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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 presymptomatic 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.

AL amyloidosis is a systemic amyloidosis and is associated with an underlying plasma cell dyscrasia. High dose intravenous melphalan and autologous stem cell transplantation was developed for the treatment of AL amyloidosis in the early 1990s and was prompted by its success in multiple myeloma. This application has evolved significantly over the past three decades. These guidelines provide a comprehensive assessment of eligibility criteria, stem cell collection and mobilisation strategies and regimens, risk-adapted melphalan dosing, role for induction and consolidation therapies, specific supportive care management, long-term outcome with respect to survival, haematologic response and relapse and organ responses following stem cell transplantation. These guidelines are developed by the experts in the field on behalf of the stem cell transplant working group of the International Society of Amyloidosis (ISA) and European Haematology Association (EHA).

Until recently, no drug was labeled for AL amyloidosis. In 2011, the Italian Medicines Agency started a program to grant access to upfront bortezomib to patients with AL amyloidosis. All subjects were enrolled in a prospective online registry. Response was evaluated after two cycles to assess the possibility of continuing treatment. A total of 764 patients were included until 2019, and 615 were evaluable. Sixteen percent of patents had advanced (stage-IIIb) heart involvement, and 27% had severe or end-stage renal failure. Bortezomib delivery was possible in stage-IIIb patients at a reduced dose. Bortezomib discontinuation was associated with increasing age, advanced heart involvement and bi-weekly administration. Fifty-nine percent of subjects attained a hematologic response and 14% a cardiac response. Bortezomib-based therapy tends to be discontinued early in elderly patients and in advanced disease. Nevertheless, early response to therapy is possible in this challenging population.

Background: Systemic AL amyloidosis is a rare disease characterized by amyloid fibril deposits, most commonly in the heart and kidneys; there are currently no health authority-approved treatments. Therapies for the treatment of multiple myeloma (MM), including bortezomib, cyclophosphamide, and dexamethasone (VCd), have been shown to improve outcomes in AL amyloidosis, but more effective therapies are needed to achieve deep and rapid hematologic responses, reverse amyloid-mediated organ dysfunction, and improve overall survival. Daratumumab is an anti-CD38 monoclonal antibody approved as monotherapy or in combination with other agents for the treatment of MM. ANDROMEDA (NCT03201965) is a randomized, open-label, active-controlled phase 3 trial of VCd ± daratumumab subcutaneous (DARA SC) in patients with newly-diagnosed AL amyloidosis. After a median follow-up of 11.4 months, the complete hematologic response rate was 53% for DARA SC + VCd (DARA-VCd) and 18% for VCd (odds ratio, 5.1; 95% CI, 3.2-8.2; P Methods: Patients with newly-diagnosed AL amyloidosis with measurable hematologic disease, ≥1 involved organ, cardiac stage (Mayo 2004) I-IIIA, eGFR ≥20 mL/min, and absence of symptomatic MM were randomized 1:1 to DARA-VCd or VCd and treated for six 28-day cycles; thereafter, patients in the DARA-VCd group received DARA SC alone every 4 weeks for up to 24 cycles. PROs were assessed on Day 1 of Cycles 1-6 for both treatment groups and every 8 weeks thereafter in the DARA-VCd group. PRO assessments included the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item (EORTC QLQ-C30), the EuroQol 5-dimensional descriptive system (EQ-5D-5L), and Short Form-36 (SF-36). Improvements in EORTC QLQ-C30 global health status (GHS) and fatigue scale scores and SF-36 mental component summary (MCS) score were secondary endpoints. Assessment of physical functioning, symptom improvement, functional improvement, and health utility as measured by the SF-36, EORTC QLQ-C30 with supplemental symptom items, and the EQ-5D-5L were exploratory outcomes. Patients completed PRO questionnaires prior to study assessments or study drug administration. Analyses of PROs were performed on the intent-to-treat analysis set; patients without a baseline or post-baseline assessment were censored at date of randomization. Compliance with PRO assessments was calculated as the number of assessments received divided by the number of assessments expected at each time point. Descriptive statistics are provided for all PRO endpoints at each time point by treatment group. A distribution-based method was used to define worsening/improvement in scores. Time to worsening/improvement, hazard ratios, and associated 95% confidence intervals were estimated using Kaplan Meier methods and Cox proportional hazards regression. Change from baseline at each time point up to Cycle 6 (Week 24) was calculated using a mixed effects model with repeated measures with patients as a random effect and baseline value, treatment group, time (weeks), treatment-by-time interaction, and stratification factors as fixed effects. Results: A total of 388 patients were randomized (DARA-VCd, n=195; VCd, n=193). Compliance rates for all PRO questionnaires were >90% at baseline and >83% through Cycle 6. Median time to improvement was shorter and median time to worsening was longer in the DARA-VCd group than in the VCd group for EORTC QLQ-C30 GHS and fatigue scales and EQ-5D-5L visual analog scale (VAS) (Table 1). Least squares mean scores for EORTC QLQ-C30 GHS and fatigue, EQ-5D-5L VAS, and SF-36 MCS remained stable in the DARA-VCd group but worsened compared with baseline in the VCd group; between-group differences are shown in Table 2. The greatest between-group differences in PRO score changes from baseline were observed at Week 16 (Cycle 4). After Cycle 6, patients in the DARA-VCd group reported improvements in mean GHS and fatigue scores that continued while on treatment (Figure). Conclusions: Patients with AL amyloidosis treated with DARA-VCd experienced clinical improvements without any decrement in health-related quality of life over 6 cycles. Following Cycle 6, improvements in GHS and fatigue were reported in patients in the DARA-VCd group. These findings further support the value of DARA-VCd in patients with AL amyloidosis. Disclosures Sanchorawala: UpToDate: Patents & Royalties; Abbvie: Other: advisory board; Proclara: Other: advisory board; Caleum: Other: advisory board; Regeneron: Other: advisory board; Oncopeptide: Research Funding; Caelum: Research Funding; Prothena: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Takeda: Research Funding. Palladini:Celgene: Other: Travel support; Jannsen Cilag: Honoraria, Other. Minnema:Servier: Consultancy; Amgen: Consultancy; Kite, a Gilead Company: Speakers Bureau; Celgene: Other: travel support, Research Funding. Jaccard:Janssen: Consultancy, Honoraria, Other: A.J. has served in a consulting or advisory role for Janssen and has received honoraria from, received research funding from, and had travel, accommodations, or other expenses paid for or reimbursed by Janssen., Research Funding; Celgene: Honoraria, Other: A.J. has served in a consulting or advisory role for Janssen and has received honoraria from, received research funding from, and had travel, accommodations, or other expenses paid for or reimbursed by Celgene., Research Funding. Lee:Janssen: Consultancy, Research Funding; Genentech: Consultancy; GlaxoSmithKline: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Genentech: Consultancy; Regeneron: Research Funding; Sanofi: Consultancy; Daiichi Sankyo: Research Funding. Gibbs:Janssen, BMS/Celgene, Amgen, Takeda, Pfizer, Caelum, Abbvie and Eidos: Membership on an entity's Board of Directors or advisory committees. Mollee:Pfizer: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees; Caelum: Membership on an entity's Board of Directors or advisory committees. Venner:Janssen, BMS/Celgene, Sanofi, Takeda, Amgen: Honoraria; Celgene, Amgen: Research Funding. Schönland:Janssen: Honoraria, Other: travel support to meetings, Research Funding; Prothena: Honoraria, Other: travel support to meetings, Research Funding; Takeda: Honoraria, Other: travel support to meetings, Research Funding. Suzuki:Bristol-Myers Squibb, Celgene and Amgen: Research Funding; Takeda, Amgen, Janssen and Celgene: Consultancy; Takeda, Celgene, ONO, Amgen, Novartis, Sanofi, Bristol-Myers Squibb, AbbVie and Janssen: Honoraria. Kim:BMS, Takeda, Amgen, Celgene, Janssen: Consultancy, Honoraria, Research Funding. Cibeira:Janssen, Akcea Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen, Celgene, Amgen: Honoraria, Other: Educational lectures. Beksac:Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Valent:Celgene: Other: Teaching, Speakers Bureau; Takeda Pharmaceuticals: Other: Teaching, Speakers Bureau; Amgen Inc.: Other: Teaching, Speakers Bureau. Wong:GSK: Research Funding; Roche: Research Funding; Janssen: Research Funding; Bristol Myers Squibb: Research Funding; Fortis: Research Funding; Amgen: Consultancy; Sanofi: Membership on an entity's Board of Directors or advisory committees. Rosenzweig:Janssen: Speakers Bureau. Bumma:Amgen: Speakers Bureau; Sanofi: Speakers Bureau. Gries:Janssen: Current Employment, Current equity holder in publicly-traded company. Fastenau:Janssen: Current Employment, Current equity holder in publicly-traded company. Tran:Janssen: Current Employment, Current equity holder in publicly-traded company. Qin:Janssen: Current Employment. Vasey:Janssen Research & Development: Current Employment, Current equity holder in publicly-traded company. Tromp:Janssen: Current Employment, Current equity holder in publicly-traded company. Weiss:Janssen: Current Employment, Current equity holder in publicly-traded company. Vermeulen:Janssen: Current Employment, Current equity holder in publicly-traded company. Comenzo:Caleum: Consultancy; Amgen: Consultancy; Janssen: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Sanofi: Consultancy; Unum: Consultancy; Karyopharm: Consultancy, Research Funding; Prothena: Consultancy, Research Funding. Kastritis:Amgen: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Genesis Pharma: Consultancy, Honoraria. Wechalekar:Takeda: Honoraria, Other: Travel; Celgene: Honoraria; Janssen: Honoraria, Other: Advisory; Caelum: Other: Advisory.

Pulmonary involvement in Sjogren syndrome (SS) could manifest as cystic lung disease (CLD). CLD in SS includes lymphocytic interstitial pneumonia (LIP) and pulmonary amyloidosis. Differential diagnosis usually requires surgical lung biopsy, whereas CT-guided percutaneous fine needle aspiration biopsy (CT-FNAB) has not yet explored. We describe the case of a 63-year-old never smoker Caucasian female with a SS diagnosis who displayed a newly detected diffuse CLD at high-resolution computed tomography, though totally asymptomatic. Given the favorable location of one big lesion at the superior left lobe, a CT-FNAB was proposed instead of a more invasive SLB. At histology examination a diagnosis of pulmonary nodular AL kappa amyloidosis in the context of SS was established. In conclusion, CT-FNAB might represent an alternative and less invasive diagnostic procedure than SLB in the differential diagnosis of CLD, even if further research is needed. Moreover, this case presents an unusual association between SS and pulmonary nodular AL kappa amyloidosis, with pulmonary nodules and cysts without systemic manifestations.

Immunoglobulin light chain (AL) amyloidosis is one of the most frequent systemic amyloidosis in Western countries. It is caused by a B-cell clone producing a misfolded light chain (LC) that deposits in organs.The review examines recent findings on pathophysiology and clinical management of AL amyloidosis. It contains an update on the recent hot topics as novel therapeutic approaches, definition of relapse, and hematologic response assessment. To review literature on AL amyloidosis, a bibliographic search was performed using PubMed.Due to the proteotoxicity of amyloidogenic LCs, the therapeutic goal is a rapid and profound decrease in their concentration. The standard treatment is a risk-adapted chemotherapy targeting the B-cell clone. Novel, promising drugs, as daratumumab, are currently under evaluation in newly-diagnosed and relapsed/refractory patients. New sensitive techniques, as mass spectrometry approach and bone marrow minimal residual disease assessment, are available to evaluate depth of response. After first-line therapy, increase in LC concentration may precede worsening of organ dysfunction and should be considered carefully. Further clarification of molecular mechanisms of the disease are shedding light on new possible therapeutic targets. Innovative treatment strategies and novel technologies will improve our ability to treat AL amyloidosis, preventing organ deterioration.

Although no therapies are approved for light chain (AL) amyloidosis, cyclophosphamide, bortezomib, and dexamethasone (CyBorD) is considered standard of care. Based on outcomes of daratumumab in multiple myeloma (MM), the phase 3 ANDROMEDA study (NCT03201965) is evaluating daratumumab-CyBorD vs CyBorD in newly diagnosed AL amyloidosis. We report results of the 28-patient safety run-in. Patients received subcutaneous daratumumab (DARA SC) weekly in cycles 1 to 2, every 2 weeks in cycles 3 to 6, and every 4 weeks thereafter for up to 2 years. CyBorD was given weekly for 6 cycles. Patients had a median of 2 involved organs (kidney, 68%; cardiac, 61%). Patients received a median of 16 (range, 1-23) treatment cycles. Treatment-emergent adverse events were consistent with DARA SC in MM and CyBorD. Infusion-related reactions occurred in 1 patient (grade 1). No grade 5 treatment-emergent adverse events occurred; 5 patients died, including 3 after transplant. Overall hematologic response rate was 96%, with a complete hematologic response in 15 (54%) patients; at least partial response occurred in 20, 22, and 17 patients at 1, 3, and 6 months, respectively. Renal response occurred in 6 of 16, 7 of 15, and 10 of 15 patients, and cardiac response occurred in 6 of 16, 6 of 13, and 8 of 13 patients at 3, 6, and 12 months, respectively. Hepatic response occurred in 2 of 3 patients at 12 months. Daratumumab-CyBorD was well tolerated, with no new safety concerns versus the intravenous formulation, and demonstrated robust hematologic and organ responses. This trial was registered at www.clinicaltrials.gov as #NCT03201965.

Daratumumab is a human monoclonal antibody targeting CD38, an antigen uniformly expressed by plasma cells in multiple myeloma and light-chain amyloidosis (AL). We report the results of a prospective multicenter phase 2 study of daratumumab monotherapy in AL (NCT02816476). Forty previously treated AL patients with a difference between involved and uninvolved free light chains (dFLC) >50 mg/L were included in 15 centers between September of 2016 and April of 2018. Patients received 6 28-day cycles of IV daratumumab, every week for cycles 1 and 2 and every 2 weeks for cycles 3 through 6. Median age was 69 years (range, 45-83). Twenty-six patients had ≥2 organs involved, with heart in 24 and kidney in 26. Median time from diagnosis to enrollment was 23 months (interquartile range, 4-122), with a median of 3 prior therapies (range, 1-5). At data cutoff (September of 2019), all patients discontinued therapy; 33 received the planned 6 cycles. Overall, 22 patients had hematological response, and 19 patients (47.5%) achieved very good partial response (dFLC

Key PointsDaratumumab is effective in treated light chain deposition disease. Daratumumab can prevent progression of renal failure in these patients.

Newly diagnosed AL amyloidosis patients were evaluated to develop a model for early assessment of treatment benefit at 6 months, integrating both hematologic (HR) and organ response (OR) assessment (testing cohort, Mayo: n = 473; validation cohort, Pavia: n = 575). Multiple OR were assessed as follows: All OR (AOR): response in all organs, mixed OR (MOR): response in some organs, no OR (NOR)]. AOR rates at 6 months improved with deepening HR; complete response (CR; 38%, 35%), very good partial response (VGPR; 30%, 26%), and partial response (PR; 16%, 21%), respectively. A composite HR/OR (CHOR) model was developed using incremental scoring based on hazard ratios with scores of 0–3 for HR (0—CR, 1—VGPR, 2—PR, 3—no response) and 0–2 for OR (0—AOR, 1—MOR, 2—NOR). Patients could be divided into two distinct CHOR groups (scores 0–3 and 4–5), with median OS in group 1 and group 2: Not reached vs. 34 months, p p

Systemic immunoglobulin light-chain (AL) amyloidosis is characterized by deposition of amyloid fibrils of light chains produced by clonal CD38+ plasma cells. Daratumumab, a human CD38-targeting antibody, may improve outcomes for this disease.We randomly assigned patients with newly diagnosed AL amyloidosis to receive six cycles of bortezomib, cyclophosphamide, and dexamethasone either alone (control group) or with subcutaneous daratumumab followed by single-agent daratumumab every 4 weeks for up to 24 cycles (daratumumab group). The primary end point was a hematologic complete response.A total of 388 patients underwent randomization. The median follow-up was 11.4 months. The percentage of patients who had a hematologic complete response was significantly higher in the daratumumab group than in the control group (53.3% vs. 18.1%) (relative risk ratio, 2.9; 95% confidence interval [CI], 2.1 to 4.1; P0.001). Survival free from major organ deterioration or hematologic progression favored the daratumumab group (hazard ratio for major organ deterioration, hematologic progression, or death, 0.58; 95% CI, 0.36 to 0.93; P = 0.02). At 6 months, more cardiac and renal responses occurred in the daratumumab group than in the control group (41.5% vs. 22.2% and 53.0% vs. 23.9%, respectively). The four most common grade 3 or 4 adverse events were lymphopenia (13.0% in the daratumumab group and 10.1% in the control group), pneumonia (7.8% and 4.3%, respectively), cardiac failure (6.2% and 4.8%), and diarrhea (5.7% and 3.7%). Systemic administration-related reactions to daratumumab occurred in 7.3% of the patients. A total of 56 patients died (27 in the daratumumab group and 29 in the control group), most due to amyloidosis-related cardiomyopathy.Among patients with newly diagnosed AL amyloidosis, the addition of daratumumab to bortezomib, cyclophosphamide, and dexamethasone was associated with higher frequencies of hematologic complete response and survival free from major organ deterioration or hematologic progression. (Funded by Janssen Research and Development; ANDROMEDA ClinicalTrials.gov number, NCT03201965.).

Background: Systemic AL amyloidosis is characterized by the deposition of insoluble amyloid fibrils produced by light chains synthesized by clonal CD38+ plasma cells. Combining daratumumab (DARA) with bortezomib, cyclophosphamide, and dexamethasone (VCd) has demonstrated significantly improved outcomes in patients with AL amyloidosis. The classification of hematologic complete response (CR) in this disease is evolving, and the absolute reduction of the involved free light chain (iFLC) and the difference between iFLC and uninvolved free light chain (dFLC) are being recognized as very meaningful endpoints. Here, we present results from the ANDROMEDA study (NCT03201965) to demonstrate the impact of achieving deep reductions of iFLC and dFLC on major organ deterioration progression-free survival (MOD-PFS), a novel, key secondary endpoint in this study. Methods: Key eligibility criteria included newly diagnosed AL amyloidosis with measurable hematologic disease (serum monoclonal protein ≥0.5 g/dL by protein electrophoresis or serum free light chain ≥5.0 mg/dL with an abnormal kappa:lambda ratio or dFLC ≥50 mg/L), ≥1 involved organ, cardiac stage I-IIIA, eGFR ≥20 mL/min, and absence of symptomatic multiple myeloma. Patients were randomized (1:1) to receive DARA-VCd or VCd alone. All patients received bortezomib (1.3 mg/m2 subcutaneous [SC] weekly), cyclophosphamide (300 mg/m2 oral [PO] or intravenous [IV] weekly), and dexamethasone (20-40 mg PO or IV weekly) for six 28-day cycles. DARA SC (1800 mg, co-formulated with recombinant human hyaluronidase PH20 in 15 mL) was administered by injection weekly in Cycles 1-2, every other week in Cycles 3-6, and every 4 weeks thereafter for up to 24 cycles. Disease evaluations occurred every 4 weeks (Cycles 1-6) and every 8 weeks (after Cycle 7) until major organ deterioration, death, end of study, or withdrawal. The primary endpoint was overall (ie, at any time) hematologic CR rate, defined here as normalization of FLC levels and ratio (FLCr) and negative serum and urine immunofixation, confirmed at a subsequent visit; normalization of uninvolved FLC level and FLCr were not required if iFLC Results: A total of 388 patients were randomized to receive DARA-VCd (n=195) or VCd alone (n=193). Baseline characteristics were well balanced between treatment groups. The median age was 64 years and 65% of patients had ≥2 organs involved. The proportions of patients with heart and kidney involvement were 71% and 59%, respectively, and the proportions of patients with cardiac stage I, II, and IIIA were 23%, 40%, and 37%, respectively. The median duration of treatment was 9.6 months for DARA-VCd and 5.3 months for VCd. Median follow-up was 11.4 months (range, 0.03-21.3+). The rates of deep hematological responses by all criteria strongly favored the DARA-VCd treatment arm (Table). MOD-PFS was longer in patients achieving deep hematological responses by all criteria (Figure). In addition, the corresponding MOD-PFS was similar regardless of the hematological response criteria used. Conclusions: Regardless of the criteria used, the addition of DARA to VCd increased the rates of deep hematologic responses in patients with newly diagnosed AL amyloidosis, which, in turn, was associated with prolonged MOD-PFS. These results support the benefit of DARA in this patient population. References 1. Comenzo RL, et al. Leukemia. 2012;26(11):2317-25 2. Sidana S, et al. Leukemia. 2019;34(5):1472-75 3. Muchtar E, et al. Leukemia. 2019;33(3):790-94 4. Manwani R, et al. Blood. 2019;134(25):2271-2280 Disclosures Comenzo: Amgen: Consultancy; Sanofi: Consultancy; Prothena: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Unum: Consultancy; Karyopharm: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Caleum: Consultancy. Kastritis:Pfizer: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Genesis Pharma: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria. Palladini:Celgene: Other: Travel support; Jannsen Cilag: Honoraria, Other. Minnema:Celgene: Other: travel support, Research Funding; Kite, a Gilead Company: Speakers Bureau; Amgen: Consultancy; Servier: Consultancy. Wechalekar:Caelum: Other: Advisory; Janssen: Honoraria, Other: Advisory; Takeda: Honoraria, Other: Travel; Celgene: Honoraria. Jaccard:Celgene: Honoraria, Other: A.J. has served in a consulting or advisory role for Janssen and has received honoraria from, received research funding from, and had travel, accommodations, or other expenses paid for or reimbursed by Celgene., Research Funding; Janssen: Consultancy, Honoraria, Other: A.J. has served in a consulting or advisory role for Janssen and has received honoraria from, received research funding from, and had travel, accommodations, or other expenses paid for or reimbursed by Janssen., Research Funding. Sanchorawala:Proclara: Other: advisory board; Abbvie: Other: advisory board; UpToDate: Patents & Royalties; Regeneron: Other: advisory board; Caleum: Other: advisory board; Janssen: Research Funding; Takeda: Research Funding; Celgene: Research Funding; Prothena: Research Funding; Caelum: Research Funding; Oncopeptide: Research Funding. Lee:Janssen: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Genentech: Consultancy; GlaxoSmithKline: Consultancy, Research Funding; Sanofi: Consultancy; Daiichi Sankyo: Research Funding; Regeneron: Research Funding; Genentech: Consultancy; Celgene: Consultancy, Research Funding; Amgen: Consultancy, Research Funding. Gibbs:Janssen, BMS/Celgene, Amgen, Takeda, Pfizer, Caelum, Abbvie and Eidos: Membership on an entity's Board of Directors or advisory committees. Mollee:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Caelum: Membership on an entity's Board of Directors or advisory committees. Venner:Celgene, Amgen: Research Funding; Janssen, BMS/Celgene, Sanofi, Takeda, Amgen: Honoraria. Schönland:Janssen, Prothena, Takeda: Honoraria, Other: travel support to meetings, Research Funding. Suzuki:Takeda, Amgen, Janssen and Celgene: Consultancy; Bristol-Myers Squibb, Celgene and Amgen: Research Funding; Takeda, Celgene, ONO, Amgen, Novartis, Sanofi, Bristol-Myers Squibb, AbbVie and Janssen: Honoraria. Kim:Amgen, BMS, Janssen, Sanofi, Takeda: Consultancy, Honoraria, Research Funding. Cibeira:Janssen, Akcea Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen, Celgene, Amgen: Honoraria, Other: Educational lectures. Beksac:Deva: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen&janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Valent:Amgen Inc.: Other: Teaching, Speakers Bureau; Takeda Pharmaceuticals: Other: Teaching, Speakers Bureau; Celgene: Other: Teaching, Speakers Bureau. Wong:Fortis: Research Funding; GSK: Research Funding; Amgen: Consultancy; Janssen: Research Funding; Roche: Research Funding; Bristol Myers Squibb: Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees. Rosenzweig:Janssen: Speakers Bureau. Bumma:Sanofi: Speakers Bureau; Amgen: Speakers Bureau. Dimopoulos:BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau. Tran:Janssen: Current Employment, Current equity holder in publicly-traded company. Qin:Janssen: Current Employment. Vasey:Janssen Research & Development: Current Employment, Current equity holder in publicly-traded company. Tromp:Janssen: Current Employment, Current equity holder in publicly-traded company. Weiss:Janssen: Current Employment, Current equity holder in publicly-traded company. Vermeulen:Janssen: Current Employment, Current equity holder in publicly-traded company.

The authors report on the subset of AL amyloidosis patients with nonlymphoplasmacytic lymphoma, emphasizing a predominance of marginal zone lymphoma, frequent delay in diagnosis, and a generally poor prognosis.

The vast majority of patients with light-chain (AL) amyloidosis are not eligible for stem cell transplant and are treated with conventional chemotherapy. Conventional regimens are based on various combinations of dexamethasone, alkylating agents, proteasome inhibitors, and immunomodulatory drugs. The choice of these regimens requires a careful risk stratification, based on the extent of amyloid organ involvement, comorbidities, and the characteristics of the amyloidogenic plasma cell clone. Most patients are treated upfront with bortezomib and dexamethasone combined with cyclophosphamide or melphalan. Cyclophosphamide does not compromise stem cell mobilization and harvest and is more manageable in renal failure. Melphalan can overcome the effect of t(11;14), which is associated with lower response rates and shorter survival in subjects treated with bortezomib and dexamethasone, or in combination with cyclophosphamide. Lenalidomide and pomalidomide are the mainstay of rescue treatment. They are effective in patients exposed to bortezomib, dexamethasone, and alkylators, but deep hematologic responses are rare. Ixazomib, alone or in combination with lenalidomide, increases the rate of complete responses in relapsed/refractory patients. Conventional chemotherapy regimens will represent the backbone for future combinations, particularly with anti-plasma-cell immunotherapy, that will further improve response rates and outcomes.

Introduction: Hereditary transthyretin-mediated amyloidosis (ATTRv; v for variant) is a rare, progressive, fatal multi-systemic disease, autosomal dominantly inherited with heterogeneous clinical phenotype caused by mutations in the TTR gene. Mutations promoting proteolytic remodeling and tetramer dissociation result in fragmented and full-length TTR monomers that misfold, aggregate and deposit at multiple sites (mainly nerves and heart) causing peripheral neuropathy and/or cardiomyopathy.Areas covered: The authors discuss patisiran, the first approved RNA interference-based therapeutic agent that suppresses the circulating levels of the amyloidogenic protein TTR both wild-type and mutant. This compound demonstrated a safe clinical profile in phase I and II studies and showed a significant clinical effect in a phase III (APOLLO) trial in ATTRv patients. An open-label-extension study is still underway but, based on the positive results, the regulatory agencies granted approval for the treatment of ATTRv with polyneuropathy in Stage I and II.Expert opinion: The patisiran program has demonstrated that substantial TTR concentration reduction is associated with significant and sustained improvement in polyneuropathy scores, quality-of-life profile and several outcome measures that capture the systemic burden of the disease. The drug resulted safe also in long term follow-up studies while its efficacy for ATTR with cardiomyopathy is under investigation.

TO THE EDITOR: Diagnosis of amyloidosis, with the possible exception of cardiac transthyretin amyloidosis (ATTR) in patients without monoclonal components,[1][1] requires demonstration of tissue amyloid deposits and identification of the amyloidogenic protein.[2][2],[3][3] The gold standard for

Amyloidoses are characterized by aggregation of proteins into highly ordered amyloid fibrils, which deposit in the extracellular space of tissues, leading to organ dysfunction. In AL (amyloid light chain) amyloidosis, the most common form in Western countries, the amyloidogenic precursor is a misfolding-prone immunoglobulin light chain (LC), which, in the systemic form, is produced in excess by a plasma cell clone and transported to target organs though blood. Due to the primary role that proteins play in the pathogenesis of amyloidoses, mass spectrometry (MS)-based proteomic studies have gained an established position in the clinical management and research of these diseases. In AL amyloidosis, in particular, proteomics has provided important contributions for characterizing the precursor light chain, the composition of the amyloid deposits and the mechanisms of proteotoxicity in target organ cells and experimental models of disease. This review will provide an overview of the major achievements of proteomic studies in AL amyloidosis, with a presentation of the most recent acquisitions and a critical discussion of open issues and ongoing trends.

Systemic light-chain (AL) amyloidosis is caused by a small B cell, most commonly a plasma cell (PC), clone that produces toxic light chains (LC) that cause organ dysfunction and deposits in tissues. Due to the production of amyloidogenic, misfolded LC, AL PCs display peculiar biologic features. The small, indolent plasma cell clone is an ideal target for anti-CD38 immunotherapy. A recent phase III randomized study showed that in newly diagnosed patients, the addition of daratumumab to the standard of care increased the rate and depth of the hematologic response and granted more frequent organ responses. In the relapsed/refractory setting, daratumumab alone or as part of combination regimens gave very promising results. It is likely that daratumumab-based regimens will become new standards of care in AL amyloidosis. Another anti-CD38 monoclonal antibody, isatuximab, is at an earlier stage of development as a treatment for AL amyloidosis. The ability to target CD38 on the amyloid PC offers new powerful tools to treat AL amyloidosis. Future studies should define the preferable agents to combine with daratumumab upfront and in the rescue setting and assess the role of maintenance. In this review, we summarize the rationale for using anti-CD38 antibodies in the treatment of AL amyloidosis.

OBJECTIVES: Multiple myeloma (MM) is a malignant plasma cell neoplasm, requiring the integration of clinical examination, laboratory and radiological investigations for diagnosis. Detection and isotypic identification of the monoclonal protein(s) and measurement of other relevant biomarkers in serum and urine are pivotal analyses. However, occasionally this approach fails to characterize complex protein signatures. Here we describe the development and application of next generation mass spectrometry (MS) techniques, and a novel adaptation of immunofixation, to interrogate non-canonical monoclonal immunoproteins. METHODS: Immunoprecipitation immunofixation (IP-IFE) was performed on a Sebia Hydrasys Scan2. Middle-down de novo sequencing and native MS were performed with multiple instruments (21T FT-ICR, Q Exactive HF, Orbitrap Fusion Lumos, and Orbitrap Eclipse). Post-acquisition data analysis was performed using Xcalibur Qual Browser, ProSight Lite, and TDValidator. RESULTS: We adapted a novel variation of immunofixation electrophoresis (IFE) with an antibody-specific immunosubtraction step, providing insight into the clonal signature of gamma-zone monoclonal immunoglobulin (M-protein) species. We developed and applied advanced mass spectrometric techniques such as middle-down de novo sequencing to attain in-depth characterization of the primary sequence of an M-protein. Quaternary structures of M-proteins were elucidated by native MS, revealing a previously unprecedented non-covalently associated hetero-tetrameric immunoglobulin. CONCLUSIONS: Next generation proteomic solutions offer great potential for characterizing complex protein structures and may eventually replace current electrophoretic approaches for the identification and quantification of M-proteins. They can also contribute to greater understanding of MM pathogenesis, enabling classification of patients into new subtypes, improved risk stratification and the potential to inform decisions on future personalized treatment modalities.

Background Renal light chain (AL) amyloidosis manifests as proteinuria with or without renal failure and is associated with a risk of progression to renal replacement therapy (RRT). A significant reduction in circulating amyloidogenic light chain is needed to achieve a renal response. Current renal response criteria are binary defining a renal response as >30% reduction in 24-h proteinuria without worsening estimated glomerular filtration rate (eGFR). Several studies suggest that greater reduction in proteinuria following successful therapy improves renal and overall survival. Methods AL amyloidosis patients diagnosed between 2010 to 2015, achieving at least hematological partial response to therapy and with renal involvement were included. Four renal response categories were formulated based on reduction level in pretreatment 24-h proteinuria in the absence of renal progression: renal complete response (renCR, 24-h proteinuria ≤200 mg/24-h); renal very good partial response (renVGPR, >60% reduction in 24-h proteinuria); renal partial response (renPR, 31-60% reduction in 24-proteinuria); and renal no response (renNR, 30% or less reduction). Renal response was assessed at landmark (6-, 12-, and 24 months from treatment initiation) and as best renal response. Graded renal responses were assessed as predictors for time from diagnosis to RRT and overall survival. Results Seven hundred and thirty-seven patients were included. The median age was 63. Renal stage I, II and III were assigned to 34%, 52% and 14% of patients, respectively. Reduction in 24-h proteinuria from baseline improved over time with a median reduction of 34%, 50% and 71%, at 6-month, 12-month and 24-months, respectively. At best response, renCR, renVGPR, renPR and renNR were achieved in 27%, 34%, 15% and 24% of patients, respectively. A renal response as early as 6 months after therapy initiation was able to predict time to RRT with an increase in RRT risk with lower level of renal response at that time point (5-year RRT 0%, 3%, 9% and 16% for renCR, renVGPR, renPR and renNR, respectively, P Conclusions We validated new graded renal response criteria based on reduction in 24-h proteinuria. These 4-level renal response criteria highlight the importance of achieving a deep renal response to improve renal and overall survival. These findings will allow clinicians to make decision on therapy changes or augmentation based on response depth as early as 6-month before irreversible renal failure has developed.

Background Binary cardiac response assessment using NT-proBNP is prognostic in light chain (AL) amyloidosis. Previous studies suggested that refining the criteria to multi-level cardiac responses improves prognostic prediction. We aimed to validate a graded cardiac response assessment tool in AL amyloidosis using NT-proBNP or BNP. Methods In this retrospective, multicenter study AL amyloidosis patients who were diagnosed between 2010 and 2015, achieved at least a hematological partial response (PR) within 12 months of diagnosis and were evaluable for cardiac response (defined as baseline NT-proBNP >650 pg/mL or BNP >150 pg/mL) were included. The following response criteria were tested: cardiac complete response (carCR, nadir NT-proBNP≤350 pg/mL or BNP≤80 pg/mL); cardiac very good partial response (carVGPR, >60% reduction in NT-proBNP/BNP); Cardiac PR (carPR 31-60% reduction); and cardiac non response (carNR, ≤30% reduction). Response was assessed at fixed time points (6, 12 and 24 months from therapy initiation) and at best response. The primary outcome was overall survival based on depth of cardiac response. Results Six hundred and fifty-one patients were included. Mayo 2004 cardiac stage II, IIIA and IIIB was present in 47.5%, 38% and 14.5% of patients, respectively (by definition, patients with Mayo stage 1 do not have cardiac amyloidosis evaluable for response). Hematological CR, hematological VGPR and hematological PR was achieved in 38%, 39% and 23% of patients, respectively. Cardiac response improved over time with a median percentage reduction in NT-proBNP/BNP compared to baseline of 15%, 37% and 54%, at 6, 12 and 24 months respectively. At best cardiac response, carCR, carVGPR, carPR and carNR were achieved in 16%, 26%, 23% and 35% of patients, respectively. Patients achieving a carCR were more likely to be in cardiac stage II compared to carVGPR or carPR patients (65% vs 47% each, P30% rise in NT-proBNP/BNP) in multivariate analysis that included age, type of first line therapy, light chain burden, cardiac stage and hematological response. Conclusions We validated the prognostic value of graded cardiac response. These response criteria allow better discrimination of patient populations and assessment of treatment effectiveness in an era of improved therapies for AL amyloidosis. The study emphasizes the importance of early diagnosis which increases the likelihood of deep and durable cardiac responses.

We thank Dr. Solomon for his interest in our article on the management of light chain (AL) amyloidosis [1]. At present, the treatment of AL amyloidosis is aimed at suppressing the production of the...

Inside and outside the brain, accumulation of amyloid fibrils plays key roles in the pathogenesis of fatal age-related diseases such as Alzheimer’s and Parkinson’s diseases and wild-type transthyretin amyloidosis. Although the incidence of all amyloidoses increases with age, for some types of amyloidosis aging is known as the main direct risk factor, and these types are typically diseases of elderly people. More than 10 different precursor proteins are known to cause age-associated amyloidosis; these proteins include amyloid β protein, α-synuclein, transthyretin, islet amyloid polypeptide, atrial natriuretic factor, and the newly discovered epidermal growth factor-containing fibulin-like extracellular matrix protein 1. Except for intracerebral amyloidoses, most age-related amyloidoses have been little studied. Indeed, in view of the increasing life expectancy in our societies, understanding how aging is involved in the process of amyloid fibril accumulation and the effects of amyloid deposits on the aging body is extremely important. In this review, we summarize current knowledge about the nature of amyloid precursor proteins, the prevalence, clinical manifestations, and pathogenesis of amyloidosis, and recent advances in our understanding of age-related amyloidoses outside the brain.

Background Amyloid transthyretin (ATTR) amyloidosis is caused by the systemic deposition of transthyretin molecules, either normal (wild‐type ATTR, ATTRwt) or mutated (variant ATTR, ATTRv). ATTR amyloidosis is a disease with a severe impact on patients’ quality of life (QoL). Nonetheless, limited attention has been paid to QoL so far, and no specific tools for QoL assessment in ATTR amyloidosis currently exist. QoL can be evaluated through patient‐reported outcome measures (PROMs), which are completed by patients, or through scales, which are compiled by clinicians. The scales investigate QoL either directly or indirectly, i.e., by assessing the degree of functional impairment and limitations imposed by the disease. Design Search for the measures of QoL evaluated in phase 2 and phase 3 clinical trials on ATTR amyloidosis. Results Clinical trials on ATTR amyloidosis have used measures of general health status, such as the Short Form 36 Health Survey (SF‐36), or tools developed in other disease settings such as the Kansas City Cardiomyopathy Questionnaire (KCCQ) or adaptations of other scales such as the modified Neuropathy Impairment Score +7 (mNIS+7). Conclusions Scales or PROMs for ATTR amyloidosis would be useful to better characterize newly diagnosed patients and to assess disease progression and response to treatment. The ongoing ITALY (Impact of Transthyretin Amyloidosis on Life qualitY) study aims to develop and validate 2 PROMs encompassing the whole phenotypic spectrum of ATTRwt and ATTRv amyloidosis, that might be helpful for patient management and may serve as surrogate endpoints for clinical trials.

© The Author(s) 2021., 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., This study was supported by a grant from CARIPLO “Molecular mechanisms of Ig toxicity in age-related plasma cell dyscrasias no. 2015-0591”, by a grant from the Black Swan Research Initiative from the International Myeloma Foundation “Automated multidimensional flow cytometry for high-sensitive screening and to monitor response in AL amyloidosis”, by a grant from CARIPLO “Structure–function relation of amyloid: understanding the molecular bases of protein misfolding diseases to design new treatments no. 2013-0964”, by a grant from the Amyloidosis Foundation “Investigating new therapies to treat AL amyloidosis”, and by a grant from Cancer Research UK, FCAECC and AIRC under the Accelerator Award 2017 Program “Early detection and intervention: understanding the mechanisms of transformation and hidden resistance of incurable hematological malignancies”, by a grant from CARIPLO “Harnessing the plasma cell secretory capacity against systemic light chain amyloidosis” (no. 2018-0257), by a grant from the Italian Ministry of Health “Towards effective, patient-tailored anti-plasma cell therapies in AL amyloidosis: predicting drug response and overcoming drug resistance” (GR-2018-12368387). This study has also supported the Centro de Investigación Biomédica en Red—Área de Oncología—del Instituto de Salud Carlos III (CIBERONC; CB16/12/00369, CB16/12/00400, and CB16/12/00489) and the Instituto de Salud Carlos III/Subdirección General de Investigación Sanitaria (FIS No. PI13/02196). G.P. is supported in part by the Bart Barlogie Young Investigator Award from the International Myeloma Society (IMS). P.M. is supported in part by a fellowship grant form Collegio Ghislieri (Pavia). We acknowledge the study coordinator and data manager Anna Carnevale Baraglia.

Background Cardiac wild type transthyretin (ATTRwt) amyloidosis, formerly known as senile systemic amyloidosis, is an increasingly recognized, progressive, and fatal cardiomyopathy. Two biomarkers staging systems were proposed based on NT-proBNP (in both cases) and troponin or estimated glomerular filtration rate, that are able to predict survival in this population. The availability of novel effective treatments requires large studies to describe the natural history of the disease in different populations. Objective To describe the natural history of the disease in a large, prospective, national series. Methods Starting in 2007, we protocolized data collection in all the patients diagnosed at our center (n=400 up to 7/2019). Results The referrals to our center increased over time: 5 cases (1%) between 2007–2009, 33 (9%) in 2010–2012, 90 (22%) in 2013–2015 and 272 (68%) in 2016–2019. Median age was 76 years [interquartile range (IQR): 71–80 years] and 372 patients (93%) were males. One hundred and seventy-three (43%) had atrial fibrillation, 63 (15%) had a history of ischemic cardiomyopathy and 64 (15%) underwent pacemaker or ICD implantation. NYHA class was I in 58 subjects (16%), II in 225 (63%) and III in 74 (21%). Median NT-proBNP was 3064 ng/L (IQR: 1817–5579 ng/L), troponin I 0.096 ng/mL (IQR: 0.063–0.158 ng/mL), eGFR 62 mL/min (IQR: 50–78 mL/min). Median IVS was 17 mm (IQR: 15–19 mm), PW 16 mm (IQR: 14–18 mm) and EF 53% (IQR: 45–57%). One-hundred and forty-eight subjects (37%) had a concomitant monoclonal component in serum and/or urine and/or an abnormal free light chain ratio. In these patients, the diagnosis was confirmed by immunoelectron microscopy or mass spectrometry. In 252 (63%) the diagnosis was based on bone scintigraphy. DNA analysis for amyloidogenic mutations in transthyretin and apolipoprotein A-I genes was negative in all subjects. The median survival of the whole cohort was 59 months. The Mayo Clinic staging based on NT-proBNP (cutoff: 3000 ng/L) and troponin I (cutoff: 0.1 ng/mL) discriminated 3 different groups [stage I: 131 (35%), stage II: 123 (32%) and stage III: 127 (33%)] with different survival between stage I and II (median 86 vs. 81 months, P=0.04) and between stage II and III (median 81 vs. 62 months, P Conclusions This is one of the largest series of patients with cardiac ATTRwt reported so far. Referrals and diagnoses increased exponentially in recent years, One-third of patients has a concomitant monoclonal gammopathy and needed tissue typing. Both the current staging systems offered good discrimination of staging and were validated in our independent cohort. Funding Acknowledgement Type of funding source: None

In systemic light-chain amyloidosis, monoclonal antibodies target antigens that are either membrane-bound or circulating or deposited in the organs. CD38 holds high promise as a target against clonal plasma cells. Multiple anti-CD38 antibodies are either approved for use or being investigated in clinical trials. Daratumumab has been investigated and has clinical efficacy in upfront or refractory settings. High rates of hematologic response are seen with daratumumab, which translates to high organ response rates. Rituximab is usually integrated into the treatment regimen for IgM amyloidosis. Anti-amyloid therapies have shown preclinical proof of principle, but lack confirmation of improvement.

PURPOSE Oral melphalan and dexamethasone (MDex) were considered a standard of care in light-chain (AL) amyloidosis. In the past decade, bortezomib has been increasingly used in combination with alkylating agents and dexamethasone. We prospectively compared the efficacy and safety of MDex and MDex with the addition of bortezomib (BMDex). METHODS This was a phase III, multicenter, randomized, open-label trial. Patients were stratified according to cardiac stage. Patients with advanced cardiac stage (stage IIIb) amyloidosis were not eligible. The primary end point was hematologic response rate at 3 months. This trial is registered with ClinicalTrials.gov identifier NCT01277016 . RESULTS A total of 109 patients, 53 in the BMDex and 56 in the MDex group, received ≥ 1 dose of therapy (from January 2011 to February 2016). Hematologic response rate at 3 months was higher in the BMDex arm (79% v 52%; P = .002). Higher rates of very good partial or complete response rates (64% v 39%; hazard ratio [HR], 2.47; 95% CI, 1.30 to 4.71) and improved overall survival, with a 2-fold decrease in mortality rate (HR, 0.50; 95% CI, 0.27 to 0.90), were observed in the BMDex arm. Grade 3 and 4 adverse events (the most common being cytopenia, peripheral neuropathy, and heart failure) were more common in the BMDex arm, occurring in 20% versus 10% of cycles performed. CONCLUSION BMDex improved hematologic response rate and overall survival. To our knowledge, this is the first time a controlled study has demonstrated a survival advantage in AL amyloidosis. BMDex should be considered a new standard of care for AL amyloidosis.

In AL amyloidosis complete response (aCR) is defined as negative serum and urine immunofixation with normalized free light chain ratio (FLCR). However, achievement of low levels of involved FLC (iFLC) or difference between iFLC and uninvolved FLC (dFLC) are also relevant endpoints for treatment. We divided 434 consecutive patients with AL amyloidosis into five groups according to response 6 months after treatment initiation: aCR, iFLC

In amyloid light chain (AL) amyloidosis, a small B-cell clone, most commonly a plasma cell clone, produces monoclonal light chains that exert organ toxicity and deposit in tissue in the form of amyloid fibrils. Organ involvement determines the clinical manifestations, but symptoms are usually recognized late. Patients with disease diagnosed at advanced stages, particularly when heart involvement is present, are at high risk of death within a few months. However, symptoms are always preceded by a detectable monoclonal gammopathy and by elevated biomarkers of organ involvement, and hematologists can screen subjects who have known monoclonal gammopathy for amyloid organ dysfunction and damage, allowing for a presymptomatic diagnosis. Discriminating patients with other forms of amyloidosis is difficult but necessary, and tissue typing with adequate technology available at referral centers, is mandatory to confirm AL amyloidosis. Treatment targets the underlying clone and should be risk adapted to rapidly administer the most effective therapy patients can safely tolerate. In approximately one-fifth of patients, autologous stem cell transplantation can be considered up front or after bortezomib-based conditioning. Bortezomib can improve the depth of response after transplantation and is the backbone of treatment of patients who are not eligible for transplantation. The daratumumab+bortezomib combination is emerging as a novel standard of care in AL amyloidosis. Treatment should be aimed at achieving early and profound hematologic response and organ response in the long term. Close monitoring of hematologic response is vital to shifting nonresponders to rescue treatments. Patients with relapsed/refractory disease are generally treated with immune-modulatory drugs, but daratumumab is also an effective option.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-associated coronavirus disease 2019 (COVID-19) is primarily manifested as a respiratory tract infection, but may affect and cause complications in multiple organ systems (cardiovascular, gastrointestinal, kidneys, haematopoietic and immune systems), while no proven specific therapy exists. The challenges associated with COVID-19 are even greater for patients with light chain (AL) amyloidosis, a rare multisystemic disease affecting the heart, kidneys, liver, gastrointestinal and nervous system. Patients with AL amyloidosis may need to receive chemotherapy, which probably increases infection risk. Management of COVID-19 may be particularly challenging in patients with AL amyloidosis, who often present with cardiac dysfunction, nephrotic syndrome, neuropathy, low blood pressure and gastrointestinal symptoms. In addition, patients with AL amyloidosis may be more susceptible to toxicities of drugs used to manage COVID-19. Access to health care may be difficult or limited, diagnosis of AL amyloidosis may be delayed with detrimental consequences and treatment administration may need modification. Both patients and treating physicians need to adapt in a new reality.

Background Hereditary amyloidosis refers to a wide spectrum of rare diseases with different causative mutations in the genes of various proteins including transthyretin, apolipoprotein AI and AII, gelsolin, lysozyme, cystatin C, fibrinogen Aα-chain, β2-microglobulin, apolipoprotein CII and CIII. Case presentation Among hereditary amyloidosis subtypes, we describe here a specific case of Apolipoprotein AI amyloidosis (AApoAI), where the diagnosis began from an almost asymptomatic hepatomegaly followed by the development of primary hypogonadism. Baseline laboratory tests showed increased liver enzymes, while imaging tests revealed a suspected infiltrative liver disease. Patient underwent into liver biopsy and histological examination detected the presence of periodic acid-Schiff (−) and Congo-red (+) amorphous eosinophilic material within normal liver tissue. In the typing of amyloid by immunoelectron microscopy, the liver appeared heavily infiltrated by anti-apoAI (+) amyloid fibrils. Gene sequencing and mutational analysis revealed a single-base mutation at position c.251 T > C resulting in an amino acid substitution from leucine to proline in the mature ApoAI protein. This amino acid change led to lower cleavage and ApoAI deposition into the involved organs. Few years later, our patient remaining without treatment, came with symptoms consistent with primary hypogonadism but testicular involvement with ApoAI deposits could not be proven since the patient refused testicular biopsy. Based on this case, we recap the diagnostic challenges, the clinical manifestations, and the potential treatment options for this indolent hereditary amyloidosis subtype. Conclusions This case-report enlarges the clinical picture of ApoAI-driven disease and its complex genetic background and in parallel suggests for a more systematic approach in any case with strong suspicion of hereditary amyloidosis.

Background: The aim of the present prospective study (ClinicalTrials.gov Identifier: NCT02111538) was to assess the prognostic value of phase angle (PhA), derived from bioimpedance vectorial analys...

Systemic immunoglobulin light chain (AL) amyloidosis is an aging-associated protein misfolding and deposition disease. This condition is caused by a small and otherwise indolent plasma cell (or B cell) clone secreting an unstable circulating light chain, which misfolds and deposits as amyloid fibrils possibly leading to progressive dysfunction of affected organs. AL amyloidosis can occur in the typical setting of other, rarer forms of systemic amyloidosis and can mimic other more prevalent conditions of the elderly. Therefore, its diagnosis requires a high degree of clinical suspicion and reliable diagnostic tools for accurate amyloid typing, available at specialized referral centers. In AL amyloidosis, frailty is dictated by the type and severity of organ involvement, with heart involvement being the main determinant of morbidity and mortality. Still, given a similar disease stage, elderly patients with AL amyloidosis are often an even frailer group, due to significant comorbidities, associated disability and polypharmacotherapy, socioeconomic restrictions, and limited access to clinical trials. Recent improvements in the use of biomarkers for early diagnosis, risk stratification and response monitoring, the flourishing of novel, effective anti-plasma cell therapies developed against multiple myeloma and adapted to treat AL amyloidosis, and possibly the introduction of anti-amyloid therapies are rapidly changing the clinical management of this disease and are reflected by improved outcomes. Of note, hematologic and organ responses in elderly patients with AL amyloidosis do translate in better outcome, advocating the importance of treating these patients and striving for a rapid response to therapy also in this challenging clinical setting.

TO THE EDITOR: Chemotherapy for light chain (AL) amyloidosis is based on combinations developed for multiple myeloma.[1][1] A better understanding of susceptibility of the AL underlying clone to specific types of treatments[2][2] and the ability to identify cytogenetic patterns with different

We analyzed 44 patients with newly diagnosed systemic light-chain amyloidosis (AL) and del 17p, a rare finding in AL. Predictors of overall and progression-free survival were cardiac involvement at diagnosis and hematologic response to therapy, respectively. Median survivals of patients with > 50% and ≤ 50% del 17p plasma cells were 28 and 52 months (P = .08). Introduction: Deletion 17p (del 17p) portends a poor prognosis in myeloma, but its significance in light-chain amyloidosis is unknown. Patients and Methods: We identified patients with light-chain amyloidosis and del 17p at diagnosis, and analyzed presenting characteristics, treatments, and clinical outcomes. All had baseline biopsy results showing amyloid and serologic and marrow studies, including standard fluorescence in-situ hybridization determinations of del 17p using commercial probes. Consensus criteria for hematologic and organ involvement, progression, and response were used. Kaplan-Meier (log rank) analyses and Cox regression analysis of baseline variables were used to identify predictors of overall and progression-free survival (PFS). Six-month landmark analyses were performed to assess the impact of treatment-related variables. Results: We identified 44 patients from 7 countries with median marrow and del 17p plasma cells of 22% (range, 3%–100%) and 30% (2%–93%). Ninety-five percent had cardiac involvement, including 44% stage III. Two-thirds of the patients initially received bortezomib-based therapy. Forty-nine percent of patients experienced complete response or very good partial response, with median time to best response of 4 months (range, 1–28 months). Median overall survival and PFS were 49 and 32 months. Cardiac stage and hematologic response were the key predictors of outcomes. Patients with > 50% and ≤ 50% del 17p in clonal plasma cells had median survivals of 28 and 52 months, respectively (P = .08). In landmark analyses, only hematologic response predicted both overall survival and PFS. Conclusion: Cardiac stage, hematologic response, and del 17p percentage impact outcomes in these cases. Emphasis should be placed on optimizing supportive care and achieving a deep hematologic response.

Light chain amyloidosis (AL amyloidosis) is a disease in which monoclonal immunoglobulin light chains, produced by clonal plasma cells are deposited extracellularly in the form of misfolded, insoluble protein complexes known as amyloid. This disease is a heterogeneous condition, due to the organ tropism, which varies among patients. Heart involvement prevails (80% of patients), whereas kidneys, liver and nervous system may be also involved. To diagnose AL amyloidosis, amyloid should be detected by staining tissue samples with Congo red, and the amyloid typing should reveal the immunoglobulin light chain character of the amyloid fibrils. The therapy usually focuses on the elimination of clonal plasma cells. Assigning the patient to the proper risk group (low, intermediate, high) is crucial. For younger patients of the low-risk group, high-dose melphalan with autologous hematopoietic stem cell transplantation (auto-HSCT) with optional bortezomib-based consolidation treatment should be considered. For the most numerous (70% of patients), intermediate-risk group, MDex (melphalan, dexamethasone), as well as bortezomib-based therapies should be given. Patients in the high-risk group should undergo a chemotherapy with reduced intensity. Refractory disease can be treated with IMIDs (immunomodulatory drugs), as well as new-generation proteasome inhibitors, bendamustine and monoclonal antibodies.

Light chain (AL) amyloidosis is the most common form of amyloidosis involving the kidney. It is characterized by albuminuria, progressing to overt nephrotic syndrome and eventually end-stage renal failure if diagnosed late or ineffectively treated, and in most cases by concomitant heart involvement. Cardiac amyloidosis is the main determinant of survival, whereas the risk of dialysis is predicted by baseline proteinuria and glomerular filtration rate, and by response to therapy. The backbone of treatment is chemotherapy targeting the underlying plasma cell clone, that needs to be risk-adapted due to the frailty of patients with AL amyloidosis who have cardiac and/or multiorgan involvement. Low-risk patients (∼20%) can be considered for autologous stem cell transplantation that can be preceded by induction and/or followed by consolidation with bortezomib-based regimens. Bortezomib combined with alkylators, such as melphalan, preferred in patients harboring t(11;14), or cyclophosphamide, is used in most intermediate-risk patients, and with cautious dose escalation in high-risk subjects. Novel, powerful anti–plasma cell agents, such as pomalidomide, ixazomib, and daratumumab, prove effective in the relapsed/refractory setting, and are being moved to upfront therapy in clinical trials. Novel approaches based on small molecules interfering with the amyloidogenic process and on antibodies targeting the amyloid deposits gave promising results in preliminary uncontrolled studies, are being tested in controlled trials, and will likely prove powerful complements to chemotherapy. Finally, improvements in the understanding of the molecular mechanisms of organ damage are unveiling novel potential treatment targets, moving toward a cure for this dreadful disease. Keywords: amyloidosis, prognosis, treatment

Systemic light chain amyloidosis is a rare and life-threatening disorder, for which accurate risk stratification is crucial. Current cardiac staging systems (MAYO2004, MAYO3b, and MAYO2012) are mainly based on biomarkers, which have uncertain reliability in the context of atrial fibrillation, arrhythmia or pacemaker stimulation as well as renal insufficiency. We compared the performance of the established staging systems with particular regard to these comorbidities in 1,224 patients with systemic light chain amyloidosis diagnosed at our center from July 2002 until March 2017. We first characterized the subsets with an estimated glomerular filtration rate50 mL/min/1.73 m

Introduction: In systemic light chain (AL) amyloidosis free light chains produced by clonal plasma cells form amyloid fibrils that are deposited in tissues and organs resulting in organ dysfunction. Cardiac involvement by AL amyloidosis is frequent and the most critical prognostic factor. Prognostic evaluation in AL is based on cardiac biomarkers and patients with very high levels of both NTproBNP (≥8500 pg/ml) and cardiac Troponins (Mayo stage 3B) are at high-risk of early death and have a median survival of just 3-6 months in most series. The outcome of stage 3B patients has not improved despite the introduction of bortezomib-based therapies and there is an urgent need for new non-toxic treatments which can also lead to rapid and deep hematologic responses. Daratumumab, an IgGκ monoclonal antibody targeting CD38, has proved highly effective either alone or in combination with bortezomib, cyclophosphamide and dexamethasone and with good tolerability in AL amyloidosis patients. Methods: EMN22 is a phase 2, open-label, multicenter study planning to enroll 40 newly diagnosed patients with stage 3B AL amyloidosis from 5 sites in Greece, the Netherlands, Italy and France. Eligible patients should have high-sensitivity troponin T (hsTnT) >54 pg/mL and NT-proBNP ≥8500 pg/mL. Primary treatment consists of daratumumab monotherapy, initially administered intravenously at 16 mg/mL, and since February 2020 administered subcutaneously at a fixed dose of 1800 mg; weekly during Cycles 1-2, every 2 weeks for Cycles 3-6 and every 4 weeks thereafter. Patients who do not achieve a hematologic VGPR or better by Cycle 4 may also receive at investigator's discretion weekly bortezomib and low dose dexamethasone. Treatment continues until disease progression according to major organ deterioration progression-free survival criteria, start of new therapy, or for a maximum of 2 years. The current analysis includes patients who started treatment at least 3 months prior to the cut-off date (16 June 2021). Results: Among 17 patients included in this analysis, 9 (53%) are still on treatment and 8 (47%) have discontinued, either due to an adverse event (n=5, 29%), or due to disease progression (n=3, 18%). Most patients were males (n=12, 71%) and median age was 65 years (range 45-84). Eastern Cooperative Oncology Group performance status was 1 for 5 (29%), 2 for 11 patients (65%), and 3 for one patient (6%). Eight (47%) patients had New York Heart Association (NYHA) class II symptoms, and 9 (53%) NYHA class IIIA. At screening, median NT-proBNP was 13,994 pg/mL (range 8,816-40,428), median hsTnT 119.1 pg/mL (range 59.8-692) and median difference of involved to uninvolved free light chains (dFLC) was 553 mg/L (range 49-2823). Apart from the heart, the median number of other organs involved was 1 (range 0-5), with nervous system (n=8, 47%) and kidneys (n=7, 41%) most commonly affected. The median number of daratumumab infusions was 13 and the median duration of therapy with daratumumab therapy was 3.7 months. Overall, 5 patients (29%) started additional treatment with bortezomib after completion of 3 cycles of daratumumab monotherapy. All 17 patients had at least one treatment-emergent adverse event. Eleven patients (65%) had a serious adverse event (SAE); 9 (53%) had at least one cardiac-related serious adverse event, and one SAE (fatigue) was related to bortezomib. Six patients (35%) suffered a fatal SAE: sepsis (n=1), sudden death (n=3), and cardiac failure (n=2). Most common grade 3 or 4 non-serious AEs were peripheral edema (n=4, 24%), dyspnea (n=3, 18%), and atrial fibrillation (n=2, 12%), and only one non-serious neutropenia grade 3 was related to daratumumab. The overall response rate was 71%, with 3 patients (18%) achieving CR, 6 (35%) VGPR, and 3 (18%) a PR, with a combined CR+VGPR rate of 53% (9/17). One-, two-, and three-month overall response rates were 65% (n=11), 71% (n=12), and 71% (n=12), and the median time to first response was 7 days while the median time to at least VGPR was 14 days. The 6-month and 12-month OS rate were 70% and 53% respectively (median OS has not been reached). Conclusions: In this prospective phase 2 study, in patients with high-risk AL amyloidosis (stage 3B), daratumumab monotherapy shows a favorable safety profile and induced very rapid and deep hematologic responses with a median time to first response of 7 days, with 53% of the patients achieving VGPR or better and a 6-month OS of 70%. Figure 1 Figure 1. Disclosures Kastritis: Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Takeda: Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Genesis Pharma: Honoraria. Minnema: Jansen-Cilag: Consultancy; Kite/Gilead: Consultancy; Alnylam: Consultancy; Celgene: Other: Hospitality; BMS: Honoraria. Dimopoulos: Amgen: Honoraria; Beigene: Honoraria; BMS: Honoraria; Takeda: Honoraria; Janssen: Honoraria. Huart: Janssen: Honoraria. Leonidakis: Health Data Specialists: Current Employment. Manousou: Health Data Specialists: Current Employment. Sonneveld: Amgen: Consultancy, Honoraria, Research Funding; Celgene/BMS: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; SkylineDx: Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding. Palladini: Pfizer: Honoraria; Siemens: Honoraria; Janssen Global Services: Honoraria, Other: advisory board fees.

Introduction: Renal light chain (AL) amyloidosis typically manifests as proteinuria with or without renal failure and is associated with a risk of progression to renal replacement therapy (RRT). A significant reduction in circulating amyloidogenic light chain is needed to achieve a renal response. Current renal response criteria are binary defining a renal response as >30% reduction in 24-h proteinuria without worsening estimated glomerular filtration rate (eGFR). Several studies suggest that greater reduction in proteinuria following successful therapy improves renal and overall survival. Methods: AL amyloidosis patients diagnosed between 2010 to 2015, achieving at least hematological partial response (hemPR) to therapy and with renal involvement (defined as 24-h non-selective proteinuria >0.5 g/24-h) were included. Four predefined renal response categories were formulated based on reduction level in pretreatment 24-h proteinuria in the absence of renal progression (≥25% decrease in eGFR): renal complete response (renCR, 24-h proteinuria ≤200 mg/24-h); renal very good partial response (renVGPR, >60% reduction in 24-h proteinuria); renal partial response (renPR, 31-60% reduction in 24-proteinuria); and renal no response (renNR, 30% or less reduction). Renal response was assessed at landmark (6-, 12-, and 24 months from treatment initiation) and as best renal response. Graded renal responses were assessed as predictors for time from diagnosis to RRT and overall survival. Results: Seven hundred and thirty-seven patients were included. The median age was 63. The breakdown of renal stage was: I, 34%; II, 52%; and III, 14%. Eighty percent of patients received 1 line of therapy within 12 months of their diagnosis. Bortezomib-based therapy was given to 60% of the patients; 28% received autologous stem cell transplantation (ASCT) as their first line therapy. Hematological CR was achieved in 44% of patients, followed by hematological very good partial response (38%) and hemPR (18%). RRT was required during follow-up in 15% of patients (n=108) with a median time from diagnosis to RRT of 18 (IQR 6-43) months. Twenty-eight percent of the patients died. The median follow-up of the surviving patients was 69 months (IQR 56-86). Reduction in 24-h proteinuria from baseline improved over time with a median reduction of 34%, 50% and 71% at 6-month, 12-month, and 24-months, respectively. At best response, renCR, renVGPR, renPR and renNR were achieved in 27% (n=199), 34% (n=247), 15% (n=112) and 24% (n=179) of patients, respectively. The median time to best renal response among renal responders was 17 (IQR 8-31) months, longer for renCR (23 months, IQR 10-40) compared to renVGPR (16 months, IQR 9-27) or renPR (11 months, IQR 6-19). A renal response as early as 6 months after therapy initiation was able to predict time to RRT with an increase in RRT risk with lower level of renal response at that time point (5-year RRT risk 0%, 3%, 9% and 16% for renCR, renVGPR, renPR and renNR, respectively, P Conclusions: We validated new graded renal response criteria based on reduction in 24-h proteinuria. These 4-level renal response criteria highlight the importance of achieving a deep renal response to improve renal and overall survival. These findings will allow clinicians to make decisions on therapy changes or augmentation based on response depth as early as 6-months, before irreversible renal failure develops. Figure 1 Figure 1. Disclosures Palladini: Janssen Global Services: Honoraria, Other: advisory board fees; Siemens: Honoraria; Pfizer: Honoraria. Milani: Celgene: Other: Travel support; Janssen-Cilag: Honoraria. Schönland: Sanofi: Research Funding; Prothena: Honoraria, Other: Travel grants; Janssen: Honoraria, Other: Travel grants, Research Funding; Takeda: Honoraria, Other: Travel grants; Pfizer: Honoraria. Hegenbart: Akcea: Honoraria; Alnylam: Honoraria; Janssen: Consultancy, Research Funding; Prothena: Research Funding; Pfizer: Consultancy, Honoraria. Dispenzieri: Oncopeptides: Consultancy; Alnylam: Research Funding; Sorrento Therapeutics: Consultancy; Pfizer: Research Funding; Takeda: Research Funding; Janssen: Consultancy, Research Funding. Kumar: Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Consultancy; Carsgen: Research Funding; Beigene: Consultancy; Novartis: Research Funding; Bluebird Bio: Consultancy; Amgen: Consultancy, Research Funding; Roche-Genentech: Consultancy, Research Funding; Takeda: Consultancy, 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; Tenebio: Research Funding; Antengene: Consultancy, Honoraria; BMS: Consultancy, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding. Kastritis: Amgen: Consultancy, Honoraria, Research Funding; Genesis Pharma: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Honoraria; Pfizer: Consultancy, Honoraria, Research Funding. Dimopoulos: Takeda: Honoraria; Janssen: Honoraria; Beigene: Honoraria; BMS: Honoraria; Amgen: Honoraria. Liedtke: Takeda: Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; 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; 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; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; Alnylam: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees. Witteles: Pfizer: Honoraria, Research Funding; Alnylam: Honoraria, Research Funding; Eidos: Research Funding. Sanchorawala: Pfizer: Honoraria; Takeda: Research Funding; Celgene: Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees; Regeneron: Membership on an entity's Board of Directors or advisory committees; 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; Oncopeptide: Research Funding; Karyopharm: Research Funding; Sorrento: Research Funding; Caelum: Membership on an entity's Board of Directors or advisory committees, Research Funding. Landau: Takeda, Janssen, Caelum Biosciences, Celgene, Pfizer, Genzyme: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Genzyme: Honoraria. Cibeira: Celgene: Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Akcea: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Wechalekar: Caelum Biosciences: Other: Clinical Trial Funding; Amgen: Research Funding; Janssen: Consultancy; Celgene: Honoraria; Takeda: Honoraria; Alexion, AstraZeneca Rare Disease: Consultancy. Gertz: Akcea Therapeutics, Alnylam Pharmaceuticals Inc, Prothena: Consultancy; Aurora Biopharma: Other: Stock option; Ionis Pharmaceuticals: Other: Advisory Board; AbbVie Inc, Celgene Corporation: Other: Data Safetly & Monitoring; Akcea Therapeutics, Ambry Genetics, Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Karyopharm Therapeutics, Pfizer Inc (to Institution), Sanofi Genzyme: Honoraria.

Introduction In patients affected by monoclonal gammopathies, tumoral B cells or plasma cells secrete a monoclonal antibody (termed M protein), which can be used to track the presence of the tumor itself. Moreover, the M protein can directly cause potentially life-threatening organ damage, which is dictated by the specific, patient's unique clonal light and/or heavy chain, as in patients affected by immunoglobulin light chain (AL) amyloidosis. Yet, the current paradigm in the diagnosis and management of these conditions treats the M protein as a simple tumor biomarker to be identified/quantified. Patients' specific M protein sequences remain mostly undefined and molecular mechanisms underlying M-protein related clinical manifestations are largely obscure. Methods By combining the unbiased amplification of expressed immunoglobulin genes with long-read, single molecule real-time DNA sequencing and bioinformatics analyses, we have established a method to identify the full-length sequence of the variable region of expressed immunoglobulin genes and to rank the obtained sequences based on their relative abundance, thus enabling the identification of the full-length variable sequence of M protein genes from a high number of patients analysed in parallel. Results The assay, which we termed Single Molecule Real-Time Sequencing of the M protein (SMaRT M-Seq), has undergone an extensive technical validation. Sequencing of contrived bone marrow samples generated through serial dilutions of plasma cell lines into control bone marrow, as well as sequencing of bona fide bone marrow samples from AL patients and comparison with gold-standard techniques of immunoglobulin gene sequencing showed: 100% sequence-accuracy at the individual base-pair level; High repeatability (CV Noteworthy, SMaRT M Seq was applied to a cohort of 86 consecutive patients with AL amyloidosis (17 κ and 69 λ; median BMPC infiltration 9%, IQR 6-13%; median dFLC 176 mg/L, IQR 75-370 mg/L), including cases with small clonal burden and M protein which was undetectable with conventional M protein studies. A full-length sequence of the variable region of the clonal light chain was obtained in all patients (median molecular clonal size of 88.3%, IQR: 70.7 - 93%). The most common κ germline genes were IGKV1-33 and IGKV4-01 (24% each of the 17 κ AL patients), and the most common λ germline genes were IGLV6-57 (26% of the 69 λ AL patients), IGLV2-14 (17%), IGLV3-01 (17%) and IGLV1-44 (10%). The most frequent λ and κ germline genes together (IGLV6-57, IGLV2-14, IGLV3-01, IGLV1-44, IGKV1-33 and IGKV4-01) accounted for 66% of all the clones. Germline gene usage correlated with selected clinical features. Sequence information was then exploited to improve mass spectrometry-based amyloid typing on fat pad aspirates and to enable the sensitive detection of clonotypic sequences using short-read DNA sequencing of the involved light chain isotype (up to 10 -7 dilution). Conclusions We have established SMaRT M-Seq as a novel valuable assay to reliably identify the full-length variable sequence of M proteins. SMaRT M-Seq has undergone extensive technical validation, showing high accuracy, repeatability and sensitivity. The latter is determined by the number of reads analyzed per sample. This is in turn dictated by the sequencing output of the employed sequencing platform, and by the number of pooled samples analyzed in a given sequencing round, thus proving to be scalable. Even when analyzing multiple samples on a sequencing platform with low sequencing output, the achieved sensitivity of SMaRT M-Seq significantly exceeds the requirements for the identification of clonal B cells/plasma cells in patients with AL amyloidosis. Sequencing disease-associated M proteins from large cohorts of patients has the potential to uncover molecular mechanisms of M protein-related clinical manifestations which have remained largely unexplored so far, and could enable approaches of personalized medicine for the sensitive detection of patients' specific M proteins at diagnosis and after anti-clonal therapy. Disclosures Milani: Celgene: Other: Travel support; Janssen-Cilag: Honoraria. Fazio: Janseen: Honoraria. Petrucci: GSK: Honoraria, Other: Advisory Board; Amgen: Honoraria, Other: Advisory Board; Takeda: Honoraria, Other: Advisory Board; BMS: Honoraria, Other: Advisory Board; Janssen-Cilag: Honoraria, Other: Advisory Board; Celgene: Honoraria, Other: Advisory Board; Karyopharm: Honoraria, Other: Advisory Board. Palladini: Pfizer: Honoraria; Siemens: Honoraria; Janssen Global Services: Honoraria, Other: advisory board fees. Nuvolone: Janssen-Cilag: Honoraria; Oncopeptides, Inc.: Research Funding.

Background: Within the spectrum of monoclonal gammopathies, there are various subgroups with unique biological and clinical profiles. Namely, the presence of multiple myeloma (MM) and light-chain amyloidosis (AL) pts with MGUS-like phenotype has been hypothesized, but the criteria to identify this subgroup are poorly defined and lack clinical validation. Aim: Develop an algorithm based on a large flow cytometry dataset across the spectrum of monoclonal gammopathies, for automated identification of MM and AL pts with MGUS-like phenotype. Methods: This study included 5,114 pts with monoclonal gammopathies and available flow cytometry data on the frequency of bone marrow (BM) plasma cells (PC) and the percentages of normal and clonal PC within the BM PC compartment, at diagnosis. An algorithm to classify pts with MGUS-like phenotype was developed based on these three parameters, obtained from 548 MGUS, 393 smoldering MM (SMM) and 2,011 MM pts. Newly diagnosed MM pts were homogeneously treated according to the GEM2000 (n = 486), GEM2005MENOS65 (n = 330), GEM2005MAS65 (n = 239), GEM2010MAS65 (n = 230), GEM2012MENOS65 (n = 450) and CLARIDEX (n = 276) protocols. The prognostic value of the MGUS-like phenotype was validated in 96 SMM pts studied in Arkansas and 1,859 MM pts treated outside clinical trials in Czech Republic. The clinical significance of the algorithm was investigated in two independent series of Spanish (n = 102) and Italian (n = 105) AL pts. Results: The frequency of BM PC and of normal and clonal PC within the BM PC compartment were used to plot MGUS, SMM and MM pts in a principal component analysis (PCA). Lines defining 1.5 standard deviations of MGUS and MM pts were used as reference to classify each of the 5,114 cases. Once plotted against the dataset, individual pts were classified as MGUS-, intermediate- or MM-like, if their location in the PCA fell inside the MGUS, the overlapping or the MM reference lines, respectively. In the training SMM series, patient classification into MGUS-, intermediate- and MM-like phenotype resulted in significantly different rates of disease progression (0%, 54% and 66% at 5y, respectively; P < .001). These results were validated in the Arkansas series (8%, 27% and 71% at 5y, respectively; P < .001). Only 5% of SMM pts with high-risk disease according to Mayo or PETHEMA criteria had an MGUS-like phenotype, and these had virtually no risk of progression at 5y. In the training MM series, pts with MGUS-like phenotype showed significantly longer progression free (PFS) and overall survival (OS) vs the remaining pts. Median PFS was 10y vs 3y (hazard ratio [HR]: 0.46, P < .001) and median OS was not reached (NR) vs 6.5y (HR: 0.48, P < .001), respectively. These results were validated in the Czech Republic series with significant differences in PFS (HR: 0.45, P < .001) and OS (HR: 0.38, P < .001) between MGUS-like vs other MM pts. MGUS-like classification in the training MM series retained independent prognostic value in multivariate analyses of PFS (HR: 0.48, P < .001) and OS (HR: 0.54, P = .033), together with ISS, LDH, cytogenetics, induction regimen, transplant-eligibility and complete remission (CR). MGUS-like pts showed similar PFS (P = .932) and OS (P = .285) regardless of having standard vs high risk cytogenetics. Notably, MGUS-like transplant-eligible MM pts treated with proteasome inhibitors, immunomodulatory drugs and corticoids during induction showed PFS and OS rates at 5y of 86% and 96%, respectively. Differences in PFS among MGUS-like MM pts achieving ≥CR vs Classification of AL pts into the MGUS-, intermediate- and MM-like phenotype resulted in significantly different PFS in the Spanish (median of 28, 20 and 1 months, respectively; P = .001) and Italian (median 32, 11 and 3 months, respectively; P < .001) cohorts. Conclusions: We developed an algorithm that can be readily installed in clinical flow cytometry software, and requires three parameters that are routinely assessed at screening. Patient' automated classification using the algorithm was validated in large series across the spectrum of monoclonal gammopathies. Because pts with MGUS-like phenotype have a distinct clinical behavior, their identification could become part of the diagnostic workup in SMM, MM and AL. Disclosures Cedena: Janssen, Celgene and Abbvie: Honoraria. Milani: Celgene: Other: Travel support; Janssen-Cilag: Honoraria. Cordon: Cytognos SL: Research Funding. Oriol: Takeda: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Janssen: Consultancy. de la Rubia: Amgen, Bristol Myers Squibb,: Honoraria, Speakers Bureau; Celgene, Takeda, Janssen, Sanofi: Honoraria; Ablynx/Sanofi: Consultancy; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; AbbVie: Consultancy; Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel Accommodations; GSK: Consultancy; Takeda: Consultancy; Sanofi: Membership on an entity's Board of Directors or advisory committees. De Arriba: Amgen: Consultancy, Honoraria; Glaxo Smith Kline: Consultancy, Honoraria; BMS-Celgene: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau. Cabañas: Janssen: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Sanofi: Honoraria. Gonzalez De La Calle: Celgene-BMS, Janssen, Amgen: Honoraria. Rodríguez-Otero: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Regeneron: Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel and other expenses. Hajek: Pharma MAR: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Jimenez-Zepeda: BMS, Amgen, Takeda, Janssen: Honoraria. Palladini: Janssen Global Services: Honoraria, Other: advisory board fees; Pfizer: Honoraria; Siemens: Honoraria. Rosinol: Janssen, Celgene, Amgen and Takeda: Honoraria. Bladé Creixenti: Janssen, Celgene, Takeda, Amgen and Oncopeptides: Honoraria. Martínez-López: Janssen, BMS, Novartis, Incyte, Roche, GSK, Pfizer: Consultancy; Roche, Novartis, Incyte, Astellas, BMS: Research Funding. Mateos: Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Regeneron: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene - Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sea-Gen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bluebird bio: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria; Oncopeptides: Honoraria. San-Miguel: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, GlaxoSmithKline, Janssen, Karyopharm, Merck Sharpe & Dohme, Novartis, Regeneron, Roche, Sanofi, SecuraBio, Takeda: Consultancy, Other: Advisory board. Paiva: Bristol-Myers Squibb-Celgene, Janssen, and Sanofi: Consultancy; Adaptive, Amgen, Bristol-Myers Squibb-Celgene, Janssen, Kite Pharma, Sanofi and Takeda: Honoraria; Celgene, EngMab, Roche, Sanofi, Takeda: Research Funding.

Shen and coworkers elegantly validated a composite hematologic and organ response (CHOR) model in 388 patients with light chain (AL) amyloidosis treated between 2008 and 2019 at the Union Medical C...

The most common form of systemic amyloidosis in Western countries is light chain amyloidosis. It is characterized by the deposition of a misfolded light chain in target organs. This amyloid precursor is produced by a usually small but dangerous B-cell clone. Areas covered: This review examines the diagnostic workup of this disease and current knowledge of biomarker-based staging systems. In addition, a risk-adapted treatment approach is presented, as well as an overview of the new treatment strategies. Expert commentary: The cornerstone of treatment is rapid and effective chemotherapy targeting the underlying plasma cell clone. In the near future, this will probably be associated with novel approaches targeting other steps of the amyloid cascade that result in amyloid deposits. Currently available effective treatments can alter its natural history if an early diagnosis is made. The availability of novel, more powerful drugs, and identification of the cellular mechanisms of organ damage and of the characteristics of the amyloidogenic plasma-cell clone all give grounds to hope that a dramatic improvement in the treatment of this disease will be seen in the near future.

Background Amyloid light chain (AL) amyloidosis is a plasma cell disease characterized by the production of light chains that form amyloid fibril deposits in tissues leading to organ dysfunction and death. Cytogenetic abnormalities are common in patients (pts) with AL amyloidosis, and some are associated with poor outcomes. The ANDROMEDA study (NCT03201965) showed that addition of daratumumab to bortezomib, cyclophosphamide, and dexamethasone (D-VCd) was superior to VCd alone, with higher rates of hematologic complete response (CR) and an acceptable safety profile. Here, we explore outcomes in pts with cytogenetic abnormalities in ANDROMEDA. Methods Pts (N=388) with newly diagnosed AL amyloidosis were randomized 1:1 to D-VCd or VCd for 6 28-day cycles; thereafter, pts in the D-VCd group received daratumumab alone every 4 weeks for ≤24 total cycles. The proportion of pts with t(11;14), amp1q21, del13q14, and del17p13 based on fluorescence in situ hybridization and/or karyotyping was calculated. Overall (at any time during the study) hematologic CR rate and cardiac and renal response rates at 6 months were evaluated for each subgroup and summarized with descriptive statistics. Within each treatment group, hematologic response among pts with and without t(11;14) or amp1q21 was compared. Results 321 pts had testing (D-VCd, n=155; VCd, n=166). In the D-VCd and VCd groups, respectively, 42.9% vs 40.0% had t(11;14), 25.4% vs 20.3% had amp1q21, 16.2% vs 22.0% had del13q14, and 6.7% vs 6.1% had del17p13. At a median follow-up of 20.3 months, the hematologic CR rate was higher with D-VCd vs VCd across all 4 cytogenetic subgroups, ranging from 56–72% vs 0–14% (P Conclusion Consistent with the primary analysis of ANDROMEDA, subgroup analyses showed the benefit of D-VCd vs VCd, irrespective of cytogenetic abnormalities. Rates of deep hematologic response were not impacted by t(11;14) and amp1q21 in patients treated with D-VCd, but were generally lower in VCd-treated patients with t(11;14) and amp1q21. These findings further support the use of D-VCd as standard of care in pts with newly diagnosed AL amyloidosis, regardless of cytogenetic abnormalities.

In 2012, the International Society of Amyloidosis (ISA) established the criteria for assessment of haematologic response to treatment in light chain (AL) amyloidosis [1]. The criteria were identifi...

The validated criteria of hematologic response in light-chain (AL) amyloidosis are based on the measurement of circulating free light chains (FLCs). Patients with a difference between involved and uninvolved FLC (dFLC)50 mg/L cannot be assessed for response and are excluded from clinical trials. We compared the clinical characteristics and outcome of 203 newly diagnosed patients with dFLC50 mg/L (low dFLC) with 866 patients with measurable dFLC (high dFLC) evaluated between 2004 and 2015. Heart involvement was significantly less common and less advanced in the low-dFLC group (43% vs 83% and Mayo stage III 45% vs 15%, both