Clinical and Cytogenetic Characterization of Light Chain Amyloidosis Patients with a Low Amyloidogenic Free Light Chain Count at First Diagnosis
Authors: Dittrich Tobias , Hegenbart Ute , Bochtler Tilmann , Kimmich Christoph , Jauch Anna , Kristen Arnt , Goldschmidt Hartmut , Ho Anthony D. , Schönland Stefan 
Published: October 2019

Abstract
Background: Systemic light chain amyloidosis (AL) is a rare and life-threatening protein-deposition disorder. The diagnosis and especially quantification of the underlying, usually small clonal B cell disorder in patients with very low levels of free kappa or lambda light chains in serum (FLC) can be challenging. DFLC (difference of involved minus uninvolved FLC) response to therapy is hardly assessable for initial values below 50 mg/l. Consequently, these patients are frequently excluded from prospective and retrospective studies.
Objective: Characterization of AL amyloidosis patients with dFLC<50.
Methods: We have retrospectively analysedthe clinical features and long-termoutcome of 611 newly diagnosed AL patients with available dFLC and cytogenetic evaluation by iFISH at their first visit to our center between 2003-2014.
Results: Clinical characteristics and detailed results are depicted in table 1. Patients with dFLC<50 significantly showed lower bone marrow plasma cell counts (6% vs. 10%, p<0.001), M-spike (7 g/l vs. 9 g/l, p<0.001) and concentrations of the monoclonal heavy chain (7 g/l vs. 10 g/l, p=0.003), while the mere presence of a monoclonal heavy chain in immunofixation (IF) was more frequent in these patients (55% vs. 38%, p=0.003). All analysed chromosomal aberrations were not associated with dFLC<50 (all p-values >0.05). Patients with cardiac (40% vs. 82%, p<0.001) and soft tissue (26% vs. 42%, p=0.005) involvement, higher Mayo Score and lower Karnofsky Index (KI) were much less frequently found in the group with initial dFLC<50, while kidney involvement was more common (85% vs. 58%, p<0.001). This, however, was not associated with a significantly worse renal function at diagnosis. Median overall survival (OS) was significantly better in patients with dFLC<50 regardless of treatment type (Figure 1): Bortezomib (77 vs. 16 months, p=0.006), Melphalan-Dexamethason (Mdex, 96 vs. 19 months, p=0.001) and high-dose Melphalan (HDM, not reached vs. 99 months, p=0.005).
Conclusion: AL patients with an initial dFLC<50 mg/l represent a distinct clinical entity characterized by infiltration of the marrow with a small plasma cell clone and frequent presence of a monoclonal intact heavy chain, but with a low clonal heavy chain load. Importantly, this group of patients is not associated with any particular chromosomal aberrations as revealed by iFISH. This entity is further associated with a distinct pattern of organ involvement, i.e. a low Mayo Score, more than 80% of patients with renal amyloidosis, and very favourable OS irrespective of primary treatment regimens. Results of prospective clinical trials might be adversely influenced by the exclusion of these patients.
Table 1. Parameter All patientsn=611 dFLC < 50 mg/ln=85 dFLC ≥ 50 mg/ln=526 p values Age in years, median [range] 66 [38-90] 65 [47-90] 66 [38-90] n.s. Sex female, no. of pts (%) 235 (39) 39 (46) 196 (37) n.s. Plasma cell related factors dFLC in mg/l, median [range] 228 [1-12.078] 29 [1-49] 279 [50-12.078] - Monoclonal heavy chain in IF, no. of pts (%) 248 (41) 47 (55) 201 (38) 0.003 M-spike in g/l, median [range]Evaluable pts (%) 9 [1-41]159 (26) 7 [1-22]31 (36) 9 [1-41]128 (24) <0.001 Involved heavy chain in g/l,median [range]Evaluable pts (%) 9.6 [0.5-197]243 (40) 6.8 [1.2-26]45 (53) 10.2 [0.5-197]198 (38) 0.003 Involved light chain λ, no. of pts (%) 490 (80) 73 (86) 417 (79) n.s. BM plasma cell count in %,median [range] 10 [1-90] 6 [1-40] 10 [1-90] <0.001 iFISH results, no. of pts (%) t(11;14) 350 (58) 42 (51) 308 (59) n.s. del 13q14 201 (33) 27 (33) 174 (33) n.s. gain 1q21 166 (27) 22 (26) 144 (27) n.s. Hyperdiploidy (Wuilleme Score) 98 (16) 12 (14) 86 (16) n.s. High-risk (del 17p13, t(4;14), t(14;16)) 47 (8) 7 (8) 40 (8) n.s. Organ involvement Number of Organs,median [range] 2 [1-6] 2 [1-6] 3 [1-6] 0.001 Heart, no. of pts (%) 463 (76) 34 (40) 429 (82) <0.001 Cardiac Mayo Score 2004: I, no. of pts (%)II, no. of pts (%)III, no. of pts (%) 101 (18)214 (38)255 (45) 35 (46)30 (40)11 (15) 66 (13)184 (37)244 (49) <0.001 Kidney, no. of pts (%) 376 (62) 72 (85) 304 (58) <0.001 MDRD, median [range] 64 [2-264] 68 [8-149] 63 [2-264] n.s. Soft Tissue, no. of pts (%) 243 (40) 22 (26) 221 (42) 0.005 KI %, median [range] 80 [40-100] 90 [50-100] 80 [40-100] 0.001 Treatment groups, no. of pts / median follow-up in months, median OS Bortezomib 214 / 2724 23 / 1977 191 / 2816 0.006 Mdex 156 / 7427 21 / 7596 135 / 7019 0.001 HDM 115 / 75129 24 / 75not reached 91 / 6999 0.005
Figure 1. Figure 1.

Disclosures
Hegenbart: Janssen: Honoraria. Bochtler:TEVA: Other: travel support. Goldschmidt:Onyx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Chugai: Honoraria, Research Funding, Speakers Bureau; Millenium: Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Schönland:Janssen, Prothena: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.