Ray Comenzo

We undertook this study to develop uniformly accepted criteria for the definition of organ involvement and response for patients on treatment protocols for immunoglobulin light-chain amyloidosis (AL). A consensus panel was convened comprising 13 specialists actively involved in the treatment of patients with amyloidosis. Institutional criteria were submitted from each, and a consensus was developed defining each organ involved and the criteria for response. Specific criteria have been developed with agreed on definitions of organ and hematologic response as a result of discussions at the 10th International Symposium on Amyloid and Amyloidosis held in Tours, France, April 2004. These criteria now form the working definition of involvement and response for the purposes of future data collection and reporting. We report criteria that centers can now use to define organ involvement and uniform response criteria for reporting outcomes in patients with light-chain AL.

Amyloid light-chain (LC) amyloidosis (AL amyloidosis) is a rare and fatal disease for which there are no approved therapies. In patients with AL amyloidosis, LC aggregates progressively accumulate in organs, resulting in organ failure that is particularly lethal when the heart is involved. A significant obstacle in the development of treatments for patients with AL amyloidosis, as well as for those with any disease that is rare, severe and heterogeneous, has been satisfying traditional clinical trial end points (for example, overall survival or progression-free survival). It is for this reason that many organizations, including the United States Food and Drug Administration through its Safety and Innovation Act Accelerated Approval pathway, have recognized the need for biomarkers as surrogate end points. The international AL amyloidosis expert community is in agreement that the N-terminal fragment of the pro-brain natriuretic peptide (NT-proBNP) is analytically validated and clinically qualified as a biomarker for use as a surrogate end point for survival in patients with AL amyloidosis. Underlying this consensus is the demonstration that NT-proBNP is an indicator of cardiac response in all interventional studies in which it has been assessed, despite differences in patient population, treatment type and treatment schedule. Furthermore, NT-proBNP expression is directly modulated by amyloidogenic LC-elicited signal transduction pathways in cardiomyocytes. The use of NT-proBNP will greatly facilitate the development of targeted therapies for AL amyloidosis. Here, we review the data supporting the use of NT-proBNP, a biomarker that is analytically validated, clinically qualified, directly modulated by LC and universally accepted by AL amyloidosis specialists, as a surrogate end point for survival.

Background: The achievement of deep and sustained hematologic response in AL amyloidosis is needed to improve organ function and overall survival. Daratumumab‐based combinations have resulted in deep responses and minimal additional toxicity in multiple myeloma, making such combinations potentially ideal in the treatment of AL amyloidosis. Aims: We present the 1‐year follow up on safety and efficacy data for the 28 patients enrolled in the safety run‐in cohort of ANDROMEDA (NCT03201965), a phase 3 study investigating subcutaneous DARA + CyBorD in patients with newly diagnosed AL amyloidosis. Methods: Eligible patients had ≥1 involved organs, Eastern Cooperative Oncology Group (ECOG) score ≤2, estimated glomerular filtration rate ≥20 mL/min/1.73m 2 , and NT‐ProBNP ≤8,500 ng/L. In the safety run‐in, patients received DARA (1,800 mg in 15 mL) co‐formulated with recombinant human hyaluronidase PH20 (rHuPH20; ENHANZE ® drug delivery technology, Halozyme, Inc.) administered subcutaneously (SC) qw Cycles 1–2, q2w Cycles 3–6, and q4w thereafter for ≤2 y. Cy 300 mg/m 2 PO or IV, Bor 1.3 mg/m 2 SC, and D 40 mg were administered qw ≤6 cycles. Hematologic response evaluations (per international amyloidosis consensus criteria, Comenzo Leukemia 2012) were q4w cycles 1–6 and every other month thereafter. Results: Patients (N = 28) had a median (range) age of 68 (35–83) years and a median of 2 (1–4) involved organs. Heart and kidney involvement affected 54% and 61% of patients, respectively; 21% were Mayo cardiac stage IIIA at screening. Median (range) follow‐up was 341 (17–449) days. Median treatment duration was 11 (0.2–14) months. Patients received a median of 11 (1–16) treatment cycles; 79% received DARA SC maintenance (>6 cycles). The overall hematologic response rate was 96% and the rate of very good partial response (VGPR) or better was 82%; 10 (36%) patients achieved CR. An additional 5 (18%) patients achieved CR based on normalization of involved free light chain (iFLC) level and negative serum and urine immunofixation, but due to suppression of uninvolved FLC (uFLC) below the lower limit of normal did not normalize the FLC ratio and thus could not be formally classified as CR. Median time to first response was 23 days, and median time to CR and VGPR were 85 (29–226) and 22 (7–228) days, respectively. At the time of data cutoff (median follow‐up 341 days), one patient (with no response to treatment) experienced disease progression. All of the 10 patients achieving CR and the 5 patients with normalized iFLC level and negative serum and urine immunofixation without normalized FLC ratio continue to respond to treatment. Median duration of CR was not reached. Six patients received subsequent autologous stem cell transplant (ASCT). Four patients have died (2 due to disease progression and 2 due to events following ASCT). The most common treatment emergent adverse events included diarrhea (64%), fatigue and peripheral edema (50% each). Two patients (7%) experienced infusion related reactions, all of which were grade 1. Summary/Conclusion: DARA‐CyBorD provides high overall hematologic response and CR rate in patients with newly diagnosed AL amyloidosis with a well‐tolerated safety profile. Enrollment into the randomized portion of ANDROMEDA is ongoing.