A Slow-Go Treatment in Newly Diagnosed AL Amyloidosis with Severe Cardiomyopathy

Background: There are few known therapeutic options for AL amyloidosis with severe cardiac involvement, often defined as Mayo stage 3B as defined by NT-proBNP ≥ 8500 pg/mL and high-sensitivity troponin T (hsTnT) > 54 pg/mL (Muchtar E et al, Blood, 2019, PMID 30545829). A recent European trial (EMN22) of Daratumumab monotherapy demonstrated 50% VGPR/CR activity (Kastritis E et al, ASH, 2023A portion of AL Amyloid patients are excluded from clinical trials related to elevated cardiac biomarkers, poor cardiac or renal function, or poor performance status. This protocol was created for fragile patients whose survival would paradoxically be shortened by full-dose aggressive treatment (Dara-VCd or RVd) and who might benefit from a slow-go approach (Palumbo A et al, Blood, 2011, PMID 21841166). This borrows from geriatric literature that uses an adjusted treatment algorithm for unfit patients where doses are reduced initially in patients with multiple comorbidities and/or poor renal function and then increased with tolerance.

Primary endpoint: An event was defined as the patient going off study within 3 months of enrollment due to toxicity or progression. The primary endpoint was the event-free proportion at 3 months; we hypothesized that this would be 40% at 3 months.

Design: Inclusion criteria were patients with high risk biopsy-proven AL Amyloidosis based on NT-proBNP>8500 ng/L, hs-cTnT ≥ 50 ng/L, BUMC 2019 stage 3b criteria [TnI>0.1 ng/mL and BNP>700 pg/mL), or Mayo 2012 stage 4 criteria [cTnT ≥ 0.025 ng/mL or hs-cTnT ≥ 40 ng/mL; plus NT-proBNP ≥ 1800 pg/mL plus dFLC ≥ 180 mg/L]. Renal function eGFR ≥ 20 mL/min and left ventricular ejection fraction ≥ 30% were required. Patients were excluded with >1 prior line of therapy, refractory to any proteasome inhibitor, or prior CD38 antibody exposure. Our phase 1 unit was uniquely suited to allow collaborative care between our staff and the amyloid heart failure team.

Patients were treated in a flexible step-wise approach starting with Isatuximab 10 mg/kg weekly x 4 and dexamethasone 4 mg [step A; 2 weeks], then Isatuximab + dexamethasone 4 + bortezomib 1 mg/m² [step b; 2 weeks], then with Isatuximab every other week with increasing dexamethasone to 12 mg weekly [step c; 1 month], increasing bortezomib to 1.3 mg/m² [step d, 1 month], adding in Cytoxan 300 mg to 500 mg [steps e, f, g; 1 month each], followed by single agent maintenance Isatuximab every other week for a year [step m].

Results: Out of a total of 11 patients treated, the first two patients were enrolled on infusional inotropes at the time of consent and the eligibility was changed to exclude these patients due to low likelihood of treatment benefit (PMID 29709420). In the remainder, three patients died between consent and treatment initiation, two patients died within 30 days of starting treatment, and two patients died between 30-90 days of starting treatment. The remaining patients are in a hematologic CR; no patients progressed while on treatment. For AEs possibly or probably related to study drug therapy, there was (1) grade 1 infusion related reaction, (1) grade 3 insomnia, (1) grade 2 AST & ALT elevation, (1) grade 3 hyperbilirubinemia, (1) grade 1 anemia, and (1) anorexia grade 2.

Conclusions: 1) Until fibril targeted treatments become available, plasma cell directed therapy appears futile in newly diagnosed patients with end-stage cardiomyopathy requiring infusional inotropes or those with poor performance status; 2) While no patients progressed on trial, this slow-go approach may result in a more gradual reduction in light chains than what was reported with Dara-VCd (ANDROMEDA, Kastritis, NEJM, 2021) without known clinical consequence; 3) Even among patients achieving a hematologic complete remission, one moved on to heart transplant while two others had an improvement in symptomatic heart function. Despite the small number of patients treated, a slow-go approach may be reasonable for patients with severe amyloid cardiomyopathy, especially if they survive the first three months of treatment.

Acknowledgements: This trial was supported as an investigator-initiated protocol by Sanofi.