scholarly journals Estimating Selection Bias in Previous Monoclonal Gammopathy of Undetermined Significance Research - the Importance of Screening: Results from the Population-Based Screening Study Iceland Screens, Treats or Prevents Multiple Myeloma (iStopMM)

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1618-1618
Author(s):  
Aðalbjörg Ýr Sigurbergsdóttir ◽  
Sæmundur Rögnvaldsson ◽  
Sigrun Thorsteinsdottir ◽  
Ingigerdur Solveig Sverrisdottir ◽  
Gudrun Asta Sigurdardottir ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Selection Bias ◽  
Light Chain ◽  
Research Funding ◽  
Protein Concentration ◽  
Kidney Diseases ◽  
Population Based ◽  
M Protein ◽  
Related Factors ◽  
M Proteins

Abstract Introduction Monoclonal gammopathy of undetermined significance (MGUS) is a plasma cell disorder preceding multiple myeloma and related disorders, present in 4.2% of the population over the age of 50. Although usually asymptomatic, MGUS has been associated with various health-related problems, including thrombosis, infections, fractures, neuropathy, and death. Because MGUS is asymptomatic, its diagnosis is typically incidental, during clinical workup for unrelated medical issues, and therefore most individuals remain undiagnosed. Consequently, MGUS cohorts in past studies may have suffered from more comorbidities than the actual population with MGUS. This might have introduced selection bias in previous studies on MGUS, which extent has not been studied in a systematic way. Therefore, previously reported associations between MGUS and various medical issues might not be as profound as formerly observed. The aim of this study was to compare characteristics of incidentally diagnosed MGUS versus MGUS diagnosed by systematic screening, with particular focus on demographics, comorbidities, and MGUS-related factors. Methods The study is based on the Iceland Screens, Treats, or Prevents Multiple Myeloma (iStopMM) study. iStopMM is a population-based screening study for MGUS and a randomized controlled trial of follow-up strategies that has included 54% (n = 80,759) of the Icelandic population above 40 years of age. In total, 75,422 participants were screened for MGUS by serum protein electrophoresis (SPEP) and free light chain (FLC) assay. Information on which individuals had incidentally diagnosed MGUS (clinical MGUS) prior to participation in iStopMM were gathered from the Icelandic cancer registry and laboratory results from Landspítali University Hospital and Læknasetrið, the only laboratories in Iceland that perform SPEP. M-protein concentration, MGUS isotype and FLC ratio were obtained from the original screening samples. Comorbidity data was acquired from two high-quality national registries: Hospital Discharge Register and Register of Primary Health Care Contacts, with >95% completeness and accuracy. MGUS diagnosed by screening was further classified into MGUS with or without M-proteins (light-chain MGUS). Those with clinical MGUS were used as the reference group in all analyses. Since all individuals with clinical MGUS had M-proteins, individuals with light-chain MGUS were excluded from this study. T-test and chi-square test were used for demographic comparison; linear regression adjusting for sex and age for continuous variables, and logistic regression adjusting for sex and age for comparison of categorical variables, regarding MGUS-related factors and comorbidities. Results The study cohort consisted of 3,300 individuals who had MGUS with M-proteins; 224 individuals with clinical MGUS and 3,076 with screened MGUS. The clinical MGUS group was significantly older (p <0.01), more likely to live in the capital area of Iceland (p 0.02), and had a 0.14 g/dL higher mean M-protein concentration (95% confidence interval [95% CI] 0.10-0.19 g/dL, p <0.001) than those with screened MGUS. Individuals with clinical MGUS were also 1.73 times more likely to have a comorbidity (odds ratio [OR] 1.73, 95% CI 1.14-2.72, p 0.01) than those with screened MGUS, reflected in a significantly higher mean number of comorbidities (2.79 vs. 2.09, p <0.001). Finally, clinical MGUS were significantly more likely to have arrhythmias (OR 1.45, p 0.05), chronic kidney diseases (OR 2.42, p <0.001), endocrine diseases (OR 1.82, p <0.001), heart failure (OR 2.60, p <0.001), neurological diseases (OR 3.07, p <0.001) or rheumatological diseases (OR 3.25, p <0.001). Discussion In this large population-based study including 75,000 screened individuals, we found clinical MGUS cases to be older, more likely to live in Iceland's capital area, and have a higher M-protein concentration than those found to have MGUS while screened on the iStopMM study. Individuals with clinical MGUS also had a higher number of underlying comorbidities and were 1.5-3.3 times more likely to suffer from arrhythmias, chronic kidney diseases, endocrine disorders, heart failure, neurological diseases, and rheumatological diseases. Our findings highlight the importance of screening studies to evaluate the true epidemiological and biological implications of MGUS and suggest selection bias in prior studies. Figure 1 Figure 1. Disclosures Kampanis: The Binding Site: Current Employment. Hultcrantz: Daiichi Sankyo: Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees, Research Funding; Curio Science LLC: Consultancy; Amgen: Research Funding; Intellisphere LLC: Consultancy. Durie: Amgen, Celgene/Bristol-Myers Squibb, Janssen, and Takeda: Consultancy; Amgen: Other: fees from non-CME/CE services . Harding: The Binding Site: Current Employment, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Landgren: Janssen: Honoraria; Janssen: Other: IDMC; Takeda: Other: IDMC; Janssen: Research Funding; Celgene: Research Funding; Amgen: Honoraria; Amgen: Research Funding; GSK: Honoraria. Kristinsson: Amgen: Research Funding; Celgene: Research Funding.

scholarly journals Prevalence of Smoldering Multiple Myeloma: Results from the Iceland Screens, Treats, or Prevents Multiple Myeloma (iStopMM) Study

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 151-151
Author(s):  
Sigrun Thorsteinsdottir ◽  
Gauti Kjartan Gislason ◽  
Thor Aspelund ◽  
Sæmundur Rögnvaldsson ◽  
Jon Thorir Thorir Oskarsson ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
High Risk ◽  
Risk Stratification ◽  
Light Chain ◽  
Research Funding ◽  
Plasma Cells ◽  
Population Based ◽  
M Protein ◽  
Screening Study

Abstract Background Smoldering multiple myeloma (SMM) is an asymptomatic precursor condition to multiple myeloma (MM). Emerging data from clinical trials indicate that - compared to watchful monitoring - initiation of therapy at the SMM stage might be indicated. Currently, there is no established screening for SMM in the general population and therefore patients are identified incidentally. Here, we define for the first time, epidemiological and clinical characteristics of SMM in the general population based on a large (N>75,000) population-based screening study. Methods The iStopMM study (Iceland Screens Treats or Prevents Multiple Myeloma) is a nationwide screening study for MM precursors where all residents in Iceland over 40 years of age and older were invited to participate. Participants with a positive M-protein on serum protein electrophoresis (SPEP) or an abnormal free light chain (FLC) analysis entered a randomized controlled trial with three arms. Participants in arm 1 continued care in the Icelandic healthcare system as though they had never been screened. Arms 2 and 3 were evaluated at the study clinic with arm 2 receiving care according to current guidelines. In arm 3 bone marrow testing and whole-body low-dose CT (WBLDCT) was offered to all participants. SMM was defined as 10-60% bone marrow plasma cells on smear or trephine biopsy and/or M-protein in serum ≥3 g/dL, in the absence of myeloma defining events. Participants in arm 3 were used to estimate the prevalence of SMM as bone marrow biopsy was performed in all participants of that arm when possible. The age- and sex-specific prevalence was determined with a fitted function of age and sex, and interaction between those. Diagnosis at baseline evaluation of the individuals in the study was used to define the point prevalence of SMM. Results Of the 148,704 individuals over 40 years of age in Iceland, 75,422 (51%) were screened for M-protein and abnormal free light chain ratio. The 3,725 with abnormal screening were randomized to one of the three arms, and bone marrow sampling was performed in 1,503 individuals. A total of 180 patients were diagnosed with SMM, of which 109 (61%) were male and the median age was 70 years (range 44-92). Of those, a total of 157 (87%) patients had a detectable M-protein at the time of SMM diagnosis with a mean M-protein of 0.66 g/dL (range 0.01-3.5). The most common isotype was IgG in 101 (56%) of the patients, 44 (24%) had IgA, 2 (1%) had IgM, and 5 (3%) had biclonal M-proteins. A total of 24 (13%) patients had light-chain SMM. Four patients (2%) had a negative SPEP and normal FLC analysis at the time of SMM diagnosis despite abnormal results at screening. A total of 131 (73%) patients had 11-20% bone marrow plasma cells at SMM diagnosis, 32 (18%) had 21-30%, 9 (5%) had 31-40%, and 8 (4%) had 41-50%. Bone disease was excluded with imaging in 167 (93%) patients (MRI in 25 patients, WBLDCT in 113 patients, skeletal survey in 27 patients, FDG-PET/CT in 1 patient), 13 patients did not have bone imaging performed because of patient refusal, comorbidities, or death. According to the proposed 2/20/20 risk stratification model for SMM, 116 (64%) patients were low-risk, 47 (26%) intermediate-risk, and 17 (10%) high-risk. A total of 44 (24%) had immunoparesis at diagnosis. Using the PETHEMA SMM risk criteria on the 73 patients who underwent testing with flow cytometry of the bone marrow aspirates; 39 (53%) patients were low-risk, 21 (29%) patients were intermediate-risk, and 13 (18%) patients were high-risk. Out of the 1,279 patients randomized to arm 3, bone marrow sampling was performed in 970, and 105 were diagnosed with SMM (10.8%). The prevalence of SMM in the total population was estimated to be 0.53% (95% CI: 0.49-0.57%) in individuals 40 years of age or older. In men and women, the prevalence of SMM was 0.70% (95% CI: 0.64-0.75%) and 0.37% (95% CI: 0.32-0.41%), respectively, and it increased with age in both sexes (Figure). Summary and Conclusions Based on a large (N>75,000) population-based screening study we show, for the first time, that the prevalence of SMM is 0.5% in persons 40 years or older. According to current risk stratification models, approximately one third of patients have an intermediate or high risk of progression to MM. The high prevalence of SMM has implications for future treatment policies in MM as treatment initiation at the SMM stage is likely to be included in guidelines soon and underlines the necessity for accurate risk stratification in SMM. Figure 1 Figure 1. Disclosures Kampanis: The Binding Site: Current Employment. Hultcrantz: Daiichi Sankyo: Research Funding; Amgen: Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees, Research Funding; Curio Science LLC: Consultancy; Intellisphere LLC: Consultancy. Durie: Amgen: Other: fees from non-CME/CE services ; Amgen, Celgene/Bristol-Myers Squibb, Janssen, and Takeda: Consultancy. Harding: The Binding Site: Current Employment, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Landgren: Janssen: Research Funding; Janssen: Other: IDMC; Celgene: Research Funding; Takeda: Other: IDMC; Janssen: Honoraria; Amgen: Honoraria; Amgen: Research Funding; GSK: Honoraria. Kristinsson: Amgen: Research Funding; Celgene: Research Funding.

scholarly journals Screening for Monoclonal Gammopathy of Undetermined Significance: A Population-Based Randomized Clinical Trial. First Results from the Iceland Screens, Treats, or Prevents Multiple Myeloma (iStopMM) Study

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 156-156
Author(s):  
Sigurdur Y Kristinsson ◽  
Sæmundur Rögnvaldsson ◽  
Sigrun Thorsteinsdottir ◽  
Elin Ruth Reed ◽  
Jon Thorir Thorir Oskarsson ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Binding Site ◽  
Monoclonal Gammopathy ◽  
Research Funding ◽  
Population Based ◽  
Advisory Committees ◽  
M Proteins ◽  
Screening Study

Abstract Background: Cancer screening is performed worldwide for several malignancies. Monoclonal gammopathy of undetermined significance (MGUS) precedes multiple myeloma (MM) and related lymphoproliferative disorders (LP). However, less than 5% of all MM patients are diagnosed during their precursor state and individuals who develop MM while being monitored for MGUS have better overall survival and fewer complications, compared to MM patients diagnosed without knowledge of MGUS. Thus, population-based screening for MGUS could identify candidates for early treatment of MM/LPs. To evaluate whether systematic screening is beneficial, we performed the Iceland Screens, Treats, or Prevents Multiple Myeloma (iStopMM) study, the first population-based screening study for MGUS that includes a randomized clinical trial (RCT) of follow-up and treatment strategies. Methods: All living residents of Iceland on September 9th, 2016 who were born before 1976 (N=148,708) were invited to participate. Of those, 80,759 (54.3%) provided informed consent for screening. Serum samples were collected from participants alongside clinical blood sampling in the Icelandic health service between September 2016 and the end of 2020. All samples were shipped to the Binding Site in Birmingham, UK, for screening. Samples were tested for M-proteins by capillary zone electrophoresis and immunofixation electrophoresis performed to confirm and characterize suspected M-proteins. Free light chains (FLCs) were measured using the FreeLite® assay. Individuals with a previous diagnosis of MM/LPs/MGUS (N=237) were excluded. Per protocol and informed consent, participants with MGUS were randomized to one of the three study arms: Arm 1 where participants are not contacted; Arm 2 where individuals are followed based on current guidelines; and Arm 3 where individuals are followed with a more intensive diagnostic and monitoring strategy. Participants who progress are offered early treatment. All participants repeatedly answered questionnaires on quality of life and mental health. Results: A total of 75,422 participants (93.4%) provided a serum sample for screening. Of those, 3,725 (4.9%) had MGUS. The prevalence of MGUS was dependent on age with 2.3%, 6.2%, and 12.9% diagnosed in age groups 40-59, 60-79, and 80-103 years, respectively. The prevalence of MGUS was higher in males, 5.9% vs 4.1% (p<0.0001). Most individuals with MGUS had either low-risk (38%) or low-intermediate (36%) risk MGUS, followed by high-intermediate (26%) risk MGUS. High-risk MGUS was only present in 0.2% of MGUS cases (n=9). The RCT includes 3,487 newly diagnosed MGUS individuals with 1164, 1159, and 1164 individuals in arms 1, 2 and 3, respectively (Table). The median age at diagnosis was 69 years in arms 1 and 2, and 70 years in arm 3. Females constituted 45.9% and the isotypes were IgG (50%), IgA (10%), IgM (18%) and biclonal (8%). The median M-protein concentration was 0.34 g/dL. A total of 428 light-chain MGUS cases were randomized. The demographic distribution was well balanced between the three arms. After a median follow-up of 3 years, 194 patients in the RCT have been diagnosed with any LP: 9 in arm 1, 92 in arm 2, and 133 in arm 3 (p<0.001). The participants in arm 1 were diagnosed with smoldering Waldenström's macroglobulinemia (SWM)(N=2), WM (N=2), chronic lymphocytic leukemia (CLL) (N=1), and MM (N=4). Participants in arm 2 were diagnosed with amyloidosis (N=1), SWM (N=18), WM (N=2), CLL (N=2), non-Hodgkin lymphoma (NHL) (N=1), smoldering MM (SMM) (N=56), and MM (N=12). Participants in arm 3 were diagnosed with amyloidosis (N=2), SWM (N=22), CLL (N=5), NHL (N=6), SMM (N=82), and MM (N=16). The difference between study arms was statistically significant for all LPs combined, and for SWM, SMM, and MM (Table). Conclusion: In this large prospective population-based screening study including >75,000 screened persons, we have identified 3,725 individuals with monoclonal gammopathy. In the RCT, after 3 years of follow-up, we show that active screening identifies significantly higher number of individuals with full-blown malignancy and smoldering disease, illustrating the fact that early detection and intervention is achievable. Although our findings are encouraging, until final results of the iStopMM study become available, including data on survival and quality of life, we advise against systematic MGUS screening in healthy individuals. Figure 1 Figure 1. Disclosures Kristinsson: Amgen: Research Funding; Celgene: Research Funding. Kampanis: The Binding Site: Current Employment. Hultcrantz: Curio Science LLC: Consultancy; Daiichi Sankyo: Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Research Funding; Intellisphere LLC: Consultancy. Durie: Amgen: Other: fees from non-CME/CE services ; Amgen, Celgene/Bristol-Myers Squibb, Janssen, and Takeda: Consultancy. Harding: The Binding Site: Current Employment, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Landgren: Janssen: Research Funding; Celgene: Research Funding; Janssen: Honoraria; Janssen: Other: IDMC; Amgen: Honoraria; Takeda: Other: IDMC; Amgen: Research Funding; GSK: Honoraria.

A Pilot Study of Pomalidomide and Dexamethasone in Previously Treated Light Chain Amyloidosis Patients.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3854-3854 ◽  
Author(s):  
Angela Dispenzieri ◽  
Morie A Gertz ◽  
Suzanne R. Hayman ◽  
Francis Buadi ◽  
Shaji Kumar ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Adverse Events ◽  
Median Time ◽  
Light Chain ◽  
Research Funding ◽  
M Protein ◽  
Autonomic Nerve ◽  
Nerve Involvement ◽  
Previously Treated ◽  
Grade 3

Abstract Abstract 3854 Poster Board III-790 Background Primary systemic amyloidosis (AL) is an incurable plasma cell disorder. Lenalidomide, especially in conjunction with dexamethasone, has been shown to be active in patients with multiple myeloma. Pomalidomide is a derivative of thalidomide that acts as an immunomodulator. Preliminary data in multiple myeloma demonstrate that this agent is highly active and well tolerated. Methods Eligible patients were accrued into an IRB approved treatment trial with pomalidomide and dexamethasone after signing informed consent. Pomalidomide (2 mg) and dexamethasone (40 mg) were scheduled to be taken orally, the former on a continuous schedule and the latter once weekly. All patients were instructed to take an aspirin daily. Patients were eligible if they had previously treated, biopsy proven, symptomatic AL. Patients were required to have measurable hematologic disease, defined as either a serum M-protein greater than 1 g/dL, a urinary M-protein greater than 200 mg/24-hours, or a serum immunoglobulin free light chain greater than 10 mg/dL. Other eligibility criteria included an ECOG PS>=2, adequate hematologic reserve (ANC>=1000/uL, platelets>=75/uL) and adequate renal function (creatinine <=2.5 mg/dL). They also were required to comply with contraceptive requirements. Patients were excluded if they had uncontrolled infection, another active malignancy, NYHA classification III or IV, a serum troponin T >0.1 ng/mL, >=grade 3 peripheral neuropathy, untreated active thrombosis, or other chemotherapy within 2 weeks of study enrollment. Thirty-four patients are to be enrolled to allow for 2 possible cancels and to provide 90% power to detect a true hematologic response rate of at least 20%. Between 11/24/08-7/28/09, 20 patients have been enrolled. Baseline characteristics and adverse events are available for 17 of the 20 enrolled patients. Results Median age was 63 years (range 52 78), with 60% male. The median time from diagnosis to study entry was 45 months (range 4.5-103). Eighty-two percent had cardiac involvement; 41% renal involvement; 18% peripheral nerve involvement; and 12% autonomic nerve involvement. The cardiac biomarker staging breakdown was: I, 13%; II, 56%; and III, 31%. Patients were heavily treated, with 100% having received prior alkylator (including prior transplant in 9), 44% prior lenalidomide, 31% prior thalidomide, and 37% prior bortezomib. Thirty-three percent of patients had non-hematological adverse events (AEs) >=grade 3 (severe) that were deemed to be at least possibly related to therapy. Thirty-three percent had >=grade 3 hematologic AEs. Neutropenia was most the most common severe hematologic AE; severe thrombocytopenia was observed in only 1 patient, and there was no severe anemia. The most common severe non-hematologic AE was fatigue, which was observed in 3 patients. The only other severe AEs, each of which was observed in one subject each, were pneumonia, weakness, dyspnea, and ascites. As of 8/14/09, 17 patients remain on active therapy. Median time on study is only 3.7 months (range 0.2-8.1). Three patients have discontinued therapy: two progressions; and one death 5 days into treatment, presumably due to cardiac amyloidosis. At the time of this writing response rates could not be calculated given the short follow-up, but hematologic responses have been observed, and details on efficacy will be presented at the meeting. Conclusions Pomalidomide is well tolerated in previously treated AL patients. More information about its activity will be provided at the meeting. Disclosures: Dispenzieri: Celgene: Research Funding. Gertz:Celgene: Honoraria. Kumar:Celgene: Research Funding. Rajkumar:Celgene: Research Funding. Witzig:Novartis: Research Funding. Greipp:Celgene: Research Funding. Fonseca:Celgene: Consultancy. Bergsagel:Celgene: Consultancy. Mikhael:Celgene: Research Funding. Roy:Celgene: Research Funding. Lacy:Celgene: Research Funding.

scholarly journals Risk of Progression in Monoclonal Gammopathy of Undetermined Significance (MGUS): Results from a Population-Based Screening Study

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5650-5650
Author(s):  
Ebba K Lindqvist ◽  
Sigrun H Lund ◽  
Rene Costello ◽  
Debra Burton ◽  
Neha S Korde ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Serum Albumin ◽  
Lymphoproliferative Disorder ◽  
Protein Concentration ◽  
Population Based ◽  
M Protein ◽  
Kaplan Meier ◽  
Risk Of Progression ◽  
Annual Risk ◽  
Low Serum

Abstract Background Monoclonal gammopathy of undetermined significance (MGUS) is a precursor condition to multiple myeloma and other lymphoproliferative disorders. In individuals with MGUS, the average risk of progression to a lymphoproliferative disorder has been estimated to be 1% per year, however, most previous studies have been performed on clinically established cohorts and very few have been population-based. A high monoclonal (M)-protein concentration, non-isotype IgG, and skewed free light chain (FLC) ratio are routinely taken into account when assessing risk for progression. Other risk factors have also been identified, such as low serum albumin. Methods The cohort under study consisted of 299 individuals, 158 men and 141 women, with MGUS, identified through screening the participants of the population-based, longitudinal AGES-Reykjavik Study using serum protein electrophoresis and FLC assessment. The median age was 78 years (range 67-93 years). The outcome was first incidence of lymphoproliferative disorder, denoting multiple myeloma, lymphoma, amyloidosis, lymphocytic leukemia, plasmacytoma, and Waldenström's macroglubulinemia. Information on outcomes was supplemented by cross-linkage to national registries, and median follow-up time was 8.8 years. A Cox proportional hazards model was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the risk of lymphoproliferative disorders. Results were adjusted for serum albumin in categories (below 35 g/L, 35-40 g/L, or above 40 g/L), M-protein concentration (above or below 15 g/L), FLC ratio, levels of free light chains, use of statins, smoking status, renal function in categories, and M-protein isotype. The multivariate model was reduced in a step-wise manner to a final model with only significant covariates. Results During follow-up, 26 of 299 individuals with MGUS proceeded to develop a lymphoproliferative disorder, representing a cumulative risk of 8.7% and an annual risk of 1.0%. MM occurred in 17 of 218 individuals with non-IgM MGUS, representing a cumulative risk of 7.8% and an annual risk of 0.9%. In multivariate analysis, the final model contained serum albumin, M-protein concentration, and isotype A versus all other isotypes. Low serum albumin (HR = 6.3, 95% CI 1.0-40.6 for <35 g/L, and HR = 3.9, 95% CI 1.1-14.2 for 35-40 g/L), high M-protein concentration (HR = 4.1, 95% CI 1.2-14.0), and isotype A (HR = 5.8, 95% CI 1.6-21.0) were significantly associated with risk of progression. In a similar model for progression to multiple myeloma only, low serum albumin, high M-protein concentration, and isotype A were also significantly associated with risk of progression, although the impact of low serum albumin was greater (HR = 33.1, 95% CI 2.4-462.2 for <35 g/L, HR = 10.97, 95% CI 1.4-88.3 for 35-40). When assigning a risk score for progression where 1 point each was assigned for isotype IgA, serum albumin <35 g/L, and M-protein concentration >15 g/L, the HRs for individuals with 1 point was 3.9 (95% CI 1.6-9.9), and for 2 points 10.02 (95% CI 2.3-43.3). No individual had 3 points. For Kaplan-Meier estimates from risk scores, see Figure. Summary and conclusions In this large, population-based screening study, we found an annual risk of progression from MGUS to lymphoproliferative disease of 1%. Low serum albumin, high M-protein concentration, and M-protein isotype A were all independent risk factors for progression. Our results are in line with results from previous studies where a low serum albumin at MGUS diagnosis also has been associated with shorter survival and/or malignant transformation. Results from our study contradict previous studies that have pointed to skewed FLC ratio as an important risk factor for progression; in our study, a skewed FLC ratio was not significantly associated with risk of progression when adjusted for other covariates. The findings in our study suggest that serum albumin is important to take into account when assessing the risk of progression for individuals with MGUS. Figure 1 Kaplan-Meier estimates for risk of progression, by risk score. Figure 1. Kaplan-Meier estimates for risk of progression, by risk score. Disclosures Korde: Medscape: Honoraria. Landgren:Merck: Honoraria; Takeda: Honoraria; Amgen: Honoraria, Research Funding; Medscape Myeloma Program: Honoraria; BMS: Honoraria; Celgene: Honoraria, Research Funding.

scholarly journals Monoclonal gammopathy of undetermined significance (MGUS) consistently precedes multiple myeloma: a prospective study

Blood ◽  
2009 ◽  
Vol 113 (22) ◽  
pp. 5412-5417 ◽  
Author(s):  
Ola Landgren ◽  
Robert A. Kyle ◽  
Ruth M. Pfeiffer ◽  
Jerry A. Katzmann ◽  
Neil E. Caporaso ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Monoclonal Gammopathy ◽  
Population Based ◽  
Serum Samples ◽  
M Proteins ◽  
Cancer Screening Trial ◽  
Risk Of Progression ◽  
Study Population ◽  
A Prospective Study ◽  
Undetermined Significance

Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant plasma-cell proliferative disorder associated with a life-long risk of progression to multiple myeloma (MM). It is not known whether MM is always preceded by a premalignant asymptomatic MGUS stage. Among 77 469 healthy adults enrolled in the nationwide population-based prospective Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, we identified 71 subjects who developed MM during the course of the study in whom serially collected (up to 6) prediagnostic serum samples obtained 2 to 9.8 years prior to MM diagnosis were available. Using assays for monoclonal (M)–proteins (electrophoresis/immunofixation) and kappa-lambda free light chains (FLCs), we determined longitudinally the prevalence of MGUS and characterized patterns of monoclonal immunoglobulin abnormalities prior to MM diagnosis. MGUS was present in 100.0% (87.2%-100.0%), 98.3% (90.8%-100.0%), 97.9% (88.9%-100.0%), 94.6% (81.8%-99.3%), 100.0% (86.3%-100.0%), 93.3% (68.1%-99.8%), and 82.4% (56.6%-96.2%) at 2, 3, 4, 5, 6, 7, and 8+ years prior to MM diagnosis, respectively. In approximately half the study population, the M-protein concentration and involved FLC-ratio levels showed a yearly increase prior to MM diagnosis. In the present study, an asymptomatic MGUS stage consistently preceded MM. Novel molecular markers are needed to better predict progression to MM in patients with MGUS.

Immunoglobulin Free Light Chains at Diagnosis: Predictors of Progression and Survival in Solitary Plasmacytoma of Bone.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5080-5080 ◽  
Author(s):  
David Dingli ◽  
Robert A. Kyle ◽  
Vincent S. Rajkumar ◽  
Grzegorz S. Nowakowski ◽  
Dirk R. Larson ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Plasma Cells ◽  
Univariate Analysis ◽  
Prognostic Indicator ◽  
M Protein ◽  
Solitary Plasmacytoma ◽  
Time To Progression ◽  
Number Of Patients ◽  
M Proteins ◽  
Risk Of Progression

Abstract Background: Solitary plasmacytoma of bone (SBP) is a localized collection of monoclonal plasma cells that is potentially curable with local radiation therapy but associated with a high risk of progression to multiple myeloma. We hypothesized that an abnormal immunoglobulin free light (FLC) ratio at diagnosis may be a prognostic indicator of transformation risk. Methods: We identified a cohort of 133 patients with SBP for whom stored serum taken at the time of diagnosis was available. The diagnosis was ascertained and serum FLC determined in 126 patients. Results: From this cohort, 48 patients have progressed to myeloma and the median time to progression among those who progressed was 1.9 years. On univariate analysis, age (p&lt;0.001), gender (p=0.035), abnormal FLC ratio at diagnosis (p=0.009) and persistence of serum or urine M-protein after therapy (p=0.0070 were all associated with a shorter overall survival (OS) and time to progression to multiple myeloma. Progression by Normal FLC(0.26–1.65) Progression by Normal FLC(0.26–1.65) On multivariate analysis, an abnormal FLC ratio retained its independence in a model that includes age at diagnosis but lost its significance when combined with persistence of the serum or urine M-protein. However, serum or urine M-proteins are not detectable in a significant number of patients with SBP and therefore not informative. Conclusion: The FLC ratio at the time of diagnosis of SBP is a powerful predictor of risk and a useful aid to management of patients with this condition.

SWOG S0120 Observational Trial for MGUS and Asymptomatic Multiple Myeloma (AMM): Imaging Predictors of Progression for Patients Treated At UAMS,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3955-3955
Author(s):  
Christoph Heuck ◽  
Rachael Sexton ◽  
Madhav Dhodapkar ◽  
Qing Zhang ◽  
Saad Usmani ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Research Funding ◽  
Cox Regression ◽  
Time Dependent ◽  
M Protein ◽  
Risk Scores ◽  
Imaging Studies ◽  
Focal Lesions ◽  
Pet Ct

Abstract Abstract 3955 Background: MGUS counts for the majority of monoclonal gammopathies and can be found in approximately 3% of adults older than 50 years. MGUS progresses to active Multiple Myeloma (MM) at a rate of 1–2% per year, thus imparting an average risk of 25% for progression (PRO) over a lifetime once diagnosed. Unfortunately no single laboratory, molecular or imaging variable can reliably predict PRO. S0120 accrued 363 patients at 69 sites across the US between January 1, 2004 and November 1, 2011, of whom 166 had MGUS and 190 AMM, defined according to IMWG criteria, on whom laboratory, gene expression and imaging studies were collected in a prospective fashion. Here we report the results of imaging studies as predictors of progression. Methods: 262 patients with evaluable follow-up were enrolled at the University of Arkansas for Medical Sciences (UAMS) site. MRI and PET-CT studies were performed at baseline and serially thereafter until PRO to symptomatic MM defined by standard variables of M-protein, bone marrow findings and CRAB criteria, according to protocol. Lab studies were performed at three months, six months and one year after registration, then every 12 months for a total of 5 years from registration as well as within 14 days of decision to discontinue observation or within 14 days of progression. MRI parameters included the number of focal lesions (FL) recognized by short TI inversion recovery (STIR) analysis of the axial bone marrow along with an account of bone marrow background intensity compared to adjacent muscles (hypo-, iso-, hyper-intense). PET-CT parameters included number of FDG-avid focal lesions (PET-FL), SUVmax of PET-FL, presence of extra-medullary disease (EMD) as well as the FDG avidity score at L5 (SUV-L5). Evaluable baseline MRI and PET studies were available for 235 and 224 patients, respectively. Results: In the 262 eligible patients enrolled and followed at UAMS, the two subgroups of MGUS and AMM differed by definition in M-protein and bone marrow plasmacytosis; in addition, IgA subclass and Hyperdiploidy molecular subgroup were overrepresented in the AMM group. Patients in the AMM group also had higher risk scores defined by the GEP 70-gene risk model (GEP70). At 24 months from study entry, 18.8% of all patients had progressed to MM (25.6% of AMM patients and 8.2% of MGUS patients) and 11.5% had begun MM therapy (15.8% of AMM patients and 4.5% of MGUS patients). Univariate Cox regression strongly indicated that age ≥ 65, serum albumin <3.5g/dL, B2M >+3.5mg/L, detection of any cytogenetic abnormalities (CA), and suppression of uninvolved light chains were adversely associated with time to PRO. The AMM-constituting features, bone marrow plasmacytosis >10%, M-protein >30g/L, and abnormal K/L ratio also conferred greater hazard of PRO. Risk scores > −0.26 and >1.5 for GEP70 and GEP80, respectively, as well as detection of focal lesions by MRI at baseline carried an elevated HR for PRO. A multivariate Cox regression showed only elevated M-protein, abnormal K/L ratio and GEP70 risk scores > =0.26 to be strongly associated with time to PRO. In the context of this MV model, disease subtype (AMM v MGUS) was insignificant. Inclusion of development of MRI-FL or and PET-FL as time-dependent variables showed that they were associated with time to PRO with HRs of 27.12 and 32.18 respectively. Abnormal K/L ratio and elevated M-protein were lost in this MV model. Analyzing variables linked to initiation of MM therapy, abnormal K/L ratio, elevated BM plasmacytosis, elevated M-protein, GEP70 risk scores >-0.26 as well as detection of MRI-FL at baseline (≥1 FL: HR=4.90; ≥3FL: HR=10.00) were univariately significant. On multivariate analysis, abnormal K/L ratio, elevated M-protein and GEP70 risk scores > – 0.26 were associated with time to treatment for MM. Inclusion of development of MRI-FL or PET-FL as a time dependent variable were associated with time to treatment with HRs of 29.12 and 36.50 respectively. Conclusion: To our knowledge, this is the first comprehensive effort that has used available imaging modalities along with established laboratory and pathology investigations in an attempt to distinguish features predictive of PRO from MGUS to active MM. In addition to the established “high-risk” MGUS/AMM features, we found that presence of MRI-FL at baseline, presence of CA and GEP70 scores >-0.26 carry a higher risk of PRO. Disclosures: Shaughnessy: Myeloma Health, Celgene, Genzyme, Novartis: Consultancy, Employment, Equity Ownership, Honoraria, Patents & Royalties. Barlogie:Celgene: Consultancy, Honoraria, Research Funding; IMF: Consultancy, Honoraria; MMRF: Consultancy; Millennium: Consultancy, Honoraria, Research Funding; Genzyme: Consultancy; Novartis: Research Funding; NCI: Research Funding; Johnson & Johnson: Research Funding; Centocor: Research Funding; Onyx: Research Funding; Icon: Research Funding.

Clinical Responses In Patients Infused With T Lymphocytes Redirected To Target κ-Light Immunoglobulin Chain

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 506-506 ◽  
Author(s):  
Carlos A. Ramos ◽  
Barbara Savoldo ◽  
Enli Liu ◽  
Adrian P. Gee ◽  
Zhuyong Mei ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Light Chain ◽  
Stable Disease ◽  
Research Funding ◽  
B Cell Malignancies ◽  
Car T Cells ◽  
Car T

Abstract Adoptive transfer of T cells with a CD19-specific chimeric antigen receptor (CAR) to treat B-cell malignancies shows remarkable clinical efficacy. However, long-term persistence of T cells targeting CD19, a pan-B cell marker, causes sustained depletion of normal B cells and consequent severe hypogammaglobulinemia. In order to target B-cell malignancies more selectively, we exploited the clonal restriction of mature B-cell malignancies, which express either a κ or a λ-light immunoglobulin (Ig) chain. We generated a CAR specific for κ-light chain (CAR.κ) to selectively target κ+ lymphoma/leukemia cells, while sparing the normal B cells expressing the reciprocal λ-light chain, thus minimizing the impairment of humoral immunity. After preclinical validation, we designed a phase I clinical trial in which patients with refractory/relapsed κ+ non-Hodgkin lymphoma (NHL) or chronic lymphocytic leukemia (CLL) are infused with autologous T cells expressing a CAR.κ that includes a CD28 costimulatory domain. The protocol also included patients with multiple myeloma with the aim of targeting putative myeloma initiating cells. Three dose levels (DL) are being assessed, with escalation determined by a continual reassessment method: 0.2 (DL1), 1 (DL2) and 2 (DL3) ×108 T cells/m2. Repeat infusions are allowed if there is at least stable disease after treatment. End points being evaluated include safety, persistence of CAR+T cells and antitumor activity. T cells were generated for 13 patients by activating autologous PBMC with immobilized OKT3 (n=5) or CD3/CD28 monoclonal antibodies (n=8). In 2 patients with >95% circulating leukemic cells, CD3 positive selection was performed using CliniMACS. After transduction, T cells (1.2×107±0.5×107) were expanded ex vivo for 18±4 days in the presence of interleukin (IL)-2 to reach sufficient numbers for dose escalation. CAR expression was 81%±13% by flow cytometry (74,112±23,000 transgene copy numbers/mg DNA). Products were composed predominantly of CD8+ cells (78%±10%), with a small proportion of naïve (5±4%) and memory T cells (17%±12%). CAR+ T cells specifically targeted κ+ tumors as assessed by 51Cr release assays (specific lysis 79%±10%, 20:1 E:T ratio) but not κ–tumors (11%±7%) or the NK-sensitive cell line K562 (26%±13%). Ten patients have been treated: 2 on DL1, 3 on DL2 and 5 on DL3. Any other treatments were discontinued at least 4 weeks prior to T-cell infusion. Patients with an absolute leukocyte count >500/µL received 12.5 mg/kg cyclophosphamide 4 days before T-cell infusion to induce mild lymphopenia. Infusions were well tolerated, without side effects. Persistence of infused T cells was assessed in blood by CAR.κ-specific Q-PCR assay and peaked 1 to 2 weeks post infusion, remaining detectable for 6 weeks to 9 months. Although the CAR contained a murine single-chain variable fragment (scFv), we did not detect human anti-mouse antibodies following treatment and CAR.κ+T cell expansion continued to be observed even after repeated infusions. We detected modest (<20 fold) elevation of proinflammatory cytokines, including IL-6, at the time of peak expansion of T cells, but systemic inflammatory response syndrome (cytokine storm) was absent. No new-onset hypogammaglobulinemia was observed. All 10 patients are currently evaluable for clinical response. Of the patients with relapsed NHL, 2/5 entered complete remission (after 2 and 3 infusions at dose level 1 and 3, respectively), 1/5 had a partial response and 2 progressed; 3/3 patients with multiple myeloma have had stable disease for 2, 8 and 11 months, associated with up to 38% reduction in their paraprotein; and 2/2 patients with CLL progressed before or shortly after the 6-week evaluation. In conclusion, our data indicate that infusion of CAR.κ+ T cells is safe at every DL and can be effective in patients with κ+ lymphoproliferative disorders. Disclosures: Savoldo: Celgene: Patents & Royalties, Research Funding. Rooney:Celgene: Patents & Royalties, Research Funding. Heslop:Celgene: Patents & Royalties, Research Funding. Brenner:Celgene: Patents & Royalties, Research Funding. Dotti:Celgene: Patents & Royalties, Research Funding.

Phase 1 Study of the Investigational Proteasome Inhibitor Ixazomib Alone or in Combination with Lenalidomide–Dexamethasone (Rd) in Japanese Patients (Pts) with Relapsed and/or Refractory Multiple Myeloma (RRMM)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5752-5752 ◽  
Author(s):  
Hiroshi Handa ◽  
Kenshi Suzuki ◽  
Takaaki Chou ◽  
Takafumi Matsushima
Keyword(s):  
Multiple Myeloma ◽  
Proteasome Inhibitor ◽  
Research Funding ◽  
Phase 1 ◽  
Single Agent ◽  
Japanese Patients ◽  
M Protein ◽  
Phase 3 ◽  
Grade 3 ◽  
Ongoing Phase

Background Ixazomib is the first oral proteasome inhibitor to be investigated clinically for the treatment of MM. Phase 1 studies have shown single-agent activity and manageable toxicities in RRMM (Kumar et al. Blood 2014) and phase 1/2 studies have suggested the feasibility and activity of weekly oral ixazomib plus Rd in previously untreated MM (Kumar et al. ASH 2012; Richardson et al. ASH 2013). These findings have led to ongoing phase 3 trials of weekly ixazomib 4 mg + Rd in RRMM and previously untreated MM. However, the early-phase studies were conducted in Western pts. This phase 1, open-label multicenter study aimed to determine the safety, tolerability, and pharmacokinetics (PK) of weekly ixazomib alone or with Rd in Japanese pts with RRMM (Japic Clinical Trials Information no. 121822). Methods Primary objectives were to evaluate the safety and tolerability, including dose-limiting toxicities (DLTs) and adverse events (AEs), and the PK of ixazomib alone or with Rd. A secondary objective was evaluation of antitumor activity. Japanese pts aged ≥20 years with RRMM who had received at least 2 prior regimens, which must have included bortezomib, thalidomide or lenalidomide, and corticosteroids, were eligible. All had measurable disease and ECOG performance status of 0–2. Pts with grade ≥2 peripheral neuropathy or grade ≥2 diarrhea at study entry were excluded. Pts received ixazomib 4 mg on days 1, 8, and 15 of 28-day cycles, alone or with Rd (lenalidomide 25 mg on days 1–21, dexamethasone 40 mg on days 1, 8, 15, and 22), per the regimen used in the ongoing phase 3 trials. AEs were graded per NCI-CTCAE v4.03. Blood samples for PK analysis were taken at multiple time points prior to and after dosing on days 1 and 15 of cycle 1. Responses were assessed per IMWG uniform response criteria. Results Fourteen pts were enrolled; 8 (57%) were male, median age was 62.5 yrs (range 53–71), 4 pts were aged ≥65 yrs, median number of prior therapies was 7. Seven pts received single-agent ixazomib and 7 received ixazomib + Rd. One pt in each cohort was excluded from the DLT-evaluable population. Two patients experienced DLTs in cycle 1: 1 pt receiving single-agent ixazomib had grade 4 thrombocytopenia and grade 3 diarrhea, hypertension, hypokalemia, hyponatremia, and nausea; 1 pt in the ixazomib + Rd cohort had grade 4 thrombocytopenia and neutropenia. All events were considered treatment-related. At data cut-off (Jan 6 2014), 6 pts remained on treatment and 8 had discontinued due to: progressive disease (PD; n=3), AEs (n=3), symptomatic deterioration, and protocol violation (each n=1). At data cut-off, pts (n=14) had received a median of 6 cycles of ixazomib (range 1–21); the 7 pts in the ixazomib + Rd cohort had received a median of 4 cycles (range 1–12) of ixazomib + Rd. Thirteen (93%) pts experienced treatment-related AEs; the most common were neutropenia (71%), thrombocytopenia (71%), leukopenia (64%), lymphopenia (57%), and diarrhea (50%). There were no cases of peripheral neuropathy. Nine (64%) pts had grade ≥3 AEs; the most common were lymphopenia (50%), neutropenia (43%), and thrombocytopenia (36%). Two (14%) pts (single-agent cohort) had serious AEs (grade 2 bronchitis in 1 pt, and grade 4 thrombocytopenia and grade 3 hypokalemia in 1 pt). Three pts discontinued due to AEs; 1 due to diarrhea in the single-agent cohort, and 1 due to neutropenia and 1 due to thrombocytopenia in the ixazomib + Rd cohort. There were no deaths. PK data showed ixazomib was rapidly absorbed with a Tmax at 1.08–1.83 hrs. Terminal half-life (geometric mean) was 5.7 days for single-agent ixazomib and 5.2 days for ixazomib + Rd. There were no substantial differences in the ixazomib PK profile between the two cohorts. Thirteen pts were response-evaluable. One pt (ixazomib + Rd cohort) had a partial response; at data cut-off, this pt remained in response with a 100% M-protein reduction (unconfirmed VGPR) and duration of response of ~10.8 months. Seven pts had stable disease (including 3 with M-protein reductions of 25–50%), 2 had PD, and 3 were not assessable. Conclusions These data suggest that ixazomib 4 mg alone or with Rd is feasible and tolerable in Japanese pts with RRMM. The AEs were manageable, reflecting the AE profile seen in Western populations, supporting the use of this dose and schedule in Japanese pts. Disclosures Handa: Celgene: Research Funding; Yakult: Research Funding; Kirin: Research Funding; Chugai: Research Funding. Off Label Use: Investigational agent ixazomib for the treatment of Japanese patients with relapsed and/or refractory multiple myeloma.. Matsushima:Takeda Pharmaceutical Company Limited : Employment.

Evaluation of the Concordance of Two Free Light Chains Assays to Identify High Risk Smoldering Myeloma Patients.

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2070-2070 ◽  
Author(s):  
Caroline Moreau ◽  
Emmanuel Rouger ◽  
Basile Henriot ◽  
Martine Escoffre ◽  
Martine Sebillot ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Binding Site ◽  
Light Chain ◽  
Research Funding ◽  
Plasma Cells ◽  
Organ Damage ◽  
Free Light Chain ◽  
Poor Correlation ◽  
Specificity And Sensitivity

Abstract Background Smoldering multiple myeloma (SMM) is a precursor disease of multiple myeloma (MM). According to 2003 classification, the IMWG (International Myeloma Working Group) recommended only to treat patients with end organ damage - often referred as CRAB criteria (hypercalcemia, renal failure, anemia and radiological bone lesions). The standard of care for SMM was to postpone treatment until progression to symptomatic disease occurred. The average annual risk of progression of SMM to MM was 10%/year. In 2014 IMWG proposed a revised classification including 3 new criteria that enable early diagnosis of MM before organ damage. The new criteria of MM needs the presence of more than 10% clonal bone marrow plasma cells combined with either the presence of end organ damage (CRAB criteria) or one of following new biomarkers of malignancy: bone marrow plasma cells ≥60%, serum free light chains (FLC) ratio ≥100 and ≥2 focal lesions on MRI. The FLC criteria were established with Freelite™ assay (The Binding Site Company) and have not been validated with other available assays. Freelite™ assay which used polyclonal antibodies was available since 2001. More recently N Latex assay (Siemens Healthyneers) using monoclonal antibodies has been commercialized in Europe. It is now well know that there is a good correlation between the 2 assays even though results in absolute values are not numerically identical. In this context, the aim of this study was to evaluate the concordance between the two assays to identify high risk SMM, when considering the biomarker of malignancy FLC ratio ≥100. Methods This is a retrospective study including 185 patients with SMM according to 2003 IMWG criteria. FLC concentration and ratio were evaluated in frozen sera with both assays in a BN Prospec and evolution status was collected. Results The average age was 62.5 (± 10.2) years old. Results revealed poor correlation between the 2 assays with a Slope Passing-Bablok value of 0.63 (0.57-0.67) for the FLC κ and of 0.44 (0.35-0.62) for the κ/ λ ratio ≥ 100, and concordance in determining the level of FLC λ with a Slope Passing-Bablok 1.16 (0.99-1.40). A Freelite™ratio ≥ 100 was found in 27 patients (14.3%), and a N Latex ratio ≥ 100 was found in 10 patients (5.3%). All but one patients with an N Latex ratio ≥ 100 had also a Freelite™ ratio ≥ 100. Mean of follow up was 2.4 years. A progression toward MM was observed in 77 (40.7%) patients. Among the 27 patients with Freelite™ ratio ≥ 100, 14 patients (55.5%) have evolved toward MM (figure 1A). Specificity and sensitivity for a Freelite™ ratio ≥ 100 were respectively 88.7% (95% CI 81.8 to 94.0%) and 20.3% (95% CI 11.8 to 31.2%). With the N Latex Assay, only 10 patients had a FLC ratio ≥ 100, in which 7 patients have evolved towards MM. Specificity and sensitivity for a N-Latex ratio ≥ 100 were respectively be 67.0% (95% CI 57.4 to 75.6%) and 53.2% (95% CI 41.5 to 64.7%). Given the poor predictive performance of a N-Latex ratio ≥ 100 we determined that a N-Latex ratio ≥ 70 have adequate specificity of 95.5% (95% CI 89.9 to 98.5%) and a sensitivity of 13.0% (95% CI 6.4 to 22.6%) (figure 1B). 15 patients (8.1%) patients had a N-Latex ratio ≥ 70. Among these, 10 patients (66.6%) have evolved toward MM. Conclusion Our study shows poor correlation between the two FLC assays in SMM patients. A Freelite™ ratio ≥ 100 had a lesser specificity than previously described (specificity 95% in Larsen study [1]). The 100 cut-off value was not performant enough for N-Latex assay. A new ratio is thus needed and was found to be 70 to have sufficient specificity and sensitivity. This result need to be validated in an independent cohort. However, with a Freelite™ ratio ≥ 100 or an N Latex ratio ≥ 70, a significant number of patients would have been overtreated. Physicians should be aware of the limits of both assays. 1.Larsen JT, Kumar SK, Dispenzieri A, Kyle RA, Katzmann JA, Rajkumar SV. Serum free light chain ratio as a biomarker for high-risk smoldering multiple myeloma. Leukemia. 2013;27:941-6. Figure 1 probability of progression to overt multiple myeloma (A) according to Freelite™ ratio (cut-off 100) (B) according to N-Latex ratio (cut-off 70) Figure 1. probability of progression to overt multiple myeloma (A) according to Freelite™ ratio (cut-off 100) (B) according to N-Latex ratio (cut-off 70) Disclosures Moreau: The Binding Site: Other: supply of free light chain assays ; SIEMENS: Other: supply of free light chain assays , Research Funding. Decaux:The Binding Site: Other: supply of free light chain assays , Research Funding; SIEMENS: Honoraria, Other: supply of free light chain assays , Research Funding.

Sign in / Sign up

Export Citation Format

Share Document