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 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 at 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.
  • Kastritis et al (2024)² presented the final analysis for major organ deterioration progression-free survival (MOD-PFS) and overall survival (OS) at a median follow-up of 61.4 months. D-VCd substantially increased hematologic CR vs VCd alone (59.5% vs 19.2%; odds ratio [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. Safety data were consistent with the known safety profiles for D-VCd and VCd.
  • Kumar et al (2023)³ 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.
  • Other relevant analyses of the ANDROMEDA study have been included in the References section for your information.^4-15 
• AQUARIUS is an ongoing, multicenter, multicohort, open-label, phase-2 study evaluating cardiac safety of 2 different D-VCd treatment schedules in patients with newly diagnosed systemic AL amyloidosis.¹⁶
  • Sanchorawala et al (2025)¹⁷ 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)¹⁸ 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 (2024)¹⁹ 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 with stage 3B newly diagnosed AL amyloidosis. At a median follow-up of 10.3 months, the ORR was 77.5% and OS rates at 6- and 12 months 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%).
• Other relevant literature has been identified in addition to the data summarized above and is listed in the References section for your information.^20-40

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 D-VCd in Patients with Newly Diagnosed AL Amyloidosis

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.¹ Kastritis et al (2024)² presented results from the final analysis for MOD-PFS and OS in the ANDROMEDA study with a median follow-up of 61.4 months.

Study Design/Methods

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

Results

Baseline Demographics and Clinical Characteristics

• Baseline demographics and clinical characteristics were balanced between both groups and are presented in Table: Baseline Demographics and Clinical Characteristics.²

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.²
  • A total of 71.3% (82/115) of patients from the VCd group received subsequent DARZALEX FASPRO-based therapy.
  • The most common reasons for DARZALEX FASPRO discontinuation were death (n=23), ASCT (n=12), and AEs (n=11).

Efficacy

• Efficacy data from the final analysis are presented in Table: Summary of Overall Hematologic Responses in the Final Analysis.²
  • The median time to a hematologic CR was 67.5 vs 85 days for the D-VCd vs VCd arm, respectively.
• D-VCd significantly improved MOD-PFS vs VCd alone.²
  • 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.
  • 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).²
  • 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.
• 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.²

Safety

• Safety data were consistent with the known safety profiles for D-VCd and VCd.²
• Safety data from the final analysis are presented in Table: Any-Grade (>25%) and Grade 3/4 (≥5%) AEs (Final Analysis).²

Phase 2 Study of D-VCd in Patients with Newly Diagnosed AL Amyloidosis

AQUARIUS (AMY2009; NCT05250973) is an ongoing, multicenter, multicohort, open-label, phase 2 study evaluating the cardiac safety of 2 different D-VCd treatment schedules in patients with newly diagnosed systemic AL amyloidosis.¹⁶ Sanchorawala et al (2025) presented the results of this study.¹⁷ 

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.¹⁷ 
  • 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.¹⁷
• 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.^16,17 
    • 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.¹⁶ 
  • Cohort 1 Arm B: DARZALEX FASPRO + deferred VCd (28-day cycles)
    • DARZALEX FASPRO: as described for Cohort 1 Arm A and Cohort 2.^16,17
    • VCd: doses as described for Cohort 1 Arm A and Cohort 2 for cycles 4-9 for a maximum of 6 cycles.¹⁶
• Primary endpoints:
  • Cohort 1: safety (cardiac events)¹⁷
  • Cohort 2: daratumumab maximum trough concentration (cycle 3 day 1 pre-dose)¹⁷
• 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 amyloidosis¹⁷

Results

Patient Characteristics and Treatment Disposition

• The baseline characteristics were well-balanced between the groups. See Table: Baseline Characteristics.¹⁷
• The median treatment duration was 10.4 months for both groups as summarized in Table: Treatment Disposition.¹⁷

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.¹⁷
  • 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.¹⁷
  • 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.¹⁷
• 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).¹⁷
• N-terminal pro b-type natriuretic peptide (NT-proBNP) and high sensitivity (HS) troponin T levels improved across both groups.¹⁷
• Cardiac signs/symptoms and 6-minute walk test distance improved across both arms.¹⁷

Safety

• There were similar rates of serious cardiac TEAEs in both groups, see Table: Summary of Cardiac TEAEs.¹⁷
• Of the 30 major cardiac TEAEs (grade >3 or serious) that occurred in 20 patients, 28 events were attributed to underlying cardiac amyloid disease.¹⁷
  • 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%).¹⁷
• 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.¹⁷

Phase 2 Study of D-Pd in Patients with Relapsed/Refractory AL Amyloidosis

Rosenbaum et al (2023)¹⁸ 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.¹⁸
  • 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.¹⁸
• 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.¹⁸
• 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.¹⁸
  • 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.¹⁸
• Overall, 16 patients were to be enrolled.¹⁸

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.¹⁸
• Patient characteristics related to prior DARZALEX exposure are summarized in Table: Patient Characteristics Related to Prior DARZALEX FASPRO Exposure.¹⁸
• 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]).¹⁸
• Three patients had not received 12 D-Pd cycles and continued on therapy.¹⁸
• 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.¹⁸

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.¹⁸
• 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.¹⁸
• 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.¹⁸
• 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.¹⁸
• Cardiac progression occurred in 2 patients after cycle 2; 1 achieved a low-dFLC PR after 11 cycles and remained on pomalidomide maintenance therapy.¹⁸

Safety

• DPd was well tolerated, and the majority of AEs were low grade.¹⁸
• 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.¹⁸
• 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).¹⁸
• All patients recovered fully and continued on study.¹⁸
• Due to grade 3 PN, 1 heavily pretreated patient with pre-existing neuropathy discontinued in cycle 3.¹⁸
• No Grade 4 non-hematologic AEs were reported.¹⁸

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

Kastritis et al (2024)¹⁹ 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.

Study Design/Methods

• Patients with newly diagnosed stage 3B AL amyloidosis were included.¹⁹
• Dosing¹⁹:
  • 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 ≥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.¹⁹
• Primary endpoint: OS rate at 6 months.¹⁹
• 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.¹⁹

Results

Patient Characteristics

• 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).¹⁹ 
  • 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).¹⁹
• The median number of DARZALEX infusions was 18 (range, 1-36).¹⁹
• Baseline patient and treatment characteristics are summarized in Table: Baseline Patient and Treatment Characteristics.¹⁹

Efficacy

• Patients who received DARZALEX/DARZALEX FASPRO monotherapy achieved a 6-month OS rate of 65.0% (95% CI, 48.2-77.6). The 12-month OS rate was 45.0% (95% CI, 29.3-59.5), and the median OS was 10.3 months (95% CI, 4.1-32.3).¹⁹
• A summary of efficacy outcomes is presented in Table: Efficacy Outcomes at Different Timepoints.¹⁹
  • Overall, 77.5% of patients achieved a partial response or better (≥PR) and 55% of patients achieved ≥VGPR.
  • Overall, 50% of patients achieved cardiac ≥PR and 40% of patients achieved cardiac ≥VGPR.

Safety

• A summary of safety outcomes is presented in Table: Summary of Safety Outcomes.¹⁹
• A list of common SAEs is presented in Table: Common SAEs.¹⁹
• 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.¹⁹

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 16 December 2025. 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 have been excluded.