Curability of Light Chain (AL) Amyloidosis with Conventional Dose Regimens

Novel immunotherapies in AL amyloidosis (AL) are associated with improved outcomes while the use of ASCT in selected patients can offer long term remissions. Since the plasma cell clones are usually small or modest, sustained hematologic remissions are not uncommon in AL amyloidosis; however, the “curability” of the disease remains to be demonstrated: even in patients (pts) who achieve deep and sustained hematologic responses, irreversible organ damage can lead to inferior survival. To identify clinical and disease characteristics that are associated with potential “functional cure” (“cure”) of the disease we analyzed a cohort of patients with AL treated without ASCT and with a follow up of at least 5 years. We defined“ ”cure“ as survival of at least 5 years without hematologic disease progression (PD) and without need for any salvage therapy.

The analysis included consecutive pts with AL, treated in the Department of Clinical Therapeutics, Athens Greece, diagnosed until 6/2018; pts who survived < 6 months were excluded to adjust for early mortality associated with severe cardiac involvement. The final cohort included 210 pts and we focused on pts who: had not had hematologic PD, had not received any salvage therapy, were still alive or had died from causes not related to AL. These pts were defined as “functionally cured” while the rest as “non-cured”. Among the “cured” we identified a group of pts that despite hematologic response they progressed to end-stage renal disease. We considered that this was “predetermined” due to the advanced organ damage already at diagnosis. Lastly, we compared the outcome of “cured” pts with the outcome of “non-cured” pts who were on CR/VGPR and had ≥1-year or ≥5-year OS.

The rate of “curability” was 17% (N=35). “Cured” pts had more often renal (84% vs 61%, p=0.045) and less frequent cardiac involvement (53% vs 62%, p=0.049), lower BM infiltration (8% vs 15%, p<0.001) and lower baseline dFLC (p=0.031) but higher levels of baseline proteinuria (p=0.031). The characteristics as well as the differences between “cured” and “non-cured” pts, are shown in Table 1.

Most “cured” pts received bortezomib-based therapies (27 pts, 77%), oral melphalan was given in 4 pts (11%), while in 15 pts (42%) treatment also included lenalidomide and in 7 (20%) daratumumab (with or without bortezomib). Regarding hematologic response, 33 (94%) “cured” pts had achieved ≥ VGPR (CR: 22, VGPR: 11) vs 46% for “non-cured” (p<0.001), 18 pts (51%) had ≥ VGPR with low dFLC response criteria (dFLC <10mg/L) vs 20% (p<0.001); 6 pts (17%) had only low dFLC VGPR and 4 (11%) were not evaluable for response due to low dFLC levels. At 1- and 3-months from start of therapy, 24 (68%) and 27 pts (77%) “cured” pts had achieved ≥VGPR. MRD evaluation was available in 19 “cured” pts, and 11 (31%) were MRD negative (vs 3 (2%) for “non-cured” pts, p<0.001). Cardiac response was observed in 9 pts (25%) and renal response in 18 “cured” pts (51%). Among “cured” pts there was a group of 7 pts (20%) with end-stage renal disease; 1 (2.8%) was already on dialysis at the time of diagnosis, while 6 (17%) initiated dialysis during disease course, despite deep hematologic responses (3 CR, 3 VGPR); 3 pts were renal stage 2 and 3 were renal stage 3. Median time to dialysis was 27 months. Baseline clinical and disease characteristics were comparable among pts with and without end-stage renal disease.

The median follow-up of the whole cohort was 88 months, and among “cured” pts, 3 (8.5%) died from causes unrelated to AL amyloidosis. The 7- year OS rate for “cured” pts was 100% and for “non-cured” was 41%, respectively. In 1- and 5-year landmark survival analysis, “cured” pts had significantly superior outcome compared to “non-cured” pts with CR/VGPR, with median OS not reached vs 66 months (p<0.001) and not reached vs 98 months (p=0.014), respectively (Fig 1).

In conclusion, a subgroup of pts with AL, not treated with ASCT, can have long-term survival (≥ 5 years) without need for additional or salvage therapy. Such patients could be considered as functionally “cured”. High rates of rapid and deep hematologic responses, relatively high rates of MRD negativity and relatively low tumor and free light chain burden characterize this subset, further emphasizing the need for early diagnosis and active therapy to maximize clonal responses. Thus, “curability” in AL amyloidosis is feasible, especially in the era of novel therapies.