Risk-Adapted Melphalan and Stem Cell Transplantation after Suboptimal Responses to Bortezomib-Based Initial Therapy in Patients with Systemic Light-Chain Amyloidosis (AL)
Authors: Wong Sandy W. , Larivee Denise , Warner Melissa , Sprague Kellie , Fogaren Terry , Comenzo Raymond L. 
Published: October 2019

Abstract
The treatment of newly diagnosed patients with AL has dramatically improved with the use of the first-in-class proteasome inhibitor bortezomib in initial therapy (Kastritis et al., Haematologica, 2007). Overall hematologic response rates of 62% have been reported in a large series with 43% of patients achieving very good partial (VGPR) or complete responses (CR), i.e.> VGPR (Palladini et al., Blood, 2015). In fact, bortezomib-based therapy is now commonly used as front-line treatment in lieu of transplant or as cytoreduction prior to ASCT. However, patients who have suboptimal hematologic responses such as partial or no response (PR, NR) to bortezomib-based therapy are likely to have inferior overall survival (Palladini et al., JCO, 2012). The clinical efficacy of risk-adapted melphalan (MEL) and autologous stem cell transplantation (ASCT) as a second-line option for such patients has not been formally studied.
We report on 12 patients, 8 men and 4 women with a median age of 58 (range, 53-70) with suboptimal responses to initial therapy who were referred for and underwent ASCT after a median of 4 cycles of bortezomib-based therapy (range, 2-8). Eight patients had NR with median involved FLC values at diagnosis and post initial therapy/pre-SCT of 180 (74-648) and 265mg/L (116-410) respectively while 4 had PR with medians of 1401 (250-9750) and 94mg/L (43-1620); in neither case were comparisons significant by paired t-test. Seven patients had 2 organs involved and 5 had one. Eight patients had cardiac involvement, seven stage 2 and one stage 3. Six patients had renal involvement, one stage 1, four stage 2, and one stage 3. Two had GI involvement.
All patients were mobilized successfully with filgrastim and plerixafor as previously described (Kaul et al., BMT, 2014). A median of 9.8 x 106 CD34+ cells/kg (range, 5.4-23.3) were collected. All patients received melphalan at doses of 200 mg/m2 (4 patients, 33%), 140 mg/m2 (7 patients, 58%), and 100 mg/m2 (1 patient, 8%). A median of 6.6 x 106 CD34 cells/kg (4.5-14.0) were infused. All patients engrafted and all had their post-SCT hematologic responses assessed. There was one treatment-related death at 2 months post-SCT in a 70 year old woman who had stage 2 cardiac and stage 2 renal disease, received MEL 100 mg/m2 and had improved her hematologic response status from NR to PR. Overall post-SCT, 75% of patients achieved > VGPR including 42% who achieved CR (n=5). Eight patients have received consolidation with bortezomib and/or lenalidomide based regimens, with four patients achieving CR. Two patients are about to start consolidation. With a median follow-up of 27 months (1-42), two renal and four cardiac responses have been achieved. Median overall survival post-SCT has not been reached (Figure).
In conclusion, risk-adapted melphalan and ASCT is a safe, feasible, timely and effective second-line therapy for patients with AL who have suboptimal responses to bortezomib-based initial therapy.
Figure Figure.

Disclosures
Comenzo: Takeda: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Prothena: Consultancy, Research Funding; Karyopharm: Research Funding.