SUMMARY

• DARZALEX for intravenous use (IV) is not approved by the regulatory agencies for the treatment of patients with immunoglobulin light chain (AL) amyloidosis. Janssen does not recommend the use of DARZALEX in a manner inconsistent with the approved labeling.
• Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
• There are no systemically collected data on the management of hematologic events with DARZALEX/DARZALEX FASPRO treatment. Clinical judgement should be exercised when managing hematologic events during DARZALEX/DARZALEX FASPRO containing treatment regimens.
• 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 (VCd) compared to VCd alone in newly diagnosed patients with systemic AL amyloidosis.^1-5
  • Pallidini et al (2020)¹ reported safety run-in results of the ANDROMEDA study in 28 patients who received D-VCd with a median follow-up of 17.6 months. Comenzo et al (2020)² reported (at the 17th International Symposium of Amyloidosis [ISA]) updated safety run-in results with a median follow-up of 22.9 months. Among the most common hematologic grade 3/4 treatment-emergent adverse events (TEAEs) were lymphopenia (18%), anemia (14%), and thrombocytopenia (7%).
  • Kastritis et al (2021)³ reported primary results of the study with a median follow-up of 11.4 months. The most common adverse events of any grade were lymphopenia (D-VCd, 18.7%; VCd, 14.9%), and neutropenia (D-VCd, 10.9%; VCd, 6.4%). Among the most common grade 3/4 adverse events were lymphopenia (D-VCd, 13.0%; VCd, 10.1%), and neutropenia (D-VCd, 5.2%; VCd, 2.7%).
  • Comenzo et al (2021)⁴ presented (at the 63rd American Society of Hematology [ASH] Annual Meeting & Exposition) updated efficacy and safety results of the ANDROMEDA study, with a median follow-up of 25.8 months. The most common hematologic grade 3/4 TEAEs were lymphopenia (D-VCd, 13%; VCd, 10%), and neutropenia (D-VCd, 5%; VCd, 3%).

• • Kastritis et al (2024)⁵ presented (at the 66th ASH Annual Meeting) the final analysis for major organ deterioration progression-free survival (MOD-PFS) and overall survival (OS) from the phase 3 ANDROMEDA study, with a median follow-up of 61.4 months. The most common hematologic adverse events of any grade were anemia (D-VCd, 25.4%; VCd, 23.4%), lymphopenia (D-VCd, 19.2%; VCd, 14.9%), and neutropenia (D-VCd, 10.9%; VCd, 6.4%). The most common grade 3/4 hematologic adverse events were lymphopenia (D-VCd, 13.0%; VCd, 10.1%), neutropenia (D-VCd, 5.2%; VCd, 2.7%), and anemia (D-VCd, 4.1%; VCd, 4.8%).
• Lee et al (2024)⁶ presented (at the European Hematology Association [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 hematologic TEAEs included lymphopenia (35%), anemia (20%), platelet count decreased (20%), hypoalbuminemia (15%), and neutrophil count decreased (15%).

PRODUCT LABELING

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

CLINICAL DATA  

Phase 3 Study in Newly Diagnosed Systemic AL Amyloidosis

ANDROMEDA (AMY3001; clinicaltrials.gov identifier: NCT03201965) is an ongoing, prospective, randomized, active-controlled, multicenter, phase 3 study evaluating the efficacy and safety of DARZALEX FASPRO + VCd compared to VCd alone in newly diagnosed patients with systemic AL amyloidosis.^1-4

Safety Run-in Results of ANDROMEDA Study

Palladini et al (2020)¹ reported safety run-in results of the ANDROMEDA study in 28 patients who received D-VCd with a median follow-up of 17.6 months. Comenzo et al (2020)² reported updated safety run-in results of ANDROMEDA with a median follow-up of 22.9 months.

Study Design/Methods

• At least 10 patients were to be enrolled in the safety run-in cohort to determine the safety and tolerability of DARZALEX FASPRO in combination with VCd.
• If no safety signal is observed after ≥1 cycle of treatment, approximately 360 patients are expected to be randomized 1:1 to receive VCd with or without DARZALEX FASPRO.
• Patients were stratified as follows:
  • Cardiac stage (I vs II vs IIIA)
  • Transplant typically offered in local country (yes vs no)
  • Creatinine clearance (>60 mL/min vs <60 mL/min)
• Primary endpoint: overall hematologic complete response rate
• Secondary endpoints: MOD-PFS, progression-free survival (PFS), organ response rate as assessed by biomarkers, OS, improvement in patient-reported fatigue.

Results - Safety - Hematologic Events in the Safety Run-in Cohort

Primary Results of ANDROMEDA Study

Kastritis et al (2021)³ presented primary results of the ANDROMEDA study, with a median follow-up of 11.4 months.

Study Design/Methods

• Primary endpoint: overall hematologic complete response rate
• Secondary endpoints: MOD-PFS, PFS, organ response rate, time to hematologic response, OS, and safety

Results - Safety - Hematologic Events

Updated Safety Results of ANDROMEDA Study

Comenzo et al (2021)⁴ presented updated efficacy and safety results of the ANDROMEDA study, with a median follow-up of 25.8 months.

Results - Safety - Hematologic Events

Most Common Grade 3/4 Hematologic TEAEs in the Updated Analysis (Median Follow-up 25.8 Months)⁴

Final Analysis for MOD-PFS and OS

Kastritis et al (2024)⁵ presented (at the 66^th ASH Annual Meeting) the final analysis for MOD-PFS and OS of the ANDROMEDA study, with a median follow-up of 61.4 months.

Results - Safety - Hematologic Events

Final Results From Phase 1 Study in Patients With AL amyloidosis

Lee et al (2024)⁶ 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 N-terminal pro B-type natriuretic peptide (NT-proBNP) >8500 ng/L, clinically overt myeloma (hypercalcemia and/or bone lesions), or who had previous ixazomib or anti-cluster of differentiation 38 (CD38) monoclonal antibody therapy or had planned high-dose chemotherapy and autologous stem cell transplant (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 creatinine clearance 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.

Safety

• A summary of any-grade hematologic TEAEs and grade ≥3 hematologic TEAEs has been presented in Table: Summary of Any-Grade Hematologic TEAEs and Summary of Grade ≥3 Hematologic TEAEs.
• 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.

Literature Search

A literature search of Ovid MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File databases (and/or other resources, including internal/external databases) was conducted on 29 January 2025. For streamlining purposes, retrospective-analyses, systematic reviews, review articles, and case reports have been excluded.

In response to your specific request, summarized in this response is the relevant data from company-sponsored studies pertaining to this topic.