Haematologist Princess Alexandra Hospital Woolloongabba, Queensland, Australia
Introduction: The achievement of rapid, deep haematological response is critical in the treatment of AL amyloidosis. The timing and depth of FLC reduction that defines suboptimal response and the need to switch to second-line therapy is uncertain. We aimed to determine the impact of haematological response after 2 months of bortezomib-based therapy on subsequent best haematological and organ responses and survival.
Methods: Subjects had a histological diagnosis of AL amyloidosis, symptomatic organ involvement and initial treatment with a bortezomib-based regimen. The impact of haematological response after 2 months of treatment on subsequent best haematological and renal response was assessed using Fisher’s exact test. The impact on OS was assessed by landmark analysis using log-rank or Cox regression analysis.
Results: 150 patients with AL amyloidosis were identified: Median age was 66 yrs and 35% were male. 75% of cases were lambda restricted, the median dFLC was 160mg/L, 75% had ≥ 10% bone marrow plasmacytosis and 9% had symptomatic myeloma. Cardiac stage was: 1 (13%), 2 (55%), 3A (17%) and 3B (15%). 71% had renal involvement with a median eGFR of 69mls/min and median proteinuria of 2.4g/d , with 9% dialysis dependent at presentation. Bortezomib regimens were: VCD (72%), VCD+daratumumab (13%), MDV (7%), VD (6%) and VRD (3%), with a median of 6 cycles delivered. Median OS was 6.2 years which was adversely associated with more advanced cardiac disease: stage 1 (not reached), stage 2 (90 months), stage 3A (52 months) and stage 3B (9 months)(p=0.0001). Haematological response after 2 months of bortezomib-based induction was: CR (17%), VGPR (40%), PR (17%) and less than PR (16%). 10% of patients died prior to 2 month response assessment. Failure to achieve PR by 2 months was associated with a low chance of achieving deep responses, with only 5% going on to achieve VGPR or better (p < 0.001). Similarly, failure to achieve PR by 2 months predicted a low likelihood of improving organ function with less chance of cardiac (6% vs 47%, p=0.001) and renal (20% vs 41%, p=0.044) responses. In a landmark analysis, failure to achieve PR after 2 months predicted worse OS (median 48 vs 93 months, p=0.041), a finding confirmed in multivariate analysis including cardiac stage. This effect was particularly evident for patients with cardiac stage 3A and 3B disease, where the early achievement of PR was associated with a median OS of 70 months vs 7 months if PR was not achieved. Failure to achieve VGPR by 2 months was not associated with therapeutic futility, with 65% of patients going on to achieve VGPR or better as their best response.
Conclusions: Failure to achieve haematological PR after 2 months of bortezomib-based therapy is associated low likelihood of subsequently achieving deep haematological response and organ responses and predicts poor survival, especially for cardiac stage 3A and 3B disease. Such patients should be switched to alternate salvage therapy.
