Patterns of Myeloma (MM) Progression After Autologous Transplant (AHCT) – Biochemical Progression Vs. Clinical Relapse

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 5097-5097
Author(s):  
Robert Frank Cornell ◽  
Jonathan Thompson ◽  
Leena Varkey Maramattom ◽  
Veerpal Singh ◽  
Ayman A Saad ◽  
...  
Keyword(s):  
Median Time ◽  
Light Chain ◽  
Conflicts Of Interest ◽  
Bone Lesion ◽  
Stage Iii ◽  
Clinical Relapse ◽  
Serum Free Light Chain ◽  
Measurable Serum ◽  
Biochemical Progression ◽  
M Spike

Abstract Abstract 5097 Background: The uniform response criteria for MM suggest that in clinical practice early biochemical progression (EBP) of MM and clinical relapse (clinREL) be distinguished to identify symptomatic patients requiring therapy. The interval between EBP and clinREL in MM is not well characterized. Biochemical progression in those with intact immunoglobulin MM (IIM) could involve serum free light chain (SFLC) progression or monoclonal component (M spike) progression by serum protein electrophoresis (SPE) or both. ClinREL could precede, be concurrent with or follow tumor marker elevation. Methods: We studied EBP and clinREL in 221 consecutive AHCT recipients for MM between 2005 and 2010. Patients with IIM and measurable M spike and SFLC elevation at diagnosis were analyzed. Patients were uniformly monitored at a single institution with SFLC and SPE every 8–12 weeks. Biochemical progression and clinREL were defined by standard IMWG criteria (Durie el al, Leukemia 2006). ClinREL was defined by new/progressive bone lesion or plasmacytoma, hypercalcemia (>11.5 mg/dl), decrease in hemoglobin ≥ 2 g/dl, rise in creatinine ≥ 2 mg/dl, or indication for new myeloma therapy. Results: 76 patients had clinREL after AHCT, 24 were excluded due to light chain predominant or oligosecretory disease, subsequent AlloHCT or other preemptive treatment. Among 52 evaluable patients, median age was 57 years (42–74), 72% had DSS stage III, 40% ISS stage III, 40% high-risk (HR) MM based on t(4;14), t(14;16), 17q del or karyotypic 13 q abnormality. Median time from AHCT to relapse was 484 days (76–1631). Three temporal patterns of MM recurrence were identified: EBP where SFLC/M spike elevation (or both) preceded clinREL (n=28, 54%); concurrent clinREL and SFLC/M spike elevation (n=22, 42%) or isolated clinREL (4%). The proportion of HR MM was similar among groups. The EBP cohort had superior OS compared to concurrent relapse cohort (log rank p <0.0001). Additionally in the EBP cohort, SFLC elevation alone (39%), M spike progression alone (22%) or concurrent SFLC and M spike (39%) progression could be the initial relapse marker. After isolated SFLC progression, median time to M spike progression was 112 days and to clinREL was 200 days. After isolated M spike progression median time to clinREL was 254 days. After simultaneous SFLC and M spike progression median time to clinREL was 234 days. In these 3 groups, overall time to clinREL after AHCT was longest for patients with M spike progression alone (17.8, 20.5 and 36.8 months, respectively; p=0.05). This was due to HR MM being more common in the first 2 groups (45% for isolated SFLC and 37% in the simultaneous SFLC/M spike group). Discussion: In this cohort of relapsed MM after transplant, 54% had isolated early biochemical progression prior to clinREL and this pattern predicted for superior survival. The category of clinREL may not be detected in advance in about one half of patients and predicts for more aggressive relapse. Present guidelines do not recommend SFLC monitoring for relapse in IIM patients with measurable serum M spike. Based on the above data early SFLC progression was seen in 20% of relapses and identified a higher risk subgroup within those with biochemical progression preceding clinREL. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Long-Term Biological Variation of Serum Protein Electrophoresis M-Spike, Urine M-Spike, and Monoclonal Serum Free Light Chain Quantification: Implications for Monitoring Monoclonal Gammopathies

2011 ◽  
Vol 57 (12) ◽  
pp. 1687-1692 ◽  
Author(s):  
Jerry A Katzmann ◽  
Melissa R Snyder ◽  
S Vincent Rajkumar ◽  
Robert A Kyle ◽  
Terry M Therneau ◽  
...  
Keyword(s):  
Serum Protein ◽  
Light Chain ◽  
Protein Electrophoresis ◽  
Free Light Chain ◽  
Serum Protein Electrophoresis ◽  
Serum Free ◽  
Serum Free Light Chain ◽  
Measurable Serum ◽  
M Spike ◽  
Serial Samples

BACKGROUND We analyzed serial data in patients with clinically stable monoclonal gammopathy to determine the total variation of serum M-spikes [measured with serum protein electrophoresis (SPEP)], urine M-spikes [measured with urine protein electrophoresis (UPEP)], and monoclonal serum free light chain (FLC) concentrations measured with immunoassay. METHODS Patients to be studied were identified by (a) no treatment during the study interval, (b) no change in diagnosis and &lt;5 g/L change in serum M-spike over the course of observation; (c) performance of all 3 tests (SPEP, UPEP, FLC immunoassay) in at least 3 serial samples that were obtained 9 months to 5 years apart; (d) serum M-spike ≥10 g/L, urine M-spike ≥200 mg/24 h, or clonal FLC ≥100 mg/L. The total CV was calculated for each method. RESULTS Among the cohort of 158 patients, 90 had measurable serum M-spikes, 25 had urine M-spikes, and 52 had measurable serum FLC abnormalities. The CVs were calculated for serial SPEP M-spikes (8.1%), UPEP M-spikes (35.8%), and serum FLC concentrations (28.4%). Combining these CVs and the interassay analytical CVs, we calculated the biological CV for the serum M-spike (7.8%), urine M-spike (35.5%), and serum FLC concentration (27.8%). CONCLUSIONS The variations in urine M-spike and serum FLC measurements during patient monitoring are similar and are larger than those for serum M-spikes. In addition, in this group of stable patients, a measurable serum FLC concentration was available twice as often as a measurable urine M-spike.

Serial serum free light chain measurements do not detect changes in disease status earlier than electrophoretic M-spike measurements in patients with intact immunoglobulin myeloma

2011 ◽  
Vol 412 (7-8) ◽  
pp. 562-568 ◽  
Author(s):  
Sacha N. Uljon ◽  
Paul G. Richardson ◽  
Peter H. Schur ◽  
Kenneth C. Anderson ◽  
Milenko J. Tanasijevic ◽  
...  
Keyword(s):  
Light Chain ◽  
Disease Status ◽  
Free Light Chain ◽  
Serum Free ◽  
Serum Free Light Chain ◽  
Serial Serum ◽  
M Spike

Efficacy of Lenalidomide-Based Regimens in Multiple Myeloma Complicated by Extramedullary Plasmacytomas at Relapse or Progression.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4952-4952 ◽  
Author(s):  
Jose Manuel Calvo-Villas ◽  
Adrian Alegre ◽  
Ricarda García-Sánchez ◽  
Miguel T Hernández ◽  
Pilar Giraldo ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Median Time ◽  
Light Chain ◽  
Conflicts Of Interest ◽  
Bone Lesions ◽  
Complete Disappearance ◽  
Toxicity Profile ◽  
Small Series ◽  
Extramedullary Plasmacytomas

Abstract Abstract 4952 Background Current clinical observations on extramedullary myeloma (EM) are based on small series of relapsed myeloma patients (pts) and, in this situation, results suggest that the disease course is often aggressive. Among novel therapies for extramedullary involvement, thalidomide has provided poor results and bortezomib is emerging as a possible useful drug. The role of lenalidomide for treatment of multiple myeloma (MM) with EM is still under investigation. Aim A multicenter retrospective study was performed by PETHEMA (Spanish Myeloma Group, Spain) to evaluate the response rate and toxicity profile of lenalidomide-based regimens in myeloma patients with extramedullary involvement at relapse or progression. All the cases were evaluated for response of MM and improvement of extramedullary plasmacytoma. Patients and Methods From October 2007 to March 2009, thirteen patients (median age 67 years; range 61–87; 7 females) treated with lenalidomide-containing regimens were recorded. Patients with bone disease without extramedullary manifestations were excluded. Response of MM was evaluated according to the new international criteria and the response of EM by measuring size changes by physical examination, CT scans and/or MR imaging. Adverse events were graded based on the WHO toxicity scale. The M-protein type was IgG in 7 cases, IgA in 5 and light chain in 1. The type of light chain was κ in 7 pts and l in 6. In eight patients the soft-tissue plasmacytomas may have developed from underlying bone lesions [(skull (n=2), rib cage (n=4) and paravertebral (n=2)], two patients had subcutaneous nodules and three had visceral involvement (liver (n=1), lung and kidney (n=1) and pleura (n=1). Multiple localizations were present in 4 pts (30.7%). Six cases (79.6%) received previous antimyeloma treatment for EM before lenalidomide therapy and the incidence of prior bone plasmacytomas was 61.5%. Median time from initial antimyeloma therapy to treatment with lenalidomide was 34 months (range 5 - 115). Median number of prior lines of chemotherapy regimens was 3 (range 1 – 4), including autologous stem cell transplantation in 2 pts, bortezomib-containing regimens in 12 (92.3%) and previous exposure to thalidomide in 1 patient. Ten pts received standard lenalidomide dose (25 mg/day every 4 weeks) plus dexamethasone (40 mg/d PO ranging from 1 to 12 doses/cycle) every 3-week; and three patients received lower doses of lenalidomide and/or different schedules. Involved-field radiotherapy was given in 2 cases. Thirty percent of patients required lenalidomide dose reduction, because of toxicity or intolerance. Results Median duration of lenalidomide treatment was 3.6 months (1 – 15). One case was not evaluable for response because of death from disease progression after one cycle. In nine out of twelve evaluable patients (75%), MM responded to lenalidomide regimens according to EBMT criteria. Three (25%) achieved complete response, five (41.6%) partial response and 1 (8.3%) minimal response. Median time to response was 63 days (range 37 – 180). Regarding EM, nine patients showed response in the size of extramedullary plasmacytomas. Seven (58.3%) achieved complete disappearance of EM and two pts reduction of the size. Response of EM was also achieved in 75% of pts previously exposed to bortezomib, and in 4/9 cases who received therapies for prior extramedullary involvement. Median follow-up period was 6.3 months (1 – 15.8). Median overall survival from the start of lenalidomide therapy was 4.7 months. At the time of analysis, seven patients were still on therapy, and ten (76.9%) were alive. Only one out of the 9 patients who had achieved a response has relapsed so far. Toxicity profile (grade 3/4) was: thrombocytopenia, 4 (30.7%); anemia, 2 (15.3%); neutropenia, 5 (46.4%); neutropenic fever, 1 (7.6%) and others, 3 (11.8%). No deep venous thrombosis (DVT) was reported. Thrombosis prophylaxis was used in most cases (92%) patients. Conclusions We report one of the first investigations specifically evaluating the activity of lenalidomide on EM. Lenalidomide-containing regimens could be an alternative promising approach to achieve clinical response in heavily treated MM patients with extramedullary disease. The duration of response and the best regimen or combination are at present unknown. These preliminary observations require further analysis and longer follow-up. Disclosures No relevant conflicts of interest to declare.

Assessment of the Performance of Serum Heavy Chains Immunoassay to Monitor Response to Treatment and Its Correlation with Other Tumor Measurements In Serial Samples From Patients with Newly Diagnosed MM

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2986-2986
Author(s):  
Attaya Suvannasankha ◽  
Sherif Farag ◽  
Stephen Harding ◽  
Brian GM Durie ◽  
Rafat Abonour
Keyword(s):  
Light Chain ◽  
Conflicts Of Interest ◽  
Assessment Tools ◽  
Response To Treatment ◽  
Newly Diagnosed ◽  
Serum Samples ◽  
Heavy Chains ◽  
M Spike ◽  
Serial Samples ◽  
Total Immunoglobulin

Abstract Abstract 2986 Currently available methods for the measurement of tumor load in multiple myeloma include the measurement of monoclonal proteins by electrophoresis, the percentage of myeloma cells in the bone marrow, and the more recently described serum free light chain (FLC) assay. The recent development of antibodies which bind to conformational epitopes spanning the junctional regions between the bound or light chains and their respective heavy chains has now allowed for the specific measurement of serum IgGκ, IgGλ, IgAκ and IgAλ concentrations (HLC). How this novel test may fit in with the other tumor measuring methods has not been fully established. We evaluated the correlation of serum HLC assays with FLC assays, serum monoclonal protein measurement by electrophoresis (M spike), and total immunoglobulin G or A, in serial samples of patients with newly diagnosed MM undergoing a lenalidomide containing induction regimen. Methods: Total immunoglobulins were quantitated by immunonephelometry. HLC and FLC concentrations were quantitated with standard reagents (The Binding Site, Ltd). M spike was evaluated by electrophoresis. Pearson's regression was used to determine correlations among the above tests. Result: Serum samples at baseline, 3 months and 6 months after therapy from 16 patients were assayed. Ig subtypes are as follows: 7 IgGκ, 1 IgGλ, 3 IgAκ, 3 IgAλ, 1 light chain and 1 nonsecretory myeloma. The FLC of the involved chain was abnormal in all but one case, including cases of light chain and nonsecretory MM. The HLC of the involved chain was abnormal in all cases, except the patient with non-secretory MM, in which case, the IgG and were both suppressed. HLC did not correlate well with FLC (r=0.08). Similarly, the HLC k/l ratio did not correlate well with FLC k/l ratio (r=0.33). The HLC moderately correlated with M spike (r= 0.49). The HLC of the involved chain correlate strongly to total immunoglobulin (r=0.9). At 3 months post treatment, HLC and FLC of the involved chains decreased dramatically from baseline levels and plateaud in most cases. HLC kinetics seemed to be slower than FLC as, in 4 cases, FLC normalized before HLC. Interestingly, in these 4 cases, the continual decline in HLC correlated better to the change in the M spike. We also observed a recovery of the previously suppressed uninvolved HLC in 6 cases, leading to the continual improvement in the HLC κ/λ ratio even after the HLC normalization. Conclusion: HLC kinetics showed differences compared to FLC and correlated better with the monoclonal spike. FLC normalized faster but, once normalized, seemed to correlate less well than HLC with M spike and ongoing clinical response. Increased HLC of the uninvolved chain was observed in a subset of patients, after therapy. The HLC κ/λ ratio, which takes into account the changes of the uninvolved chain, is an appealing tool for disease monitoring once HLC of the involved chain normalized. HLC is complimentary to other tumor assessment tools and needs to be further explored in a larger patient cohort. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Comparing the Performance of Serum Free Light Chain Measurements with Urine Electrophoresis and Immunofixation for Monitoring and Assessing Response to Therapy in Patients with Multiple Myeloma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3347-3347 ◽  
Author(s):  
Thomas Dejoie ◽  
Michel Attal ◽  
Philippe Moreau ◽  
Jean-Luc Harousseau ◽  
Herve Avet-Loiseau
Keyword(s):  
Light Chain ◽  
Conflicts Of Interest ◽  
Free Light Chain ◽  
Response To Therapy ◽  
Stage I ◽  
Reference Ranges ◽  
Serum Free ◽  
Post Transplant ◽  
Serum Free Light Chain ◽  
Measurable Disease

Abstract The introduction of the serum free light chain (sFLC) changed the diagnostic paradigm for patients with B cell disorders. IMWG guideline recommends the assay as a replacement for 24h urine at diagnosis, however with the exception of oligosecretory disease the assay is not recommended as a tool to monitor patients. One rationale for this recommendation is that to date, studies have compared the concentrations of FLC as measured by the two tests rather than determine which test provides the more reliable clinical assessment. Here we compare the sensitivities of FLC and 24h urine and comment on the reliability of each to monitor patients. Sequential sera from 25 LCMM (14 FLCκ, 11 FLCλ; stage I: 10, II: 10, III: 5) and 157 IIMM patients (79 IgGκ, 34 IgGλ, 26 IgAκ, 18 IgAλ; Stage I: 46, II: 75, III: 35, 1 missing) enrolled onto the IFM 2007-02 MM trial were analysed. Serum FLCκ and FLCλ levels were measured by Freelite® in samples collected at presentation, after cycles 2 and 4 of therapy and post ASCT. Results were compared to previously published sFLC reference ranges (sFLCκ 3.3-19.4 mg/L, sFLCλ 5.7-26.3 mg/L, sFLCκ/λ ratio 0.26-1.65), SPEP, UPEP sIFE and uIFE. IMWG guidelines were used to define measurable disease and to assess response the therapy. Quadratic Weighted Kappa (WK) analysis was performed to assess agreement in responses assigned by sFLC and urine tests. All 25 LCMM patients had abnormal sFLC ratios (14 FLCκ, 11 FLCλ) and measurable disease at presentation (iFLC 3620 (689-22000) mg/L). Similarly, all patients were positive by uIFE and had measurable disease by UPE (1940 (490-42000) mg/24h). However, in keeping with previous reports quantitative correlation between the two assays was poor (r=0.27). Responses assigned by sFLC and UPEP were concordant in 11/25 (44%) patients, although in 4/11 (40%) timing of the response was different (UPEP 89 (58-118) days; sFLC 226 (216-227) days). In the remaining 14/25 patients the responses assigned using the two tests differed. In 7/14 patients UPEP and uIFE became negative whilst the FLC ratio remained abnormal; in 1/7 patient sIFE confirmed the presence of the M protein. In 3 patients FLC identified relapse, while UPEP was negative or indicated response. In a further 2 patients FLC identified no response whilst UPEP initially identified a response and subsequent relapse. Overall, a moderate concordance was identified between the responses assigned by sFLC and urine tests (WK (95% CI): 0.59 (0.36-0.82)). At presentation, 154/157 (98%) IIMM patients had abnormal FLC ratios (FLCκ ratio 57 (2-33191); FLCλ ratio 0.009 (0.00003-0.25)), whereas only 85/157 (54%) patients were positive by uIFE and 67/157 (43%) by UPEP. 98/157 (62%) had measurable disease using sFLC (κFLC 491 (101-15600) mg/L; λFLC 441 (101-14100) mg/L), and 55/157 (35%) had measurable disease by UPEP (1000 (210-9200) mg/24h). 53/157 (34%) patients had measurable disease by both methods. The correlation between sFLC and UPEP measurements was poor (r=0.36) as was the correlation between intact immunoglobulin measurements by SPEP and sFLC (r=-0.06) or UPEP (r=-0.26). In 53 IIMM patients with measurable disease by both FLC and UPEP, sFLC ratios normalised in 14/53 patients (in 8/14 sIFE remained positive) while uIFE became negative in 33/53 patients (20/33 remained sIFE positive). WK showed better agreement for response assignment between intact immunoglobulin and sFLC measurements (WK (95% CI): 0.63 (0.48-0.79); substantial agreement) than with urine tests (0.49 (0.27-0.72); moderate agreement). Additionally, there was an association between depth of response by sFLC pre- and post-transplant: patients achieving >VGPR before transplant were more likely to achieve >VGPR post-transplant compared with patients who achieved <VGPR prior to transplant (96.2% vs. 63.2%, respectively; p=0.001). Finally 5/157 IIMM patients were oligosecretory and had measurable levels of disease by both UPEP and sFLC, but not by SPEP. In all 5 patients UPEP became negative by cycle 2; however, an abnormal sFLC ratio and positive sIFE indicated persistent disease. sFLC was a more sensitive tool and showed a greater degree of concordance with IFE and SPEP than UPEP in LCMM and IIMM patients respectively during patient monitoring. Furthermore, >90% reduction in sFLC prior to transplant was associated with post-transplant response in IIMM patients. Larger studies with patient outcome are required to validate our findings. Disclosures No relevant conflicts of interest to declare.

Hevylite™ Assays Detect a Hidden Immunoparesis Associated with Adverse Biology in Myeloma Precursor Disease: A Prospective Clinical Study

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 5065-5065
Author(s):  
Rene Costello ◽  
Karina Espana ◽  
Neha Korde ◽  
Mary Kwok ◽  
Adriana Zingone ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Prospective Study ◽  
Heavy Chain ◽  
Light Chain ◽  
Conflicts Of Interest ◽  
Prospective Clinical Study ◽  
Biological Features ◽  
Increased Risk ◽  
M Spike

Abstract Abstract 5065 Recent studies have found immunoparesis (suppression of an uninvolved heavy-chain immunoglobulin (Ig) isotype; e.g. low quantitative IgA and/or IgM levels in a patient with an IgG M-spike) to be an independent risk factor for transformation from smoldering multiple myeloma (SMM) to multiple myeloma (MM). About 70–80% of SMM patients have evidence of immunoparesis. Among remaining 20–30% of SMM patients without immunoparesis, it is currently unknown whether there could be a hidden immunoparesis, reflected in suppression of the uninvolved light chain counter part of the same heavy-chain Ig isotype (e.g. IgG kappa in a patient with an IgG lambda M-spike), which in turn may be associated with adverse biology. A total of 50 SMM patients were enrolled in the first analysis of this prospective study (target: 124 SMM patients). At baseline, a bone marrow core biopsy/aspirate was conducted, and comprehensive immunohistochemistry and flow cytometry analyses were done to confirm the diagnosis and to generate risk profile data for individual patients. For each patient we obtained peripheral blood at baseline. Using serum, we performed the following clinical analyses: serum protein electrophoresis (SPEP); immunofixation electrophoresis (IFE); serum free light chains (sFLC); and quantitative Ig levels for IgG, IgA, and IgM. Using the Hevylite™ assay on a SPAplus (Specialty Protein Analyzer) platform, for each patient, we measured the heavy-light chain (HLC) protein pairs for the complete pair of the patient's heavy-chain Ig isotype (e.g. IgG kappa and IgG lambda for a patient with an IgG M-spike). Consistent with the literature; overall, we found 32/50 (64%) SMM patients to have immunoparesis of an uninvolved heavy-chain Ig isotype; 31 (97%) of these patients also had suppression of the uninvolved HLC counterpart. Among remaining SMM patients without immunoparesis of an uninvolved heavy-chain Ig isotype, using the Hevylite™ assay we found 8/18 (44%) to have a hidden immunoparesis of the uninvolved HLC counterpart. Compared to SMM patients without any type of Ig suppression, adverse biological features were profound in patients with a hidden immunoparesis of the uninvolved HLC counterpart. For example, the FLC-ratios were more skewed (mean: 14.2 vs. 2.5), the distribution of abnormal/normal plasma cells was more pronounced (90.1% vs. 80.3%), the concentration of the M-spike was higher (1.4 g/dL vs. 1.0 g/dL), and the plasma cell percentage in the bone marrow was higher (15.1% vs. 11.9%). In conclusion, using the Hevylite™ assay we identified, for the first time, among SMM patients without immunoparesis, a hidden immunoparesis of the uninvolved HLC counterpart, associated with adverse biological features. Our ongoing prospective study will evaluate whether immunoparesis of the uninvolved HLC counterpart is associated with an increased risk of progression to MM. Disclosures: No relevant conflicts of interest to declare.

No Recurrent Mutation of SF3B1, U2AF1 and SRSF2 Spliceosomal Gene in Multiple Myeloma but Polymorphisms of These Genes Are Associated with the Prediction of Worse Prognosis

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3958-3958
Author(s):  
Trang Nguyen Thi Dai ◽  
Hye-Ran Kim ◽  
Min-Gu Kang ◽  
Stephanie J. Won ◽  
Hwan-Young Kim ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Light Chain ◽  
Somatic Mutations ◽  
Conflicts Of Interest ◽  
Bone Lesion ◽  
Disease Free Survival ◽  
Free Light Chain ◽  
Immunoglobulin Level ◽  
Exon 2 ◽  
Number Of Patients

Abstract Abstract 3958 Background: Recently, a striking example of the effects on acquired somatic mutations in splicing factors such as SF3B1, U2AF1, and SRSF2 has been described. The sequencing of the DNA from abnormal blood cells from patients with several types of leukemia such as AML, CLL, CMML, pre-leukemic syndromes, and MDS, has shown that a high proportion of these cases are associated with somatic mutations in spliceosomal proteins. Also, evidence of cancer-specific alternative splicing and oncogenic somatic mutations in spliceosome subunits has been steadily growing. However, there is not much research regarding aberrant splicing pathways in Multiple myeloma (MM) patients. Therefore, we tried to investigate the presence and prognostic implication of mutation of the SF3B1 and U2AF1 protein in these patients in South Korea. Materials and Methods: We examined a cohort of 87 MM patients and 100 healthy controls for somatic mutations in SF3B1, U2AF1 and SRSF2 by using direct sequencing method. The medical records were reviewed for age, sex, plasma cell percentage, serum M protein, immunoglobulin level, free light chain ratio, calcium, creatinine, hemoglobin, bone lesion, albumin, beta 2 microglobulin, lactate dehydrogenase, treatment outcome, and so on. The collected data was analyzed by SPSS for Windows version 18.0. We performed Pearson's chi-square tests, one way ANOVA analysis, and Student t-test. Survival rates of myeloma patients according to the result of SF3B1, U2AF1 and SRSF2 sequencing were analyzed using Kaplan-Meier log-rank test. Results: Our 87 MM patients showed no mutation including known recurrent ones in SF3B1, U2AF1 and SRSF2 genes. However, the patients displayed 39198T>T/C polymorphism (70.1%) in exon 18 of SF3B1, 8345T>T/G polymorphism (13.8%) in exon 2 of U2AF1 and 5399C/T polymorphism (100%) in exon 1 of SRSF2. In the entire cohort, the number of patients with no polymorphism, one polymorphism, two polymorphisms and three polymorphisms was counted up to 0%, 24.1%, 67.8% and 8.0%, respectively. The T/C polymorphism at position 39198 of SF3B1 exon 18 and the T/G polymorphism at position 8345 of U2AF1 exon 2 were analyzed by allele-specific PCR using normal control. Results in 100 normal controls, polymorphism of SF3B1 exon 18 was taken into account of 82.0%, the remaining is non polymorphism while U2AF1 exon 2 showed 10.0% polymorphism and 90.0% non polymorphism. Sex (p=0.048) and free light chain ratio (p=0.002) showed significant results according to polymorphism status while other clinical characteristics were not associated. The patient with polymorphisms in both SF3B1 and U2AF1 had worse overall survival (P=0.042) and disease-free survival (P<0.01), compared to patients without polymorphism. Conclusion: Our results show no recurrent SF3B1, U2AF1 and SRSF2 mutations in MM patients rather polymorphisms in SF3B1 and U2AF1 gene were significantly implicated in the prediction of poor prognosis. Disclosures: No relevant conflicts of interest to declare.

Evaluation Of Immunoglobulin Variations (Clonal Changes) In Symptomatic Multiple Myeloma (MM) Patients’ Course

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3173-3173
Author(s):  
Eftychia Nikolaou ◽  
Panayiotis Panayiotidis ◽  
Katerina Sarris ◽  
Dimitrios Maltezas ◽  
Efstathios Koulieris ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Light Chain ◽  
Conflicts Of Interest ◽  
Median Number ◽  
Immunoglobulin M ◽  
Rank Test ◽  
Clinical Relapse ◽  
Cell Competition ◽  
Number Of Treatment

Abstract Changes in the production of monoclonal intact immunoglobulin (M-Ig) or of serum free light chains (sFLC) during symptomatic MM patients’ relapse eventually reflect molecular myeloma cells changes and / or reveal clonal cell competition. We aimed to study changes in Ig production (CIg) in symptomatic MM patients and to evaluate related frequency and corresponding specific disease characteristics. Patients and Methods 232 symptomatic MM patients with available follow-up sFLC measurements, were retrospectively studied. Light chain escape (LCE) was defined as sFLC increase with stable or falling M-Ig concentrations, M-Ig escape (MCE) as decreasing sFLC with increasing M-Ig, de-differentiation (DD) as clinical relapse with normal or decreased M-Ig and sFLC and Clonal Domination (CD) as normalization of formerly increased IgG, IgA or FLC in relapsing patients presenting increase of another component. Survival was calculated from diagnosis or from CIg date to last follow-up or death, survival curves were plotted by Kaplan-Meyer Method and assessed by the log-rank test. Results There were 94 women and 128 men, median aged 66 years; 29%, 42%, 29% and 22%, 30%, 48% were in Durie-Salmon and ISS stages I, II, III and 1, 2, 3 respectively. MM type was IgG MM in 59%, IgA in 21%, light chain only in 17%, IgD in 2% and non-secretory in1%. Median survival of the whole cohort was 46,4 months. CIg was observed in 39 patients (17%), consisting in LCE in 15 patients (6%), MCE in 7 (3%), DD in 5 (2%) and CD in 10 (4%); two additional patients (1 IgD and 1 LC) transiently produced another monoclonal component that was IgG in both cases, while in stringent complete remission. In CD patients, the dominated clone was IgG in 9 out of 10 patients, while the dominating one was LC in 8 and IgA in 2. LCE and MCE were more frequent in IgG patients. The median number of treatment lines received prior CIg was 5 for LCE, 4 for MCE, 2 for DD and 1 for CD. LCE and MCE patients had all received novel agents and/or ASCT. The median time from CIg to last follow-up or death was 2,6 months (2,2-3) for LCE, 3,3 months (2,2-4,4) for MCE, 6,3 months (1,1-11,6) for DD and 31,1 months (23,6-38,6) for CD. Patients presenting LCE, MCE and DD had a considerably shorter survival after CIg compared to patients presenting CD (p=0,0002). However because CIg was usually a late event in the course of the disease the overall survival of CIg patients was 60,6 months. In conclusion, LCE, MCE and DD are late events in the course of MM, mainly observed in patients whose previous treatments included with novel drugs. They reflect a very aggressive disease behavior with shortened survival thereafter, probably due to the emergence of a new resistant clone. CD was mainly observed in patients secreting low IgG levels and FLCs, and possibly reflect IgG clone remission in biclonal patients, given that thereafter, the disease behaves as a usual multiple myeloma, secreting however the other clone. Disclosures: No relevant conflicts of interest to declare.

Immunoglobulin Heavy/Light Chain Immunoassays for Response Evaluation in Multiple Myeloma: Comparison with Immunofixation, Serum Free Light Chain, and Multicolor Flow- Cytometry

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3366-3366 ◽  
Author(s):  
Yasuhito Suehara ◽  
Keisuke Seike ◽  
Kouta Fukumoto ◽  
Manabu Fujisawa ◽  
Masafumi Fukaya ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Flow Cytometry ◽  
Light Chain ◽  
Conflicts Of Interest ◽  
Free Light Chain ◽  
Multicolor Flow Cytometry ◽  
Serum Free ◽  
Serum Free Light Chain ◽  
Normal Ranges ◽  
Best Response

Abstract BACKGROUND: Monitoring of multiple myeloma (MM) patients is required to assess and determine the treatment response. The serum immunoglobulin (Ig) heavy/light chain immunoassays are a new method that enables separate quantification of the different light chain types of each Ig class, i.e., IgGk, IgGl, IgAk, and IgAl. Although the contribution of these tests to disease evaluation has been assessed, available data are still limited. Here, we compared the serum Ig heavy/light chain immunoassays with the conventional methods for disease evaluation. PATIENTS AND METHODS: Three hundred and three samples were obtained from a total of 101 patients with IgG and IgA type MM recruited at Kameda Medical Center and Kanazawa University Hospital. The median age of the patients was 68 years (range: 44 – 89). The median follow-up was 36 months (range: 2.5 – 189.6). The proportions of patients in International Scoring System (ISS) stages I, II, and III were 25%, 35%, and 40%, respectively. Paraprotein type was IgG in 64 patients (44 Gk, 20 Gl) and IgA in 37 (20 Ak, 17 Al). Samples were taken at various times after treatment and analyzed retrospectively with serum Ig heavy/light chain immunoassays (Hevylite®; Binding Site, Birmingham, UK) on a SPAPLUS® turbidimeter. The heavy/light chain ratio (HLCR) was calculated with the Ig' k (either G or A) as the numerator and compared to normal ranges (IgGk:3.84-12.07g/L; IgGl:1.91-6.74g/L; IgGk/IgGl: 1.12-3.21; IgAk:0.57-2.08g/L; IgAl:0.44-2.04g/L; IgAk/IgAl:0.78-1.94). Results were compared to serum protein electrophoresis (SPEP), immunofixation electrophoresis (IFE), and serum free light chain immunoassays (FLC). HLC-pair suppression was defined as the uninvolved immunoglobulin of the same isotype 50% below the lower limit of the normal range (IgGk, IgGl, IgAk, IgAl). Residual neoplastic plasma cells (MM-PCs) in bone marrow samples were assessed by multicolor flow cytometry (MFC) simultaneously in 140 samples from 64 patients at very good partial response (VGPR), complete response (CR), and stringent CR (sCR). The MFC negativity was defined at a level of < 10-4 MM-PCs. Overall survival (OS) and progression-free survival (PFS) were estimated by the Kaplan–Meier method, and survival was compared using the log rank test. RESULTS: Myeloma responses were assessed serially after induction therapy and were assigned according to international response criteria. Patients' samples at various responses were: sCR, n = 86 (28%); CR, n = 31 (10%); VGPR, n = 116 (38%); and PR, n = 70 (23%). Normal HLCR was obtained at sCR, CR, and VGPR in 73 (85%), 28 (90%), and 69 (59%) cases, respectively. Discordance in the depth of response between standard electrophoretic methods and HLCR was more commonly seen in IgG compared to IgA MM; possibly reflecting the dose dependent half life of IgG immunoglobulins. In the sera from patients who achieved a CR or better, abnormal HLCR and FLC ratio were seen at rates of 12.8% and 26.5%, respectively. Discordance between normalization of HLCR and FLC ratio was seen in 42% of patients with a CR or better; however, a good correlation between normalization of HLCR and FLC ratio was still observed (Fisher's exact test, P = 0.004). Among the 71 sera from patients with a CR or better in which simultaneous MFC data were available, 16 (22.5%) sera were MFC-negative. Among the patients who achieved a VGPR or better, patients with a normal HLCR had fewer MM-PCs than those with an abnormal HLCR (median 9.8x10-4vs. 46.0x10-4, respectively, P=0.062), although the difference was not statistically significant. Abnormal HLCR in CR samples was seen more frequently in patients with IgA type (19%) than IgG type (7.7%). Longer PFS and OS were observed in patients who achieved HLCR normalization at best response than in those who did not (PFS; 83.8 months vs. 41.8 month, respectively, P = 0.016 and OS; not reached vs. not reached, P = 0.018). When patients at best response were divided into with or without uninvolved HLC pair suppression, the latter group showed significantly better OS compared to the former group (not reached vs. not reached, P=0.019). CONCLUSIONS: The findings presented here suggest the potential usefulness of heavy/light chain immunoassays for monitoring of myeloma response in patients with IgA myeloma and residual MM-PC assessment at VGPR or better. Presence of abnormal HLCR at best response and HLC pair suppression were also associated with poorer survival. Disclosures No relevant conflicts of interest to declare.

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