Therapy For Light Chain Amyloidosis Research Articles

Novel monoclonal antibodies: A really specific therapy for light chain amyloidosis.

Light chain amyloidosis is a rare disease caused by clonal plasma cells in the bone marrow generating an excessive amount of immunoglobulin light chains. These chains misfold and produce insoluble fibrils that deposit in various organs, including the heart, kidneys, liver, nervous system, and digestive tract. Life expectancy and symptoms during the course of the disease vary depending on which and how many organs are affected. Targeted plasma cell therapy has significantly advanced the clinical management of amyloidosis, with ongoing progress. However, current clinical studies are investigating innovative targets, drug combinations and treatment strategies to improve therapeutic outcomes by minimizing adverse effects and refining patient prognosis in these challenging hematological conditions. In this paper, we review the state of the art regarding the use of anti-amyloid antibodies, as a revolutionary and innovative approach in the current scenario of amyloid treatment.

Outcomes of Second Line Therapy for Light Chain Amyloidosis after Initial Therapy with a Bortezomib Based Regimen

Introduction: There are a lack of randomized trials to guide therapy for relapsed AL amyloidosis with treatment regimens generally extrapolated from experience in multiple myeloma. Methods: We conducted a retrospective review of bortezomib exposed patients that received second line therapy for AL amyloidosis at three Amyloidosis centres in Australia (Brisbane, Perth and Sydney). Of 190 patients treated with bortezomib based therapy upfront, 98 (52%) had transitioned to second line therapy during the study period and comprised the study cohort. Results: Baseline characteristics for the study cohort were typical for a cohort with AL amyloidosis. Median age was 66 years, with 38% of patients being male. Cardiac and renal involvement was present in 70% of patients respectively. Seven patients (7%) had frontline therapy that included daratumumab. Median duration of frontline therapy was 5 months (range 2-18 months) and median time from diagnosis to second line therapy was 9 months (range 2-65 months). We categorized treatment regimens according to commonly used combinations and drug classes to further analyse outcomes. Six categories of therapy regimens were identified; autologous stem cell transplant (ASCT) (n=17), thalidomide based (n=12), lenalidomide based (n=13), proteasome inhibitor (PI) based (n=9), Anti-CD38 monoclonal antibody (mAB) based (n=38) and melphalan based (n=4). Five patients were excluded from this analysis as they received an atypical therapy/regimen not commonly used for AL amyloidosis. Overall response rate (ORR) for the whole cohort was 84%. The ORR was lowest for thalidomide and melphalan based therapy (67% and 50% respectively) and highest for patients receiving an ASCT or anti-CD38 mAB therapy (94% and 92% respectively), Figure 1a. Median event free survival (EFS) for the cohort from second line therapy was 17 months. Median duration of follow up from second line therapy for the cohort was 26 months . Median EFS was shortest for patients treated with thalidomide and melphalan based regimens (6 and 12 months respectively) and longest for those who received an ASCT (28 months) or anti- CD38 mAB therapy (not reached), Figure 1b. When comparing immunomodulatory drugs lenalidomide treated patients had a longer EFS (median 6 months for thalidomide vs 16 months for lenalidomide, p=0.09). The median overall survival (OS) for the cohort was 81 months. OS was longest amongst patients receiving an ASCT or anti-CD38 mAB therapy (median of 91 months and not reached, respectively). Survival was similar amongst patients treated with a PI or Immunomodulatory drug (median 41 months for thalidomide, 44 months for lenalidomide and 36 months for PI based therapy). Conclusion: In bortezomib exposed AL amyloidosis patients, second line therapy with anti CD38 mAB's induced deep responses and prolonged survival. Amongst immunomodulatory agents, the second generation agents appear to be more effective. In our cohort the small group of patients receiving repeat therapy with a PI also appeared to respond to treatment. Although an intensive treatment with significant risks, our data show that in select individuals an ASCT can induce deep and long lasting remissions. Our data highlights the variability in second line therapies for AL amyloidosis given the paucity of evidence to guide treatment. The recent addition of daratumumab as a standard of care for upfront therapy further limits options in the relapsed setting and highlights the need for trials using next generation novel anti plasma cell agents in this patient population.

Beyond Andromeda: Improving Therapy for Light Chain Amyloidosis.

Therapy for light chain amyloidosis (AL) continues to evolve, and a new standard of care for the disease is rapidly forming. The risk of early death however, mainly from cardiac complications, remains an important benchmark yet to be definitively improved upon. This brief review explores recent advances in plasma cell directed therapy for AL, highlighting unique factors specific to these patients and AL biology driving differences in treatment strategies and clinical development compared with multiple myeloma. Improving upon proteasome inhibitor based upfront therapy combinations with the addition of anti-CD38 antibodies has shown promise with improved response rates in the ANDROMEDA (NCT03201965) study. Though depth and kinetics of achieving deep hematologic response as well as rates of biomarker defined organ response were improved with the addition of daratumumab to the combination of bortezomib, cyclophosphamide, and dexamethasone, death rates in each arm remained similar. Evaluation of other targeted and novel therapies in AL is ongoing, and we highlight efforts evaluating B-cell maturation antigen (BCMA) directed therapy, BCL-2 family inhibitors, and other novel agents in the field. We also look ahead to efforts to reimagine the clinical development of anti-fibrillar therapies after late phase study failures. Upcoming anti-amyloid fibril antibody studies explore opportunities to improve outcomes for the sickest AL patients with advanced cardiac disease, focusing on improving overall patient survival and reducing the risk of early death in this uniquely frail population.

A prospective observational study of 915 patients with systemic AL amyloidosis treated with upfront bortezomib

AbstractBortezomib is a standard therapy in light-chain amyloidosis (AL), but little is known about response duration. A difference in involved amyloidogenic and uninvolved serum-free light chains (dFLC) < 10 mg/L (low dFLC response) predicts survival in AL patients with low presenting dFLC (20-50 mg/L). We report outcomes in the largest AL cohort treated with upfront bortezomib and explore the impact of posttreatment dFLC < 10 mg/L (“stringent dFLC response”). A total of 915 newly diagnosed AL patients treated with bortezomib and assessed at our center were included. Hematologic responses, 6-month dFLC, organ responses, overall survival (OS), and time-to-next-treatment (TNT) (excluded patients who died without starting second-line treatment) were evaluated. Overall response rate (intent-to-treat) was 65%, with 49% complete response (CR)/very good partial response/low dFLC response and with a stringent dFLC response, dFLC 10-40 mg/L, and dFLC > 40 mg/L was 30%, 22%, and 48%, respectively. Median OS was 72 months. A total of 289 patients died without progressing to second-line treatment. Median TNT was not reached, and 55% had not progressed to further treatment at 7 years. Patients with stringent dFLC responses had significantly better OS and TNT than did those with lesser responses. A total of 72% of CR patients did not progress to further treatment at 3 years compared with 84% with stringent dFLC responses. Cardiac responses were better in those with stringent dFLC responses (61%) compared with lesser responses (45%; P = .005). Upfront bortezomib confers durable hematologic responses. A stringent dFLC response predicts prolonged TNT and impressive organ responses.

Impact of involved free light chain (FLC) levels in patients achieving normal FLC ratio after initial therapy in light chain amyloidosis (AL).

Achievement of a normal FLC ratio (FLCr) following treatment indicates hematologic response and suggests better outcomes in light chain amyloidosis (AL). We examined if elevated involved free light chain (hiFLC) impacts outcomes in patients achieving normal FLCr. We retrospectively analyzed 345 AL patients who were diagnosed within a 10-year period (2006-2015) and had 2 consecutive normal FLCr values after 1st line treatment. Among these, patients with hiFLC at 1st reading of normal FLCr (hiFLC1; n = 166; 48.1%) were compared to those who did not (n = 179; 51.9%). Patients with AL who have hiFLC1 after initial therapy had higher rates of multi-organ involvement (63.3 vs 46.4%; P = .002) and patients in advanced Mayo stage (42.9 vs 32.2%; P = .04) at diagnosis. The median progression free survival [PFS; 38.2 (95%CI; 26.4, 55.4) vs 67.1 (95%CI; 55.8, 88) months; P = .0002] and overall survival [OS; 94.4 (95%CI; 78, 107.1) vs not reached (NR, 95%CI; 116.1, NR) months; P < .0001] were lower in those who had hiFLC1. A more stringent comparison for patients with 2 consecutive hiFLC (hIFLC2; n = 111; 32.2%) versus not (n = 2234; 67.8%) showed consistent results [PFS; 27.1 (95%CI; 23, 53.8) vs 63.3 (95%CI; 55.4, 77) months; P < .0001 and OS; 78 (95% CI; 54.6, 98.8) vs NR (95%CI; NR, NR); P < .0001]. This poor prognostic impact of hiFLC on survival was independent of serum creatinine, Mayo stage, negative immunofixation status and inclusion of transplant in initial therapy on multivariate analysis. Hence, persistent elevation of iFLC predicts poor prognosis even among patients achieving normal ratio after initial therapy in AL.

Predictors of early treatment failure following initial therapy for systemic immunoglobulin light-chain amyloidosis

We analysed factors predicting early treatment failure (ETF), after first-line therapy for light-chain amyloidosis (AL). AL amyloidosis patients seen at Mayo Clinic within 90 days of diagnosis, from 2006 to 2015, excluding those who died within 3 months of initial therapy, were analysed retrospectively. ETF was defined as progression requiring treatment change or death within 12 (ETF12) or 24 (ETF24) months of first-line treatment. Non-ETF included those with a follow-up of more than 12 or 24 months who had progression beyond 12 or 24 months. A total of 724 patients met the study criteria; 244 (33.7%) had ETF12 and 388 (53.6%) had ETF24. Patients with ETF12 were older (64.1 vs. 62.2 years) with higher prevalence of cardiac (81 vs. 64.1%) and multi-organ involvement (67.2 vs. 45.4%) and higher proportion of patients with t(11; 14) (58.5 vs. 44.3%) or in higher Mayo 2012 stage (58.5 vs. 41.1%).The median follow-up was 5.4 years from start of initial therapy. In multivariate analysis, presence of t(11; 14) and non-incorporation of autologous transplant in initial therapy are significant predictors of ETF12 (p = .01and p = .003) and ETF24 (p = .0001 and p = .005) while Mayo stage is predictive of ETF24 (p = .002), but not ETF12.

Outcomes according to involved free light chain (FLC) levels in patients with normal FLC ratio after initial therapy in light chain amyloidosis (AL).

8049 Background: Complete response in AL is defined as normal FLC ratio with negative serum and urine immunofixation. It is not clear if high involved serum FLC (hIFLC) in a patient with normal ratio may contribute to ongoing amyloid formation and hence affect outcomes. Methods: Data of 1308 patients (pts) with systemic AL seen within 90 days of diagnosis, at Mayo Clinic between 2006-2015, was analyzed retrospectively. Among these, 369 pts had 2 consecutive normal FLC ratio values after 1st line treatment and form the study population. Log rank test was used to estimate survival differences. Results: Among these 369 pts, pts with hIFLC at 1streading of normal FLC ratio (hIFLC1; n=170; 46.1%) were compared to those who did not (n=199; 53.9%). At diagnosis, the median age [61.5 vs 60.8 years (y); p=0.2], proportion of males (62.4 vs 58.3%; p=0.4), percentage of pts with renal involvement (73.5 vs 64.8%; p=0.07), in mayo stage I / II / III / IV (32.9% / 23%/ 27.3% / 16.8% vs 43.6 %/ 22.9% / 18.1% / 15.4%; p=0.1), with bone marrow plasma cells &gt;10% (24.2 vs 30%; p=0.2) and with presence of t(11; 14)(48.4 vs 60; p=0.08) was similar, while cardiac (67.5 vs 53.3%; p=0.006) and hepatic (18.2 vs 9.1%; p=0.01) involvement was higher in hIFLC1 group. The median follow-up from diagnosis was 6.1 y (95% CI; 5.6, 6.8). The median progression free survival (PFS) in pts who had hIFLC1 was lower than for those who did not; 2.6 y (95% CI; 1.9, 4.5) vs 5.2 y (95% CI; 4.6, 6.4), p&lt;0.0001, as was the median overall survival [OS; 6.7 y (95% CI; 4.5, 8.3) vs not reached (NR), p&lt;0.0001]. We performed a more stringent comparison for pts with 2 consecutive hIFLC values (hIFLC2; n=112; 30.4%) versus not (n=257; 69.6%). The median PFS (3.2 y; 95%CI; 2.2, 4.5 vs 5.6 y; 95% CI; 4.7, 7.1; p&lt;0.0001) and OS (7.8 y; 95% CI; 6.4, NR vs NR; 95%CI; 9.5, NR; p&lt;0.0001) were significantly reduced in pts with hIFLC2 versus not as well. A multivariate analysis confirmed an impact of hIFLC1 and hIFLC2 on PFS/OS independent of serum creatinine. Conclusions: In pts with systemic AL, persistent elevation of the involved FLC predicts for poor prognosis (independent of serum creatinine) even among those who achieved normal FLC ratio after 1st line treatment.

Continuous ambulatory peritoneal dialysis as a promising therapy for light chain amyloidosis with congestive heart failure

Continuous ambulatory peritoneal dialysis as a promising therapy for light chain amyloidosis with congestive heart failure