Predictors of Hematologic Complete Response Achievement and Maintenance in Patients with AL Amyloidosis Treated with Non-Transplant Chemotherapy

Introduction: Hematologic response, particularly complete remission (CR), is the goal of therapy and predicts survival in light chain (AL) amyloidosis patients. Therefore, CR is an endpoint in clinical trials, such as the ANDROMEDA study that showed that the addition of daratumumab to cyclophosphamide, bortezomib (B) and dexamethasone improved the rate of CR. However, it is not clear if baseline disease biomarkers can predict CR achievement and its duration. Gustine et al. recently investigated factors influencing the attainment and maintenance of CR in AL patients who received autologous stem cell transplant (ASCT). However, only a minority of AL patients receive ASCT. Herein we attempt to identify biomarkers able to predict achievement and maintenance of CR in AL patients treated with non-transplant chemotherapy.

Methods: The prospectively maintained database of the Pavia Center was searched for patients who received upfront non-transplant chemotherapy from January 2004 to December 2020. Hematologic response was assessed 6 months after first-line therapy initiation according to the International Society of Amyloidosis (ISA) criteria. In patients who achieved CR, relapse was defined as the detection of the monoclonal protein at serum and/or urine immunofixation and/or an abnormal FLC ratio [with involved FLC (iFLC) higher than uninvolved FLC]. Duration of CR (DOR-CR) was defined as the time from the achievement of CR to relapse. The following variables were assessed by logistic regression analysis as possible prognostic factors for CR: age, sex, NT-proBNP, troponin I, alkaline phosphatase, percentage of bone marrow plasma cell (BMPC), light chain isotype and difference between iFLC and uninvolved free light chain (dFLC), B-based regimen. Receiver operator characteristic analyses were used to derive best cut-offs of evaluated factors for achievement of CR. Cox models were fitted to compute hazard ratios (HR) and 95% confidence intervals (CI) for DOR-CR and OS for BMPC, B-exposure, and baseline and post-treatment dFLC and iFLC.

Results: A total of 942 patients were included with 160 (17%) in hematologic CR. Of all the assessed variables, only dFLC and BMPC were identified as predictors of CR. The dFLC and BMPC cut-offs best predicting CR were 130 mg/L and 13% respectively. Because BMPC and dFLC were weakly correlated (R²= 0.04) we included both variables in a single multivariate model, that showed dFLC> 130 mg/L (odds ratio [OR] 0.65, CI 95% 0.43-0.96, P=0.034) and BMPC> 13% (OR 0.59, CI 95% 0.38-0.91, P=0.019) independently predicted CR attainment. Treatment with B-based regimen was positively related to CR achievement and was not able to modify the predicting ability of dFLC and BMPC. In patients with dFLC above or below the cut-off, CR were 13% and 21%, respectively (P<0.001). While in patients having BMPC above or below the threshold CR was obtained in 11% and 20% of cases, respectively (P<0.003). In the subset of transplant eligible patients (N=179, 19%) who did not receive ASCT, only dFLC> 130mg/L was associated with a lower rate of CR (OR 0.39, CI 95% 0.17-0.86, P=0.019), while BMPC> 13% was not (P=0.228). Median OS of patients achieving a CR was 12.1 years (CI 95% 10.3-16.6) with a median follow-up of living patients of 8.5 years (CI 95% 7.5-18.1). Median DOR-CR was 9.4 years (CI 95% 5.9-11.3). By univariate analysis, the only variable that predicts DOR-CR was post-treatment dFLC< 10mg/L (HR 0.52, CI 95% 0.28-0.95, P=0.035). Moreover, DOR-CR was not influenced by the use of B-based regimen (P=0.281).

Conclusion: Baseline dFLC> 130mg/L and BMPC> 13% allow to identify patients with a lower chance to achieve a CR to front-line non-transplant chemotherapy. In agreement with Gustine et al., dFLC was the only predictive factor for CR achievement in transplant eligible setting, although with a lower threshold. These factors should be considered for stratification in clinical trials based on CR as a primary endpoint. Further studies are warranted to assess whether dFLC and BMPC also affect the rate of CR in dara-treated subjects. Moreover, we found that attaining a very deep reduction of dFLC (<10 mg/L) correlates with long-term maintenance of CR. This finding corroborates previous observations that very low post-treatment FLC levels can identify patients with a better outcome among those who attain CR and suggests that more sensitive tools are needed to define very deep responses (minimal residual disease).

Milani:Pfizer: Honoraria, Research Funding; Jansenn-Cilag: Honoraria. Basset:Janssen-Cilag: Honoraria. Foli:Janssen-Cilag: Honoraria. Nuvolone:Oncopeptides AB: Research Funding; Pfizer: Research Funding; Gate Bioscience: Research Funding; Jansenn-Cilag: Other: Travel Support. Merlini:Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees. Palladini:Argobio: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees; Protego: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gate Bioscience: Research Funding; Sebia: Honoraria; Siemens: Honoraria; The Binding Site: Honoraria, Research Funding; Prothena: Honoraria.

Bortezomib in AL amyloidosis