FDA Approval Sought for Subcutaneous Daratumumab in AL Amyloidosis

A supplemental biologics license application has been submitted to the FDA for daratumumab plus hyaluronidase-fihj for the treatment of patients with amyloid light chain amyloidosis.

A supplemental biologics license application (sBLA) has been submitted to the FDA for daratumumab plus hyaluronidase-fihj (Darzalex Faspro) for the treatment of patients with amyloid light chain (AL) amyloidosis, according to an announcement from The Janssen Pharmaceutical Companies of Johnson & Johnson.1

The application is based on data from the phase 3 ANDROMEDA trial (NCT03201960), which demonstrated the superiority of subcutaneous daratumumab formulation plus cyclophosphamide, bortezomib, and dexamethasone (CyBorD) over CyBorD alone. Results showed that the subcutaneous daratumumab combination resulted in deeper and more rapid hematologic responses, thus meeting the primary end point of the trial.2

Results presented during the 2020 European Hematology Association Congress showed a hematologic complete response (CR) of 53% with subcutaneous daratumumab/CyBorD versus just 18% with CyBorD alone (odd ratio [OR], 5.1; 95% CI, 3.2-8.2; P <.0001). Moreover, the 6-month organ response rate achieved with the investigational regimen was approximately double that achieved with the control regimen for both cardiac (42% vs 22%, respectively) and renal (54% vs 27%) responses.

Subcutaneous daratumumab/CyBorD elicited higher rates of overall hematologic response compared with CyBorD alone, at 92% versus 77%, respectively; the very good partial response (VGPR) rate achieved with the daratumumab combination was also higher than CyBorD alone, at 79% versus 49%. The median time to response was also shorter with the investigational regimen. Moreover, the major organ deterioration progression-free survival (MOD-PFS) also favored the investigative regimen (HR, 0.58; 95% CI, 0.37-0.93; P = .0230).

“Without exaggeration, this is the most significant filing in the modern history of therapeutic developments for patients with AL amyloidosis,” Raymond L. Comenzo, MD, director of the John C. Davis Myeloma and Amyloid Program at Tufts Medical Center told OncLive.

“There are 3 reasons. First, there are no agents that are approved for [this disease]; having an FDA-approved combination therapy, based on phase 3 data, will expedite coverage and treatment for patients,” explained Comenzo. “Second, the combination…is extraordinarily effective at shutting down the factory of clonal plasma cells producing the pathologic light chains and, importantly, the reduction in light-chain production is very rapid. Third, daratumumab is given subcutaneously in a small volume, allowing [patients with] AL amyloidosis with heart involvement complicated by volume overload to receive therapy without the burden of a liter or half-liter of intravenous fluid.”

A total of 388 patients with newly diagnosed AL amyloidosis were enrolled to the open-label phase 3 ANDROMEDA trial. Participants had measurable hematologic disease with 1 or more organs affected and an ECOG performance status of 0-2.3 If they received prior treatment for AL amyloidosis or multiple myeloma, had a previous or current diagnosis of symptomatic multiple myeloma, and evidence of significant cardiovascular conditions, they were excluded from inclusion.

The primary end point of the trial was overall complete hematologic response rate in the intent-to-treat population. Key secondary end points included MOD-PFS, organ response rate, time to hematologic response, survival, and safety.

All participants were given cyclophosphamide at a weekly dose of 300 mg/m2 either orally or intravenously (IV), subcutaneous bortezomib at a weekly dose of 1.3 mg/m2, and dexamethasone at 20 mg to 40 mg either orally or IV for the duration of six 28-day cycles. Subcutaneous daratumumab was given via injection once weekly in cycles 1 and 2, once every 2 weeks in cycles 3-6, and once every 4 weeks thereafter for up to 24 treatment cycles.

No new safety signals were reported with the daratumumab combination. The rate of discontinuation because of treatment-emergent adverse effects (TEAEs) was 4% in both cohorts. Fifty-six deaths were reported; 29 of these deaths occurred in the daratumumab/CyBorD arm and 27 occurred in he CyBorD-alone arm.

The most commonly experienced TEAEs that were grade 3 or 4 in severity included lymphopenia (13% with the daratumumab combination vs 10% with CyBorD alone), pneumonia (8% vs 4%, respectively), diarrhea (6% vs 4%), cardiac failure (6% vs 5%), neutropenia (5% vs 3%), syncope (5% vs 6%), and peripheral edema (3% vs 6%). Fourteen, or 7%, of participants reported systemic administration–related reactions with the investigative regimen, but all were grade 1 or 2 in severity; most of these cases were experienced during the first infusion.

“The outlook for newly diagnosed patients will change dramatically if this combination is approved and approval will also provide additional incentive for clinicians to [patients with] diagnose AL amyloidosis earlier in the course of their disease,” Comenzo concluded.

In May 2020, the FDA approved daratumumab and hyaluronidase-fihj for adult patients with newly diagnosed or relapsed/refractory multiple myeloma based on data from the phase 3 COLUMBA (MMY3012) trial, which established noninferiority of the subcutaneous formulation compared with the IV formulation with regard to efficacy.4


  1. Janssen submits application seeking US FDA approval of Darzalex Faspro (daratumumab and hyaluronidase-fihj) for the treatment of patients with light chain (AL) amyloidosis. News release. Janssen Pharmaceutical Companies of Johnson & Johnson. September 10, 2020. Accessed September 10, 2020. https://prn.to/2GOFX6R.
  2. Kastritis E, Palladini G, Minnema MC, et al. Subcutaneous daratumumab + cyclophosphamide, bortezomib, and dexamethasone (CyBorD) in patients with newly diagnosed light chain (AL) amyloidosis: primary results from the phase 3 ANDROMEDA study Presented at: the 25th Annual European Hematology Congress: Virtual. June 11-21, 2020. Abstract #LB2604.
  3. A study to evaluate the efficacy and safety of daratumumab in combination with cyclophosphamide, bortezomib and dexamethasone (CyBorD) compared to CyBorD alone in newly diagnosed systemic amyloid light-chain (AL) amyloidosis. ClinicalTrials.gov. Updated June 26, 2020. Accessed September 10, 2020. https://clinicaltrials.gov/ct2/show/NCT03201965.
  4. FDA approves daratumumab and hyaluronidase-fihj for multiple myeloma. News release. FDA. May 1, 2020. Accessed September 10, 2020. https://bit.ly/2zJvs0Y.