Normal Free Light Chain Ratio Research Articles

Progression free survival of myeloma patients who become IFE-negative correlates with the detection of residual monoclonal free light chain (FLC) by mass spectrometry

Deeper responses are associated with improved survival in patients being treated for myeloma. However, the sensitivity of the current blood-based assays is limited. Historical studies suggested that normalisation of the serum free light chain (FLC) ratio in patients who were negative by immunofixation electrophoresis (IFE) was associated with improved outcomes. However, recently this has been called into question. Mass spectrometry (MS)-based FLC assessments may offer a superior methodology for the detection of monoclonal FLC due to greater sensitivity. To test this hypothesis, all available samples from patients who were IFE negative after treatment with carfilzomib and lenalidomide-based induction and autologous stem cell transplantation (ASCT) in the Myeloma XI trial underwent FLC-MS testing. FLC-MS response assessments from post-induction, day+100 post-ASCT and six months post-maintenance randomisation were compared to serum FLC assay results. Almost 40% of patients had discordant results and 28.7% of patients with a normal FLC ratio had residual monoclonal FLC detectable by FLC-MS. FLC-MS positivity was associated with reduced progression-free survival (PFS) but an abnormal FLC ratio was not. This study demonstrates that FLC-MS provides a superior methodology for the detection of residual monoclonal FLC with FLC-MS positivity identifying IFE-negative patients who are at higher risk of early progression.

B-371 Two Cases of Multiple Myeloma Achieving Complete Remission But Presenting Residual M-protein by the EXENT® Solution

Abstract Background Disappearance of the monoclonal component is a condition for achieving complete response (CR), which requires confirmation by bone marrow biopsy for the absence of clonal plasma cells. Electrophoretic methods used for monitoring these patients lack sufficient sensitivity to identify low-level M-protein, potentially missing the presence of serological residual disease once the tests become negative. The EXENT® solution (in development by The Binding Site, part of Thermo Fisher scientific) uses matrix-assisted laser-desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS) for the identification and quantification of M-proteins. The technique offers high sensitivity and specificity for identifying and tracking M-proteins. The aim of this study is to determine whether the superior analytical sensitivity of mass spectrometry conveys any clinical benefit to patient monitoring. Methods We present two multiple myeloma patients seen during routine practice. Baseline and longitudinal samples were available. Serum samples were retrospectively analysed with the EXENT® solution. Briefly, diluted samples were separately incubated with antisera specific for IgG, IgA, IgM, total-κ and total-λ conjugated to paramagnetic beads. Purified immunoglobulins were reduced and eluted from the beads, the solution mixed with matrix, spotted onto MALDI plates, and acquired by MALDI-TOF-MS to determine mass-to-charge (m/z), isotype and concentration of the M-proteins. Results were compared to serum protein electrophoresis (SPE) and free light chains (FLC; Freelite, The Binding Site). The EXENT solution responses were modelled on those from the International Myeloma Working Group. CR by MS refers to absence of the original monoclonal peak during follow-up. Results Case 1 is a 68-year-old white male presenting with 11.7 g/L monoclonal IgGκ on SPE and abnormal FLC ratio (3.06). After initiating therapy, FLC ratio normalized at month 2, whereas SPE became negative at month 8, at which time a CR was confirmed. The patient stayed in remission for over two-and-a-half years before relapsing at month 40, as determined by re-appearance of the M-protein on SPE (2.20 g/L). The EXENT solution also identified an IgGκ peak at baseline (m/z = 11629, 11.9 g/L). The peak remained present until month 19, disappeared for over a year, then reemerged at month 36 (0.39 g/L) to indicate progression. Thus, the EXENT solution identified the presence of residual M-protein (<1 g/L) for an additional eleven months after standard monitoring methods indicated CR; and recognized relapse from CR four months before SPE.Case 2 is a 76-year-old Asian male presenting with 32.9 g/L monoclonal IgGλ on SPE and normal FLC ratio (0.43). The EXENT solution reported an IgGλ peak (m/z = 11250, 44.3 g/L) at this time. SPE became negative ten months after starting treatment; and identified relapse from CR one year after. The EXENT solution remained positive throughout and was the only method detecting low-level M-protein (≤1.25 g/L) during the 1-year remission period. Conclusion EXENT demonstrates a potentially superior performance over electrophoretic methods for identifying residual serological disease during monitoring; and shows potential as a serum biomarker of early relapse in myeloma. The improved sensitivity of MS suggests it may delay and, in some cases, avoid the need for invasive methods to determine response to therapy.

Kappa Free Light Chain Drift Prompts the Need for a New Upper Limit of Normal Free Light Chain Ratio to Avoid an Epidemic of Kappa Light Chain Monoclonal Gammopathy of Undermined Significance.

Multiple laboratory tests are employed for detection of monoclonal proteins in patients and include serum protein electrophoresis (SPEP), immunofixation electrophoresis, free light chain (FLC) immunoassay, and mass spectrometry (Mass-Fix). Recently, reports on a drift in FLC quantitation results have been brought to light. We studied a cohort of 16 887 patients whose sera were tested for a monoclonal protein by a FLC assay, serum protein electrophoresis, and Mass-Fix. This is a retrospective study designed to assess the impact of a drift on the performance of FLC ratio (rFLC) in groups of patients with and without detectable plasma cell disorders (PCDs). The results demonstrated that 63% of patients with monoclonal protein equal or higher than 2 g/L (by SPEP) had an abnormal rFLC (reference range 0.26-1.65). Conversely, 16% of patients with undetectable monoclonal protein by other methods (i.e., SPEP and Mass-Fix) who also had no record of treated PCD had an abnormal rFLC. In these cases, there was an imbalance in the number of kappa high rFLCs to lambda low rFLCs of 201 to 1. The results of this study suggest decreased specificity of rFLC for a monoclonal kappa FLC in the 1.65 to 3.0 range.

MO114: Incidence and Spectrum of Biopsy-Proven Dysproteinemic Kidney Diseases: A Single-Centre Experience

Abstract BACKGROUND AND AIMS We aimed to evaluate the incidence and clinical features of patients with biopsy-proven dysproteinemic kidney diseases (group 1), as well as spectrum of biopsy-proven kidney diseases of patients with monoclonal gammopathy (MG) or abnormal free light chain (FLC) ratio (group 2) at our institution. METHOD This was a single-centre retrospective study of all patients who had native kidney biopsies at the Singapore General Hospital between October 2015 and December 2021. Demographic, clinical, laboratory and histological data were retrieved from electronic medical records to identify patients with biopsy-proven dysproteinemic kidney diseases (group 1) and patients with positive MG and/or abnormal FLC (κ to λ) ratio who underwent kidney biopsy (group 2). Patients were considered to have MG if they tested positive on any of the following tests: serum protein electrophoresis, serum immunofixation, urine protein electrophoresis or urine immunofixation. Abnormal FLC ratio is defined as a ratio outside the range of 0.27–1.65 in patients with eGFR ≥60 mL/min/m2 or 0.37–3.10 in patients with eGFR <60 mL/min/m2. RESULTS Out of 1066 patients who underwent kidney biopsy between October 2015 and December 2021, 25 (2.3%) patients were diagnosed with dysproteinemic kidney diseases (group 1). The median age of the patients at diagnosis was 65.6 years (IQR 58.6, 68.2), and majority was male (17/25; 68.0%). Haematological diagnoses present in this cohort include multiple myeloma (5/25; 20.0%), chronic lymphocytic leukaemia (2/25; 8.0%), Waldenstrom's macroglobulinaemia (2/25; 8.0%) and mantle cell lymphoma (1/25; 4.0%). Two-thirds of the patients had acute kidney injury (AKI) at time of biopsy (17/25; 68.0%). All patients presented with proteinuria, and nephrotic syndrome was noted in approximately half of the patients (15/25; 60.0%). Hypocomplementemia was present in a third (7/21; 33.3%) of the patients who had complement levels performed prior to biopsy, with low C3 and low C3/C4 observed in 5 and 2 patients, respectively. The most common histological lesion is immunoglobulin-related amyloidosis (8/25; 32.0%), followed by proliferative glomerulonephritis with monoclonal immune deposits (PGNMID) (6/25; 24.0%) and light-chain cast nephropathy (4/25; 16.0%). Sixteen (64%) patients fulfilled criteria for monoclonal gammopathy of renal significance (MGRS). All patients with PGNMID had undetectable MG and normal FLC ratio at diagnosis. Among these 1066 patients who underwent kidney biopsy, 396 patients had serum/urine electrophoresis, serum/urine immunofixation and/or FLC performed prior to biopsy. A total of 44 (11.1%) patients with detectable MG and/or abnormal FLC ratio were identified (group 2), 5 of whom had previously known haematological conditions. Dysproteinemic kidney diseases were diagnosed in 14 (31.8%) patients. Amongst patients with non-dysproteinemic diagnosis, diabetic/hypertensive nephropathy was the most frequent (15/30; 50.0%). Majority of the remaining patients had a variety of glomerulonephritides and renal vasculitides (10/30; 33.3%), or tubulointerstitial diseases (2/30; 6.7%). In univariate analysis, non-diabetic status (P < .001), presence of AKI (P = .032) and abnormal FLC ratio (P = .005) increased the likelihood of diagnosing dysproteinemic kidney disease in this group of patients. CONCLUSION AKI and proteinuria are common in dysproteinemia kidney diseases. Non-diabetic status, presence of AKI and abnormal FLC ratio increased the likelihood of diagnosing dysproteinemic kidney disease.

Prognostic Impact of Serum Free Light Chain Ratio Normalization in Patients with Multiple Myeloma Treated within the GMMG-MM5 Trial.

Simple SummaryFor multiple myeloma (MM) patients with measurable disease, there is no recommendation to monitor serum free light chains during therapy. However, this could provide important information in terms of prognosis. We investigated the prognostic impact of serum free light chain ratio (FLCr) normalization in 590 patients with secretory MM during first-line treatment within the German-Speaking Myeloma Multicenter Group MM5 trial. We are able to show that there is an increasing percentage of patients who achieve FLCr normalization during therapy. Importantly, we demonstrate that FLCr normalization at any time before the start of maintenance is significantly associated with prolonged progression-free and overall survival in multivariable time-dependent Cox regression analyses. This suggests that FLCr normalization during therapy is an important and simple way to assess prognostic factor in MM and supports the serial measurement of serum free light chains during therapy, even in patients with secretory MM.We investigated the prognostic impact of time-dependent serum free light chain ratio (FLCr) normalization in 590 patients with secretory multiple myeloma (MM) during first-line treatment within the German-Speaking Myeloma Multicenter Group MM5 trial. Serum free light chains (sFLC) were assessed by the Freelite test at baseline, after induction, mobilization, autologous blood stem cell transplantation, consolidation and every three months during maintenance or follow up within two years after the start of maintenance. The proportion of patients with a normal or normalized FLCr increased from 3.6% at baseline to 23.2% after induction and 64.7% after consolidation. The achievement of FLCr normalization at any one time before the start of maintenance was associated with significantly prolonged progression-free survival (PFS) (p < 0.01, hazard ratio (HR) = 0.61, 95% confidence interval (95% CI) = 0.47–0.79) and overall survival (OS) (p = 0.02, HR = 0.67, 95% CI = 0.48–0.93) in multivariable time-dependent Cox regression analyses. Furthermore, reaching immune reconstitution, defined as the normalization of uninvolved immunoglobulins, before maintenance was associated with superior PFS (p = 0.04, HR = 0.77, 95% CI = 0.60–0.99) and OS (p = 0.01, HR = 0.59, 95% CI = 0.41–0.86). We conclude that FLCr normalization during therapy is an important favorable prognostic factor in MM. Therefore, we recommend serial measurements of sFLC during therapy until achieving FLCr normalization, even in patients with secretory MM.

Comparison of Residual Neoplastic Plasma Cell Number Using Multicolor Flow Cytometry and Various Stages of International Myeloma Working Group-Defined Responses in Patients with Multiple Myeloma

【Introduction】Urine and serum immunofixation electrophoresis (IFE) and free light chain (FLC) are used for measuring paraprotein levels produced by neoplastic plasma cells and are widely accepted as standard tests for diagnosis and monitoring of multiple myeloma (MM). Treatment response criteria defined by the International Myeloma Working Group (IMWG) largely relies on the decrease in paraprotein levels of intact immunoglobulin with or without serum FLC. However, the paraprotein levels vary widely between patients and even in the same patient during the course of the disease. Therefore, considerable discrepancy often exists between the extents of decrease in neoplastic tumour cell burden and paraprotein levels in response to chemotherapy. We retrospectively compared the bone marrow plasma cell (BM-PC) levels using 6- to 8-color flow cytometry (FCM) with various levels of IMWG-defined responses after treating patients with MM.【Methods】We included patients with MM (light chain only multiple myeloma (LCMM), n =35 ; intact immunoglobulin multiple myeloma (IIMM), n =115 ) who were treated at Kameda Medical Center, Japan and Kanazawa University Hospital, Japan, between April 2007 and June 2017. Among them, 130 patients (LCMM; n=35 , IIMM; n=95 ) who achieved partial response (PR) or better response were selected on the basis of the co-availability of serum and urine test data, FLC data, and multicolor flow cytometry (MFC)-generated BM-PC quantitation data. MFC-mediated assessment of BM-PCs was performed during diagnosis and when each IMWG-defined treatment response was obtained. The residual BM-PC level was compared with the IMWG-defined responses using Kruskal-Wallis analysis. Oligosecretary and non-secretary myeloma were excluded from this study. This study conformed to the principles of the Declaration of Helsinki.【Result】Complete data set of IFE, FLC, and MFC during diagnosis, PR, very good partial response (VGPR), complete response (CR), and stringent CR (sCR) were available in 37, 58, 10, and 50 samples in IIMM and in 4, 21, 15, and 21 samples in LCMM. Mean BM-PCs during diagnosis in IIMM and LCMM was 2.1 x 10-1 and 2.2 x 10-1, respectively. In patients with IIMM, mean residual BM-PCs at PR, VGPR, CR, and sCR in IIMM were 1.8 × 10-2 (range: 1.4 × 10-5-7.5 × 10-2), 2.0 × 10-3 (range: 1.4 × 10-5-2.9 × 10-2), 4.4 × 10-4 (range: 2.1 × 10-5-2.0 × 10-3), and 4.8 × 10-4 (range: 2.0 × 10-6-5.3 × 10-3), respectively. Although significant difference in residual BM-PC levels was observed between PR vs. VGPR (P < 0.01), there were no statistically significant difference between VGPR vs. CR (P = 0.08) and CR vs. sCR (P = 0.9). Of note, 58% patients had residual MM cells ≥ 10-4 even when they achieved sCR. The amount of involved intact immunoglobulin at diagnosis was significantly higher in these patients than those who achieved residual MM cells <10-4 (mean: 5206.1 vs. 3954.7 p = 0.04).In patients with LCMM, mean residual BM-PCs cells at PR, VGPR, CR, and sCR were 3.5 × 10-2 (range: 5.1 × 10-3-7.7 × 10-2), 8.9 × 10-3 (range: 4.0 × 10-4-8.9 × 10-2), 2.0 × 10-3 (range: 4.0 × 10-5-1.0 × 10-2), and 1.1 × 10-4 (range: 2.0 × 10-6-7.0 × 10-4), respectively. Significant difference in the amount of residual BM-PC was only observed between CR and sCR, but not in PR vs. VGPR and VGPR vs. CR (PR vs. VGPR: p = 0.08, VGPR vs. CR: p = 0.08, CR vs. sCR: p = 0.03). Normal FLC ratio was highly predictive of lower residual BM-PCs (> 10-4) in LCMM. (Figure 1)Figure 2 shows the proportion of residual BM-PCs at various IMWG responses. The percentages of samples with residual BM-PCs at the levels of ≥ 10-3, 10-3 > - ≥ 10-4 , and < 10-4 in IIMM were 86.8% (n = 32/37), 7.8% (n = 3/37), and 5.2% (n = 2/37) for PR, 31.0% (n = 18/58), 56.8% (n = 33/58), and 12.0% (n = 7/58) for VGPR, 20% (n = 2/10), 40% (n = 4/10), and 40% (n = 4/10) for CR, and 12% (n = 6/50), 46% (n = 23/50), and 42% (n = 21/50) for sCR, respectively. In the case of LCMM, these figures were 100% (n = 4/4), 0% (n = 0/4), and 0% (n = 0/4) for PR, 66.6% (n = 14/21), 33.3% (n = 7/21), and 0% (n = 0/21) for VGPR, 20% (n = 3/15), 66.6% (n = 10/15), and 13.3% (n = 2/15) for CR, and 0% (n = 0/21), 23.8% (n = 5/21), and 76.1% (n = 16/21) for sCR, respectively.【Conclusion】The depth of residual BM-PCs response did not parallel that of IMWG response, and ~20% patients with CR had high level of residual BM-PCs (≥ 10-3). Although paraprotein-based assessment is feasible for disease monitoring in MM, our data indicates that response to treatment could be better assessed by BM-PC. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Impact of Bone Marrow Biopsy on Risk Stratification of Low-Risk IgG MGUS Patients

▪Introduction: Multiple myeloma (MM) is a plasma cell malignancy accounting for 10% of all hematological malignancies and characterized by significant inter and intra-patient heterogeneity. MM usually progresses from asymptomatic precursor stages, namely monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM). Previous recommendation by the IMWG indicated that bone marrow evaluation should be deferred in patients with low levels of IgG M-protein (< 1.5g/dL). Here, we sought to examine the clinical characteristics and progression patterns of patients who are defined as low risk MGUS by IMWG criteria but who also had a bone marrow biopsy performed.Methods: A total of 244 patients with an IgG M-protein < 1.5 g/dL were identified from two cancer centers, Dana-Farber Cancer Institute, Boston, MA, USA and the Department of Clinical Therapeutics, Athens, Greece, in the period between 1998 to 2016. Patients who had undergone bone marrow biopsy immediately following the detection of M-protein in their serum were included in our cohort. Patients with IgA type or free light chain (FLC) disease were excluded because of their known high risk of progression. Continuous variables were summarized as median and interquartile range (IQR). Time-to-event endpoints were estimated using the method of Kaplan and Meier. The multivariate analysis was undertaken using Cox proportional-hazards regression, likelihood ratio model to identify independent predictors of progression among this group of patients. Subgroup analysis was performed according to the FLC ratio.Results: Median age at diagnosis was 63 years and male to female ratio was 1.31. IgG k was present in 62.3%, while IgG l in 46.3% of patients. Median FLC ratio was 1.7 (IQR 0.9-3.2) and 51% of patients had an abnormal FLC ratio. In 54.5% of the patients, bone marrow infiltration by clonal plasma cells was ≥ 10%, reclassifying these patients as having SMM rather than MGUS. The time to progression to MM was significantly different between the patients with and without BM infiltration ≥ 10% in the Kaplan-Meier estimate (log-rank p= 0.004) (Figure 1). Subgroup analysis showed that patients with abnormal FLC ratio had a higher percentage of BM involvement (12% vs. 6%, p < 0.001) and 67% had ≥10% BM plasma cells vs. 44% of those with normal FLC ratio (p= 0.002); M-spike was also higher in those with abnormal FLC ratio (0.9 vs. 0.6, p < 0.001), as well as the probability of disease progression (median time-to-event: 9.2 years vs. not reached, log-rank p= 0.015).Conclusion: Our findings indicate that over 50% of patients previously classified as low risk MGUS, based on the presence of an IgG monoclonal protein < 1.5 g/dL, would be reclassified as having SMM. Indeed, these patients had a higher risk of disease progression to symptomatic MM. Patients with less than 10% plasma cells and normal FLC had a negligible risk of progression. Thus, our data suggests that patients with M spike of < 1.5gm/dL should still undergo a bone marrow biopsy to complete their disease evaluation and help improve risk assessment for disease progression. Further validation of these results in other cohorts is warranted. [Display omitted] DisclosuresKastritis:Prothena: Honoraria; Janssen: Honoraria; Genesis pharma: Honoraria; Takeda: Honoraria; Amgen: Honoraria, Research Funding. Laubach:Novartis, Takeda, Celgene, Onyx: Research Funding; Novartis, Takeda, Celgene: Consultancy. Anderson:Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; MedImmune: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Membership on an entity's Board of Directors or advisory committees; Oncopep: Other: scientific founder; Millenium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; C4 Therapeutics: Other: scientific founder. Richardson:Takeda: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Oncopeptides AB: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Dimopoulos:Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Onyx Pharmaceuticals, an Amgen subsidiary, Takeda Oncology: Consultancy, Honoraria, Other: Advisory Committee: Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Onyx Pharmaceuticals, an Amgen subsidiary, Takeda Oncology; Genesis Pharma: Research Funding; Novartis: Consultancy, Honoraria.

VRD-CEP: An Effective and Tolerable Chemo-Mobilization and Debulking Regimen for Multiple Myeloma

Introduction: Autologous stem cell transplant is the standard of care for fit patients with multiple myeloma (MM). However, many patients experience inadequate stem cell harvest after myeloid growth factor-based mobilization or suboptimal response to induction therapy. In the setting of high disease burden or heavy pretreatment, combination chemotherapy regimens, sometimes with addition of novel agents, may offer successful mobilization and debulking and include VTD-PACE, DCEP, and V-DCEP. We sought to offer a mobilization regimen that could 1) overcome mobilization failure and 2) debulk aggressive or refractory disease. We formulated the novel regimen VRD-CEP to achieve tolerability similar to that of DCEP but improve efficacy by combining a second-generation IMiD with a PI.Methods: We performed a retrospective, single-institution evaluation of fit MM patients with history of inadequate mobilization, inadequate response to induction, or aggressive disease characteristics. Patients received bortezomib 1 mg/m2 SC days 1, 4, 8, and 11; DCEP (dexamethasone, cyclophosphamide, etoposide, and cisplatin) in standard fashion days 4-7; and lenalidomide 25 mg daily days 4-7 and again upon achieving platelet > 50. Patients received filgrastim 10 mcg/kg SC beginning day 10.Results: Five patients were available for analysis; the median age was 59 (range 32-71). 2 patients were over 65, and 1 had ESRD. 2 patients underwent prior unsuccessful G-CSF + plerixafor mobilization, 2 patients had suboptimal response to induction, and 1 patient had aggressive disease features (plasmablastic histology, del 17p) with complete marrow replacement; 4 of 5 had ISS stage III disease. All patients received 1 cycle of the regimen. Three of the 4 mobilization patients achieved deepening of response based on M-protein or serum free light chains; one patient achieved near-complete elimination of plasma cells in the marrow and free light chain ratio normalization but could not undergo harvest due to logistical reasons. 3 of 5 patients were considered to have a PR or better. All patients treated with mobilization intent collected > 6 million CD34+ cells/kg (median 7.86; range 6.07-10.58 million/kg). The median time from the start of DCEP to apheresis was 13.5 days (range 13-18); the median number of apheresis days was 1.5 (range 1-3). No patients required dosing of plerixafor.Toxicities were acceptable. Grade 4 thrombocytopenia occurred in 3 patients, grade 4 neutropenia occurred in 4, and PRBC transfusions were given to 2. 1 patient was hospitalized for neutropenic fever. 1 patient developed reversible grade 2 renal insufficiency, and 1 patient developed grade 3 hyponatremia attributed to cyclophosphamide. No patients experienced worsening neuropathy, syncope, hypotension, deep vein thrombosis, grade 3-4 nausea/vomiting, or diarrhea. Patient-specific details are listed in Table 1.Discussion: Stem cell mobilization using G-CSF and plerixafor may be subject to inadequate yields in 1-40% of patients. Patients with significant residual plasma cell marrow involvement may require additional therapy to achieve adequate mobilization and cytoreduction prior to autologous transplant. VTD-PACE, DCEP, and V-DCEP have shown efficacy in relapsed or refractory MM patients. Such regimens are also useful for chemo-mobilization of stem cells. However, the efficacy of DCEP in the relapsed/refractory setting may be limited (40-50%), and VTD-PACE may have more limited applicability due to its higher toxicity burden. We believe that the addition of bortezomib and lenalidomide to DCEP achieves the desired potency to debulk refractory or high-risk disease while maximizing tolerability. More significantly, mobilization results were excellent, and we were able to achieve excellent stem cell yields in patients who had experienced inadequate growth factor mobilizations. The regimen merits further exploration in a larger cohort of patients.Conclusion: In a preliminary cohort of 5 MM patients, VRD-CEP appears to be an effective and safe mobilization regimen in patients with residual marrow disease or those who failed prior mobilization attempts. VRD-CEP led to efficient cytoreduction in patients with high-risk cytogenetics and heavy burden of disease. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

MO209NUOVI PROTOCOLLI TERAPEUTICI NEI PAZIENTI NON IDONEI AL TRAPIANTO CON AMILOIDOSI AL: FOLLOW UP A LUNGO TERMINE

Abstract Background and Aims Immunoglobulin light-chain (AL)amyloidosis is a rare life-threatening disease caused by light chains that are toxic to vital organs such as the kidneys. New therapeutic strategies with bortezomib and lenalidomide have improved the prognosis. The aim of our study was to evaluate the long term efficacy of therapeutic protocol utilizing bortezomib in induction and in conditioning with lenalidomide for PRR (partial renal response) AL renal Amyloidosis transplant-ineligible patients. Method This is a prospective analysis of 16 transplant-ineligible patients with histological diagnosis of renal amyloidosis admitted to our Nephrology Department from 01/2010 to 01/10/2020. All patients have overt nephrotic syndrome at the diagnosis. Two/thirds of them have renal failure. The diagnosis of amyloid is based on the kidney biopsy finding, by light microscopic examination, of amorphous extracellular Congo red positive deposits, which display characteristic dichroism and apple green birefringence under polarised light. Bortezomib-based (BD) regimen is used (Bortezomib 1.3mg/m2 subcutaneously; Cyclophosphamide 200mg/m2 and Dexamethasone 40mg) for 9 cycles. Hematological and organ response were evaluated according to the novel criteria of the International Society of Amyloidosis. The patients with partial renal response (PRR: decreased of 24 hour urine protein and serum creatinine &amp;gt; 50% over baseline) were treated with cycles of Lenalidomide (dose adjustments for renal function, orally on days 1 trough 21 of each 28-days cycle) in combination with dexamethasone and prophylactic anti-thrombotic treatment. Results The mean age was 63±7 years and 7/16 (43.7%) were males. By immunohistochemistry the protein composition of the amyloid deposits was FLC k in 6/16 and FLC lambda in 10/16. Periombelical fat aspirate was positive in 5 patients (31.2%). At onset the mean proteinuria was 13.1 ± 3.6 gr/24h with average MDRD of 37.2 ml/min (III stage CKD), average pro-BNP 420.1 and SIV 12.5 mm. At onset three patients (18.7%) had confirmed multiple myeloma (Clone of plasma cells proliferation &amp;gt; 30% in the bone marrow). 3/16 patients died for cardiac arrhythmia at 3 and 4 months after CyBorD cycles initiation. Therefore CyBorD regimen was completed in 13/16 patients. After 9 CyBorD cycles: 3/13 patients showed a complete renal response (CRR: MDRD &amp;gt; 90 ml/min, proteinuria/24h&amp;lt; 300 mg) and CHR (normal serum FLC ratio); 10/13(76.9%) showed a PRR and PHR (dFLC decrease &amp;gt;50% compared to baseline), one patient died for Sepsis, All patients with CRR or PRR showed a complete cardiological response (normal BNP and SIV). Adverse events during therapy: HZV nevralgy in 3. The 9 patients in PRR were treated with Lenalidomide. After median 6 treatment cycles 7/9 (77.7%) patients showed a CRR and CHR. Haemodialysis was started in 2/9 (22.2%) patients. We decided to discontinue the therapy for adverse events in 3 patients: breast cancer in one, transient troponin I increase and angina in an other patient, pneumonia events in one. The pneumoniae infectious and anginal episodes regressed with drug discontinuation. Median follow-up time from diagnosis of Renal Amyloidosis was 46 months. Median follow-up from the start of Lenalidomide was 36 months. One patients died for breast cancer, but in CRR. All the others patients with CRR (9/13, 69.2%), including the two who suspended Lenalidomide for its toxic effects have been in remission for 30 months on average. Conclusion We conclude the following Lenalidomide therapy is very effective at increasing the number of CRR. In addition, the two treatment regimens (induction therapy with CyBorD and conditioning with Lenalidomide) kept patients in remission for more than 30 months on average. Further studies on larger samples are needed to validate the data.

Early Serum Free Light Chain Response after High-Dose Melphalan and Stem Cell Transplantation Predicts Hematologic Response in AL Amyloidosis

Introduction Immunoglobulin light chain (AL) amyloidosis is a rare disease caused by a clonal plasma cell dyscrasia producing monoclonal light chains that misfold and form amyloid fibrils which can deposit in a variety of tissues and organs. This deposition of amyloid fibrils can lead to progressive organ impairment, multi-organ failure, and death if left untreated. High-dose melphalan and autologous stem cell transplantation (HDM/SCT) is known to improve patient outcomes with hematologic complete responses (CR) rates of 25-67%. Hematologic CR is currently defined as the absence of monoclonal protein in serum and urine by immunofixation electrophoreses and normal serum free light chain ratio (FLCR). Studies have shown that even among patients achieving a normal FLCR after initial therapy with HDM, persistent elevation of the involved FLC (hiFLC) predicts poor prognosis. Serum half-life of FLCs is approximately 2-6 hours, even with diminished glomerular filtration rates, and could be a tool for early treatment response evaluation. We sought to determine the extent to which early FLC responses after HDM/SCT predict hematologic complete response (CR) at 6 months. Methods We analyzed patients with AL amyloidosis who underwent HDM/SCT from 2012-2019 at Boston Medical Center. Exclusion criteria included death within 100 days, lack of FLC data at any time point, pre-SCT normal FLC concentrations and ratio, and chronic renal insufficiency (serum creatinine &amp;gt;1.3 mg/dL) with a normal FLC ratio. All subjects received a total of 140-200 mg/m2 melphalan IV in equally divided doses on days -3 and -2. Stem cells were infused on day 0. FLC measurements were obtained early in the peri-SCT period (&amp;lt; 1 month), at 6 months, and at 12 months after HDM/SCT. The patients were evaluated for response according to the consensus response criteria at 6 months. Statistical analysis to compare CR at 6 months and early post-SCT free light chain levels was performed by Chi-square with significance considered at p&amp;lt;0.05. Results Of the 113 patients with AL amyloidosis treated with HDM/SCT during the specified time period, 32 were excluded (4 died within 100 days of SCT, 15 had normal FLCs pre-SCT, 5 lacked data, and 8 had chronic renal insufficiency (Cr &amp;gt;1.3 mg/dL) with normal FLCR. A total of 81 subjects (females=30) were analyzed. Median follow-up from SCT was 27.6 months (range, 6-145). Median time of early post-SCT FLC measurement was 8 days (range, 7-30). Median age at diagnosis was 58 years (range 30-79) and the iFLC was lambda in 81.5% (n = 66) of patients. Median number of bone marrow plasma cells was 10% (range, 1-50). The mean absolute involved FLC was 196 mg/L ±221 prior to SCT, 60 mg/L ± 77 in the early post-SCT period, 92 mg/L ± 152 at 6 months post-SCT. In early post-SCT period, 39.5% (n=32) had iFLC &amp;lt;20 mg/L, 28% (n=16/57) had dFLC&amp;lt;10 mg/L, and 84% (n=48/57) had normal FLCR. Early post-SCT dFLC &amp;lt;10 mg/dL and early post-SCT iFLC &amp;lt;20 mg/L were statistically associated with prediction of hematologic CR at 6 months (p=0.025 and p=0.001, respectively). However, early post-SCT normal FLCR was not associated with predicting hematologic CR at 6 months. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of early post-SCT iFLC &amp;lt;20 mg/L, dFLC &amp;lt;10 mg/L and normal FLCR to predict hematologic CR at 6 months are presented in table 1. Conclusion This study concludes that achievement of dFLC &amp;lt;10 mg/L and iFLC &amp;lt;20 mg/L in the early post-SCT period is associated with prediction of hematologic CR at 6 months. Early post-SCT dFLC &amp;lt;10 mg/L could be considered a tool for early evaluation of treatment response following HDM/SCT in AL amyloidosis. Key words: immunoglobulin light chains; AL amyloidosis, HDM/SCT Disclosures Sarosiek: Spectrum: Research Funding. Sanchorawala:Caelum: Research Funding; Prothena: Research Funding; Celgene: Research Funding; Takeda: Research Funding; Proclara: Other: advisory board; Abbvie: Other: advisory board; UpToDate: Patents &amp; Royalties; Oncopeptide: Research Funding; Regeneron: Other: advisory board; Caleum: Other: advisory board; Janssen: Research Funding.

Light Chain Deposition Disease: First Analysis of an International Study in 359 Patients

Introduction: Light chain deposition disease (LCDD) is a rare complication of monoclonal gammopathies, defined by non-amyloid linear monoclonal light chain (most commonly kappa) deposits in the kidney and other organs. The rarity of LCDD has hampered clinical studies and staging systems and response criteria are lacking. The International Kidney Myeloma Working Group (IKMG) started a clinical data collection from all participating centers in order to define the natural history of LCDD, and to establish prognostic factors and response criteria in a large, international, unselected patient population. Methods: Eight referral centers have yet participated in the data collection at the data lock of July 31, 2020. Patient inclusion is ongoing and expected accrual is 500 patients. The diagnosis of LCDD had to be biopsy-proven. The patients were diagnosed between 1992 to 2020. Response was assessed 6 months after treatment initiation according to the criteria used in light chain (AL) amyloidosis. Renal survival (RS) was defined as time from diagnosis to dialysis or last follow-up. Patients who died without requiring dialysis were censored at the time of death. The analysis of factors predicting RS was performed in patients whose baseline estimated glomerular filtration rate (eGFR) was &amp;gt;15 mL/min. The cutoffs of baseline variables, as well as the cutoffs measured at the time of response, best predicting RS or OS at 12 months were identified by means of Receiver Operator Characteristics (ROC) analyses. All patients gave written informed consent for their clinical data to be used for research purposes. Results: Overall, 359 patients have been included in this first analysis. Sixteen (4%) subjects had concomitant cast nephropathy. The main clinical characteristics are reported in the Table. Median overall survival (OS) was 13 years and RS was 12 years (Figure1 A and 1B) and median survival of living patients is 4.5 years. At univariate analysis the only baseline variables predicting RS were proteinuria [best cutoff 2.5 g/24h, HR 2.25 (95%CI 1.13-4.60), P=0.02], and eGFR [best cutoff &amp;gt;30 mL/min, HR 0.50 (95%CI 0.26-0.96) P=0.037], but at multivariate analysis only proteinuria predicted RS [HR 2.17 (95% CI 1.08, 4.33), P=0.027]. At univariate analysis, a higher bone marrow plasma cell infiltrate (best cutoff ≥20%) at diagnosis was associated with a significantly lower OS [HR 1.96 (95% CI 1.23-3.13) P=0.004], as was having end stage renal disease (ESRD) defined as an eGFR &amp;lt;15 mL/min [HR 1.81 (95%CI 1.11-2.92) P=0.015]. We then tested the ability of the hematologic response criteria for AL amyloidosis to discriminate groups with different survival after treatment in a 6 months landmark analysis. Our choice of adopting the amyloidosis response criteria was corroborated by the results of the ROC analysis showing that the difference between involved and uninvolved free light chains (dFLC) cutoff (40 mg/L) used in AL amyloidosis to define very good partial response (VGPR) had 87% sensitivity and 65% specificity in identifying patients who needed dialysis within 12 months. Partial response (PR, 19% requiring dialysis at 3 years) was not associated with a RS benefit over no-response (29% requiring dialysis at 3 years, P=0.511). However, VGPR conferred a significant RS advantage (10% requiring dialysis at 3 years) over PR (P=0.002). No significant difference in RS was seen between complete response (CR, 0% requiring dialysis at 3 years) and VGPR (P=0.178). Thus, achieving VGPR or CR by amyloidosis response criteria [post-treatment dFLC&amp;lt;40 mg/L (VGPR by AL criteria), with or without negative serum and urine immunofixation and normal FLC-ratio (CR by AL criteria)] was adopted as a provisional criterion for hematologic response in LCDD (Figure 1D). LCDD response was also associated with prolonged OS (Figure 1C). Conclusions: Almost one-third of patients with LCDD are diagnosed when they already have ESRD resulting in shorter OS. The degree of proteinuria and of bone marrow plasma cell infiltration predict RS and OS, respectively. Achievement of post treatment dFLC &amp;lt;40 mg/L or negative serum and urine immunofixation at 6 months is proposed as a provisional criterion for hematologic response, being able to predict both improved RS and OS. Planned expanded recruitment might allow a validation analysis of the results, the analysis of organ response data and the evaluation of different time-points for response assessment. Disclosures Milani: Celgene: Other: Travel support; Janssen: Other: Speaker honoraria; Pfizer: Other: Speaker honoraria. Kastritis:Pfizer: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Genesis Pharma: Consultancy, Honoraria. Schönland:Janssen, Prothena, Takeda: Honoraria, Other: travel support to meetings, Research Funding. Bridoux:Baxter: Consultancy; Janssen: Honoraria; Celgene: Honoraria. Tuchman:Celgene: Honoraria, Research Funding, Speakers Bureau; Oncopeptides: Consultancy; Amgen: Research Funding; Caelum: Honoraria; Sanofi: Honoraria, Research Funding; Janssen: Research Funding; Roche: Research Funding; Karyopharm: Honoraria, Research Funding. Jimenez-Zepeda:Janssen, Celgene, Amgen, Takeda: Honoraria. Palladini:Jannsen Cilag: Honoraria, Other; Celgene: Other: Travel support. Wechalekar:Celgene: Honoraria; Caelum: Other: Advisory; Janssen: Honoraria, Other: Advisory; Takeda: Honoraria, Other: Travel.

Comparing measures of hematologic response after high-dose melphalan and stem cell transplantation in AL amyloidosis

Hematologic complete response (hemCR) in AL amyloidosis requires absence of monoclonal protein by immunofixation electrophoreses (IFE) and normal serum free light chain ratio (FLCR). Recent literature suggests that an involved free light chain (iFLC) <20 mg/L or difference in free light chains (dFLC) <10 mg/L may more accurately predict outcomes after treatment. We evaluated overall survival in 340 patients treated with high-dose melphalan and stem cell transplantation (SCT). Of 305 patients evaluable 6 months after SCT, 90 (30%) achieved hemCR, 132 (43%) dFLC <10 mg/L, 118 (39%) iFLC <20 mg/L, and 176 (58%) normal FLCR. Of 215 patients without hemCR, 65 (30%) had dFLC <10 mg/L and 86 (40%) had normal FLCR. Overall survival (OS) in those achieving dFLC <10 mg/L or normal FLCR without hemCR was inferior to those achieving hemCR (p = 0.013 and p = 0.001). OS was not significantly different in patients achieving iFLC <20 mg/L without hemCR compared with hemCR (p = 0.243). Of those with hemCR, OS was not significantly improved if dFLC <10 mg/L was also achieved (p = 0.852), but OS was improved for those with hemCR who also attained iFLC <20 mg/L (p = 0.009). Multivariate analysis demonstrated absence of monoclonal protein in IFE and iFLC <20 mg/L as independent predictors of survival. Attainment of hemCR remains a treatment goal, although achieving iFLC <20 mg/L may also predict improved OS.

P0204PREVALENCE AND PREDICTIVE FACTORS OF BIOPSY-PROVEN NEPHROPATHY RELATED TO MONOCLONAL GAMMOPATHY

Abstract Background and Aims The prevalence of monoclonal gammopathy (MG) and kidney disease increases with age. When a patient present with both conditions, it is often necessary to perform a kidney biopsy in order to rule out a Monoclonal Immunoglobulin-Related Nephropathy (MIRN) that may require a specific therapy that targets either an overt hematological malignancy or a MG or Renal Significance (MGRS). The aim of our study was to identify factors that predict the presence of MIRN in this setting. Method This retrospective monocentric study included all patients who underwent a kidney biopsy between 2007 and 2018 with concurrent presence of GM, as defined by positive serum immuno-electrophoresis and/or Bence-Jones proteinuria. Results 328 patients were included, representing 11.8% of all kidney biopsies performed in our center during this period. Indication of biopsy was renal failure (eGFR &amp;lt;60ml/min/1.73m) in 77.4% of cases and/or proteinuria (urine protein-to-creatinine ratio &amp;gt;0.5g/g) in 75.9% of them. Median (IQR) serum creatinine was 155 μmol/L (111-233), eGFR 37.5 (22-56) ml/min/1.73m, serum albumin 29.5 (24-35) g/l. Median age was 67 (57/75), the M/F ratio was 198/130, diabetes mellitus was present in 21.3% of cases, hypertension in 53.1%. Kidney biopsy revealed that nephropathy was related to MG in 91/328 patients (27.7%). Myeloma cast nephropathy and AL amyloidosis were the most common histopathological subtypes (36 and 34% respectively), followed by monoclonal immunoglobulin deposition disease (15%) and cryoglobulinemic glomerulonephritis (8%). Patients with MIRN had more severe renal function impairment with median (IQR) serum creatinine of 176 (119-307) vs 149 (108-216) μmol/l (p=0.003) and heavier proteinuria, 3.9 (2.2-8.2) vs 2.0 (0.9-5.2) g/g (p&amp;lt; 0.001), when compared to non-MIRN patients. Hematological malignancy was diagnosed in 83 cases (25,3%) (Multiple Myeloma in 62, non-Hodgkin Lymphoma in 6, Waldenström Macroglobulinemia in 6, Chronic Lymphoid Leukemia in 6, Plasmocytoma in 3). Among them, MIRN was diagnosed in 51 (61%) cases but tumoral lympho-plasmocytic infiltration was observed in 9 (11%) cases. In this subgroup of patients, no laboratory test could predict the presence of a specific nephropathy. Among patients with no hematological malignancy (n=245), MIRN was diagnosed in 40 cases (16%) to confirm MGRS diagnosis. The markers that were most commonly associated with the presence of MGRS were positive Bence-Jones proteinuria (OR 4.7; 95%CI 2.2-10.3; p&amp;lt; 0.001), abnormal serum Free Light Chain (FLC) ratio (OR 4.2; 95%CI 1.7-10.7; p&amp;lt; 0.001), and serum electrophoresis spike &amp;gt;1.5 g/l (OR 5.9; 95%CI 2.6-13.5; p&amp;lt; 0.001). However, none of those markers had sufficient power to formally predict the result of the biopsy, as positive (PPV) or negative (NPV) predictive values were 36/41/45 % and 89/86/88 % respectively. Conclusion Almost one-third of patients with MG and kidney disease referred to our Department have biopsy-proven related nephropathy. Although negativity of Bence-Jones proteinuria and a normal serum FLC ratio are frequently associated with the absence of MGRS, kidney biopsy, beyond its diagnostic and prognostic interest, remains the most discriminating test.

Clinical characteristics and outcomes of oligosecretory and non-secretory multiple myeloma.

Secretion of monoclonal immunoglobulins (MIg) detected in the serum and/or urine is one of the typical features of multiple myeloma (MM). However, some patients secrete MIg in quantities below "measurable" (termed oligosecretory MM) and others have no detectable MIgs by standard serum and urine immunofixation (termed non-secretory MM). In a cohort of 852 consecutive patients with active myeloma, we identified 100 (11.7%) patients with oligo/non-secretory MM, including 20 (2.3%) with non-secretory MM. Compared to patients with secretory MM, these were younger, less anemic, and had less often renal dysfunction and less extensive bone marrow infiltration. Presence and extent of bone disease were similar, however, hypercalcemia was less common and more often is ISS (International Staging System)-1 and, in those with available FISH (Fluoresense In Situ Hybridization), high-risk cytogenetics were less common. FLCs (Free Light Chains) were available in 17 patients with non-secretory MM: only 3 had normal FLC ratio; the others had abnormal ratio and 9/14 had involved FLC ≥ 100mg/L. The 4-year OS for patients with oligo/non-secretory disease was 64% vs 58% for secretory MM. In multivariate analysis, oligo/non-secretory disease was not an independent prognostic factor per se. Thus, 12% of MM patients present with oligo/non-secretory disease at diagnosis and have different biologic characteristics but similar outcome to other MM patients.

The Quest for Indicators of Profound Hematologic Response in AL Amyloidosis: Complete Response Remains the Optimal Goal of Therapy

Background: The International Society of Amyloidosis validated the criteria of hematologic response to therapy in AL amyloidosis, based on the reduction of free light chain (FLC) concentration and serum and urine immunofixation. Complete response (CR) predicted the longest survival and was defined by negative serum and urine immunofixation (s&amp;u-IFE) with a normal FLC ratio (FLCR). Subsequently, we and others showed that, in patients with a difference between involved and uninvolved FLC (dFLC) between 20 and 49 mg/L, achieving a dFLC &lt;10 mg/L was associated with an improvement of overall and renal survival. This criterion was then proposed as a goal of therapy in the general population of patients with AL amyloidosis. These studies questioned whether the definition of CR should be reconsidered. In the present study, we compared the outcome of patients who obtained a profound reduction of FLC but do not qualify for CR with the outcome of subjects who reached CR. Methods: The prospectively maintained database of the Pavia Amyloidosis Center was searched for patients who were newly-diagnosed between 2004 and 2018 and who reached at least one the following endpoints 6 months after treatment initiation: 1) complete response (CR) or, in patients who do not qualify for CR, 2) normalization of involved-FLC concentration (normal-iFLC group), dFLC &lt;10 mg/L (dFLC10 group) and normalization of FLCR (normal-FLCR group). We calculated overall survival (OS) and time to next line of therapy or death (TNTD) from the time of response assessment (6 months after treatment initiation). Results: A total of 434 patients (Table) were included, that were divided into the following groups: CR (161), normal-iFLCN (114), dFLC10 (144) and normal-FLCR (220). As expected, there was a partial overlap between the non-CR groups. No difference was seen between the CR and all the other groups in baseline variables: age, sex, organ involvement, Mayo 2004/European staging, and renal staging. Treatment was bortezomib-based in 261 subjects, melphalan/dexamethasone (MDex) in 128, IMiDs-based in 21, autologous stem cell transplant in 14, and therapy for IgM clones in the remaining 10 subjects. The reasons for not qualifying for CR in the normal-iFLC group was abnormal FLCR only in 4 (3%), positive s&amp;u-IFE only in 81 (72%), and both in 29 (25%). The reason for not qualifying for CR in the dFLC10 group was abnormal FLCR only in 4 (3%), positive s&amp;u-IFE only in 104 (72%) and both in 36 (25%). The median follow-up of living patients was 60 months. Patients who achieved CR enjoyed a significantly longer OS (58% alive at 10 years) compared to patients who reached any of the other endpoints but did not qualify for CR (Figure). Also median TNTD was significantly longer in patients who obtained CR (75 months) compared to the normal-iFLC group (33 months, P&lt;0.001), the dFLC10 group (39 months, P&lt;0.001), and the normal-FLCR group (24 months, P&lt;0.001). We then evaluated whether achieving a normal iFLC or a dFLC &lt;10 mg/L was associated with a better survival among patients who did qualify for CR. In the CR group, 103 (64%) patients achieved a normal iFLC and 86 (53%) a dFLC &lt;10 mg/L. There was no significant difference in OS and TNTD between subgroups of patients in CR according to iFLC or dFLC response. Conclusion: Undetectable clonal disease by both negative serum and urine IFE and normal FLCR (CR) is associated with best survival in AL amyloidosis and should be the goal of therapy if tolerability and patient frailty allow. However, it is possible that novel immunotherapies, such as daratumumab, affect the concentration of uninvolved FLC, thus interfering with dFLC and FLCR, and this study should be validated in patients exposed to these agents. Approximately 40% of patients in CR relapse and eventually die. New sensitive tools to identify residual clonal disease (mass-spectrometry on serum and urine, next generation sequencing and next generation flow cytometry on bone marrow) are urgently needed to detect these patients and intervene before relapse. Disclosures Milani: Janssen: Honoraria; Pfizef: Honoraria. Palladini:Janssen-Cilag: Other: Travel grant; Janssen-Cilag: Honoraria; Celgene: Other: Travel grant; Sebia: Honoraria.

Prevalence of Monoclonal Gammopathy of Undetermined Significance in a Large Population with Annual Physical Examination in Beijing, China

Introduction Monoclonal gammopathy of undetermined significance (MGUS) is a clinically asymptomatic premalignant plasma cell disorder. Previous studies in Western countries have described the prevalence of MGUS in Caucasians. However, data is limited in Chinese population. We therefore performed this study to ascertain the prevalence and characteristics of MGUS among Chinese population. Methods A total of 154597 consecutive healthy participants from Beijing who underwent annual physical examination between December 2013 and April 2019 at Peking Union Medical College Hospital were enrolled. Serum M protein was evaluated by capillary electrophoresis. Patients with a positive or suspicious serum M protein were suggested to be referred to the hematological clinic for immunofixation electrophoresis (IFE) and free light chain (FLC) assays. MGUS was defined in accordance with previous definitions. We calculated age-specific and sex-specific prevalence and described laboratory characteristics of patients with MGUS among those participants. Results MGUS were diagnosed in 843 patients (0.55%, 95%CI 0.51% to 0.59%). The median age at presentation was 58 years, with a range of 25-96 years. The overall prevalence of MGUS was 1.14% among participants aged 50 years or older and 2.6% among those aged 70 years or older. In both sexes, the prevalence increased with age: 0.1% (&lt;40 years), 0.36% (40-49 years), 0.78% (50-59 years), 1.28% (60-69 years), 2.19% (70-79 years), and 3.77% (≥80 years) separately (Figure 1). The prevalence among men were higher than that among women (0.67% vs. 0.40%, OR =1.719, 95% CI 1.490 to 1.983, P&lt;0.001) (Figure 1). The median concentration of serum Monoclonal protein was 1.4 g/L (0.1 -27.8 g/L). M protein level was less than 0.5g/L in 220 patients (26.1%), less than 5 g/L in 81.1% and more than 15 g/L in only 1.9% of 843 persons. There was no significant difference in the concentration of the monoclonal protein among the age groups. Of the 519 patients who were tested for IFE, the isotype of the monoclonal immunoglobulin was IgG in 344 (66.3%), IgA 112 (21.6%), IgM in 48 (9.2%), IgD in 2 (0.4%), light-chain in 3 (0.6%) and biclonal in 10 (1.9%). The serum light-chain type was kappa in 260 (50.1%), lambda in 255 (49.1%) patients, while 4 patients (0.8%) with biclonal M protein have both kappa and lambda light-chain. Of the 180 people who were tested for FLC, 42 (23.3%) had an abnormal FLC ratio. IgG isotype, M protein &lt;15 g/L and normal FLC ratio were found in 102 patients (56.7%) and the remaining 78 people (43.4%) had 1(30.6%) or 2(12.8%) abnormal factors. Conclusions MGUS was found in 1.14% of persons 50 years of age or older and 2.6% among those 70 years of age or older among healthy Chinese population. The prevalence of MGUS increases with age. Males have a higher frequency of MGUS than Females. These observations offer the overall situation of MGUS epidemiology in a large Chinese population. Disclosures No relevant conflicts of interest to declare.

Treatment with Daratumumab in Patients with Multiple Myeloma Associated AL Amyloidosis

Treatment with Daratumumab in Patients with Multiple Myeloma Associated AL Amyloidosis

PS1352 DISSECTING THE BONE MARROW IMMUNE MICROENVIRONMENT IN THE COMPLETE SPECTRUM OF MONOCLONAL GAMMOPATHIES: POTENTIAL IMPLICATIONS IN DISEASE PATHOGENESIS

Background: To discriminate different outcomes among patients in CR the IMWG introduced a more stringent CR (sCR) criteria by adding to the pre-existing CR criteria the requirement of a normal free-light chain ratio (sFLCr) plus the absence of clonal plasma cells (PCs) in bone marrow (BM) by immunohistochemistry (IHC). In 2011, the low-sensitivity cytometry was included as alternative methodology to IHC to define sCR. However, the prognostic significance of the kappa/lambda ratio values is not clear. Aims: To verify the conclusion of our previous study (Blood 2015. 126:858–62) regarding the lack of influence in the prognosis of abnormal serum free light chain ratios (sFLCr) in a more extensive series of newly diagnosed multiple myeloma (NDMM) patients in CR or sCR Methods: NDMM patients aged ≤65 years enrolled in GEM2012MENOS65 (NCT01916252). Of 458 patients, 8 discontinued early and were not evaluable. The definition of CR and sCR was made according to the IMWG criteria. SFLCr (FREELITE assay) was classified as normal (0.26–1.65) or abnormal (<0.26 if the patient was λ; >1.65 if the patient was κ). MRD was assessed using next-generation flow cytometry. The median limit of detection was of 3x10–6. All the CR with normal sFLCr and absence of clonal PCs by MFC with a sensitivity of 10–2 were considered sCR. Median follow-up was 47.5 months. Results: After induction, 425 patients were evaluable for response; 201 (47%) reached ≥CR. Data from sFLCr and MRD was available in 192 and 193 patients, respectively. In the CR evaluable patients for sCR assessment (n = 184), the rate of sCR was 64% (n = 117). In a landmark from the end of induction (median follow-up 39 months), sCR didn’t show significantly differences in PFS (2 years-PFS 89% vs 87%; P = .7) (fig 1a) neither in OS (2 years-OS 94% vs 94%; P = .9). Interestingly, patients with abnormal (n = 67) vs normal (n = 125) sFLCr showed superimposable PFS (2 years-PFS 88% vs 87%; P = .9) (fig 1b) and OS (2 years-OS 96% vs 94%; P = .8).By contrast, the few patients (n = 3) in whom BM clonality was detected by the low-sensitivity IHC-adapted MFC method had significantly worse PFS (2 years-PFS 89% vs 67%; P = .03) (fig 1c) and OS (2 years-OS 95% vs 67%; P = .8) than patients in whom BM clonality was undetectable or detected at levels below the threshold proposed for IHC assessment. On using our traditional MRD method, persistent MRD (>10–4) was detectable among 39 of the 193 (20%) patients who, compared with MRD-negative cases, had significantly inferior PFS (2-years PFS 91% vs 80%; P = .01) (fig 1b) and OS (2 years-OS 96% vs 87%; P = .01).As validation, we reproduced the analysis in the ASCT end-point. Of the 395 evaluable patients; 238 (60%) reached ≥CR. Once again, in the landmark analysis, sCR didn’t show significantly differences in PFS in respect to CR (P = .3) neither in OS (P = .6). Patients with abnormal (n = 51) vs normal (n = 173) sFLCr showed superimposable PFS (P = .9) and OS (P = .6). Patients with persistent MRD (>10–4), had significantly inferior PFS (P = .003) but similar OS (P = .2).Summary/Conclusion: These results confirm our previous analysis based on GEM05menos65/ GEM10mas65 clinical trials. For MM patients in CR, the stringent CR criteria does not predict a different outcome. If this essential criterion in the definition of sCR lacks for the prognosis connotations, it is not justified to maintain a response category whose real significance depends on the combination of the traditional CR criteria with a negative MRD status based on very low (IHC) or low resolution (<104) levels, today outdated.

Depth of Response in Waldenstrom Macroglobulinemia

IntroductionRecent advances in the understanding of the WM pathobiology led to the expansion of our therapeutic options in this disease. A number of targeted drugs are either available or under investigation and are poised to change the chemo-immunotherapy paradigm in the treatment of WM. Now more than ever, an individualized treatment approach for patients with WM is possible, where patient characteristics and preferences can be matched by different treatment goals and side effect profiles. While deep responses have been associated with longer disease-free survival in other hematologic malignancies, data on patients with WM are sparse. We report the impact of depth of response in disease-free and overall survival (OS) in WM.MethodsWM patients consecutively seen at Mayo Clinic between 01/1998 and 12/2016 were reviewed for response to therapy and disease burden. The best response achieved after the treatment of interest (TOI) was classified using the IWWM-7 Response Criteria. The included TOI were: BR, DRC, BDR and high-dose chemotherapy followed by ASCT. All time-to-event analyses were performed from the TOI initiation date using the Kaplan-Meier method and the log-rank test. A landmark analysis from the date-of-best response was also performed for OS to prevent immortal-time bias. Univariate and multivariate analyses of progression-free survival (PFS) and time-to-next therapy (TTNT) were performed using the Cox regression method.ResultsA total of 181 patients had disease response assessed after the TOI. Baseline characteristics at time of diagnosis are summarized in table 1. The median follow up from TOI was 3.8 years (95% CI: 3-4), the majority of patients received TOI as salvage therapy [n=112 (63%); median 2nd line (rage 1-11)]. Best response rates with the corresponding 5-year PFS and TTNT are summarized in table 2.The median OS from TOI was longer in patients who achieved at least a PR [median 7.2 years (95% CI: 5-NR) vs 3.7 years (95% CI: 1.6-NR), p=0.01]. A trend towards a longer OS was also seen with deeper responses (PR or better) achieved with frontline therapy [median 5.8 years (95% CI: 5.8-NR) vs 3.4 years (95% CI: 1.6-NR), p=0.24]. Figure 1 shows the correlation between deeper responses with PFS and TTNT.Among patients achieving a PR or VGPR, those with a normal FLC ratio post TOI demonstrated a longer PFS and TTNT [PFS: median NR (95% CI: 3.4-NR) vs 4.9 years (95% CI: 2.8-8.7), p=0.01; TTNT: median NR (95% CI: 3.5-NR) vs 5.2 years (95% CI: 4.2-9.4), p=0.04], figure 2. In a multivariate analysis including normal FLC ratio, normal IgM level and minimal BM involvement (<5%) post TOI, normal FLC ratio remained an independent prognostic factor for longer PFS and TTNT. Similar trends were seen when considering treatment naïve and relapsed/refractory patients independently (data not shown).DiscussionOur results not only suggest an association between depth of response with PFS and TTNT, but also with OS in patients with WM. A normal FLC ratio (not part of the IWWM-7 response criteria) seems to predict a longer disease-free interval in patients achieving a PR or VGPR. [Display omitted] DisclosuresGertz:Ionis: Honoraria; Apellis: Consultancy; annexon: Consultancy; Prothena: Honoraria; janssen: Consultancy; Physicians Education Resource: Consultancy; Alnylam: Honoraria; Teva: Consultancy; spectrum: Consultancy, Honoraria; Medscape: Consultancy; celgene: Consultancy; Research to Practice: Consultancy; Amgen: Consultancy; Abbvie: Consultancy. Kapoor:Takeda: Research Funding; Celgene: Research Funding. Ailawadhi:Amgen: Consultancy; Janssen: Consultancy; Takeda: Consultancy; Pharmacyclics: Research Funding; Celgene: Consultancy. Reeder:Affimed: Research Funding. Witzig:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Dispenzieri:Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding. Lacy:Celgene: Research Funding. Kumar:Janssen: 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, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Ansell:Seattle Genetics: Research Funding; Celldex: Research Funding; Bristol-Myers Squibb: Research Funding; LAM Therapeutics: Research Funding; Trillium: Research Funding; Pfizer: Research Funding; Takeda: Research Funding; Merck & Co: Research Funding; Affimed: Research Funding; Regeneron: Research Funding.

Light Chain Amyloidosis and Non-Hodgkin's Lymphomas: A Peculiar Association with Distinct Clinical Features and Outcome

Bakground. The association of light chain (AL) amyloidosis with lymphoplasmacytic lymphoma/Waldenström's Macroglobulinemia is well established. However, both localized and systemic AL amyloidosis have been also reported in other types of lymphoma, but a detailed description of these cases is still lacking.Methods. We systematically searched the database of 1,415 newly diagnosed consecutive patients (pts) with AL amyloidosis of the Pavia Amyloidosis Research and Treatment Center for pts with non-lymphoplasmacytic lymphoma and AL amyloidosis, and identified 34 pts diagnosed between 2004 and 2018.Results. Seventeen pts (50%) had a diagnosis of marginal zone lymphoma (MZL), mainly extranodal MZL (EMZL). Median age at the time of lymphoma diagnosis was 65 years (45-81) and 23 pts (68%) were males. An autoimmune disease was documented in 8 pts (24%), with Sjögren Syndrome as the commonest type. Clinical characteristics of pts according to type of lymphoma (MZL vs non-MZL) and type of AL (systemic vs localized) are presented in Tables 1 and 2. The amyloid deposits were characterized as AL-type by immunoelectron microscopy or mass spectrometry in all cases.Twelve pts (35%) had a concomitant diagnosis of AL (within 12 months before or after the diagnosis of lymphoma). In 2 cases the diagnosis of lymphoma occurred after 16 and 45 months from diagnosis of AL, respectively. In 20 pts (10 MZLs), the lymphoma was diagnosed a median time of 58.6 months (range: 13.6-320.8 months) before AL diagnosis: all but 1 of these cases were treated for the underlying lymphoma and 16 of them had a complete remission at the time of AL diagnosis.Twenty-nine pts (85%) had positive serum and/or urine immunofixation and/or an abnormal free light chains ratio (FLCR), while 5 pts had no detectable monoclonal component (MC) and normal FLCR: these pts developed only localized AL amyloidosis. Localized AL was documented in 10 pts (29%), 7 of them had a MZL. Involved organs were represented by MALT sites (6 nodular pulmonary, 1 tracheobronchial, 2 skin, 1 bladder).Eleven pts with systemic AL amyloidosis died for progression of amyloidosis and 1 because of gastric cancer, while no patient with localized AL died during follow-up. The median overall survival (OS) from the diagnosis of AL amyloidosis was 42.5 months (Fig.1).Conclusions. In our series collected in a referral center, MZL is the most common non-lymphoplasmacytic lymphoma that associates with AL amyloidosis. Hematologists should be aware that MZL is associated not only with localized light chain deposition at the lymphoma site, but also with systemic AL amyloidosis. Systemic AL amyloidosis could be itself an indication to start a specific treatment for the lymphoproliferative disease, even in otherwise asymptomatic lymphomas. The presence of a MC and elevated FLC are clues for systemic AL amyloidosis. [Display omitted] DisclosuresMerlini:Prothena: Consultancy; Janssen: Consultancy; Ionis: Consultancy; Millenium: Consultancy; Akcea: Consultancy; Pfizer: Consultancy. Palladini:Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Other: Travel support; Prothena: Honoraria.