Prospective urinary albumin/creatinine ratio for diagnosis, staging, and organ response assessment in renal AL amyloidosis: results from a large cohort of patients

Objectives Quantification of 24 h-proteinuria is the gold standard for diagnosing, staging, and monitoring of patients with renal AL amyloidosis. However, 24 h-urine collection is cumbersome and may result in preanalytical error. In this prospective study, we investigated the role of urinary albumin/creatinine ratio (UACR) (cut-off: 300 mg/g) identifying renal involvement, evaluated a UACR-based staging system (UACR cut-off: 3,600 mg/g) and assessed whether UACR response (UACR decrease >30% without worsening in eGFR >25%) predicts renal outcome in 531 patients with newly-diagnosed AL amyloidosis. Methods From October 2013 paired 24 h-proteinuria and UACR (on first morning void) were measured in all newly-diagnosed patients with AL amyloidosis. Correlation between 24 h-proteinuria and UACR at baseline was assessed by Pearson’s r test. Impact of UACR response on renal outcome was assessed in randomly created testing (n=354) and validation (n=177) cohorts. Results A strong linear correlation was found between 24 h-proteinuria and UACR at baseline (r=0.90; p<0.001). After a median follow-up of 31 months, 57 (11%) patients required dialysis. A UACR-based renal staging system identified three stages with significantly higher dialysis rate at 36 months comparing stage I with stage II and stage II with stage III. Achieving a renal response, according to a UACR-based criterion, resulted in lower dialysis rate in both testing and validation cohorts. Conclusions UACR is a reliable marker for diagnosis, prognosis, and organ response assessment in renal AL amyloidosis and can reliably replace 24 h-proteinuria in clinical trials and individual patients’ management.

Updated Organ Response Results of an Open-Label Study to Evaluate the Safety and Tolerability of Cael-101 in Patients with AL Amyloidosis Receiving Anti-Plasma Cell Therapy

Background: CAEL-101 is an IgG1 monoclonal antibody intended to enable immune clearance of AL amyloid deposits. This study (NCT04304144) data allowed dose selection of CAEL-101 for the ongoing Phase 3 studies in patients with Mayo stage IIIa and IIIb AL amyloidosis cardiomyopathy newly diagnosed and treated with bortezomib, cyclophosphamide, and dexamethasone (CyBorD) alone or in combination with daratumumab. Methods: 13 patients were treated with CAEL-101 and CyBorD and an additional 5 patients were treated with CAEL-101, daratumumab, and CyBorD. Organ response data on assessable patients were evaluated per consensus criteria as per institutional standard of care. Safety, pharmacokinetic and anti-drug antibody data will be reported separately. Results: The follow up for patients receiving CAEL-101 and CyBorD is 12 to 15 months and for the CAEL-101, Daratumumab, and CyBorD is 4 to 6 months. 16 of 18 patients remain on treatment. One discontinuation was due to death from E. coli sepsis and the other due to lack of hematologic response with deterioration of heart function requiring heart transplant after only 6 doses of CAEL-101. Organ response in cardiac patients by NT pro BNP criteria occurred in 4 of 8 evaluable patients treated with CAEL-101 and CyBorD (time to organ response range 2 - 12 months) and in 2 of 3 patients treated with CAEL-101, daratumumab, and CyBorD (time to organ response range 3 - 5 months). Four patients have had repeat echocardiogram 1 year from start of CAEL-101 based therapy with interpretable global peak longitudinal strain (GLS). The GLS improved in 2 patients by -5% (-6.4% to -11.4%) and -5.1% (-12.8% to -17.9%). GLS remained stable in the other 2 patients. All 9 patients with evaluable kidney involvement by 24 hour urine protein achieved an organ response. Responses occurred in as little as 2 months in 5 patients (range 2 - 7 months). The time to organ response were similar in the daratumumab and non-daratumumab treated patients. One patient with hematologic stable disease and persistent 71% improvement in 24 hour urine protein at 10 months from start of CAEL-101 based therapy is most notable. Conclusions: CAEL-101 with anti-plasma cell therapy remains reasonably well tolerated with no unanticipated adverse effects. Organ responses, most notably renal response, have occurred early in the course of therapy and appears to be durable. Organ responses in some patients have also improved over time with some significant improvement in patient GLS evaluations by echocardiogram. These results encourage clinical trial participation in the ongoing CAEL-101 clinical trials in Mayo stage IIIa and IIIb AL amyloidosis patients. Disclosures Valent: Celgene Corporation: Speakers Bureau; Amgen: Speakers Bureau; Caelum Biosciences: Other: Clinical Trial Funding; Takeda Pharmaceuticals: Speakers Bureau. Silowsky: Caelum Biosciences: Current Employment. Kurman: Caelum Biosciences: Other: Medical Monitor. Daniel: Caelum Biosciences: Current Employment. Jobes: Caelum Biosciences: Current Employment. Harnett: Caelum Biosciences: Current Employment. Spector: Caelum Biosciences: Current Employment. Anwer: GlaxoSmithKline: Research Funding; Allogene Therapeutics: Research Funding; Janssen pharmaceutical: Honoraria, Research Funding; BMS / Celgene: Honoraria, Research Funding. Zonder: BMS: Consultancy, Research Funding; Janssen: Consultancy; Caelum Biosciences: Consultancy; Intellia: Consultancy; Regeneron: Consultancy; Amgen: Consultancy; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Alnylam: Consultancy. Liedtke: Kura Oncology: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Alnylam: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Caelum: Membership on an entity's Board of Directors or advisory committees, Other: Clinical Trial Funding; Celgene: Membership on an entity's Board of Directors or advisory committees. Sobolov: Caelum Biosciences: Current Employment. OffLabel Disclosure: CAEL-101 is a monoclonal antibody directed at AL amyloid deposits. The purpose is to promote immune clearance of amyloid deposits.

The Pattern of Organ Responses Varies in Patients with Systemic Light-Chain Amyloidosis and Heart or Kidney or Heart and Kidney Involvement Who Achieve Deep Hematologic Responses

Introduction: In systemic light-chain amyloidosis (AL) aberrant clonal free immunoglobulin light chains (FLC) misfold and deposit in vital organs causing severe dysfunction (Nat Rev Dis Primers 2018;4:38). With anti-plasma cell therapy that reduces or eliminates the involved FLC (iFLC), defined organ responses can occur (N Engl J Med 2021;385:46, Blood Rev 2019;37:100581, Leukemia 2017;31:136, Blood 2014;124:2325). We asked whether the timing of individual organ responses may be influenced by the number of organs involved at diagnosis; therefore we evaluated the pattern of responses in patients with the two most commonly involved organs (heart, kidney) who achieved deep hematologic responses to therapy (CR=complete response, VGPR=very good partial response)(J Clin Oncol 2012;30:4541). We examined whether the rate of and time to organ response varied in patients with only heart or kidney or heart and kidney involvement, and whether the depth of hematologic response impacted the pattern of organ response. Methods: We performed a retrospective analysis AL patients diagnosed by tissue biopsy between 2007-2019 who had heart and/or kidney involvement at diagnosis and achieved hematologic CR/VGPR with treatment. Mann-Whitney was used to compare rates of organ responses and log-rank tests were applied to compare times to organ response among the subgroups as well as overall survival (OS) differences based on iFLC responses and on organ responses. Results were considered to be significant if two-sided P-value was less than or equal to 0.05. Results: We identified 111 patients with a median age of 62.5 years (range, 40-80) who met these criteria, 65 of whom (59%) were male. Cardiac involvement only was present in 34 (30.6%), renal involvement only in 31 (28.0%), and both cardiac and renal involvement in 46 (41.4%). Table 1 highlights patient characteristics. The median OS for the entire cohort was 112 months (95% CI 100-NA). The overall cardiac response rate was 62.5%, with a median time to response of 8 months (range, 1-73 months). Overall renal response rate was 67.1% with a median time to response of 10 months (range, 1-57 months). Log-rank analysis showed a significant difference in the OS based on post treatment iFLC levels (&lt;10 vs. 10-20 vs. &gt;20 mg/L) as we have previously described (Am J Hematol 2021;96:E20). Patients with kidney involvement only had significantly improved overall survival (OS) compared to those with cardiac involvement only (p=0.05), as expected. However, there was no difference in the OS of patients with cardiac only vs. cardiac and renal involvement (p=0.58), while there was a trend towards shorter OS in patients with cardiac and renal vs renal (p=0.09). The lower iFLC levels achieved post-treatment influenced cardiac response rate (p=0.07), and significantly impacted renal response rate (p&lt;0.01). For patients with cardiac involvement, iFLC responses did not have a significant impact on time to cardiac response, whereas for patients with renal involvement, faster responses were noted in those achieving lower iFLC levels (p=0.017) (Figure 1). There was no significant difference in time to cardiac response between patients with cardiac only vs. cardiac and renal involvement (p=0.93) whereas patients with renal only vs cardiac and renal involvement had a faster time to renal response (medians 14 (range, 10-29) vs 43 (13-not reached) months, p=0.018) (Figure 2). Conclusion: In AL patients with renal involvement who achieve CR/VGPR with treatment, post-treatment iFLC levels and co-presence of cardiac involvement play significant roles in the timing of renal responses. In AL patients with cardiac involvement who achieve CR/VGPR, post-treatment iFLC levels but not the co-presence of renal involvement influences the rate of cardiac response but neither influences the timing. These differences may be due to organ-specific factors such as proteomic adaptations or relative iFLC toxicity or complex cardio-renal hormonal interactions. Further hypothesis-driven study of these differences is warranted in this era of new and effective anti-plasma cell therapies. Figure 1 Figure 1. Disclosures Comenzo: Prothena Biosciences: Consultancy, Research Funding; Karyopharm: Research Funding; Takeda: Research Funding; Unum: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi-Aventis: Membership on an entity's Board of Directors or advisory committees; Caelum: Consultancy, Research Funding; Janssen: Patents & Royalties: WO2016187546A1, Research Funding.

Predictive Factors of Overall Survival in Patients with Relapsed AL Amyloidosis Treated with Single Agent Daratumumab

Background: Two prospective phase II studies evaluated the efficacy of the anti-CD38 monoclonal antibody Daratumumab as a single agent (sDARA) in patients with relapsed AL amyloidosis and reported impressive hematologic and organ response rates. However, both studies included small number of patients and in one study sDARA was administered for 6 cycles (n=40) while in the other study, it was administered until hematologic progression, toxicity or for up to 24 months (n=22). Furthermore, predictive factors associated with hematologic and organ responses, and optimal duration of therapy remain unclear. Methods: We retrospectively studied the clinical and biological characteristics of patients with AL amyloidosis treated with sDARA, between April 2017 and December 2020, to identify factors associated with hematologic and organ response rates and impact on progression-free survival and overall survival (OS). Criteria for hematologic and organ response were defined according to the consensus criteria of ISA. Major organ deterioration progression-free survival (MOD-PFS) was used as a composite of endpoints from the time between sDARA initiation and whichever of the following occurred first: death, development of end stage cardiac or renal failure, or hematologic progression. OS was defined as the length of time between initiation of sDARA and the date of death or last follow-up. To account for immortal time bias, a landmark analysis for MOD-PFS and OS starting at the 12-month mark was performed to evaluate the impact of treatment duration on outcomes. Results: Eighty six patients with AL amyloidosis received sDARA. The median age was 67 years (range, 39-86) and 65% were male, 75% with lambda AL amyloidosis. Of the 86 patients, 38% had t(11;14) and 11% had 1q gain. At time of sDARA initiation, 35% of patients had &gt;2 organs involved, including 22% with BU stage III (14% IIIa and 8% IIIb) and 13% with renal stage III disease. Majority (44%) of the patients received sDara as 2 nd line therapy, but 2% received as frontline, 21% as 3 rd line and 33% as 4 th line or more. Half of the patients (45%) were previously treated with HDM/SCT and 87% with proteasome inhibitor based regimen. Patients received a median of 12 cycles of sDARA (range 1-36) with a median follow-up time of 21.6 months (range 1.2-48.3). Hematologic CR and VGPR were achieved by 44% and 37% of patients, respectively and significantly associated with prolonged MOD-PFS and OS (Figure A and B). The median time to cardiac and renal responses were 6.8 months (range 0.9-12) and 6.7 months (range 1.8-42), respectively. At 12 months, cardiac and renal responses were observed in 47% and 61%, respectively and correlated with depth of hematologic response. The median OS and MOD-PFS were not reached (95% CI 40-NR) and 36 months (95% CI 28-NR), respectively. Achievement of cardiac response was associated with improved MOD-PFS (42 vs. 25 months; HR 0.25, 95% CI 0.08-0.78; p=0.01) and OS (NR vs 26 months; HR 0.20, 95% CI 0.04-0.89; p=0.02) and achievement of renal response was associated with improved MOD-PFS (NR vs. 13 months; HR 0.06, 95% CI 0.02-0.20; p&lt;0.0001) and OS (NR vs. 25 months; HR 0.19, 95% CI 0.05-0.65; p=0.004). Importantly, presence of t(11;14) and number of previous lines of therapy did not impact MOD-PFS and OS. On an univariate analysis, several variables including dFLC &gt;180 mg/L, bone marrow infiltration &gt;10%, 24h proteinuria &gt;3.5 g and NTproBNP &gt;8500 pg/mL were significantly associated with lower MOD-PFS and OS, but only achievement of VGPR or CR and presence of 1q Gain were independently associated with MOD-PFS and OS (Figure C and D) on a multivariate analysis. Finally, on a landmark analysis, patients who received &gt;12 cycles vs &lt;12 cycles had significantly longer MOD-PFS (30 vs. 13 months; HR 0.47, 95% CI 0.31-0.72; p=0.0018)) and OS (NR vs. 15 months; HR 0.09, 95% CI 0.03-0.37; p&lt;0.0001). Conclusion: sDARA confers very high rates of hematologic responses (81% of patients achieving &gt;VGPR) in patients with relapsed AL amyloidosis and leads to prolonged OS and MOD-PFS, which is independent of the number of previous lines of treatment. Our data confirmed that achievement of hematologic response is a major predictor of OS and MOD-PFS in AL amyloidosis, and revealed that presence of 1q Gain is associated with lower response rate to sDARA. Longer duration of therapy (&gt;12 cycles) with sDARA was associated with prolonged MOD-PFS and OS. Figure 1 Figure 1. Disclosures Sloan: Stemline: Honoraria; Abbvie: Honoraria; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees; Pharmacosmos: Membership on an entity's Board of Directors or advisory committees. Sanchorawala: Karyopharm: Research Funding; Pfizer: Honoraria; Regeneron: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees, Research Funding; Proclara: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Caleum: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sorrento: Research Funding.

Amyloidosis Composite Response Score Incorporating the Depth of Organ Response

Background: Systemic light chain (AL) amyloidosis is a plasma cell disorder characterized by multisystem deposition of misfolded immunoglobulin light chains produced by clonal plasma cells. Hematologic and organ responses with treatment have been shown to correlate with survival as early as 3 months from initiation of first-line treatment. Our group recently developed and validated a model integrating organ and hematologic responses for assessment of treatment outcomes at 6 months. Although current organ response criteria do not consider the depth of organ response, this has been shown to have prognostic utility in newly diagnosed patients. So, we designed this study to evaluate a composite hematologic and organ scoring system that also considers the depth of organ response at 1 to 6 months from initiation of first-line treatment. Methods: We included patients with AL amyloidosis who had at least one major organ involvement (cardiac, renal and/or liver involvement) and who had not started a second line treatment by 6 months from the time of initiating first-line treatment. For each patient, we calculated an organ response score and a hematologic response score at 1, 2, 3, 4, 5, and 6 months from initiation of first-line treatment. A score was assigned for each depth of hematologic response as follows: complete response=0, very good partial response=1, partial response=2, and no response/progressive disease=3). To calculate organ response, a score was assigned to each organ based on the depth of organ response (Muchtar et al. 2018): non-evaluable=0, complete response=1, very good partial response=2, partial response=3, and no response=4. The final organ response score was obtained by calculating the average of the individual involved organ scores. We then calculated the composite hematologic and organ response (HOR) score by adding the organ and hematologic responses at each interval and compared overall survival (OS) between patients with HOR score ≤ 5 (group 1) and those with score &gt; 5 (group 2). Results: The cohort included 730 patients diagnosed with AL amyloidosis between February 10 th, 2006 and July 9 th, 2019. Median age was 63 (IQR: 56-69), and 65% were male. The involved light chain was Lambda in 75% of cases. Cardiac, renal, and liver involvement were found in 81%, 61%, and 17% of patients, respectively. Among all patients, 28% underwent autologous stem cell transplantation during their disease course. The median follow up in the entire cohort was 7.0 (95%CI: 6.4-8.0) years and OS was 3.6 (95%CI: 2.6-4.4) years. At 1 to 4 months, we observed a statistically significant difference in OS between patients with HOR score ≤5 vs. &gt;5. However, there was no difference in OS between the 2 groups at 5 and 6 months. These results are presented in Table 1. Conclusion: A composite hematologic and organ response score that takes into consideration the depth of organ response can discriminate 2 groups of patients with distinct survival outcomes as early as 1 month from treatment initiation and maintains its predictive ability for up to 4 months. The lack of predictive ability beyond 4 months in this study may be due to limited sample size especially in group 2 as more patients achieve deeper responses with time. This approach can provide the basis for early changes in treatment but needs validation in future studies. Figure 1 Figure 1. Disclosures Dispenzieri: Janssen: Consultancy, Research Funding; Takeda: Research Funding; Sorrento Therapeutics: Consultancy; Oncopeptides: Consultancy; Pfizer: Research Funding; Alnylam: Research Funding. Gertz: Ionis Pharmaceuticals: Other: Advisory Board; Akcea Therapeutics, Ambry Genetics, Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Karyopharm Therapeutics, Pfizer Inc (to Institution), Sanofi Genzyme: Honoraria; Aurora Biopharma: Other: Stock option; Akcea Therapeutics, Alnylam Pharmaceuticals Inc, Prothena: Consultancy; AbbVie Inc, Celgene Corporation: Other: Data Safetly & Monitoring. Kapoor: Ichnos Sciences: Research Funding; Karyopharm: Consultancy; Glaxo SmithKline: Research Funding; Pharmacyclics: Consultancy; Amgen: Research Funding; Cellectar: Consultancy; Sanofi: Consultancy; BeiGene: Consultancy; Regeneron Pharmaceuticals: Research Funding; Karyopharm: Research Funding; Sanofi: Research Funding; Takeda: Research Funding; AbbVie: Research Funding. Dingli: GSK: Consultancy; Sanofi: Consultancy; Janssen: Consultancy; Novartis: Research Funding; Apellis: Consultancy; Alexion: Consultancy. Kumar: Oncopeptides: Consultancy; Merck: Research Funding; Antengene: Consultancy, Honoraria; Bluebird Bio: Consultancy; Roche-Genentech: Consultancy, Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Research Funding; Novartis: Research Funding; Carsgen: Research Funding; Tenebio: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Beigene: Consultancy; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

How I Treat AL Amyloidosis

The treatment of patients with systemic light chain (AL) amyloidosis is a challenge to hematologists. Despite its generally small size, the underlying clone causes a rapidly progressing, often devastating multiorgan dysfunction through the toxic light chains that form amyloid deposits. Clinical manifestations are deceitful and too often recognized at an irreversible stage. However, hematologists are in the unique position to diagnose AL amyloidosis at a pre-symptomatic stage checking biomarkers of amyloid organ involvement in patients with monoclonal gammopathies at higher risk to develop the disease. Adequate technology and expertise are needed for a prompt and correct diagnosis, particularly for ruling out non-AL amyloidoses that are now also treatable. Therapy should be carefully tailored based on severity of organ involvement and clonal characteristics, and early and continual monitoring of response is critical. Three recent randomized clinical trials moved AL amyloidosis to evidence-based era. Above all, the daratumumab-bortezomib combination is a new standard-of-care for newly diagnosed patients inducing rapid and deep responses that translate into high rates of organ response. The availability of new effective drugs allows to better personalize the therapy, reduce toxicity, and improve outcomes. Patients should be treated within clinical trials whenever possible.

Amyloidosis with Cardiac Involvement: Identification, Characterization, and Management

Purpose of Review Amyloidosis is a protein deposition disease whereby a variety of precursor proteins form insoluble fibrils that deposit in tissues, causing organ dysfunction and, many times, death. Accurate characterization of the disease based on the nature of the precursor protein, organ involvement, and extent of disease is paramount to guide management. Cardiac amyloidosis is critical to understand because of its impact on prognosis and new treatment options available. Recent Findings New imaging methods have proven to be considerably valuable in the identification of cardiac amyloid infiltration. For treating clinicians, a diagnostic algorithm for patients with suspected amyloidosis with or without cardiomyopathy is shown to help classify disease and to direct appropriate genetic testing and management. For patients with light chain disease, recently introduced treatments adopted from multiple myeloma therapies have significantly extended progression-free and overall survival as well as organ response. In addition, new medical interventions are now available for those with transthyretin amyloidosis. Summary Although cardiac amyloidosis contributes significantly to the morbidity and mortality associated with systemic disease, new tools are available to assist with diagnosis, prognosis, and management.

Clinical presentation and outcome of patients with AL amyloidosis requiring salvage therapy.

e20043 Background: The diagnosis and upfront management of immunoglobulin light chain (AL) amyloidosis have greatly improved in recent years. However, little is known about the presentation, treatment, and outcome of these patients at first relapse/progression (R/P). Methods: All patients with AL amyloidosis who received salvage therapy for first R/P disease at Moffitt Cancer Center between 2008 and 2020 were included in this retrospective review. Definitions of hematologic and organ R/P were based on 2012 consensus. Overall survival was measured from the time of salvage to last follow up/death. Survival was assessed by Kaplan-Meier with log-rank comparison. Results: Sixty-nine patients were included. The median age at diagnosis was 62 years and 61% were male. Upfront therapy included high dose melphalan with autologous transplant in 36% and bortezomib in 52%. At salvage, 19% had disease refractory to upfront therapy and 40% had not achieved an organ response. The median time from upfront to salvage therapy was 22 months. Salvage regimens included proteasome inhibitors, daratumumab and immunomodulatory drugs in 55%, 13% and 22%, respectively. At least a very good partial response and organ response were achieved in 35% (22/62) and 39% (21/54) with measurable disease. The median overall survival was 60 months. Based on salvage indication, patients were classified into hematologic (n = 29) and organ R/P (n = 40), and the latter showed more frequent lambda-light chain disease (59% vs. 83%, p = 0.028) and low difference of involved-uninvolved free light chain at diagnosis (< 50 mg/L, 8% vs. 44%, p = 0.002). Negative prognostic markers for survival included bone marrow plasma cells ≥20% at diagnosis (median 17 months vs. not reached; p < 0.001) and organ, particularly cardiac R/P (median, 31 months vs. not reached; p = 0.003). Salvage ( p = 0.48) or prior regimens ( p = 0.11) did not impact post-salvage survival. Conclusions: Our study highlights the unmet need of salvage in R/P AL amyloidosis in a real-world setting, given the low rate of deep responses regardless of current salvage options. Patients with bone marrow plasma cells ≥20% at diagnosis and organ R/P at salvage had inferior survival, supporting use of intensive upfront regimens for the former and adjustment of therapy if deep response is not achieved.[Table: see text]

Clinical Value of Minimal Residual Disease Assessed by Multiparameter Flow Cytometry in Amyloid Light Chain Amyloidosis

Purpose: To assess the feasibility and prognostic value of minimal residual disease (MRD) evaluated by multiparameter flow cytometry (MFC) in newly diagnosed amyloid light chain (AL) amyloidosis.Methods: Clinical data from 25 consecutive newly diagnosed AL amyloidosis patients with MRD data tested at 3 months after first-line therapy completion were retrospectively analysed in a single centre from 2012 to 2019. First-line therapy included 8 courses of VD or 4 courses of VD plus sequential autologous stem cell transplantation (ASCT), both without maintenance therapy.Results: Of 25 patients with very good partial response (VGPR) or better, 19 (76%) achieved MRD negativity. Baseline characteristics were not different between MRD-negative and MRD-positive patients. More ASCT patients than non-ASCT patients (90.0% vs 53.3%, P＝0.043) achieved MRD negativity. In the MRD-negative and MRD-positive groups, cardiac response was observed in 93% and 25% (P=0.019) and any organ response in 94% and 50%, respectively (P=0.023). At a median follow-up of 25.1 months, MRD-negative patients showed significantly longer progression-free survival (PFS) from diagnosis than MRD-positive patients (24.52 vs 76.39 months, P=0.004).Conclusions: MRD negativity measured by MFC at 3 months after first-line therapy completion in patients with AL amyloidosis is measurable and associated with improved organ response rates and PFS over a long follow-up.

Minimal residual disease negativity by next-generation flow cytometry is associated with improved organ response in AL amyloidosis

Light chain (AL) amyloidosis is caused by a small B-cell clone producing light chains that form amyloid deposits and cause organ dysfunction. Chemotherapy aims at suppressing the production of the toxic light chain (LC) and restore organ function. However, even complete hematologic response (CR), defined as negative serum and urine immunofixation and normalized free LC ratio, does not always translate into organ response. Next-generation flow (NGF) cytometry is used to detect minimal residual disease (MRD) in multiple myeloma. We evaluated MRD by NGF in 92 AL amyloidosis patients in CR. Fifty-four percent had persistent MRD (median 0.03% abnormal plasma cells). There were no differences in baseline clinical variables in patients with or without detectable MRD. Undetectable MRD was associated with higher rates of renal (90% vs 62%, p = 0.006) and cardiac response (95% vs 75%, p = 0.023). Hematologic progression was more frequent in MRD positive (0 vs 25% at 1 year, p = 0.001). Altogether, NGF can detect MRD in approximately half the AL amyloidosis patients in CR, and persistent MRD can explain persistent organ dysfunction. Thus, this study supports testing MRD in CR patients, especially if not accompanied by organ response. In case MRD persists, further treatment could be considered, carefully balancing residual organ damage, patient frailty, and possible toxicity.