Daratumumab Monotherapy in Previously Untreated High-Risk Patients with Stage 3B Light Chain (AL) Amyloidosis: A Phase II Multicenter Study By European Myeloma Network (EMN)

Background: Advances in the anti-plasma cell therapy with the introduction of bortezomib-based therapies have improved the outcomes of patients with systemic light chain (AL) amyloidosis. However, patients with more severe cardiac involvement, (i.e., those with stage 3B disease defined as increased troponin levels with NT-proBNP level > 8500 pg/ml) still have a dismal prognosis with a median survival of 4-9 months. A delay in hematologic response and potential treatment related toxicities, may not allow for improvement in the outcome of these high-risk patients. Unfortunately, patients with stage 3B disease are excluded from clinical trials; their management remains a challenge and new treatment options are urgently needed.

Daratumumab is a human IgG1ĸ monoclonal antibody that binds with high affinity to a unique epitope on CD38. It acts on plasma cells that express CD38 via different mechanisms, including direct apoptotic activity and immune system mediated responses. In patients with relapsed or refractory AL amyloidosis, daratumumab monotherapy has shown rapid, deep and high response rates, which are durable. Moreover, daratumumab has shown an excellent toxicity profile and no signal of cardiotoxicity. An ongoing prospective randomized trial evaluates the addition of daratumumab to standard bortezomib-based therapy in previously untreated patients with AL amyloidosis but patients with stage 3B are excluded. In order to offer high risk AL patients a new treatment option we designed this phase 2 trial aiming to enroll exclusively patients with stage 3B disease.

Study Design and Methods: This is an open-label, multicenter, Phase 2 study in subjects with newly diagnosed stage 3B AL amyloidosis. Approximately 40 subjects will receive primary therapy with daratumumab. Subject participation will include a Screening Phase, a Treatment Phase, a Post-Treatment Observation Phase, and a Long-term Follow-up Phase.

A safety run-in will include 6 subjects treated with daratumumab for at least 1 cycle to establish safety of the study drug in stage 3B AL amyloidosis patients. Dosing of these 6 patients will be staggered so that no subject will receive their first dose sooner than 48 hours after the previously enrolled subject. Safety evaluation will be performed by a Data Safety Monitoring Board after at least 1 cycle is completed for all 6 patients. If no safety signal is observed, the enrollment of the rest of the patients will begin.

Subjects will initially receive daratumumab IV at a dose of 16 mg/kg, and by the end of 2019 will switch to daratumumab SC at a fixed dose of 1800 mg. Daratumumab will be administered weekly for Cycles 1-2, every 2 weeks for Cycles 3-6, and every 4 weeks thereafter. Each Cycle will last 28 days. The treatment will continue until disease progression according to Major Organ Deterioration Progression-Free Survival (MOD-PFS) criteria, start of subsequent therapy, or a maximum of 2 years. Patients who after 3 cycles of daratumumab monotherapy, have not achieved at least a hematologic VGPR or a hematologic PR with improved major organ function (i.e., cardiac or renal response per updated response criteria) may receive at the Investigator's discretion, bortezomib (1.3 mg/m² weekly, for a maximum of 6 cycles) with low dose dexamethasone, in addition to daratumumab (Figure 1).

The primary objective is to evaluate the overall survival (OS) rate at 6 months. The secondary objectives include evaluation of overall, VGPR and CR hematologic response rates at 3 and 6 months, MOD-PFS, PFS, organ response rate, treatment effects on patient-reported outcomes, time to and duration of response, safety and tolerability of daratumumab in patients with stage 3B AL amyloidosis.

Minimal residual disease (MRD) may be monitored in subjects who achieve hematologic CR using high sensitivity methodologies (such as the Clonoseq NGS assay, or NGF based on the EuroFlow protocol). Safety will be measured by adverse events, laboratory tests, electrocardiograms, echocardiograms, vital sign measurements, physical examination and ECOG performance status. Health-related quality of life will be assessed via patient-reported outcome questionnaires.

The study will run in 3 countries (Italy, Greece, and Netherlands), and will open for enrollment in August 2019. The recruitment is expected to last for 18 months, and the maximum time of treatment under the study protocol is 24 months.