)
   ISA criteria
2.82
(1.08-7.36)
0.0342
0.58
6.62
(1.53-28.66)
0.0115
0.67
   ANDROMEDA
   study criteria
4.16
(1.45-11.96)
0.0082
0.60
8.33
(1.92-36.12)
0.0046
0.70
MOD-EFS by hematologic response (<CR vs CR)
   ISA criteria
5.30
(2.44-11.51)
<0.0001
0.62
9.55
(3.45-26.45)
<0.0001
0.68
   ANDROMEDA
   study criteria
8.66
(3.50-21.42)
<0.0001
0.64
15.86
(4.95-50.82)
<0.0001
0.71
MOD-PFS by hematologic response (<VGPR vs ≥VGPR)
   ISA criteria
4.49
(2.16-9.33)
<0.0001
0.68
3.74
(1.46-9.59)
0.0062
0.65
   ANDROMEDA
   study criteria
5.13
(2.42-10.88)
<0.0001
0.68
4.26
(1.64-11.08)
0.0030
0.65
MOD-EFS by hematologic response (<VGPR vs ≥VGPR)
   ISA criteria
5.65
(3.51-9.07)
<0.0001
0.72
5.65
(3.29-9.68)
<0.0001
0.70
   ANDROMEDA
   study criteria
6.64
(4.08-10.81)
<0.0001
0.73
6.50
(3.77-11.20)
<0.0001
0.71
Abbreviations: CR, complete response; EFS, event-free survival; HR, hazard ratio; ISA, International Society of Amyloidosis; MOD, major organ deterioration; PFS, progression-free survival; VGPR, very good partial response.

Literature Search

A literature search of MEDLINE®, Embase®, BIOSIS Previews®, and Derwent Drug File (and/or other resources, including internal/external databases) was conducted on 09 January 2025. This information is intended to include clinical trial data, rather than being all-inclusive; therefore, case reports have been excluded.

References

Show
1 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.  
2 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. Oral Presentation presented at: The 63rd American Society of Hematology (ASH) Annual Meeting & Exposition; December 11-14, 2021; Atlanta, GA/Virtual.  
3 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.  
4 Palladini G, Kastritis E, Maurer MS, et al. Daratumumab plus CyBorD for patients with newly diagnosed AL amyloidosis: safety run-in results of ANDROMEDA. Blood. 2020;136(1):71-80.  
5 Comenzo R, Kastritis E, Maurer M, et al. Subcutaneous daratumumab + cyclophosphamide/bortezomib/dexamethasone in newly diagnosed AL amyloidosis: updated safety run-in results of ANDROMEDA. Oral Presentation presented at: The 17th International Symposium on Amyloidosis; September 14-18, 2020; Tarragona, Spain.  
6 Palladini G, Wechalekar A, Kastritis E, et al. Assessing clinical outcomes in patients with AL amyloidosis across different criteria for hematologic complete response: results from ANDROMEDA. Poster presented at: XVIII International Symposium on Amyloidosis; September 4-8, 2022; Heidelberg, Germany.  
7 Kumar S, Dispenzieri A, Bhutani D, et al. Impact of cytogenetic abnormalities on treatment outcomes in patients with amyloid light-chain amyloidosis: subanalyses from the ANDROMEDA study. Amyloid. 2023;30(3):268-278.  
8 Kumar S, Dispenzieri A, Bhutani D. Supplement to: Impact of cytogenetic abnormalities on treatment outcomes in patients with amyloid light-chain amyloidosis: subanalyses from the ANDROMEDA study. Amyloid. 2023;30(3):268-278.  
9 Suzuki K, Wechalekar AD, Kim K, et al. Daratumumab plus bortezomib, cyclophosphamide, and dexamethasone in Asian patients with newly diagnosed AL amyloidosis: subgroup analysis of ANDROMEDA. Ann Hematol. 2023;102(4):863-876.  
10 Comenzo R, Kastritis E, Minnema M, et al. Reduction in absolute involved free light chain and difference between involved and uninvolved free light chain is associated with prolonged major organ deterioration progression-free survival in patients with newly diagnosed AL amyloidosis receiving bortezomib, cyclophoshpamide, and dexamethasone with or without daratumumab: results from ANDROMEDA. Oral presentation presented at: 62nd American Society of Hematology (ASH) Annual Meeting & Exposition; December 5-8, 2020; Virtual meeting.  
11 Wechalekar A, Palladini G, Merlini G, et al. Rapid and deep hematologic responses are associated with improved major organ deterioration progression-free survival in newly diagnosed AL amyloidosis: results from ANDROMEDA. Poster presented at: 62nd American Society of Hematology (ASH) Annual Meeting & Exposition; December 5-8, 2020; Virtual meeting.  
12 Minnema M, Dispenzieri A, Merlini G, et al. Outcomes by cardiac stage in newly diagnosed AL amyloidosis: results from ANDROMEDA. Poster presented at: 62nd American Society of Hematology (ASH) Annual Meeting & Exposition; December 5-8, 2020; Virtual meeting.  
13 Sanchorawala V, Palladini G, Minnema M, et al. Health-related quality of life in patients with light chain amyloidosis treated with bortezomib, cyclophosphamide, and dexamethasone +/- daratumumab: results from the ANDROMEDA study. Am J Hematol. 2022;97(6):719-730.  
14 Grogan M, Maurer M, Witteles R, et al. Effect of daratumumab, bortezomib, cyclophosphamide, and dexamethasone on cardiac function and health-related quality of life in patients with newly diagnosed AL amyloidosis with cardiac involvement: results from the phase 3 ANDROMEDA study. Poster presented at: 70th Annual Scientific Session & Expo of the American College of Cardiology (ACC); May 15-17, 2021; Virtual meeting.  
15 Havasi A, Lachmann HJ, Leung N, et al. Effect of daratumumab/ bortezomib/ cyclophosphamide/ dexamethasone on renal function and HRQoL in patients with newly diagnosed AL amyloidosis with renal involvement: results from the phase 3 ANDROMEDA study. Poster presented at: International Society of Nephrology (ISN) Virtual World Congress of Nephrology (WCN) Meeting; April 15-19, 2021; Virtual.  
16 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.  
17 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.  
18 Palladini G, Schönland SO, Sanchorawala V, et al. Clarification on the definition of complete haematologic response in light-chain (AL) amyloidosis. Amyloid. 2021;28(1):1-2.