The Majority of Patients with Relapsing Light Chain (AL) Amyloidosis Are Not Eligible for Enrollment Onto Clinical Trials: Using Screen Failures to Define Major Unmet Medical Needs

Background: Hematologic response criteria in AL amyloidosis are based on reduction of FLCs and correlate with organ improvement and survival in the front-line setting (Palladini 2012). Hematologic progression is defined from complete response (CR) as any detectable monoclonal (m) protein or abnormal FLC ratio (light chain must double); and from partial response (PR) as a 50% increase in serum or urine m-protein to > 0.5g/dl or 200mg/d respectively; or a 50% increase in FLC to > 10mg/dL based on consensus criteria (Gertz 2005); while cardiac and renal progression criteria have recently been validated (Palladini 2012 & 2014). Trials enrolling relapsed pts define measurable disease by a difference in FLC (dFLC) >5mg/dl such that accurate responses (VGPR, PR) can be assessed. However, many pts with hematologic and/or organ progression fail to meet dFLC > 5mg/dL set by inclusion criteria (if progression from CR) or the high bar of FLC > 10mg/dL set by the progression criteria and are ineligible for clinical trials. Composite criteria for progression of disease involving both hematologic measures and biomarkers of organ damage do not exist. The goal of the current study was to characterize pts with AL and evidence of progressive disease who were ineligible for clinical trials in order to determine the magnitude of this problem and define potential AL study populations whose medical needs are not being met.

Methods: Previously treated AL pts screened for clinical trials from 5/2013 to 5/2015 at Memorial Sloan Kettering Cancer Center and Tufts Medical Center were reviewed retrospectively. Trials included 1) phase I/II trial of carfilzomib (NCT01789242), 2) phase I trial of ixazomib (NCT01318902) and 3) phase III trial of ixazomib/dexamethasone versus physician's choice (NCT01659658). Inclusion for all 3 required relapsed AL with dFLC >5mg/dl and evidence of organ damage. Pts with progressive hematologic and/or organ disease (by consensus or validated criteria) who were screened for these trials were included in this analysis.

Results: Among 36 pts screened, 33% (N=12) enrolled. Yet, 67% (N=24) with hematologic (N=14), cardiac (N =6) and/or renal (N=11) progression were ineligible. Median age was 61 years (range, 41-78); prior lines of therapy were 1 in 38%, 2 in 38% and >2 in 25%. Median BNP, TROP, serum ALB, eGFR and 24hr urine total protein were: 283pg/mL (36-2197), 0ng/mL (0-0.09), 3.4g/dL (1.3-4.8), 66ml/min (7-128) and 1800 mg/24hrs (trace-12,875), respectively. Median involved FLC was 6.48mg/dl (0.93-52.6) and dFLC 4.69mg/dl (0.01-52). 58% (14/24) were ineligible due to dFLC <5mg/dl, which was the most common reason for screen failure despite meeting hematologic and/or organ criteria for progression. Others were excluded for multiple myeloma (N=2), cardiac stage III (N=4), prior malignancy (N=1), number of prior therapies (N=1) and low creatinine clearance (N=2). 92% (22/24) have received therapy: 19 off study, 2 on alternate trials and 1 eventually qualified with dFLC >5mg/dl; 2 are being monitored for FLC progression with unclear clinical implications. One-third of patients ineligible for these trials have died.

Conclusions: The finding that only 1/3 of pts with AL amyloidosis and hematologic or organ progression requiring therapy are eligible for clinical trials demonstrates the limitations of the current definitions of progression and "measurable disease" criteria for enrolling relapsed pts on trials. The necessary decision to treat pts with organ progression in advance of their meeting a criterion for FLC progression (to >10mg/dl) indicates that this arbitrarily defined value needs to be revised. Moreover, time to next therapy rather than progression free survival (as currently defined) is a more relevant clinical trial end point. More sensitive, validated hematologic progression and composite criteria defining progression of hematologic and organ disease are critically needed to identify patients whose level of hematologic disease progression and risk of organ damage is at variance with current criteria as defined by FLCs. This will enable novel therapies that have the potential to reduce the risks of end-stage organ failure and death to be tested in this population.