DARZALEX + DARZALEX FASPRO - Use in Immunoglobulin Light Chain (AL) Amyloidosis

SUMMARY

• DARZALEX for intravenous (IV) use is not approved by the regulatory agencies for the 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 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 bortezomib, cyclophosphamide and dexamethasone (VCd) alone in newly diagnosed patients with systemic AL amyloidosis.¹

• • Kastritis et al (2026)² published 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 updated hematologic CR rate was 59.5% for D-VCd vs 19.2% for VCd (OR, 6.03; 95% CI, 3.80-9.58; P<0.0001). There was an improvement for D-VCd vs VCd in MOD-PFS (hazard ratio [HR], 0.44; 95% CI, 0.31-0.63; P<0.0001) and OS (HR, 0.62; 95% CI, 0.42-0.90; P=0.0121). Safety data for D-VCd were consistent with the primary analysis.  
  • Other relevant analyses of the ANDROMEDA study have been included in the References section for your information.^3-13 
• AQUARIUS is a phase 2, multicenter, multicohort, open-label study evaluating cardiac safety of 2 different D-VCd treatment schedules in patients with newly diagnosed systemic AL amyloidosis.¹⁴
  • Sanchorawala et al (2025)¹⁵ presented the results of the study. The best hematologic overall response rate was 93.2% for patients in the DARZALEX FASPRO + Immediate VCd arm vs 97.4% in the DARZALEX FASPRO + Deferred VCd arm. Serious cardiac TEAEs occurred in 7.8% of patients in the immediate group vs 7.7% of patients in the deferred group, with higher rates of cardiac TEAEs correlating to initiation of VCd.
• Rosenbaum et al (2023)¹⁶ presented a phase 2, single-arm, multicenter study that evaluated DARZALEX FASPRO in combination with pomalidomide and dexamethasone (D-Pd) in patients with relapsed/refractory AL amyloidosis who were previously exposed to DARZALEX. Overall response 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 (2026)¹⁷ published results from a phase 2 European Myeloma Network (EMN) 22 study evaluating the efficacy and safety of DARZALEX monotherapy in patients with stage 3B newly diagnosed AL amyloidosis at a median follow-up of 44.6 months. The OS rate at 6 months was 65.0% (95% CI, 48.2-77.6) and the median OS was 10.4 months (95% CI, 4.1-30.8). The most common serious TEAEs were cardiac failure (25.0%), sudden cardiac death (10.0%), and acute kidney injury (7.5%).
• Lee et al (2026)¹⁸ published results from a phase 1, investigator-initiated study evaluating the safety and efficacy of DARZALEX or DARZALEX FASPRO in combination with ixazomib and dexamethasone (D-Id) in patients with AL amyloidosis. The overall best hematologic response rate was 100% and the hematologic very good partial response or better (≥VGPR) was 80%. The most common grade ≥3 TEAEs were lymphopenia (35%), lung infection (30%), and hypertension (25%).
• Other relevant literature has been identified in addition to the data summarized above and is listed in the References section for your information.^19-23

PRODUCT LABELING

• DARZALEX (daratumumab) [Prescribing Information]. Horsham, PA: Janssen Biotech, Inc.; www.janssenlabels.com/package-insert/product-monograph/prescribing-information/DARZALEX-pi.pdf
• DARZALEX FASPRO (daratumumab and hyaluronidase-fihj) [Prescribing Information]. Horsham, PA: Janssen Biotech, Inc.; www.janssenlabels.com/package-insert/product-monograph/prescribing-information/DARZALEX+Faspro-pi.pdf

CLINICAL DATA

Phase 3 Study of DARZALEX FASPRO in Combination with VCd in Patients with Newly Diagnosed AL Amyloidosis

ANDROMEDA (AMY3001; NCT03201965) is a phase 3, randomized, prospective, active-controlled, multicenter study evaluating the efficacy and safety of D-VCd compared to VCd alone in newly diagnosed patients with systemic AL amyloidosis.¹

Study Design/Methods

• The study design is presented in Figure: ANDROMEDA Study Design.¹

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

Kastritis et al (2026)² published results of the final analysis of MOD-PFS and OS from the ANDROMEDA study with a median follow-up of 61.4 months (range, 0.0-71.2).

Results

Baseline Demographics and Clinical Characteristics

• Baseline demographics and clinical characteristics were balanced between both arms and are presented in Table: Baseline Demographics and Clinical Characteristics.²⁴

Treatment Exposure and Patient Disposition

• At the cutoff of April 17, 2024, all patients completed study treatment and 124/193 patients in the D-VCd arm completed 2 years of DARZALEX FASPRO treatment.²
• The median duration of treatment was 21.3 months (range, 0.03-26.7) in the D-VCd group and 5.3 months (range 0.03-7.3) in the VCd group.²
• The most common reasons for discontinuation in the D-VCd arm were death (n=23), subsequent therapy (n=17), and adverse events (n=11).²

Efficacy

• Hematologic CR was achieved by 116 patients (58.5%) in the D-VCd group vs 37 patients (19.2%) in the VCd group (OR, 6.03; 95% CI, 3.80-9.58; nominal P<0.0001).²
  • Of these, 131 patients achieved hematologic CR within 6 months (D-VCd, n=99; VCd, n=32).
  • Median time to hematologic CR 67.5 days (range, 8.0-879.0) in the D-VCd group and 85.0 days (range, 14.0-617.0) in the VCd group.
  • The median duration of hematologic CR was not reached in either group.
• Efficacy data from the final analysis are presented in Table: Summary of Responses in the Final Analysis - ITT Population.²

• When accounting for non-cross-resistant subsequent therapy and censoring, the hazard ratio for MOD-PFS was 0.44 (95% CI, 0.31-0.63; P<0.0001 [crossing prespecified boundary of 0.0495]).²
• Subgroup analyses of MOD-PFS demonstrated similar results across clinically relevant subgroups.²⁴
• The median OS was not reached in either group.²
  • There were 46 deaths (23.6%) in the D-VCd group vs 66 deaths (34.2%) in the VCd group (HR, 0.62; 95% CI, 0.42-0.90; P=0.0121 [crossing prespecified boundary of 0.0163]).
• The estimated 5-year OS rates were 76.1% (95% CI, 69.3-81.6) for D-VCd vs 64.7% (95% CI, 57.1-71.2) for VCd.²
• Subgroup analyses of OS demonstrated similar results across clinically relevant subgroups.²⁴
• A total of 235 patients were evaluable for cardiac response (D-VCd, n=118; VCd, n=117) and 230 for renal response (D-VCd, n=117; VCd, n=113). Responses are summarized in Table: Cardiac and Renal Responses in Final Analysis.²
  • The median time to cardiac ≥VGPR was 14.9 months vs 16.4 months and the median time to cardiac CR was 16.3 months bs 20.9 months for D-VCd vs VCd, respectively.

Safety

• Safety data for D-VCd were consistent with the primary analysis results.²
• The most common grade 3/4 AEs were lymphopenia, pneumonia, diarrhea, cardiac failure, neutropenia, syncope, fatigue, hypokalemia, and peripheral edema as summarized in Table: Most Common Any-Grade and Grade 3/4 AEs.²

• Serious AEs occurred in 47.2% of patients in the D-VCd arm vs 36.2% in the VCd arm.²
  • The most common serious AEs were pneumonia (D-VCd, 7.3%; VCd, 4.8%) and cardiac failure (D-VCd, 7.3%; VCd, 4.3%).
• Study treatment was discontinued due to AEs in 5.2% vs 4.3% of patients in the D-VCd and VCd groups, respectively.²
• Deaths due to AEs within 30 days of the last study treatment occurred in 22 patients (11.4%) in the D-VCd arm and 14 patients (7.4%) in the VCd arm. Most deaths were determined to be unrelated to study treatment.²
• Systemic ARRs with DARZALEX FASPRO occurred in 14 patients (7.3%); all were grade 1/2 and 86% occurred during the first injection.²

Phase 2 Study of DARZALEX FASPRO in Combination with VCd in Patients with Newly Diagnosed AL Amyloidosis

AQUARIUS (AMY2009; NCT05250973) is a phase 2, multicenter, multicohort, open-label study evaluating the cardiac safety of 2 different D-VCd treatment schedules in patients with newly diagnosed systemic AL amyloidosis.¹⁴

Study Design/Methods

• Key eligibility criteria:
  • Cohort 1: newly diagnosed AL amyloidosis, no prior therapy for AL amyloidosis or MM, Mayo cardiac stage II-IIIA with or without other organ involvement.¹⁵ 
  • Cohort 2: newly diagnosed AL amyloidosis with ≥1 impacted organ (cardiac safety analysis includes only patients with cardiac involvement), no prior therapy for AL amyloidosis or MM, self-identified racial and ethnic minorities.¹⁵
• Dosing schedules:
  • Cohort 1 Arm A and Cohort 2: DARZALEX FASPRO + immediate VCd (28-day cycles)
    • DARZALEX FASPRO: weekly (QW) for cycles 1-2, every 2 weeks (Q2W) for cycles 3-6, every 4 weeks (Q4W) for cycle 7 onwards until a maximum of 24 cycles of treatment or the start of subsequent therapy.^14,15 
    • VCd: V, 1.3 mg/m² QW SC; C, 300 mg/m² QW orally (PO) or IV; d 40 mg QW PO or IV for cycles 1-6 for a maximum of 6 cycles.¹⁴ 
  • Cohort 1 Arm B: DARZALEX FASPRO + deferred VCd (28-day cycles)
    • DARZALEX FASPRO: as described for Cohort 1 Arm A and Cohort 2.^14,15
    • VCd: doses as described for Cohort 1 Arm A and Cohort 2 for cycles 4-9 for a maximum of 6 cycles.¹⁴
• Primary endpoints:
  • Cohort 1: safety (cardiac events)¹⁵
  • Cohort 2: daratumumab maximum trough concentration (cycle 3 day 1 pre-dose)¹⁵
• Key secondary endpoints: hematologic CR and ≥VGPR rates, time to hematologic CR and ≥VGPR, duration of hematologic CR and ≥VGPR, organ response, clinical signs and symptoms of cardiac AL amyloidosis¹⁵

Primary Efficacy and Safety Analysis of the AQUARIUS Study

Sanchorawala et al (2025) presented the primary efficacy and safety results of this study.¹⁵ 

Results

Patient Characteristics and Treatment Disposition

• The baseline characteristics were well-balanced between the groups. See Table: Baseline Characteristics.¹⁵
• The median treatment duration was 10.4 months for both groups.¹⁵

Efficacy

• Hematologic CR rate was 62.1% (n=64) in the DARZALEX FASPRO + Immediate VCd group vs 59.0% (n=23) in the DARZALEX FASPRO + Deferred VCd group.¹⁵
  • The median time to CR was 63.5 days vs 113.0 days in the Immediate VCd vs Deferred VCd groups, respectively.
• In the DARZALEX FASPRO + Immediate VCd group, 87 patients achieved VGPR or better vs 36 patients in the DARZALEX FASPRO + Deferred VCd group.¹⁵
  • The median time to VGPR was 29.0 days vs 72.5 days in the Immediate VCd vs Deferred VCd groups, respectively.
• Best hematologic response rates are described in Table: Best Hematologic Responses.¹⁵
• Of the 85 patients in the DARZALEX FASPRO + Immediate VCd group that were cardiac response-evaluable, 47 patients (55.3%) achieved a cardiac response at 6 months (95% CI, 44.1-66.1) vs 20/34 patients (58.8%) in the DARZALEX FASPRO + Deferred VCd group (95% CI, 40.7-75.4).¹⁵
• N-terminal pro b-type natriuretic peptide (NT-proBNP) and high sensitivity (HS) troponin T levels improved across both groups.¹⁵
• Cardiac signs/symptoms and 6-minute walk test distance improved across both arms.¹⁵

Safety

• There were similar rates of serious cardiac TEAEs in both groups, see Table: Summary of Cardiac TEAEs.¹⁵
• Of the 30 major cardiac TEAEs (grade >3 or serious) that occurred in 20 patients, 28 events were attributed to underlying cardiac amyloid disease.¹⁵
  • Patients who experienced major cardiac TEAEs had more advanced cardiac disease at baseline.
• Cardiac TEAEs of any grade were more frequent in Mayo stage III vs Mayo stage II patients, independent of treatment schedule (DARZALEX FASPRO + Immediate VCd: 73.0% vs 35.9%; DARZAELX FASPRO + Deferred VCd: 68.8% vs 57.1%).¹⁵
• Most cardiac TEAEs emerged during cycles 1-6, with a higher rate correlating to the start of VCd, as summarized in Table: Emergence of Cardiac TEAEs.¹⁵

Phase 2 Study of DARZALEX FASPRO in Combination with Pd in Patients with Relapsed/Refractory AL Amyloidosis

Rosenbaum et al (2023)¹⁶ presented a phase 2, single-arm, multicenter study that evaluated D-Pd 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.¹⁶
  • 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 D-Pd treatment.¹⁶
• 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.¹⁶
• Dosing: Patients received D-Pd for 12 cycles with optional continuation of DARZALEX FASPRO and/or pomalidomide with or without dexamethasone if they achieved ≥VGPR after 12 cycles.¹⁶
  • 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 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.¹⁶
• Overall, 16 patients were to be enrolled.¹⁶

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.¹⁶
• Patient characteristics related to prior DARZALEX exposure are summarized in Table: Patient Characteristics Related to Prior DARZALEX FASPRO Exposure.¹⁶
• Five patients have completed all 12 cycles on study; 3 of the 5 patients remained on optional maintenance therapy beyond 12 cycles (D-Pd [n=1]; pomalidomide alone [n=2]).¹⁶
• Three patients had not received 12 D-Pd cycles and continued on therapy.¹⁶
• One heavily pretreated patient with 6 prior LOTs and pre-existing neuropathy discontinued the study without response in cycle 3 due to grade 3 peripheral neuropathy.¹⁶

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.¹⁶
• Of the 5 patients who completed 12 cycles of D-Pd, 2 of 2 (100%) with measurable dFLC achieved CR (100%), and 2 of 3 (67%) with low dFLC achieved low-dFLC PR.¹⁶
• Of the 5 patients who completed 12 cycles of D-Pd, 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.¹⁶
• 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.¹⁶
• Cardiac progression occurred in 2 patients after cycle 2; 1 achieved a low-dFLC PR after 11 cycles and remained on pomalidomide maintenance therapy.¹⁶

Safety

• D-Pd was well tolerated, and the majority of AEs were low grade.¹⁶
• 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.¹⁶
• 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).¹⁶
• All patients recovered fully and continued on study.¹⁶
• Due to grade 3 PN, 1 heavily pretreated patient with pre-existing neuropathy discontinued in cycle 3.¹⁶
• No Grade 4 non-hematologic AEs were reported.¹⁶

Phase 2 Study of DARZALEX Monotherapy in Patients with Stage 3B Newly Diagnosed AL Amyloidosis

Kastritis et al (2026)¹⁷ published results from a phase 2 European Myeloma Network (EMN) 22 study evaluating the efficacy and safety of DARZALEX monotherapy in patients with stage 3B newly diagnosed AL amyloidosis at a median follow-up of 44.6 months (range, 0.1-63.4).

Study Design/Methods

• Key inclusion criteria: newly diagnosed stage 3B AL amyloidosis, ECOG PS score 0-3, eGFR ≥20 mL/min.¹⁷
• Dosing¹⁷:
  • Patients initially received monotherapy with DARZALEX 16 mg/kg IV; following a protocol amendment in September 2019, all patients received DARZALEX FASPRO 1800 mg SC.
  • 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 ≥VGPR 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.¹⁷
• Primary endpoint: OS rate at 6 months.¹⁷
• Key secondary endpoints: Hematologic ORR, time to response, duration of response, organ response rate, organ response rate for heart/kidney/liver, MOD-PFS.¹⁷

Results

Patient Characteristics

• A total of 40 patients were enrolled in the study.¹⁷
• Baseline patient and treatment characteristics are summarized in Table: Key Baseline Patient and Treatment Characteristics.¹⁷

• By trial completion, 27 patients had discontinued treatment (death, n=14; disease progression,  n=7; AEs, n=3; physician decision, n=2; consent withdrawal, n=1).²⁸

Efficacy

• At 6 months, the OS rate was 65.0% (95% CI, 48.2-77.6). The median OS was 10.4 months (95% CI, 4.1-30.8).¹⁷
  • The 1-, 3-, and 12-month OS rates were 90.0% (95% CI, 75.5-96.1), 72.5% (95% CI, 55.9-83.7), and 45.0% (95% CI, 29.3-59.5), respectively.
• Best hematologic response rates overall and at 1, 3, and 6 months are summarized in Table: Best Hematologic Response Rates.¹⁷
  • The median time to achieve best hematologic response was 3.2 months (range, 0.2-30.0).

• The median MOD-PFS was 9.5 months (95% CI, 2.8-27.0).¹⁷
• The 3-, 6-, and 12-month cardiac response rates were 22.5% (9/40), 30.0% (12/40), and 37.5% (15/40), respectively.¹⁷
  • The median time to first cardiac response was 1.8 months (range, 0.2-11.1).
• Among the 20 patients with renal involvement, the 3- and 6-months renal response rates were 5.0% and 15.0%, respectively.¹⁷

Safety

• At least 1 serious TEAE occurred in 31 patients (77.5%).¹⁷
• A summary of the most common TEAEs is listed in Table: Most Common (≥10%) TEAEs.¹⁷

Phase 1 Investigator-Initiated Study of D-Id in Patients with AL Amyloidosis

Lee et al (2026)¹⁸ published results from a phase 1, investigator-initiated study evaluating the safety and efficacy of DARZALEX or DARZALEX FASPRO in combination with ixazomib and dexamethasone (D-Id) in patients with AL amyloidosis.  

Study Design/Methods

• Key eligibility criteria: systemic AL amyloidosis, treatment-naïve or previously treated with evidence of clonal relapse or refractory disease (less than hematologic VGPR to prior therapy).¹⁸
• Dosing per 28-day cycles²⁹ :
  • DARZALEX 16 mg/kg IV or DARZALEX FASPRO 1800 mg SC QW for cycles 1-2, Q2W for cycles 3-6, and Q4W for cycles 7-12.
    • All patients who initially received DARZALEX IV were switched to DARZALEX FASPRO SC after a protocol amendment in June 2021.
  • Ixazomib 4 mg PO on days 1, 8, and 15; reduced to 3 mg if CrCl <30 mL/min.
  • Dexamethasone 20 mg on days 1, 8, 15, and 22 for cycle 1; on days 1, 2, 8, 9, 15, 16, 22, and 23 for cycles 2+ if tolerated.
• Primary objectives: confirm safety, tolerability, and recommended phase 2 dosing (RP2D).¹⁸

Results

Patient Characteristics

• A total of 20 patients were enrolled, including newly diagnosed (n=14) and previously treated (n=6) patients.¹⁸
• Key baseline characteristics are summarized in Table: Key Select Baseline Characteristics.¹⁸

• A median of 12 cycles (range, 1-12) of D-Id were administered.¹⁸
  • Ten patients received DARZALEX IV, 7 patients received DARZALEX FASPRO SC, and 3 patients transitioned from IV to SC after implementation of the protocol amendment.
• The most common reason for discontinuation was intent to proceed to ASCT (20% [n=4]).¹⁸

Efficacy

• Response rates were comparable between the newly diagnosed and previously treated groups as summarized in Table: Hematologic Responses.¹⁸

• Of the 8 cardiac-evaluable patients, the cardiac response rate was 75%; among the 11 renal amyloid patients, the renal response rate was 73%.¹⁸
• At a median follow-up of 32.3 months, the OS was not reached (NR).¹⁸
• The median hematologic PFS was 20.3 months (95% CI, 13.6-NR).¹⁸
• The median duration of response was 19.4 months (95% CI, 12.7-NR).¹⁸
• After treatment with D-Id, 9 patients (45%) underwent consolidative ASCT prior to hematologic progression.¹⁸
  • Six patients were in hematologic VGPR and 3 patients were in hematologic PR at the time of ASCT.

Safety

• The most common any-grade TEAEs were dyspnea (70%), nausea (70%), and hypoalbuminemia (65%).¹⁸
• The most common grade ≥3 TEAEs were lymphopenia (35%), lung infection (30%), and hypertension (25%).¹⁸
• Grade 1 or 2 peripheral neuropathy occurred in 5 patients (25%), 4 of whom had baseline peripheral neuropathy and/or prior bortezomib exposure.¹⁸
• One dose-limiting toxicity of grade 3 lung infection occurred and was deemed possibly related to study treatment.¹⁸

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 06 August 2026. The search was limited to publications from 2020 to present. This information is intended to include clinical trial data rather than being all‑inclusive; therefore, case reports and retrospective studies have been excluded.