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DARZALEX® (daratumumab)

Medical Information

Use of DARZALEX + DARZALEX FASPRO in Immunoglobulin Light Chain Amyloidosis

Last Updated: 07/25/2025

SUMMARY

  • DARZALEX for intravenous (IV) use is not approved by the regulatory agencies for the impact treatment of patients with systemic immunoglobulin light-chain (AL) amyloidosis. Janssen does not recommend the use of DARZALEX in a manner that is inconsistent with the approved labeling.
  • ANDROMEDA is an ongoing, 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 bortezomib, cyclophosphamide and dexamethasone (VCd alone) in newly diagnosed patients with systemic 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 best response of hematologic complete response (CR) was achieved by 53.3% of the D-VCd arm vs 18.1% of the VCd arm, respectively (relative risk ratio, 2.9; 95% confidence interval [CI], 2.1-4.1; 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 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], 6.0; 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.
    • Palladini et al (2020)3 reported safety run-in results of the ANDROMEDA study with a median follow-up of 17.6 months. Comenzo et al (2020)4 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)5 evaluated the consistency of the results of the ANDROMEDA study as per the revised International Society of Amyloidosis (ISA) criteria vs the original ANDROMEDA study criteria for CR. With a median follow-up of 11.4 months, the rate of hematologic CR was 31.3% vs 14% for ISA criteria and 38.0% vs 10.9% for ANDROMEDA criteria in the D-VCd vs VCd arm, respectively.
    • Sanchorawala et al (2022)6 reported the patient-reported outcomes (PRO) data collected during treatment in the ANDROMEDA study. This analysis is referenced below.
    • Kumar et al (2023)7 reported a post hoc analysis of the ANDROMEDA study evaluating the impact of cytogenetic abnormalities on treatment outcomes in patients with AL amyloidosis. At a median follow-up of 20.3 months, the rates of hematologic CR in the D-VCd vs VCd arm across all subgroups of patients with cytogenetic abnormalities were: del17p13, 55.6% vs 0 (OR, not evaluable [NE]; 95% CI, NE-NE; P=0.0294); t(11;14), 59.3% vs 12.5% (OR, 10.18; 95% CI, 3.90-26.60; P<0.0001); del13q14, 72.2% vs 14.3% (OR, 15.60; 95% CI, 3.56-68.39; P=0.0001); and amp1q21, 59.4% vs 10.7% (OR, 12.18; 95% CI, 3.03-48.89; P=0.0001), respectively.
    • Suzuki et al (2023)8 reported a post hoc analysis of the ANDROMEDA study evaluating the efficacy and safety endpoints in a subgroup of Asian patients. This analysis has been referenced below.
    • Kastritis et al (2024)9 presented (at the 66th ASH Annual Meeting) the final analysis for MOD-PFS and overall survival (OS) in the ANDROMEDA study with a median follow-up of 61.4 months. It 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 higher rates of hematologic response. MOD-PFS was observed in 79/195 vs 118/193 patients from the D-VCd vs VCd group, respectively (hazard ratio [HR], 0.44; 95% CI, 0.31-0.63; P<0.0001). The median MOD-PFS was not reached in the D-VCd group and was 30.2 months in the VCd group. At a median follow-up of 61.4 months, D-VCd vs VCd significantly improved OS, despite crossover in >70% of patients on VCd who received DARZALEX FASPRO as subsequent therapy (HR, 0.62; 95% CI, 0.42-0.90; P=0.0121). D-VCd was associated with 2 to 3 times higher cardiac and renal response rates vs VCd across study timepoints. Safety data were consistent with the known safety profiles for D-VCd and VCd.
  • Rosenbaum et al (2023)10 presented a phase 2, single-arm, multicenter study that evaluated DARZALEX FASPRO in combination with pomalidomide and dexamethasone (DPd) in patients with relapsed/refractory AL amyloidosis who were previously exposed to DARZALEX, including those with low dFLC (20-50 mg/L) at relapse. OR was 67%. Grade 3 non-hematologic adverse events (AEs) were respiratory infection (n=2), pulmonary embolus (n=1), and cellulitis (n=1).
  • Kastritis et al (2024)11 presented (results from an ongoing, phase 2, open-label, multicenter, European Myeloma Network (EMN) 22 study evaluating the efficacy and safety of DARZALEX monotherapy in patients (N=40) with stage 3B newly diagnosed AL amyloidosis (data cutoff of December 15, 2023). At a median follow-up duration of 10.3 months, the ORR was 77.5% and OS rates at 6- and 12-month were 65% (95% CI, 48.2-77.6) and 45.0% (95% CI, 29.3-59.5), respectively. At least one serious TEAE was reported by 32 patients (80%), and fatal serious adverse events (SAEs) were reported by 17 patients (42.5%). Kastritis et al (2024)12 presented updated results of the study at the 66th ASH Annual Meeting (data cutoff of May 31, 2024).
  • Hagen et al (2024)13 reported a phase 3, randomized study (NCT06022939) evaluating the safety and efficacy of D-VCd induction followed by autologous stem cell transplant (ASCT) vs D-VCd consolidation and DARZALEX maintenance in patients newly diagnosed with AL amyloidosis. Results are not available at this time.
  • AQUARIUS is an ongoing, multicenter, multicohort, open-label, phase-2 study evaluating D-VCd in patients with newly diagnosed systemic AL amyloidosis. Results are not available at this time.14
  • Lee et al (2024)15 presented (at the EHA Annual Meeting) the final results of a phase 1, single-center, open-label, investigator-initiated study, which evaluated the safety and preliminary efficacy of the novel combination of DARZALEX/DARZALEX FASPRO, ixazomib, and dexamethasone (DId) in patients with AL amyloidosis. Most common grade ≥3 TEAEs included lymphopenia (n=7), lung infection (n=6), and hypertension (n=5). Median time to best hematologic response was 28 days. Median time to hematologic very good partial response (VGPR) among 16 patients with very good partial response or better (≥VGPR) was 28 days.
  • Other relevant literature has been identified in addition to the data summarized above and is listed in the References section for your information.16-45

PRODUCT LABELING

CLINICAL DATA

DARZALEX FASPRO - Phase 3 Study

ANDROMEDA is an ongoing, prospective, randomized, active-controlled, multicenter, phase 3 study (AMY3001; NCT03201965) 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)46 presented updated efficacy and safety results of the ANDROMEDA study at 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.

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 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

Baseline Characteristics
  • Baseline patient demographics and disease characteristics from the primary results are presented in Table: Baseline Characteristics of Patients.
  • 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 (range) age, 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)
Sex, 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 (81.0) / 37 (19.0)
149 (77.2) / 44 (22.8)
Median (range) time since diagnosis, days
48 (8-1611)
43 (5-1102)
dFLC
   Median (range) baseline dFLC, 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 (59.0) / 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 (39.0) / 70 (35.9) / 2 (1.0)
43 (22.3) / 80 (41.5) / 64 (33.2) / 6 (3.1)
Renal Stagef, 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)
1746.0 (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; dFLC, difference between involved and uninvolved free light chain; D-VCd, DARZALEX FASPRO + bortezomib + cyclophosphamide + dexamethasone; ECOG, Eastern Cooperative Oncology Group; FLC, free light chain; GFR, glomerular filtration rate; ITT, intention-to-treat; 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).
fRenal stage is based on the combination of estimated GFR and urinary protein excursion.

Post Hoc Subgroup Analyses of Patients with Cytogenetic Abnormalities

Kumar et al (2023)7 reported a post hoc analysis of the ANDROMEDA study evaluating the impact of the presence of cytogenetic abnormalities on treatment outcomes in patients with AL amyloidosis.

Results

Patient Characteristics
  • The distribution of cytogenetic abnormalities (del17p13, t[11;14], del13q14, and amp1q21) across treatment arms in the ANDROMEDA study is summarized in Table: Distribution of Cytogenetic Abnormalities.
  • The most commonly detected cytogenetic abnormality was t(11;14), which was detected individually in 78 patients, in combination with amp1q21 in 19 patients, and in combination with del13q14 in 17 patients. One patient had all the 4 evaluated cytogenetic abnormalities.
  • The median duration of follow-up was 20.3 months.
  • Baseline demographics and disease characteristics of patients with cytogenetic abnormalities are summarized in Table: Baseline Demographic and Disease Characteristics of Patients with Cytogenetic Abnormalities.

Distribution of Cytogenetic Abnormalities7
Parameter
D-VCd (n=195)
VCd (n=193)
Total (N=388)
FISH/karyotype test performed, n (%)
155 (79.5)
166 (86.0)
321 (82.7)
Cytogenetic abnormality, n/N (%)
   del17p13
9/134 (6.7)
9/148 (6.1)
18/282 (6.4)
   t(11;14)
54/126 (42.9)
56/140 (40.0)
110/266 (41.4)
   del13q14
18/111 (16.2)
28/127 (22.0)
46/238 (19.3)
   amp1q21
32/126 (25.4)
28/138 (20.3)
60/264 (22.7)
Cytogenetic abnormality + ≥1 additional chromosome abnormalitya, n/N (%)
   del17p13
9/133 (6.8)
6/147 (4.1)
15/280 (5.4)
   t(11;14)
27/124 (21.8)
30/137 (21.9)
57/261 (21.8)
   del13q14
16/111 (14.4)
26/127 (20.5)
42/238 (17.6)
   amp1q21
27/126 (21.4)
25/138 (18.1)
52/264 (19.7)
Abbreviations: D-VCd, DARZALEX FASPRO + bortezomib + cyclophosphamide + dexamethasone; FISH, fluorescence in situ hybridization; ITT, intention-to-treat; VCd, bortezomib + cyclophosphamide + dexamethasone.
aFor FISH/karyotype, numerator = abnormality of the specified gene plus 1 additional chromosomal abnormality and denominator = total number of patients with the specified chromosome tested plus ≥1 additional gene tested from FISH test and the number of patients who had whole bone marrow karyotype performed.

Baseline Demographic and Disease Characteristics of Patients with Cytogenetic Abnormalities7
Characteristic
del17p13 (n=18)
t(11;14) (n=110)
del3q14 (n=46)
amp1q21 (n=60)
ITT (N=388)
Median age (range), years
66.5
(45-79)
63.0
(41-87)
64.0
(43-79)
65.0
(44-83)
64.0
(34-87)
Male, n (%)
7 (38.9)
80 (72.7)
27 (58.7)
30 (50)
225 (58.0)
ECOG performance status, n (%)
   0
2 (11.1)
46 (41.8)
22 (47.8)
31 (51.7)
161 (41.5)
   1
12 (66.7)
53 (48.2)
23 (50.0)
26 (43.3)
192 (49.5)
   2
4 (22.2)
11 (10.0)
1 (2.2)
3 (5)
35 (9.0)
Median number of organs involved (range)
2 (1-6)
2 (1-5)
2 (1-6)
2 (1-6)
2 (1-6)
Organ involvement, n (%)
   Heart
14 (77.8)
85 (77.3)
34 (73.9)
46 (76.7)
277 (71.4)
   Kidney
12 (66.7)
65 (59.1)
30 (65.2)
42 (70.0)
229 (59.0)
Cardiac stage, n (%)
   I
2 (11.1)
19 (17.3)
10 (21.7)
8 (13.3)
90 (23.2)
   II
6 (33.3)
45 (40.9)
17 (37.0)
26 (43.3)
156 (40.2)
   IIIa
38 (44.4)
44 (40.0)
17 (37.0)
25 (41.7)
134 (34.5)
   IIIba
2 (11.1)
2 (1.8)
2 (4.3)
1 (1.7)
8 (2.1)
Baseline dFLC, mg/L
   Median (range)
248.8
(1-4567)
225.4
(4-1586)
188.3
(31-3256)
152.3
(4-3256)
187.1
(1-9983)
   <18 mg/dL, n (%)
7 (38.9)
48 (43.6)
21 (45.7)
33 (55.0)
190 (49.0)
   ≥18 mg/dL, n (%)
11 (61.1)
62 (56.4)
25 (54.3)
27 (45.0)
198 (51.0)
Plasma cells, n (%)
   <10%
5 (27.8)
42 (38.2)
13 (28.3)
16 (26.7)
169 (43.6)
   10-20%
9 (50.0)
49 (44.5)
25 (54.3)
28 (46.7)
165 (42.5)
   >20%
4 (22.2)
19 (17.3)
8 (17.4)
16 (26.7)
54 (13.9)
Median M-protein (range), g/L
4.5 (0-19)
0 (0-22)
1.5 (0-23)
8.0 (0-23)
0 (0-64)
Abbreviations: dFLC, difference between involved and uninvolved serum free light chains; ECOG, Eastern Cooperative Oncology Group; ITT, intention-to-treat.
aPatients in the IIIb category were excluded from participation in the study per protocol. All patients were known IIIa at screening; however, 8 turned into IIIb at cycle 1 day 1.
Efficacy

Hematologic Response Rates Across Cytogenetic Abnormality Subgroups7,47
Parameter
del17p13
t(11;14)
del13q14
amp1q21
≥2 Cytogenetic Abnormalitiesa
ITT
D-VCd
VCd
D-VCd
VCd
D-VCd
VCd
D-VCd
VCd
D-VCd
VCd
D-VCd
VCd
n
9
9
54
56
18
28
32
28
25
29
195
193
ORR, %
88.9
55.6
98.1
71.4
94.4
78.6
93.8
89.3
96.0
82.8
91.8
76.7
   CRb, %
55.6
0
59.3
12.5
72.2
14.3
59.4
10.7
64.0
3.4
59.0
19.2
      ORc
      (95%
      CI)
NE (NE-NE)
10.18
(3.90-26.60)
15.60
(3.56-68.39)
12.18
(3.03-48.89)
49.78
(5.77-429.63)
5.90
(3.72-9.37)
P value
0.0294d
<0.0001d
0.0001d
0.0001d
<0.0001d
<0.0001e
≥VGPR, %
77.8
33.3
77.8
46.4
83.3
50.0
81.3
53.6
80.0
44.8
79.0
50.3
   VGPR, %
22.2
33.3
18.5
33.9
11.1
35.7
21.9
42.9
16.0
41.4
20.0
31.1
PR, %
11.1
22.2
20.4
25.0
11.1
28.6
12.5
35.7
16.0
37.9
12.8
26.4
NR/NE/PD, %
11.1
44.4
1.9
28.6
5.6
21.4
6.3
10.7
4.0
17.2
8.2
23.3
Abbreviations: CI, confidence interval; CR, complete response; D-VCd, DARZALEX FASPRO + bortezomib + cyclophosphamide + dexamethasone; ITT, intention-to-treat; NE, not evaluable; NR, not reached; OR, odds ratio; ORR, overall response rate; PD, progressive disease; PR, partial response; VCd, bortezomib + cyclophosphamide + dexamethasone; VGPR, very good partial response.
aAt least two abnormal genes among del17p13, t(11;14), del13q14, and amp1q21.
bHematologic CR rate with D-VCd and VCd across cytogenetic subgroups up to the data cutoff.
cFor the subgroup analyses, the OR and 95% CI were from unstratified Mantel-Haenszel estimate of the common OR. For the ITT population, Mantel-Haenszel estimate of the common OR for stratified tables was used. The stratification factors from the interactive web response system were: cardiac staging (I, II, IIIa), countries that typically offer or not offer transplant for patients with AL amyloidosis (List A, List B), and baseline renal function (CrCl ≥60 mL/min or CrCl <60 mL/min).
dP value from Fisher’s exact test.
eP value from the Cochran-Mantel-Haenszel Chi-Squared test.

Time to Hematologic Response in Patients with t(11;14)7
Parameter
D-VCd (n=53)
VCd (n=40)
Patients achieving CR, n
32
7
   Median time to achieving CR (range)a, days
57 (11-394)
142 (58-340)
Patients achieving PR, n
53
40
   Median time to achieving PR (range)b, days
11 (5-87)
24 (8-115)
Abbreviations: CR, complete response; D-VCd, DARZALEX FASPRO + bortezomib + cyclophosphamide + dexamethasone; PR, partial response; VCd, bortezomib + cyclophosphamide + dexamethasone.
aTime from randomization date up to the first response of CR.
bTime from randomization date up to the first response of PR or better.

Impact of the Presence or Absence of t(11; 14) on Responses by Treatment Received7
Patients, n (%)
D-VCd
VCd
With t(11;14) (n=54)
Without t(11;14) (n=72)
P Valuea
With t(11;14) (n=56)
Without t(11;14) (n=84)
P Valuea
Hematologic CR
32 (59.3)
44 (61.1)
0.8558
7 (12.5)
20 (23.8)
0.1264
≥VGPR
42 (77.8)
58 (80.6)
0.8245
26 (46.4)
47 (56.0)
0.3027
Abbreviations: CR, complete response; D-VCd, DARZALEX FASPRO + bortezomib + cyclophosphamide + dexamethasone; PR, partial response; VCd, bortezomib + cyclophosphamide + dexamethasone; VGPR, very good partial response.

Impact of the Presence or Absence of amp1q21 on Responses by Treatment Received7
Patients, n (%)
D-VCd
VCd
With amp1q21 (n=32)
Without amp1q21 (n=94)
P Valuea
With amp1q21
(n=28)
Without amp1q21 (n=110)
P Valuea
Hematologic CR
19 (59.4)
56 (59.6)
>0.999
3 (10.7)
21 (19.1)
0.4068
≥VGPR
26 (81.3)
76 (80.9)
>0.999
15 (53.6)
55 (50.0)
0.8333
Abbreviations: CR, complete response; D-VCd, DARZALEX FASPRO + bortezomib + cyclophosphamide + dexamethasone; PR, partial response; VCd, bortezomib + cyclophosphamide + dexamethasone; VGPR, very good partial response.

Deep Response Dataa, 7
Parameter
D-VCd
VCd
Response-evaluable patients in the ITT population, n
195
193
   Patients achieving deep response, %
74.9
33.7
Response-evaluable patients in the t(11;14) group, n
54
56
   Patients achieving deep response, %
75.9
17.9
Abbreviations: dFLC, difference between involved minus uninvolved serum free light chains; D-VCd, DARZALEX FASPRO + bortezomib + cyclophosphamide + dexamethasone; iFLC, involved free light chain; ITT, intention-to-treat; VCd, bortezomib + cyclophosphamide + dexamethasone.
aDeep response was defined as dFLC <10 mg/L or iFLC ≤20 mg/L.

Rate of Cardiac and Renal Response at 6 Months7
Cytogenetic Abnormality Subgroup
D-VCd
VCd
ORa (95% CI)
P value
n
% of Patients With Response
n
% of Patients With Response
Cardiac Response
   del17p13
8
12.5
6
16.7
0.71 (0.04-14.35)
1.000b
   t(11;14)
37
43.2
36
27.8
1.98 (0.75-5.26)
0.2231b
   del13q14
12
58.3
15
33.3
2.80 (0.58-13.48)
0.2576b
   amp1q21
23
47.8
17
29.4
2.20 (0.58-8.28)
0.3322b
   ≥2 cytogenetic
   abnormalitiesc
18
50.0
17
23.5
3.25 (0.76-13.89)
0.1642b
   ITT
118
41.5
117
22.2
2.44 (1.35-4.42)
0.0029d
Renal Response
   del17p13
7
85.7
4
0
NE (NE-NE)
0.0152b
   t(11;14)
33
42.4
33
21.2
2.74 (0.93-8.08)
0.1118b
   del13q14
11
54.5
17
35.3
2.20 (0.47-10.35)
0.4410b
   amp1q21
23
47.8
18
22.2
3.21 (0.81-12.75)
0.1138b
   ≥2 cytogenetic
   abnormalitiesc
18
50.0
18
33.3
2.00 (0.52-7.69)
0.4998b
   ITT
117
53.0
113
23.9
3.88 (2.15-6.99)
<0.0001d
Abbreviations: CI, confidence interval; D-VCd, DARZALEX FASPRO + bortezomib + cyclophosphamide + dexamethasone; ITT, intention-to-treat; OR, odds ratio; VCd, bortezomib + cyclophosphamide + dexamethasone.
aFor the subgroup analyses, the OR and 95% CI were from unstratified Mantel-Haenszel estimate of the common OR. For the ITT population, the Mantel-Haenszel estimate of the common OR for stratified tables was used. The stratification factors from the interactive web response system were: cardiac staging (I, II, IIIa), countries that typically offer or not offer transplant for patients with AL amyloidosis (List A, List B), and baseline renal function (CrCl ≥60 mL/min or CrCl <60 mL/min).
bP value from Fisher’s exact test.
cAt least two abnormal genes among del17p13, t(11;14), del13q14, and amp1q21.
dP value from the Cochran-Mantel-Haenszel Chi-Squared test.

MOD-PFS and MOD-EFS Across Cytogenetic Abnormality Subgroups7
Subgroup
D-VCd
VCd
HR
(95% CI)a
Event/N (%)
Median, months
Event/N (%)
Median, months
MOD-PFS
   del17p13
1/9 (11.1)
NE
4/9 (44.4)
7.5
0.18 (0.02-1.62)a
   t(11;14)
7/54 (13.0)
NE
11/56 (19.6)
NE
0.55 (0.21-1.43)a
   del13q14
1/18 (5.6)
NE
6/28 (21.4)
NE
0.19 (0.02-1.62)a
   amp1q21
6/32 (18.8)
NE
5/28 (17.9)
NE
0.89 (0.27-2.93)a
   ITT
34/195 (17.4)
NE
53/193 (27.5)
NE
0.58 (0.36-0.93)b
MOD-EFS
   del17p13
2/9 (22.2)
NE
6/9 (66.7)
7.0
0.23 (0.05-1.17)a
   t(11;14)
10/54 (18.5)
NE
27/56 (48.2)
8.6
0.32 (0.16-0.67)a
   del13q14
3/18 (16.7)
NE
14/28 (50.0)
9.4
0.23 (0.07-0.80)a
   amp1q21
9/32 (28.1)
NE
13/28 (46.4)
13.44
0.53 (0.23-1.25)a
   ITT
46/195 (23.6)
NE
92/193 (47.7)
8.8
0.39 (0.27-0.56)c
Abbreviations: CI, confidence interval; D-VCd, DARZALEX FASPRO + bortezomib + cyclophosphamide + dexamethasone; EFS, event-free survival; HR, hazard ratio; ITT, intention-to-treat; MOD, major organ deterioration; NE, not evaluable; PFS, progression-free survival; VCd, bortezomib + cyclophosphamide + dexamethasone.aHR and 95% CI for each cytogenetic subgroup are from an unstratified Cox proportional hazards model with treatment as the sole explanatory variable.
bHR and 95% CI for the ITT population are from unstratified weighted Cox proportional hazards model, including treatment group as the sole explanatory variable by using Inverse Probability of Censoring Weighting method.
cHR and 95% CI for the ITT population are from a Cox proportional hazards model with treatment as the sole explanatory variable and stratified with cardiac stage (Stage I, II, and IIIa), countries that typically offer or not offer transplant for patients with AL amyloidosis, and renal function (CrCl ≥60 mL/min or CrCl <60 mL/min) as randomized.

Hematologic CR and Organ Responses According to Baseline dFLC and Plasma Cell Percentage7
Parameter
Hematologic CR
Cardiac Response
(at 6 months)
Renal Response
(at 6 months)
D-VCd (n=195)
VCd (n=193)
D-VCd (n=118)
VCd (n=117)
D-VCd
(n=117)
VCd
(n=113)
Baseline dFLC, n/N (%)
   <18 mg/dL
59/94 (62.8)
24/96 (25.0)
19/54 (35.2)
11/47 (23.4)
38/62 (61.3)
15/68 (22.1)
   ≥18 mg/dL
56/101 (55.4)
13/97 (13.4)
30/64 (46.9)
15/70 (21.4)
24/55 (43.6)
12/45 (26.7)
Baseline plasma cell percentage, n/N (%)
   <10%
52/81 (64.2)
17/88 (19.3)
15/42 (35.7)
10/51 (19.6)
30/53 (56.6)
15/52 (28.8)
   10-20%
55/87 (63.2)
16/78 (20.5)
26/57 (45.6)
11/44 (25.0)
23/47 (48.9)
9/45 (20.0)
   >20%
8/27 (29.6)
4/27 (14.8)
8/19 (42.1)
5/22 (22.7)
9/17 (52.9)
3/16 (18.8)
Abbreviations: CR, complete response; dFLC, difference between involved and uninvolved serum free light chains; D-VCd, DARZALEX FASPRO + bortezomib + cyclophosphamide + dexamethasone; VCd, bortezomib + cyclophosphamide + dexamethasone.
Safety

Treatment Discontinuations7
n/N (%)
D-VCd
VCd
ITT
67/195 (34.4)
129/193 (66.8)
t(11;14)
15/54 (27.8)
42/56 (75.0)
amp1q21
9/32 (28.1)
23/28 (82.1)
del13q14
3/18 (16.7)
18/28 (64.3)
del17p13
2/9 (22.2)
7/9 (77.8)
Two or more abnormal genes
6/25 (24.0)
21/29 (72.4)
Abbreviations: D-VCd, DARZALEX FASPRO + bortezomib + cyclophosphamide + dexamethasone; ITT, intention-to-treat; VCd, bortezomib + cyclophosphamide + dexamethasone.

Final Analysis for MOD-PFS and OS

Kastritis et al (2024)9 presented (at the 66th ASH Annual Meeting) results from the final analysis for MOD-PFS and OS in the ANDROMEDA study with a median follow-up of 61.4 months.

Results

Baseline Demographics and Clinical Characteristics

Baseline Demographics and Clinical Characteristics9
Characteristic
D-VCd
(n=195)
VCd
(n=193)
Age
   Median age (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 (81.0)
149 (77.2)
   Kappa
37 (19.0)
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 (71.0)
      Kidney
115 (59.0)
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 (39.0)
80 (41.5)
   IIIA
70 (35.9)
64 (33.2)
   IIIBf
2 (1.0)
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 is 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 includes the gastrointestinal tract, lungs, peripheral nervous system, autonomic nervous system, and soft tissues.
eCardiac stage was classified in accordance with the European modification of the staging system of the 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 is based on the combination of estimated GFR and urinary protein excretion.
Treatment Exposure and Subsequent Therapy
  • Details of treatment exposure and subsequent therapy over a median follow-up of 61.4 months 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 group, respectively, received subsequent therapy.9
    • A total of 71.3% (82/115) of patients from the VCd group received subsequent DARZALEX FASPRO-based therapy.9
    • The most common reasons for DARZALEX FASPRO discontinuation were death (n=23), ASCT (n=12), and AEs (n=11).9

Treatment Exposure and Subsequent Therapy9
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)
24.0 (1.0-25.0)
6.0 (1.0-6.0)
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 group received a maximum of 6 cycles of treatment, whereas the maximum treatment duration was 2 years for patients in the D-VCd group.
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.9
    • 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.9
  • D-VCd significantly improved MOD-PFS vs VCd alone.9
    • At a median follow-up of 61.4 months, the median MOD-PFS was not reached in the D-VCd group and was 30.2 months in the VCd group.
    • The estimated 60-month MOD-PFS rate was 60.2% vs 33.2% for the D-VCd vs VCd group, respectively.
    • MOD-PFS was observed in 79/195 vs 118/193 patients from the D-VCd vs VCd group, 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 group, respectively.
    • Analyses of the MOD-PFS rate in prespecified subgroups appeared to consistently favor D-VCd over VCd across relevant subgroups; 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 without hematologic/cardiac 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 patients on VCd who received DARZALEX FASPRO as subsequent therapy (HR, 0.62; 95% CI, 0.42-0.90; P=0.0121).9
    • The 60-month OS rate was 76.1% vs 64.7% for the D-VCd vs VCd group, 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 across study timepoints; results are summarized in Table: Cardiac and Renal Responses in the Final Analysis.

Summary of Overall Hematologic Responses in the Final Analysis9
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
79.0
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 Subgroups9
Subgroups
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, a left ventricular assist device, or an intra-aortic balloon pump), end-stage renal disease (requiring hemodialysis or a renal transplant), hematologic progression per consensus guidelines, or death.

OS in Prespecified Subgroups9
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 Analysis9
Parameter
D-VCd
VCd
Patients with evaluable 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, %
39.0
12.8
   48 months, %
27.1
9.4
Cardiac CR, %
40.7
13.7
Cardiac ≥VGPR, %
64.4
31.6
Patients with evaluable 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
15.0
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,9
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 (25.0)
2 (1.1)
Dyspnea
49 (25.4)
5 (2.6)
32 (17.0)
6 (3.2)
Lymphopenia
37 (19.2)
25 (13.0)
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 study treatment.
bAEs of any grade that were reported in >25% of patients in either treatment group and grade 3/4 AEs that were reported in ≥5% of patients in either treatment group are listed.

DARZALEX FASPRO - Phase 2 Study

Rosenbaum et al (2023)10 presented a phase 2, single-arm, multicenter study that evaluated DPd in patients with relapsed/refractory AL amyloidosis who were previously exposed to DARZALEX, including those with low dFLC (20-50 mg/L) at relapse.

Study Design/Methods

  • Eligibility criteria: relapsed or refractory disease, ≥1 prior line of therapy (LOT) with ≥8 DARZALEX doses in any prior line, and negative Calcium elevation, Renal dysfunction, Anemia and Bone disease (CRAB) criteria.
    • Patients with low dFLC were eligible with adapted response criteria used for low-dFLC partial response (PR; dFLC <10 mg/L).
  • Primary objective: hematologic best response within 12 months of DPd treatment.
  • Secondary objectives: hematologic ORR and VGPR, stringent dFLC response, low dFLC PR rates (in low dFLC patients only),minimal residual disease (MRD)-negative rates using next generation sequencing (NGS), serum mass spectrometry (MS) M-protein detection, time to first/best hematologic response, time to next therapy, median hematologic PFS/OS, renal and/or cardiac response rates, and duration of/time to organ response.
  • Dosing: Patients received DPd for 12 cycles with optional continuation of DARZALEX FASPRO and/or pomalidomide with or without dexamethasone if they achieved ≥VGPR after 12 cycles.
    • DARZALEX FASPRO 1800 mg SC QW for 8 weeks; 1800 mg SC Q2W for 8 weeks; and 1800 mg SC monthly starting cycle 7
    • Pomalidomide 4 mg orally (PO) on days 1-21 and day 28
    • Dexamethasone 20 mg IV cycle 1 days 1 and 8; 20 mg PO cycle 1 days 2 and 9; 40 mg PO QW through cycle 6; and 20 mg QW cycle 7 day 1 and beyond
      • Starting dexamethasone 20 mg allowed for patients with cardiac and/or renal disease.
  • Serum MS and NGS data were collected from bone marrow at baseline, at best response, and after 12-,18-, and 24-month follow-up.
  • Overall, 16 patients were to be enrolled.

Results

Patient Characteristics
  • As of the data cutoff of September 7, 2023, a total of 9 patients were enrolled; 4 patients had measurable dFLC, and 5 patients had met the criteria for low dFLC. Baseline patient characteristics are summarized in Table: Baseline Patient Characteristics.
  • Patient characteristics related to prior DARZALEX exposure are summarized in Table: Patient Characteristics Related to Prior DARZALEX FASPRO Exposure.
  • Five patients have completed all 12 cycles on study; 3 of the 5 patients remained on optional maintenance therapy beyond 12 cycles (DPd [n=1]; and pomalidomide alone [n=2]).
  • Three patients had not received 12 DPd cycles and continued on therapy.
  • One heavily pretreated patient with 6 prior LOTs and pre-existing neuropathy discontinued the study without response in cycle 3 due to grade 3 PN.

Baseline Patient Characteristics10
Characteristic
N=9
Median age, years (range)
62 (49-74)
Male, n (%)
4 (44)
Race and ethnicity, n (%)
   Non-Hispanic white
7 (78)
   Non-Hispanic black
1 (11)
   Hispanic
1 (11)
ECOG PS, n (%)
   0
2 (22)
   1
7 (78)
Median time from diagnosis, months (range)
40 (10-98)
Median number of prior LOTs, range
2 (1-6)
Median dFLC, mg/L (range)
49 (26-219)
Median organ involvement at screening (range)
1 (0-3)
Multiorgan involvement (≥2 organs), n (%)
4 (44)
Involved organsa, n (%)
   Cardiac
5 (56)
   Renal
6 (67)
   Peripheral neuropathy
1 (11)
   Soft tissue (carpal tunnel, macroglossia)
2 (22)
Mayo cardiac stage, n (%)
   I
5 (56)
   II
3 (33)
   III
1 (11)
   Evaluable for cardiac responseb
5 (56)
NYHA Classc, n (%)
   I
3 (60)
   II
2 (40)
Median NT-proBNP, pg/mL (range)
   Cardiac response (evaluable for response, n=5)
1364 (872-8876)
Renal stage, n (%)
   I
3 (33)
   II
6 (67)
   III
0 (0)
   Evaluable for renal responsed
6 (67)
Median baseline eGFR, n (%)
   >50 mL/min/1.73 m2
5 (56)
   ≤50 mL/min/1.73 m2
4 (44)
Median 24-hour urine protein, mg/24 h (range)
   Renal response (evaluable for response, n=6)
3742 (920-5704)
Abbreviations: dFLC, difference between involved minus uninvolved serum free light chains; ECOG PS, Eastern Cooperative Oncology Group Performance Status; eGFR, estimated glomerular filtration rate; ISA, International Society of Amyloidosis; LOT, line of therapy; NYHA, New York Heart Association; NT-proBNP, pro-B-type natriuretic peptide.
aSymptomatic involvement.
bCardiac response criteria (Palladini et al 201248).
cSymptomatic cardiac patients (n=5).
dISA renal involvement criteria (Gertz et al 200549); Renal response criteria (Palladini et al 201450).

Patient Characteristics Related to Prior DARZALEX FASPRO Exposure10
Characteristic
Daratumumab refractory (at study screening), yes
4 (44)
Median time from last daratumumab to cycle 1 day 1, months (range)
12 (3-42)
Median number of prior daratumumab cycles (range)
24 (2-53)
Prior daratumumab regimens received
   Daratumumab monotherapy, n (%)
5 (56)
   DVd, n (%)
2 (22)
   D-VCd, n (%)
1 (11)
   Daratumumab-venetoclax, n (%)
1 (11)
Best hematologic response to prior daratumumab
   CR, n (%)
2 (22)
   VGPR, n (%)
4 (44)
   PR, n (%)
2 (22)
   SD, n (%)
1 (20)
Organ response to prior daratumumab
   Cardiac (of evaluable patients during prior daratumumab line)
      Response, n/n (%)
4/6 (67)
      Progression, n/n (%)
1/6 (16)
      Unknown, n/n (%)
1/6 (16)
   Renal (of evaluable patients during prior daratumumab line)
      Response, n/n (%)
4/7 (57)
      No response, n/n (%)
2/7 (29)
      Progression, n (%)
0 (0)
      Unknown, n (%)
1 (14)
Abbreviations: CR, complete response; D, daratumumab; PR, partial response; DVd, daratumumab + bortezomib + dexamethasone; PR, partial response; SD, stable disease; VCd, bortezomib + cyclophosphamide + dexamethasone; VGPR, very good partial response.

Results

Efficacy
  • Hematologic and organ responses in measurable- and low-dFLC patients are presented in Table: Hematologic and Organ Responses in Measurable- and Low-dFLC Patients.
  • Of the 5 patients who completed 12 cycles of DPd, 2 of 2 (100%) with measurable dFLC achieved CR (100%), and 2 of 3 (67%) with low dFLC achieved low-dFLC PR.
  • Of the 5 patients who completed 12 cycles of DPd, 3 who received continued maintenance therapy beyond 12 cycles had sustained hematologic and renal responses at 15, 20, and 28 months from the start of treatment.
  • After completing 1 treatment cycle, 1 patient who achieved an early renal response experienced renal progression 14 months after therapy, while maintaining the renal response up to 24 months.
  • Cardiac progression occurred in 2 patients after cycle 2; 1 achieved a low-dFLC PR after 11 cycles and remained on pomalidomide maintenance therapy.

Hematologic and Organ Responses in Measurable- and Low-dFLC Patients10
Response, n (%)
Measurable dFLC
>50 mg/L
(n=4)
Low dFLC
20-50 mg/L
(n=5)
All
(N=9)
Overall response
4 (100)
2 (40)
6 (67)
CR
3 (75)
0 (0)
3 (33)
VGPR
1 (25)
-
-
Low-dFLC PR
-
2 (40)
-
Cardiac responsea,n/n (%)
0/2 (0)
1/3 (33)
1/5 (20)
Renal responseb, n/n (%)
2/2 (100)
3/4 (75)
5/6 (83)
Abbreviations: CR, complete response; dFLC, difference between involved and uninvolved free light chain; PR, partial response; VGPR, very good partial response.
aEvaluable for cardiac response, n=5 (56%).
bEvaluable for renal response, n=6 (67%).
Safety
  • DPd was well tolerated, and the majority of AEs were low grade.
  • Grade 3/4 neutropenia was reported in 2 patients; 1 patient had suspected Duffy antigen-null neutropenia and remained on study with pomalidomide reduced to 2 mg.
  • Grade 3 non-hematologic AEs included respiratory infection (n=2), pulmonary embolus after air travel (n=1; managed by apixaban), and cellulitis after a traumatic fall (n=1).
  • All patients recovered fully and continued on study.
  • Due to grade 3 PN, 1 heavily pretreated patient with pre-existing neuropathy discontinued in cycle 3.
  • No Grade 4 non-hematologic AEs were reported.

Phase 2 Study on DARZALEX Monotherapy in Stage 3B AL Amyloidosis

Kastritis et al (2024)11 presented results from an ongoing, phase 2, open-label, multicenter, EMN 22 study that evaluated the efficacy and safety of DARZALEX monotherapy in patients with stage 3B newly diagnosed AL amyloidosis. Kastritis et al (2024)12 presented updated results of the study at the 66th ASH Annual Meeting.

Study Design/Methods

  • Patients with newly diagnosed stage 3B AL amyloidosis were included.11,12
  • Dosing11,12
    • All patients initially received monotherapy with DARZALEX 16 mg/kg IV, followed by DARZALEX FASPRO 1800 mg SC (since February 2020).
    • Treatment was administered on days 1, 8, 15, and 22 during cycles 1-2; on days 1 and 15 during cycles 3-6; and on day 1 during cycle 7+ until disease progression, start of a new therapy, or for a maximum of 2 years.
  • Patients unable to achieve either a hematologic very good partial response (VGPR) or better or a hematologic PR with a major organ response by cycle 4 could additionally receive bortezomib 1.3 mg/m2 weekly (maximum 6 cycles) and low-dose dexamethasone at investigator’s discretion.11,12
  • Key inclusion criteria12:
    • AL amyloidosis diagnosis with cardiac involvement.
    • Measurable disease: serum protein electrophoresis ≥0.5 g/dL, serum free light chain (sFLC) ≥20 mg/L with an abnormal κ:λ ratio, or dFLC ≥20 mg/L.
    • Mayo stage 3B: high-sensitivity troponin T >54 pg/mL and NT-proBNP ≥8500 pg/mL.
    • Eastern Cooperative Oncology Group Performance Status <3.
    • Estimated glomerular filtration rate ≥20 mL/min.
  • Key exclusion criteria12:
    • Prior symptomatic MM diagnosis: lytic bone disease, plasmacytomas or ≥60% bone marrow plasma cells (BMPCs), and/or hypercalcemia.
    • Prior treatment for MM or any other malignancy other than AL amyloidosis.
    • Significant cardiovascular condition (NYHA stage IIIB/IV or heart failure due to ischemic heart disease).
  • Primary endpoint: OS rate at 6 months11,12
  • Key secondary endpoints: Hematologic ORR at 3 and 6 months, organ response rate, MOD-PFS (from cycle 1 day 1 until death, clinical manifestation of cardiac/renal failure, or development of hematologic progression of PD as per consensus guidelines), safety, and tolerability of DARZALEX.11,12

Results

Patient Characteristics
  • At a clinical data cutoff of December 15, 2023, 40 patients had been enrolled in the study, of whom 10 (25.0%) patients had completed the study treatment, 4 (10.0%) patients continued the treatment, and 26 patients discontinued the treatment (PD, n=7; safety event, n=3; death, n=14; consent withdrawal, n=1; physician's decision, n=1).11
    • The median follow-up was 10.3 months (range, <0.1-50.1).
  • As of the cutoff date of May 31, 2024, 12 patients (30%) successfully completed study treatment. One (2.5%) patient was still undergoing treatment, whereas 27 (67.5%) patients had to discontinue. The reasons for discontinuation included progressive disease (n=7), safety events (n=3), deaths (n=14), consent withdrawal (n=1), and physician's decision (n=2).12 
    • The median follow-up was 10.3 months (range, <0.1-55.6).
  • The median therapy was 6.6 months (range, <0.1-25.3).11,12
  • The median number of DARZALEX infusions was 18 (range, 1-36).11,12
  • Baseline patient and treatment characteristics are summarized in Table: Baseline Patient and Treatment Characteristics.

Baseline Patient and Treatment Charateristics11,12
Characteristics
N=40
Age, median (range)
70.5 (45.0-86.0)
Male, n (%)
22 (55.0)
NYHA classification II/IIIAa, n (%)
16 (40.0)/24 (60.0)
NT-proBNP, pg/mLa
14,353.0 (8,516.0-72,522.0)
HS troponin T,pg/mLa
136.0 (55.1-692.0)
dFLC, mg/La
427.0 (36.0-2,823.0)
LVEF value , % (range)a
44.5 (26.0-68.0)
Revised Mayo 2012 stage III/IV, n (%)
10 (25.0)/30 (75.0)
Patients with isolated heart involvement, n (%)
7 (17.5)
Patients with organ involvement apart from the heart, n (%)
33 (82.5)
   Patients with more than 2 organs involved apart  from heartb, n (%)
17 (51.5)
   Number of organs involved apart from heartb, range
1.0 (0.0-5.0)
Organ involvement apart from heart, n (%)
 
   Kidney
20 (50.0)
   Nerve
12 (30.0)
   Gastrointestinal tract
10 (25.0)
   Soft tissue
9 (22.5)
   Liver
5 (12.5)
   Lung
1 (2.5)
   Other Organ
1 (2.5)
Patients with at least 1 CAa,c, n (%)
15 (46.9)
Patients with t (11;14)a,c, n (%)
11 (40.7)
Abbreviations: dFLC, difference between involved free light chain and uninvolved free light chain; FISH, fluorescent in situ hybridization; HS troponin T, high sensitivity troponin T; LVEF, left ventricular ejection fraction; NT-proBNP, N-terminal pro-B-type natriuretic peptide; NYHA, New York Heart Association.
aPatient characteristics were assessed at screening.
bPercentages and medians (ranges) are based on the 33 patients with at least 1 organ involved, apart from the heart (n=33).
cCA assessment was not mandatory as per protocol and was performed as per the standard of care at each site. The assessment was performed by FISH for the following CAs: 17p13, 1q21, t (4;14), t (11;14), and t (14;16). Percentages are based on the number of patients who had evaluable assessments (CAs, n=32; t (11;14), n=27).
Efficacy
  • Patients who received DARZALEX/DARZALEX FASPRO monotherapy achieved a 6-month OS rate of 65.0% (95% CI, 48.2-77.6).12 The 12-month OS rate was 45.0% (95% CI, 29.3-59.5), and the median OS was 10.3 (95% CI, 4.1-32.3) months.12
  • A summary of efficacy outcomes is presented in Table: Efficacy Outcomes at Different Timepoints.
    • Overall, 77.5% of patients achieved a partial response or better (≥PR) and 55% of patients achieved ≥VGPR.12
    • The median time to first ≥PR was 7 (range, 6-125) days.12
    • The median time to first ≥VGPR was 1.8 (range, 0.2-7.3) months.12
    • Overall, 50% of patients achieved cardiac ≥PR and 40% of patients achieved cardiac ≥VGPR.12

Efficacy Outcomes at Different Timepoints11,12
DARZALEX / DARZALEX FASPRO (N=40)
Parameter
Timepoints
Overall
1 Month
3 Months
6 Months
ORRa, n (%)
26 (65.0)
28 (70.0)
31 (77.5)
31 (77.5)
   CR
1 (2.5)
2 (5.0)
5 (12.5)
11 (27.5)
   VGPR
9 (22.5)
13 (32.5)
15 (37.5)
11 (27.5)
      Time to first VGPR or better response,
      median (range), months
-
-
-
1.8
(0.2-7.3)
   PR
16 (40.0)
13 (32.5)
11 (27.5)
9 (22.5)
      Time to first PR or better response,
      median (range), days
-
-
-
7 (6-125)
Median survival duration, 95% CI, months
-
-
-
10.3
(4.1-32.1)
   6-month OS rate, % (95% CI)
-
-
65
(48.2-77.6)
-
   12-month OS rate, % (95% CI)
-
-
-
45.0
(29.3-59.5)
Organ responsea, n (%)
   Any organ
-
10 (25.0)
13 (32.5)
-
   Heart
-
9 (22.5)
11 (27.5)
-
   Kidney
-
1 (2.5)
3 (7.5)
-
   Liver
-
0 (0.0)
1 (2.5)
-
Best cardiac responseb, n (%)
   Overall response
-
-
-
20 (50.0)
      CR
-
-
-
4 (10.0)
      VGPR
-
-
-
12 (30.0)
      PR
-
-
-
4 (10.0)
Abbreviations: CI, confidence interval; CR, complete response; NT-proBNP, N-terminal pro b-type natriuretic peptide; ORR, overall response rate; OS, overall survival; PR, partial response; VGPR, very good partial response.
aProportions are calculated using the intention-to-treat population (N=40) as the denominator.
bBest cardiac response was evaluated using the minimum NT-proBNP post-baseline value. PR, 30-59% NT-proBNP reduction from baseline; VGPR, ≥60% NT-proBNP reduction from baseline; CR, NT-proBNP <450 pg/mL.
Safety
  • A summary of safety outcomes is presented in Table: Summary of Safety Outcomes.
  • A list of common SAEs is presented in Table: Common SAEs.
  • The early mortality rate was 7.5% (n=3) and 10.0% (n=4) at 15 days and 1 month after cycle 1 day 1, respectively.12

Summary of Safety Outcomes11,12
Parameter, n (%)
DARZALEX/DARZALEX FASPRO (N=40)
At least 1 TEAE
40 (100.0)
At least 1 nonserious TEAE
38 (95.0)
At least 1 serious TEAE
32 (80.0)
At least 1 nonserious TEAE related to the study treatment
17 (42.5)
At least 1 nonserious TEAE grade 3/4
21 (52.5)
At least 1 nonserious TEAE grade 3/4 related to study treatment
6 (15.0)
With fatal SAEs
17 (42.5)
At least 1 serious TEAE related to study treatment
6 (15.0)
Abbreviations: SAE, serious adverse event; TEAE, treatment-emergent adverse event.

Common SAEsa,b,11,12
SAEs, n (%)
Grade 3
Grade 4
Grade 5
Cardiac SAEs
   Cardiac failure
5 (12.5)
-
2 (5.0)
   Sudden cardiac death
-
-
4 (10.0)
   Congestive cardiac failure
1 (2.5)
1 (2.5)
1 (2.5)
   Atrial fibrillation
1 (2.5)
-
-
   Atrial thrombosis
-
-
1 (2.5)
   Coronary artery stenosis
1 (2.5)
-
-
   Ventricular fibrillation
-
-
1 (2.5)
Acute kidney injury
2 (5.0)
1 (2.5)
-
Performance status decreased
-
-
2 (5.0)
COVID-19
1 (2.5)
-
1 (2.5)
Sepsis
-
-
2 (5.0)
Septic shock
-
-
2 (5.0)
Cerebrovascular accidentc
-
-
1 (2.5)
Abbreviations: COVID-19, coronavirus disease-2019; ITT, intent-to-treat; SAE, serious adverse event.
aSAEs observed at a rate of at least 5%.
bPercentages are calculated over the ITT population (n=40).
cOne grade 2 (2.5%) cerebrovascular accident was reported.

Hagen et al (2024)13 have reported a phase 3, randomized study (clinicaltrials.gov identifier: NCT06022939) that aims to compare the safety and efficacy of D-VCd induction followed by ASCT vs D-VCd consolidation and DARZALEX maintenance in patients newly diagnosed with AL amyloidosis.

Study Design/Methods

  • The study, conducted within the United States, aims to enroll 143 patients per study arm.
  • Primary objective: MOD-PFS (defined as the time from randomization to death, cardiac/renal progression, or hematologic progression) in patients receiving ASCT vs those receiving 3 cycles of D-VCd consolidation following 3 cycles of uniform D-VCd induction.
  • Secondary objectives: OS, hematologic PFS, cardiac and renal responses, MRD-negativity (both by peripheral blood mass spectrometry and bone marrow next-generation flow cytometry), delayed utilization of ASCT, and quality of life.
  • Following the assigned consolidation, all patients are to receive 18 months of DARZALEX maintenance therapy.
  • Key eligibility criteria: nonsevere cardiac AL amyloid (NT-proBNP <5000 pg/ml, TnT <0.06 ng/L, NYHA I or II, and ejection fraction ≥40%), CrCl ≥30 mL/min, serum dFLC >2 mg/dL, and supine systolic blood pressure (BP) ≥90 mmHg.
    • Patients are permitted to receive up to 1 full cycle or 28 days of any plasma cell-directed therapy prior to enrollment.
  • This trial was activated on December 1, 2023, with the first patient enrolled on July 1, 2024.

AQUARIUS (clinicaltrials.gov Identifier: NCT05250973) is an ongoing, multicenter, multicohort, open-label, phase 2 study evaluating D-VCd in patients with newly diagnosed systemic AL amyloidosis.14 Results are not available at this time.

Study Design/Methods

  • Approximately 150 patients are to be enrolled and divided into two cohorts.
    • Cohort 1: approximately 120 patients with cardiac involvement stratified by Mayo Cardiac Stage based on the AL amyloidosis Mayo Clinical Cardiac Staging System and randomized to 2:1 to receive DARZALEX FASPRO + immediate VCd (Arm A) or DARZALEX FASPRO + deferred VCd (Arm B).
    • Cohort 2: approximately 30 patients of racial or ethnic minorities (including ≥15 Black or African American patients) will receive DARZALEX FASPRO + immediate VCd51
  • Key eligibility criteria:
    • New diagnosis of systemic AL amyloidosis based on both:
      • Tissue deposition of amyloid in any organ other than bone marrow
      • An underlying clonal plasma cell disorder as demonstrated by one of the following: clonal plasma cells in the bone marrow; monoclonal gammopathy in the serum or urine; abnormal free light chain ratio.
      • Measurable disease at screening defined by one of the following: dFLC ≥40 mg/L per central laboratory; serum monoclonal protein (M-protein) ≥0.5 g/dL
      • ECOG performance status score of ≤2 Pre-treatment clinical laboratory values meeting the following criteria during the screening phase: hemoglobin ≥8 g/dL (≥5 mmoL/L); platelets ≥50 x 109/L; absolute neutrophil count ≥1.0 x 109/L; aspartate aminotransferase and alanine aminotransferase ≤2.5 x upper limit of normal (ULN); total bilirubin ≤1.5 x ULN; estimated glomerular filtration rate ≥20 mL/min/1.73m2
    • Cohort 1: cardiac involvement with or without organ(s) involved
    • Cohort 2: ≥1 organ impacted (heart, kidney, liver, nerve, gastrointestinal tract, lung, or soft tissue)
    • No prior therapy for systemic AL amyloidosis or MM that targets CD38, except dexamethasone or equivalent corticosteroid
    • No evidence of significant cardiovascular conditions
  • Dosing schedule:
    • Cohort 1 Arm A and Cohort 2: DARZALEX FASPRO + immediate VCd
      • Cycle 1 and 2: DARZALEX FASPRO QW
      • Cycles 3-6: DARZALEX FASPRO Q2W
      • Cycles 7 and onward: DARZALEX FASPRO every 4 weeks until a maximum of 24 cycles of treatment or the start of a subsequent therapy
      • VCd (V, 1.3 mg/m2 QW SC; C, 300 mg/m2 QW PO or IV; d 40 mg QW PO or IV) for cycles 1 through 6 for a maximum of 6 cycles.
    • Cohort 1 Arm b: DARZALEX FASPRO + deferred VCd
      • DARZALEX FASPRO as described for Cohort 1 Arm A and Cohort 2
      • VCd (doses as described for Cohort 1 Arm A and Cohort 2) for cycles 4 through 9 for a maximum of 6 cycles.
  • Primary endpoints: incidence of any toxicity grade cardiac events for the various D-VCd regimens and trough serum concentration of DARZALEX FASPRO at the end of QW dosing (Cycle 3 Day 1 pre-dose)
  • Secondary endpoints: Overall hematologic CR rate; hematologic CR rate at 6 months; hematological ≥VGPR rate; time to and duration of hematologic CR (or ≥VGPR); OS; organ response rate at 6 and 12 months for kidney, heart, and liver; time to subsequent therapy for AL amyloidosis; incidence and severity of AEs; pharmacokinetic profile of DARZALEX FASPRO; immunogenicity of DARZALEX FASPRO and rHuPH20; clinical signs and symptoms of cardiac AL amyloidosis at baseline and change over time.

Lee et al (2024)15 presented the final results of a phase 1, single-center, open-label, investigator-initiated study (clinicaltrials.gov identifier: NCT03283917), which evaluated the safety and preliminary efficacy of the novel combination of DId in patients with AL amyloidosis.

Study Design/Methods

  • Key inclusion criteria: patients with treatment-naïve AL amyloidosis or with previously treated AL amyloidosis with evidence of clonal relapse or refractory to prior therapy defined as less than a hematologic VGPR.
  • Key exclusion criteria: patients with NT-proBNP >8500 ng/L, clinically overt myeloma (hypercalcemia and/or bone lesions), or who had previous ixazomib or anti-cluster of differentiation 38 monoclonal antibody therapy or had planned high-dose chemotherapy and ASCT within the first 6 cycles of treatment.
  • Dosing: Treatment was administered on a 28-day cycle for up to 12 cycles.
    • DARZALEX/DARZALEX FASPRO: 16 mg/kg or 1800 mg SC (initially administered
      16 mg/kg IV, but later changed to 1800 mg SC, with a protocol amendment) on
      days 1, 8, 15, and 22 for cycles 1-2; on days 1 and 15 for cycles 3-6; and on day 1 for cycles 7-12.
    • Ixazomib: 4 mg (3 mg if CrCl is <30 mL/min) on days 1, 8, and 15 for all cycles.
    • Dexamethasone: 20 mg on days 1, 2, 8, 9, 15, 16, 22, and 23 (20 mg on days 1, 8, 15, and 22 for cycle 1 only and increased to 30 mg days 1, 2, 8, 9, 15, 16, 22, and 23 for cycle 2 and beyond depending on patient’s tolerance).
  • Primary objective: safety and tolerability of DId in patients with AL amyloidosis.

Results

Patient Dispositions and Baseline Characteristics
  • As of the data cutoff of December 18, 2023, a total of 20 patients had enrolled in the study and completed study treatment.
    • Of these 20 patients, 14 were treatment-naïve and 6 were previously treated with a median of 1 prior line of therapy (bortezomib exposed, n=5 [83%]; bortezomib refractory, n=1 [17%]; and prior ASCT, n=2 [33%]).
  • Median DId treatment cycles were 12 (range, 1-12). A total of 11 (55%) patients completed all 12 treatment cycles.
    • Five patients (25%) discontinued treatment early due to intention to proceed with high dose chemotherapy and ASCT, which was the most common reason for discontinuation.
  • Baseline patient characteristics have been presented in Table: Baseline Patient Characteristics.

Baseline Patient Characteristics15
Characteristic
N=20
Median age, (range)
65 (39-75)
Sex, n (%)
   Male
10 (50)
   Female
10 (50)
ECOG performance status, n (%)
   0
3 (15)
   1
16 (80)
   2
1 (5)
Race, n (%)
 
   White or Caucasian
17 (85)
   Black
3 (15)
Previous treatment, n (%)
   No prior treatment
14 (70)
   1 line
5 (25)
   2 lines
1 (5)
   Bortezomib exposed
5 (25)
Light chain isotype, n (%)
   Kappa
4 (20)
   Lambda
16 (80)
Median baseline dFLC (range), mg/L
194 (71-2787)
Translocation (11;14), n (%)
   Yes
8 (40)
   No
11 (55)
   N/A
1 (5)
Cardiac stage, n (%)
   I
4 (20)
   II
13 (65)
   IIIA
3 (15)
   IIIB
0 (0)
Renal stage, n (%)
   I
10 (50)
   II
7 (35)
   III
3 (15)
Median organs involved (range)
2 (1-4)
   ≥2 organs, n (%)
13 (65)
   Heart, n (%)
10 (50)
   Kidney, n (%)
11 (55)
   Gastrointestinal, n (%)
3 (15)
   Liver, n (%)
1 (5)
   Peripheral nerve, n (%)
7 (35)
   Other, n (%)
5 (25)
Abbreviations: ECOG, Eastern Cooperative Oncology Group; dFLC, difference between the involved and uninvolved free light chain; N/A, not applicable.
Safety
  • A summary of any-grade TEAEs and grade ≥3 TEAEs has been presented in Table: Summary of Any-Grade TEAEs and Summary of Grade ≥3 TEAEs.
  • Treatment-emergent PN occurred in 5 patients (25%, all grade 1 and grade 2), among whom 4 patients had baseline grade 1 PN and/or prior bortezomib exposure.
  • Three deaths occurred in the study; all unrelated to treatment.
    • One death was related to post-operative complications from small bowel obstruction due to congenital Meckel’s diverticulum.
    • One death was related to progressive hepatic amyloidosis.
    • One death was related to pulmonary embolus in the setting of coronavirus disease 2019 (COVID-19).
  • Stopping criteria for the study were not met.

Summary of Any-Grade TEAEsa,15
TEAE
n (%)
Dyspnea
14 (70)
Nausea
14 (70)
Anemia
13 (65)
Hypoalbuminemia
13 (65)
Thrombocytopenia
13 (65)
Fatigue
12 (60)
AST increased
11 (55)
Constipation
11 (55)
Diarrhea
11 (55)
Dizziness
11 (55)
Edema limbs
11 (55)
Lymphopenia
10 (50)
Mucositis oral
10 (50)
Anorexia
9 (45)
Cough
9 (45)
Hypokalemia
9 (45)
Hyponatremia
9 (45)
Infusion-related reaction
9 (45)
Myalgia
9 (45)
Sinus tachycardia
9 (45)
Vomiting
9 (45)
Blurred vision
8 (40)
Bruising
8 (40)
Creatinine increased
8 (40)
Dry eye
8 (40)
Fever
8 (40)
Headache
8 (40)
Hyperglycemia
8 (40)
Hypertension
8 (40)
Lung infection
8 (40)
Peripheral neuropathy
8 (40)
Back pain
7 (35)
Acute kidney injury
6 (30)
ALP increased
6 (30)
Alopecia
6 (30)
Dry mouth
6 (30)
Hypercalcemia
6 (30)
Hypernatremia
6 (30)
Hypophosphatemia
6 (30)
Hyperphosphatemia
6 (30)
Memory impairment
6 (30)
Abbreviations: ALP, alkaline phosphatase; AST, aspartate aminotransferase; NCI-CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Events; TEAE: treatment-emergent adverse event.
aTEAEs of any grade occurring in at least 30% of patients.
Note: As per NCI-CTCAE v4.

Summary of Grade ≥3 TEAEsa,15
TEAE
n (%)
Lymphopenia
7 (35)
Lung infection
6 (30)
Hypertension
5 (25)
Anemia
4 (20)
Edema limbs
4 (20)
Platelet count decreased
4 (20)
Chronic kidney disease
3 (15)
Fatigue
3 (15)
Hypoalbuminemia
3 (15)
Hypotension
3 (15)
Neutrophil count decreased
3 (15)
Sepsis
3 (15)
Abbreviations: NCI-CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Events; TEAE: treatment-emergent adverse event.
aGrade ≥ 3 TEAEs occurring in at least 15% of patients.
Note: As per NCI-CTCAE v4.
Efficacy
  • The median time to initial hematologic response and median time to best hematologic response were both 28 days each.
  • The median time to hematologic VGPR among 16 patients with ≥VGPR was 28 days.
  • Cardiac response rate was 75% among 8 response-evaluable patients (baseline
    NT-proBNP ≥650 ng/L). Best hematologic response on DId study treatment has been presented in Table: Best Hematologic Response on DId Study Treatment.
  • Renal response rate was 73% among 11 renal amyloid patients.

Best Hematologic Response on DId Study Treatment15
%
Overall Hematologic
Response Rate
(≥PR)
Hematologic ≥VGPR
Response Rate
Hematologic
CR
Response Rate
dFLC 
≤10 mg/L
iFLC ≤20 mg/L
All patients
(N=20)
100
80
15
40
45
Treatment naïve
(n=14)
100
71
14
36
43
Previously treated
(n=6)
100
100
17
50
50
Abbreviations: CR, complete response; dFLC, difference between the involved and uninvolved free light chain; DId, DARZALEX/DARZALEX FASPRO, ixazomib, and dexamethasone; iFLC, involved serum free light chain values; PR, partial response; 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 29 January 2025. This information is intended to include clinical trial data, rather than being all-inclusive; therefore, case reports have been excluded.

 

References

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