Trial in Progress: Phase II Study Evaluating Maintenance in Light Chain Amyloidosis (EMILIA)

Background: Light chain (AL) amyloidosis is a rare and understudied plasma cell disorder. It is caused by abnormal misfolding of monoclonal immunoglobulin light chains, leading to extracellular deposition of amyloid, ultimately resulting in organ dysfunction and death. Since AL amyloidosis is uncommon, therapies are adapted from the more common plasma cell disorders like multiple myeloma. Daratumumab, a monoclonal antibody targeting CD38, was first tested in several prospective and retrospective studies in AL patients with relapsed refractory disease.

The ANDROMEDA study (Kastritis E et al, NEJM 2021) established daratumumab in combination with CyBorD (Cyclophosphamide-Bortezomib-Dexamethasone) followed by daratumumab maintenance as the new standard of care compared to CyBorD alone for newly diagnosed patients. Consequently, daratumumab maintenance has become universally offered to all newly diagnosed AL amyloidosis patients. Notably, there was no second randomization before the initiation of maintenance therapy in ANDROMEDA. Hence, a critical question that remains is whether the superior efficacy observed in the investigational arm of the ANDROMEDA trial is solely a result of the addition of daratumumab during the induction phase or if the maintenance phase contributed to the favorable outcomes in the investigational arm. We hypothesize that a shorter duration of maintenance would prove non-inferior to the standard duration of daratumumab maintenance in patients with AL amyloidosis that have responded to Daratumumab-CyBorD induction. To answer this question we are conducting a pragmatic phase 2 randomized trial assessing the optimal duration of daratumumab maintenance in patients with AL amyloidosis who have responded to Daratumumab-CyBorD induction.

Study Design, Patients and Methods: We use broadened eligibility criteria consistent with pragmatic trial design. The estimated total enrollment is up to 96 patients. The main eligibility criteria are patients with biopsy-proven AL Amyloidosis who have completed 6 cycles of Dara-CyBorD-based induction treatment and achieved an adequate response to induction (defined as hematological complete response (CR), hematological very good partial response (VGPR), or hematological partial response (PR) with at least one organ response). Patients in whom bortezomib and/or cyclophosphamide were omitted from induction due to toxicity concerns or adverse effects are allowed. The major exclusion criteria are patients who were concomitantly diagnosed with multiple myeloma based on International Myeloma Working Group (IMWG) criteria.

This phase II, open-label, multicenter trial (NCT05898646) randomizes patients who have attained an adequate response to 6 cycles of Dara-CyBorD-based induction in a 1:1 ratio, using a dynamic allocation procedure that balances the marginal distributions of the stratification factors (age, cardiac stage, and t(11;14) status). Randomization is to either single-agent daratumumab maintenance of 6 cycles duration (experimental arm) or 18 cycles of daratumumab maintenance (control arm) (cycle = 28 days). Treatment is allowed to be given at a local facility After completing maintenance treatment, patients will follow up every 3 months for up to 36 months from registration.

The primary endpoint of the trial is to evaluate the non-inferiority of a shorter (6 cycles) daratumumab maintenance measured by event-free survival (EFS) compared to the standard maintenance of 18 cycles in newly diagnosed AL amyloidosis who receive 6 cycles of daratumumab-CyBorD based induction. EFS in this study is defined as time from registration to any of the following events: hematological progression, organ progression, subsequent anti-plasma cell therapy in the absence of hematological progression but with persistent organ dysfunction or death, whichever occurs first. Secondary endpoints are depth of hematological and organ response, bone marrow measurable residual disease negativity rate, duration of response, quality of life, and survival. By investigating whether a shorter duration of maintenance is non-inferior to the standard duration, we aim to inform clinical practice and potentially reduce the toxicities associated with prolonged maintenance therapy, including hypogammaglobulinemia, recurrent infections, the need for intravenous gammaglobulin replacement, and financial toxicity.

Gertz:Medscape: Honoraria; Abbvie: Other: personal fees for Data Safety Monitoring board ; Ionis/Akcea: Honoraria; Alexion: Honoraria; Dava Oncology: Honoraria; Johnson & Johnson: Other: personal fees; Astra Zeneca: Honoraria; Janssen: Other: personal fees; Sanofi: Other: personal fees; Prothena: Other: personal fees; Alnylym: Honoraria. Dispenzieri:Pfizer: Research Funding; Takeda: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Alnylam: Research Funding; Janssen: Research Funding; HaemaloiX: Research Funding; Alexion: Consultancy, Research Funding. Fonseca:Patent for FISH in MM - ~$2000/year: Patents & Royalties: Patent for FISH in MM - ~$2000/year; AbbVie, Adaptive, Amgen, Apple, Bayer, BMS/Celgene, Gilead, GSK, Janssen, Kite, Karyopharm, Merck Sharp & Dohme, Juno Therapeutics, Takeda, Arduro Biotech, Oncotracker, Oncopeptides, Pharmacyclics, Pfizer, RA Capital, Regeneron, Sanofi: Consultancy; Antengene: Membership on an entity's Board of Directors or advisory committees; Celgene, Bristol Myers Squibb, Bayer, Amgen, Janssen, Kite, a Gilead company, Merck Sharp & Dohme, Juno Therapeutics, Takeda, AbbVie, Aduro Biotech, Sanofi, OncoTracker: Honoraria. Chhabra:GlaxoSmithKline, Sanofi: Honoraria; Omeros: Speakers Bureau; Bristol Myers Squibb, Amgen, Janssen, Novartis, Syndax, Ionis, Sanofi, and GlaxoSmithKline: Research Funding. Bergsagel:Omeros: Consultancy; Oncopeptides: Consultancy; Cellcentric: Consultancy; Janssen: Consultancy; Sanofi: Research Funding; Novartis: Research Funding; BMS/Celgene: Research Funding; Pfizer: Research Funding. Kapoor:Janssen: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Research Funding; BeiGene: Membership on an entity's Board of Directors or advisory committees, Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees, Research Funding; Ichnos: Research Funding; Karyopharm: Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Research Funding; Regeneron: Research Funding; Kite: Membership on an entity's Board of Directors or advisory committees; Mustang Bio: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Angitia Bio: Membership on an entity's Board of Directors or advisory committees; Loxo Pharmaceuticals: Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; X4 Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; CVS Caremark: Consultancy; Keosys: Consultancy. Leung:Checkpoint Therapeutics: Current holder of stock options in a privately-held company; AbbVie: Current holder of stock options in a privately-held company. Kourelis:Novartis: Research Funding; Pfizer: Research Funding. Cook:Geron Corp: Other: Held $600 Geron Stock for one week and sold without profit . Dingli:Sorrento: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; K36 Therapeutics: Research Funding; Genentech: Consultancy; BMS: Consultancy, Honoraria; MSD: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Apellis: Consultancy, Honoraria, Research Funding; Regeneron: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Alexion: Consultancy, Honoraria. Kumar:Oncopeptides: Other: Independent review committee participation; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Research Funding; Merck: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; MedImmune/AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding. Sher:Caelum pharma: Other; Alpha: Consultancy, Membership on an entity's Board of Directors or advisory committees; 2 Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Prothena: Other. Muchtar:Protego: Consultancy.