Abnormal Free Light Chain Ratio Research Articles

Serum markers alone can define high-risk smouldering multiple myeloma: new insights from the Czech Myeloma Group model.

The overall risk of developing symptomatic multiple myeloma (MM) from the asymtomatic precursor state, smoldering multiple myeloma (SMM), is 10% per year, but varies greatly with the presence of certain risk factors.1 The heterogeneous clinical course of SMM has led the International Myeloma Working Group (IMWG) to propose that patients with an 80% risk of progression at two years after an SMM diagnosis should be regarded as symptomatic MM patients and offered treatment.2 Therefore, the updated diagnostic MM criteria included three biomarker sassociated with a very high risk of progression; BMPC% ≥60, sFLCr ≥100 and/or more than one focal lesion on MRI.2 Within the last decades, several variables have been identified as associated with an increased risk of SMM progression to MM. Most risk-models are composed of a combination of serum markers3, 4 or a combination of serum markers along with bone marrow biopsy5, 6 flow-cytometry,7 imaging8 or molecular markers.9, 10 However, there is still no international consensus on which factors should be used as the standard risk stratification. Furthermore, one study found poor consistency between two widely used risk-models (PETHEMA and Mayo Clinic) when applied to the same patient cohort.11 Also, in the Danish study we found that the two-year progression-risk of having an abnormal FLC ratio ≥100 was only 30% and thus nowhere near the >80% risk as shown in the two studies which formed the basis of the IMWG guidelines.4 There are two important problems with the different SMM risk-models published so far: (i) the models are usually based on single-centre observations, and (ii) not all models consist of easily accessible markers for risk stratification. Together, this increases the risk of bias and to a certain degree compromises the ability of the risk-models to be used in the broader SMM population. It seems reasonable to assume that the lack of reproducibility of SMM high-risk models is also influenced by the biological heterogeneity of precursor diseases. A study analysing the whole genome sequence of pared tumour samples from 10 patients progressing from SMM to MM showed that the complexity of the genomic profile is generally not associated with a shorter time-to-progression (TTP) and that both a static and spontaneous sub-clonal evolution was found among the tested patients.12 How conventional serum and/or bone marrow markers serve as the correct proxy for the underlying genomic profile of the individual SMM patient is unknown. In this issue of the journal, Hájek et al. presents a new risk-model based on the data from the Czech Myeloma Group (CMG) and Heidelberg group. Based on data from the nationwide CMG registry, the authors first identified a high-risk subpopulation of SMM patients with a 78·7% two-year progression risk using immunoparesis, M-protein level ≥2·3 g/l and a FLC ratio >30 risk factors only. The risk-model was subsequently tested externally in the Heidelberg cohort, which arguably represents a specialised MM centre. Interestingly, the authors found a remarkably similar two-year progression risk (81·3%) when the model was tested in the Heidelberg population. Furthermore, Hájek et al. used the same data for a post-hoc comparison with other published risk-models and found that the CMG data did not meet the 80% progression rate threshold, indicating that the CMG model is more robust than previously proposed risk-models. Do we need more risk-models for SMM? With the QuiRedex study we saw that upfront treatment with lenalidomide-dexamethasone of high-risk patients does prolong TTP and overall survival (OS).13 Side effects were fairly modest with few grade 3 events.13 Arguably, if patients have a better OS and side effects are manageable, then the risk of doing more harm than good when starting anti-MM treatment is low. However, if high-risk SMM patients with high-risk features are to be considered as symptomatic MM patients, standard treatment should arguably involve three-drug induction treatment followed by ASCT for younger as well as fit elderly patients. Recently, daratumumab monotherapy for high-risk SMM patients was evaluated in the phase 2 Centaurus trial.14 The study did not meet the co-primary endpoint of CR >15%, thus indicating that a more aggressive multi-drug regimen is probably needed for disease eradication. Several clinical trials using different risk-models are underway to evaluate intensive treatment approaches in SMM. A real strength with the new CMG model is the external validation and use of accessible serum risk factors which makes this model practical for inclusion in future clinical trials or for the evaluation of SMM patients in everyday clinical practice.

Imaging of Monoclonal Gammapathy of Undetermined Significance and Smoldering Multiple Myeloma.

Multiple myeloma (MM) is always preceded by an initial monoclonal gammopathy of undetermined significance (MGUS) that then develops into asymptomatic or smoldering multiple myeloma (SMM), which constitutes an intermediate clinical stage between MGUS and MM. According to a recent study, risk factors for faster MGUS to MM progression include an M protein of 1.5 g/dL or more and an abnormal free light chain ratio in patients with non-IgM MGUS. Therefore, the International Myeloma Working Group (IMWG) decided to recommend whole-body computed tomography (WBCT) for patients with high-risk MGUS in order to exclude early bone destruction. Studies evaluating magnetic resonance imaging (MRI) in SMM found an optimal cutoff of two or more focal lesions to be of prognostic significance for fast progression into symptomatic disease and considered this biomarker as a myeloma-defining event (MDE) needing to start therapy with the aim to avoid progression to harmful bone lesions. Moreover, studies assessing positron emission tomography (PET) with computed tomography (CT) using 18F-deoxyglucose (FDG) (FDG-PET/CT) in SMM showed that presence of focal bone lesion without underlying osteolysis is associated with a rapid progression to symptomatic MM. Latest IMWG guidelines recommended to perform WBCT (either CT alone or as part of an FDG-PET/CT protocol) as the first imaging technique at suspected SMM and, if these images are negative or inconclusive, to perform whole-body MRI. The goal of this paper is to clarify the role of different imaging modalities in MGUS and SMM workups.

Short-Term Risk of Progression of Patients with Asymptomatic Monoclonal Gammopathies to Active Multiple Myeloma: The Critical Impact of the Tumoral Mass

The identification of risk factors for progression is critical in the clinical management and appropriate follow up of patients with pre-malignant Asymptomatic Monoclonal Gammopathies (AMG) including Monoclonal Gammopathy of Undetermined Significance (MGUS) and Smoldering Multiple Myeloma (SMM). The development of prognostic score and consequently the early identification of patients with possible short-term progression to Multiple Myeloma (MM) could lead to anticipate the treatment. In this study, we retrospectively evaluated possible risk factors of short-term progression to active MM in a large cohort of MGUS and SMM patients admitted to a single haematological center (Hematology and BMT Unit, University Hospital of Parma) between 2010 and 2018. We analysed a total cohort of 235 patients diagnosed with AMG (81 MGUS and 154 SMM) according to the IMWG recently updated diagnostic criteria. All patients analysed underwent to Bone Marrow (BM) examination; moreover, imaging evaluation was performed in 22 MGUS and 123 SMM patients, in order to exclude the presence of bone disease. In a subgroup of AMG patients (n=50), bone mineral density (BMD) evaluation by Dual-energy X-ray Absorptiometry (DXA) was also available. Median age of the AMG patients analysed was 68 years (range 35-93 years). Median percentage of BM plasma cells (BMPCs) was 12% (range 2-55%) in the entire population, 7% (range 2-9) in MGUS and 15% (range 10-55) in SMM patients. Median serum M-protein was 1.7 g/dL (range: 0.17-4.5), 1.5 g/dL (range 0.17-4.5) in MGUS and 1.8 g/dL (range 0.4-2.7) in SMM patients. An abnormal free light chain (FLC) ratio was found in 70% of AMG patients, among the ones that performed the analysis; regarding SMM patients, FLC ratio value was available in 97 patients: in 72 (76%) the ratio was unbalanced, 37 (39%) had a FLC ratio ≤ 0.125 or ≥ 8 and in 14 (15%) it was > 20; among MGUS patients, value was collected in 41 patients and in 21 (51%) it was <0.26 or >1.65. The presence of immunoparesis in one or two uninvolved immunoglobulins occurred in 59% of the entire population. The median follow up time was 18 months (range 0 - 111 months) for whole population. Overall 44 patients of the entire cohort progressed to MM (41 SMM and 3 MGUS) with a median TTP of 14.5 months. By univariate analysis we found that percentage of BMPCs, entity of M-protein and presence of immunoparesis were significantly correlated with progression to active MM (p<0.001 for each variable). On the other hand, abnormal FLC ratio did not reach a statistical significance, as well as value of the involved FLC (p=0.059). Nevertheless, the presence of a FLC ratio < 0.125 or > 8 (as used in Mayo scoring system for SMM) showed a relationship at the limit of statistical significance in this subgroup of patients (p=0.052). Any significant correlation was not observed with age, sex, Ig isotype, light chain's type and the BMD values (p=NS). Afterwards, we applied Kaplan Meier method on risk factors resulted significant in univariate analysis demonstrating that they also significantly influenced the time to progression to MM. Finally, through a binomial logistic regression, we developed a new prognostic score for whole population. By combining the values of M-protein (< 2, score=0 or ≥ 2 g/dL, score=1) and the percentage of BMPC (<10%, score=0, 10-20%, score=1 and >20%, score=2), we obtained six groups at different probability of progression to active MM (Table 1). Given that result, we stratified patients in 3 groups: low-risk (score=0), intermediate-risk (score=1) and high-risk (score≥2); log-rank test confirmed that high-risk patients had a significantly shorter time to progression to symptomatic MM as compared to intermediate and low-risk patients (p<0.001). In conclusion, our results show that in patients with AMG the clinical factors, which mostly impact on the short-term risk of progression to active MM, are the entity of the PCs infiltrate and the MC related to the tumoral mass. The development of a clinical score based on BMPCs and M-protein will permit to overcome the traditional distinction between MGUS and SMM in the evaluation of the progression of AMG patients to active MM. Disclosures Giuliani: Janssen: Research Funding.

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&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 <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 <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&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&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<0.001), the dFLC10 group (39 months, P<0.001), and the normal-FLCR group (24 months, P<0.001). We then evaluated whether achieving a normal iFLC or a dFLC <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 <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.

Renal Pathology in Patients with Monoclonal Gammopathy or Multiple Myeloma: Monoclonal Immunoglobulins Are Not Always the Cause

Renal disease in monoclonal gammopathies (MGs) is associated with several different pathologies with prognostic and treatment implications. In symptomatic MM, cast nephropathy is a leading cause of renal dysfunction and acute renal failure (ARF) but in patients with other MGs the diagnoses may be diverse and monoclonal gammopathy of renal significance (MGRS) is well described. Renal biopsy is required in such cases in order to establish the diagnosis, especially if selective Bence Jones proteinuria is absent. MGs are more frequent in the elderly, in which renal diseases are also common, associated with underlying co-morbidities (diabetes, hypertension etc). However, although common, there is limited data on the frequency of monoclonal immunoglobulin (MIg)-unrelated pathologies in patients with a known MG presenting with renal dysfunction. Thus, we evaluated the frequency of non-MIg related renal pathologies in patients with known MGs, in a series of consecutive patients from a single referral center (Department of Clinical Therapeutics, Athens , Greece). We reviewed our database and identified 79 patients with known MGs that had a renal biopsy for evaluation of renal dysfunction, and which was performed after the diagnosis of MG. We excluded patients in which renal biopsy was performed before the diagnosis of the MG. At the time of renal biopsy, median age was 69 years (range 39-84), 63% were males, 28% had diabetes, 72% hypertension, 22.5% CAD, 7% an autoimmune disease ; 45% had known symptomatic MM (N=36) and 55% a prior diagnosis of MGUS or SMM. Median eGFR was 33 ml/min/1.73 m2 (range 4-110), 15% required dialysis, median proteinuria was 3.1 gr/d and was >0.5 gr/d in 93%. Abnormal FLC ratio was present in 69.5%, median dFLC level was 85 mg/L and 62% had dFLC>50 mg/L. In urine protein electrophoresis (PEP), median albumin proportion was 40% (range 3-100%) and median urine monoclonal protein was 2% (range 0-97%) of the total urine protein. Reasons leading to renal biopsy included proteinuria (with <50% creatinine increase) in 61% and ARF (with or without proteinuria) in 39%. Renal pathology revealed a MIg-related diagnosis in 68%, which included cast nephropathy in 13%, MIDD in 25%, AL amyloidosis in 25% and other MGRS in 5%. A non MIg-related diagnosis was established in 32%, and included diabetic nephropathy in 5%, hypertension-associated in 14%, single cases of IgA nephropathy, chinese herb nephropathy, obesity-related GN and in 8% was drug related. Among MM patients, 26/36 were on therapy when renal biopsy was performed, 19/36 (53%) were in hematologic remission. Notably, in 11/19 (58%) of MM patients in remission, renal pathology was not related to MIg vs 6/17 (35%) of those not in remission or at the time of MM diagnosis. Factors that were associated with MIg-related pathology included serum albumin <3 gr/dl (88% vs 60%, p=0.007), proteinuria >1.7 gr/d (82% vs 48%, p=0.004), a positive UIFE (75% vs 33%, p=0.039), urine monoclonal protein >100 mg/d (68% vs 25%, p=0.003), dFLC > 50 mg/L (76% vs 37%, p=0.003) and abnormal FLC ratio (78% vs 53%, p=0.044). The presence of other co-morbidities (diabetes, hypertension, history of CAD, history of autoimmune disease) or the presence of hematuria or the reason leading to renal biopsy (proteinuria or ARF) were not associated with a diagnosis of non MIg-related renal pathology. In multivariate analysis, only urine monoclonal protein >100 mg/d (HR:7.95, 95% CI 1.3-47, p=0.024) was independently associated with a diagnosis of MIg-related pathology. If parameters of urine PEP (urine monoclonal protein, urine IFE) were not included in the analysis, then total proteinuria >1.7 gr/d (HR: 4.5, 95% CI 1.1-18, p=0.036) and dFLC>50 mg/L (HR:5.8, 95% CI 1.15-29, p=0.033) were the only independent predictors. By using these two parameters 7% of those without any vs 30% with any of the two vs 63% with both factors had a MIg related renal pathology. In conclusion, among patients with known monoclonal gammopathies and renal dysfunction, 32% had a non MIg-related diagnosis, which had implications in their management. Urine protein electrophoresis can help identify those at higher probability of MIg-related renal disease and should be evaluated in all patients with MGs; otherwise, dFLC > 50 mg/L and proteinuria >1.7 gr/d can be used. Renal dysfunction should not attributed to the underlying MIg without careful consideration of the other parameters and of a renal biopsy. Disclosures Kastritis: Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Honoraria; Pfizer: Honoraria; Prothena: Honoraria; Genesis: Honoraria. Gavriatopoulou:Genesis: Honoraria, Other: Travel expenses; Amgen: Honoraria; Janssen: Honoraria, Other: Travel expenses; Takeda: Honoraria, Other: Travel expenses. Terpos:Medison: Honoraria; Genesis: Honoraria, Other: Travel expenses, Research Funding; Takeda: Honoraria, Other: Travel expenses, Research Funding; Janssen: Honoraria, Other: Travel expenses, Research Funding; Celgene: Honoraria; Amgen: Honoraria, Research Funding. Dimopoulos:Sanofi Oncology: Research Funding.

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% (<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<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 <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.

Clinical Impact of an Early Response and of Early Initiation of Salvage Therapy in Patients with Systemic Light Chain (AL) Amyloidosis

Clinical Impact of an Early Response and of Early Initiation of Salvage Therapy in Patients with Systemic Light Chain (AL) Amyloidosis

Treatment with Daratumumab in Patients with Multiple Myeloma Associated AL Amyloidosis

Treatment with Daratumumab in Patients with Multiple Myeloma Associated AL Amyloidosis

Use of Quantitative Immunoprecipitation Mass Spectrometry to Resolve the Complexity of Plasma Cell Populations in Multiple Myeloma

Clonal heterogeneity and evolution of neoplastic plasma cells are common events in multiple myeloma (MM). Myeloma cells can produce M-proteins as intact immunoglobulins (Ig) with or without excess free light chains (FLC), FLC only or, rarely, no detectable M-protein. Ig are characterized by serum immunofixation electrophoresis (IFE) whereas FLC are quantified by turbidimetry (Freelite), two methods that are not always in concordance. Approximately 95% of MM patients have an abnormal FLC ratio but do not always show the abnormal FLC by IFE.

Prognostic impact of rapid involved light chain reduction in first line therapy with Bendamustine, Prednisone and Bortezomib (BPV) in myeloma patients

Light chain involvement is observed in almost every newly diagnosed multiple myeloma (MM). While 15-20% of MM patients suffer of a light chain only myeloma, 70-80% of IgA and IgG myeloma present an additional abnormal free light chain ratio (FLCR), too. Due to a shorter half life period a rapid reduction of the involved light chain (iFLC) could be of prognostic value in order to personalize and optimize treatment options.

Direct Detection of Monoclonal Free Light Chains in Serum by Use of Immunoenrichment-Coupled MALDI-TOF Mass Spectrometry

Free light chain (FLC) quantification is the most analytically sensitive blood-based method commercially available to diagnose and monitor patients with plasma cell disorders (PCDs). However, instead of directly detecting monoclonal FLCs (mFLCs), FLC assays indirectly assess clonality based on quantifying κ and λ FLCs and determination of the к/λ FLC ratio. Often an abnormal FLC ratio is the only indication of a PCD, and confirmation by a direct method increases diagnostic confidence. The aim of this study was to develop an analytically sensitive method for direct detection of mFLCs. Patient sera (n = 167) previously assessed by nephelometric FLC quantification and immunofixation electrophoresis (IFE) were affinity enriched for IgG, IgA, and total and free κ and λ light chains and subjected to MALDI-TOF MS. Relative analytical sensitivity of these methods was determined using serially diluted sera containing mFLCs. In sera with abnormal FLC ratios (n = 127), 43% of monoclonal proteins were confirmed by IFE, 57% by MALDI-TOF MS without FLC enrichment, and 87% with FLC enrichment MALDI-TOF MS. In sera with normal FLC ratios (n = 40), the FLC MALDI-TOF MS method identified 1 patient with an mFLC. Serial dilution and analysis of mFLC containing sera by IFE, nephelometry, and FLC MALDI-TOF MS demonstrated that FLC MALDI-TOF MS analysis had the highest analytical sensitivity. FLC immunoenrichment coupled to MALDI-TOF MS enables direct detection of mFLCs and significantly increases the confirmation of abnormal serum FLC ratios over IFE and MALDI-TOF MS without FLC enrichment, thereby providing added confidence for diagnosing FLC PCDs.

Monoclonal Gammopathy Of Unknown Significance - A Common Incidental Finding - What is to be thought of? What has to be done?

Monoclonal gammopathy of unclear significance (MGUS) is detected at high frequency in a variety of disciplines as an incidental finding. MGUS can be associated with non-malignant diseases, but it also can be a precursor of malignant lymphoproliferative disorders (multiple myeloma, Waldenstroem's disease, other non-Hodgkin's lymphoma, light chain (AL) - amyloidosis). However, many of these patients remain asymptomatic throughout their lives. Screening is performed by serum protein electrophoresis, immunofixation and determination of quantitative immunoglobulins and free light chains in serum. Currently, general population screening is not recommended. There are three subtypes with different rates and types of progression: IgM-MGUS, non-IgM-MGUS, and light-chain MGUS. The scope of further diagnostics and follow-up is based on the clinical findings and risk stratification (monoclonal protein in serum < or ≥ 15 g/l and normal or abnormal free light chain ratio in serum). If paraprotein-associated disease is detected, gammopathy is of clinical significance and should not be referred to as MGUS.

PS1392 CONSOLIDATION WITH A SHORT COURSE OF DARATUMUMAB CAN SIGNIFICANTLY IMPROVE COMPLETE RESPONSE RATES IN PATIENTS WITH AL AMYLOIDOSIS OR LCDD

Background:A deep hematologic response is associated with the highest probability of organ function and survival improvement in patients with AL amyloidosis. Bortezomib‐based therapy is the primary therapy for patients with AL amyloidosis but less than 40% achieves a CR. Further improvement of hematologic response may be achieved by consolidation strategies but HDM‐ASCT is associated with significant toxicity, and only a minority of AL patients is eligible for this treatment. Recent data indicate that even a short course of daratumumab (DARA) was able to induce hematologic responses in patients with relapsed or refractory AL. Thus, DARA may be a unique treatment to improve the outcomes of patients with AL amyloidosis.Aims:To evaluate the feasibility and activity of a short course of daratumumab as a consolidation strategy, in patients with AL or LCDD which had achieved either PR or VGPR after completing their primary therapy, with bortezomib‐based therapy.Methods:The endpoint of this exploratory approach was improvement of response post completion of DARA consolidation. All patients received 4 weekly infusions of daratumumab 16 mg/kg with dexamethasone 20 mg. Pre‐emptive therapy for IRR was given starting two days before the first infusion of DARA. In all patients next generation flow (NGF) according to Euroflow protocol was performed before and after consolidationResults:26 patients (23 AL and 3 with LCDD) received DARA consolidation. Median age is 67 and 73% were males. Kidneys and heart were involved in 80% and 73% respectively, baseline Mayo stage was 20%, 67% and 13% for stage 1,2 &amp; 3 respectively. Baseline immunofixation in serum or urine was positive in all patients (19/23 of AL patients were lambda). Median time from start of first line therapy to DARA consolidation was 8 months and all patients had completed the planned bortezomib‐based treatment. Before consolidation all patients were in either VGPR (23/23 AL patients and 2/3 LCDD patients) or in PR (1/3 LCDD patients); all patients had positive serum and/or urine immunofixation with or without abnormal FLC ratio. All but one patient received the planned 4 infusion of DARA. Mild IRR (Gr1) were observed in 3 patients. After consolidation with DARA, 42% of the patients (10/23 with AL and 1/3 with LCDD) achieved a CR. In 9/26 patients small monoclonal IgGk was observed 1 month post DARA and in all but one patient IgGk resolved at 2–3 months post DARA. The patient that received only one dose of daratumumab also achieved a CR. In all patients MRD by NGF was positive before DARA consolidation while DARA 6/11 patients in CR became MRDnegative. All patients that did not achieve a VGPR remained MRD positive. One patient with IgGk AL that remained with positive immunofixation after DARA was MRD(neg). Because of interference with daratumumab we repeated immunofixation, which 2 months after daratumumab became negative.Summary/Conclusion:Consolidation with a short course of DARA can improve the depth of response in patients with AL or LCDD that have not achieved a CR after primary therapy, including MRD negative disease in some.We will further explore this strategy in a formal clinical trial with a longer duration of daratumumab therapy so that CR and MRD negative rates may improve further.

E3A06: Randomized phase III trial of lenalidomide versus observation alone in patients with asymptomatic high-risk smoldering multiple myeloma.

8001 Background: Smoldering multiple myeloma (SMM) is a precursor to myeloma, wherein current standard of care is observation (obs). Data from a randomized Spanish trial (Mateos et al, NEJM 2015) suggest that lenalidomide(len)/dexamethasone improves time to developing myeloma (TTP) and overall survival (OS) for patients (pts) with high risk (HR) SMM over obs. However, pts were not screened with advanced imaging techniques, used a HR definition that is not routinely available, and combination therapy limited the ability to isolate the effect of len, and thus has not become standard of care. Methods: E3A06 is a randomized phase III intergroup trial, testing the effect of single agent len compared with obs for pts with intermediate or high risk SMM. In an initial phase II run in all pts received len to demonstrate safety. Eligibility required ≥10% PCs and abnormal serum FLC ratio (&lt;0.26 or &gt;1.65). The primary endpoint was progression PFS was estimated by the Kaplan-Meier method and compared using the one-sided stratified log-rank test. Results: PII enrolled 44 pts and PIII randomized 182 pts to either len (n=90) or obs (n=92) [stratified on time since SMM diagnosis ≤1y vs &gt;1y]. Baseline characteristics were similar between the arms. 80% (PII) and 51% (PIII) are off len, primarily due to adverse events (AE) or pt withdrawal. Among the len treated pts, G3/4 non-hematologic AE occurred in 28% of PIII pts with fatigue being most common (n=5). G4 hematologic AE rate was 5.7%, primarily neutropenia (n=4). 3-year cumulative incidence of invasive SPMs was 5.2% (len) and 3.5% (obs). Overall response rate was 47.7% for the phase II study, and in phase III, 48.9% for the len arm, and 0% for the obs arm. Median follow up was 71 months (PII), and 28 months (PIII). 3-year PFS was 87% for the PII cohort. One, 2 and 3-year PFS was 98%, 93%, and 91% for len, and 89%, 76%, and 66% for the obs arm (HR 0.28, p=0.0005) favoring the len arm. No difference in QOL score was noted between arms. Conclusions: Overall, this trial represents the largest randomized trial in SMM to date. In conjunction with the Spanish data, this trial may support a change in clinical practice. Clinical trial information: NCT01169337. [Table: see text]

Elevated IgM and abnormal free light chain ratio are increased in relatives from high-risk chronic lymphocytic leukemia pedigrees

Abnormal serum immunoglobulin (Ig) free light chains (FLC) are established biomarkers of early disease in multiple B-cell lymphoid malignancies, including chronic lymphocytic leukemia (CLL). Heavy chains have also been shown to be biomarkers in plasma cell disorders. An unanswered question is whether these Ig biomarkers are heritable, i.e., influenced by germline factors. CLL is heritable but highly heterogeneous. Heritable biomarkers could elucidate steps of disease pathogenesis that are affected by germline factors, and may help partition heterogeneity and identify genetic pleiotropies across malignancies. Relatives in CLL pedigrees present an opportunity to identify heritable biomarkers. We compared FLCs and heavy chains between relatives in 23 high-risk CLL pedigrees and population controls. Elevated IgM (eIgM) and abnormal FLC (aFLC) ratio was significantly increased in relatives, suggesting that these Ig biomarkers are heritable and could offer risk stratification in pedigree relatives. Within high-risk CLL pedigrees, B-cell lymphoid malignancies were five times more prevalent in close relatives of individuals with eIgM, prostate cancer was three times more prevalent in relatives of individuals with aFLC, and monoclonal B-cell lymphocytosis increased surrounding individuals with normal Ig levels. These different clustering patterns suggest Ig biomarkers have the potential to partition genetic heterogeneity in CLL and provide insight into distinct heritable pleiotropies associated with CLL.

Utility of the Serum Free Light Chain Assay in the Diagnosis of Light Chain Amyloidosis in Patients With Heart Failure

ObjectiveTo determine the utility of the serum free light chain (FLC) assay for routine screening of light chain amyloidosis (AL) in patients with heart failure. Patients and MethodsWe studied consecutive new patients referred to the Heart Failure Clinic who had the FLC assay performed for routine screening at Mayo Clinic's campus in Rochester, Minnesota, from January 1, 2011, through December 31, 2015. An FLC ratio between 0.26 and 1.65 was considered normal. ResultsOf the 1173 patients in the study (mean age, 64±15 years), 207 had an abnormal FLC ratio. Light chain amyloidosis was diagnosed in 0.5% of all patients (6 of 1173) and in 2.9% of those with an abnormal FLC ratio (6 of 207). To increase the pretest probability of an abnormal FLC ratio in predicting AL, we considered patients with an N-terminal pro B-type natriuretic peptide level of 5000 pg/mL or greater (to convert to pmol/L, multiply by 0.1182) and a left ventricular posterior wall thickness of 13 mm or greater; this increased the diagnostic yield to 66.7% (6 of 9). ConclusionThe prevalence of AL in patients with heart failure could be 0.5% or higher. Compared with the use of the serum FLC assay for routine screening, a targeted approach of the serum FLC assay in those with higher N-terminal pro B-type natriuretic peptide level (≥5000 pg/mL) and increased posterior wall thickness (≥13 mm) has a markedly higher yield for the diagnosis of AL.

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.

Mass Spectrometry to Measure Response in Immunoglobulin Light Chain Amyloidosis (AL)

Mass Spectrometry to Measure Response in Immunoglobulin Light Chain Amyloidosis (AL)

Smoldering Multiple Myeloma: Usefulness of Serum Heavy/Light Chain Measurements for the Evaluation of Evolving Pattern

Introduction: Smoldering multiple myeloma (SMM) is an asymptomatic and biologically heterogeneous clonal plasma cell disorder. A number of prognostic factors to identify patients at a higher risk of progression have been described, such as the size of the M protein, proportion of abnormal bone marrow plasma cells (BMPCs), immunoparesis and serum free light chain (FLC) k/l ratio. More recently, isotype-specific uninvolved heavy and light chain (HLC) pair suppression measured with the Hevylite assay was also associated with an increased risk of progression. Recent studies have evaluated the key prognostic impact of an increase in M-protein levels during follow-up (“evolving” pattern). However, an important limitation could be the evaluation of M-protein level variations based on serum protein electrophoresis (SPE) in patients with a small size M-spike. The aim of this study was to prospectively analyze the changes in M-protein according to SPE and HLC measurements, as well as other risk factors for progression, in patients with SMM.Methods: Thirty patients newly diagnosed with SMM at a single institution from January 2014 through September 2017 were prospectively included in the study. For each patient, baseline levels of known prognostic factors (serum M-protein, serum and urine immunofixation, clonal BMPCs percentage, total immunoglobulins, involved/uninvolved FLC and involved/uninvolved HLC pairs) were recorded. During the follow up, M-protein level, FLC and isotype specific HLC pairs were also analyzed. Evolving change in M-protein level according to SPE was defined as ³ 10% increase within the first 6 months of diagnosis (if M-protein was ³ 30 g/L) and/or ³ 25% increase within the first 12 months (for any level of M-protein); evolving change according to HLC was defined as a ³ 10% increase in the involved pair. A sequential increase in each of three or more consecutive measurements from diagnosis was considered an evolving change regardless of its magnitude.Results: The clinical characteristics of the total of patients, as well as of the patients with evolving changes in M-protein according to HLC are summarized in Table 1.During the study period, 5/30 (17%) of patients demonstrated an evolving behavior of the M-protein according to SPE. Four of these patients (4/5) also showed a progressive increase in the M-protein in the HLC measurements. One patient showed stable HLC levels even though both the M-protein and the involved FLC progressively increased. This patient was of intermediate and low risk according to Mayo Clinic and PETHEMA scores, respectively. On follow up, no progressive suppression of the isotype-specific uninvolved HLC pair or increase in the FLC ratio was noted, and there have been no signs of progression after a follow up of 3 years.According to involved HLC-pair levels, 12/30 (40%) of patients demonstrated an evolving behavior. Five out of 7 patients that were not classified as evolving by SPE, were IgA isotype. Eight out of 12 patients showed severe isotype-specific suppression of the uninvolved HLC-pair (> 50% below lower level of normal) as well as a highly abnormal FLC ratio (<0.125 or >8). Three out of the 4 remaining patients showed either severe isotype-specific HLC pair suppression or highly abnormal FLC ratio in follow up measurements. Compared to patients with no “HLC-evolving pattern”, evolving patients were more likely to have highly abnormal FLC ratios (90 vs. 33%, p=0.009), severe suppression of the other isotypes (64 vs. 19%, p=0,024), highly abnormal isotype-specific HLC ratios (67 vs. 33%, p=NS), severe isotype-specific HLC-pair suppression (75 vs. 50%, p=NS), and immunoparesis (67 vs. 39%p=NS).Five patients progressed to symptomatic multiple myeloma during follow up; 4 of them showed a progressive increase in the involved HLC pair from diagnosis. The remaining patient demonstrated a progressive increase in the involved HLC pair that started 19 months prior to progression, followed 4 months later with an increase in M-protein as measured by SPE.Conclusions: In our series, the Hevylite assay allowed us to identify patients with a progressive increase in M-protein (clonal heavy/light chain pair) that was not evident with SPE measurements. This “HLC evolving pattern” was associated with other risk factors for progression to symptomatic disease and with worsening of other prognostic parameters during follow up. [Display omitted] DisclosuresRosinol:Janssen, Celgene, Amgen, Takeda: Honoraria. Bladé:Janssen: Honoraria.

Relapse after complete response in newly diagnosed multiple myeloma: implications of duration of response and patterns of relapse.

Achieving a complete response (CR) is associated with improved overall survival (OS) in multiple myeloma (MM), but data on duration of CR (DurCR) are limited. We evaluated 351 patients (2004-2016), achieving CR with first-line therapy. Patients with sustained DurCR ≥ 24 months (n = 177) had better OS; 150 vs. 81 months, p < 0.001. DurCR ≥ 24 months remained a significant predictor for OS (HR: 0.3, 95% CI: 0.2-0.5, p < 0.001) after adjusting for age, revised ISS stage, transplant and maintenance therapy. Landmark analysis at 24 months demonstrated similar results, OS: 150 vs. 83 months, p < 0.001. Survival benefit persisted even after loss of CR, with median OS being 89 vs. 56 months (p = 0.005), respectively. Patterns of loss of CR were heterogeneous, with biochemical relapse in 59 (25%); symptomatic relapse in 58 (24%); positive immunofixation/monoclonal protein rise not meeting relapse/progression criteria in 88 (37%) and abnormal free light chain ratio in LC MM in 34 (14%) patients. OS from start of first-line therapy was superior in patients starting second-line treatment for biochemical vs. symptomatic relapse (125 vs. 81 months, p = 0.001). This is likely attributable to underlying disease biology and prevention of end-organ damage by early treatment initiation, as benefit was independent of R-ISS stage.