IgD Myeloma Research Articles

IGD myeloma with acute renal failur: About a case

IGD myeloma with acute renal failur: About a case

B-179 Development of a Reflex Mass Spectrometric Workflow for Confirmation of IgE and IgD Specificity Paraproteins Utilising the EXENT® Platform

Abstract Background The EXENT® (GAM) assay is a MALDI-TOF (Matrix Assisted Laser Desorption Ionisation Time of Flight) mass spectrometry-based solution which utilises IgG, IgA, IgM, total kappa and total lambda specific paramagnetic beads, which could be used in the investigation of monoclonal proteins in multiple myeloma and other plasma cell disorders (in development by The Binding Site (TBS), part of Thermo Fisher Scientific). Rare cases of IgD and IgE myelomas will be partially typed with the current iteration of the EXENT (GAM) assay. We present here a workflow to confirm the heavy chain specificity of such paraproteins as IgD or IgE using reflex LC-MS analysis of EXENT eluates. Methods Samples known to contain IgD (2) or IgE (3) paraproteins were provided from either routine workload at the immunology laboratory at Birmingham Heartlands Hospital, UK or an internal library of historical myeloma samples. Capillary zone electrophoresis (CZE) and immunofixation (IFE) were performed on Capillarys2™ and Hydrasys2 Scan™ platforms, respectively (Sebia, France). Serum free light chain (sFLC) measurement was performed using Freelite® reagents (The Binding Site, UK) on a Cobas c501 turbidimeter (Roche, Switzerland). Samples were prepared via EXENT (GAM) assay, by separately incubating diluted serum with antisera specific for IgG, IgA, IgM, total kappa and total lambda conjugated to paramagnetic beads. After washes, purified immunoglobulins were treated to reduce and elute the light chain component. Samples were mixed with matrix, spotted onto a MALDI target plate and acquired by MALDI-TOF MS. Once light-chain specificity of the suspected IgD or IgE paraprotein was determined, repeat immuno-precipitation with the same light-chain bead was carried out. Eluted samples were neutralised, transferred to fresh tubes, reduced, alkylated and digested with trypsin for 3 h. After acidification digested samples were analysed by C18 reverse phase UPLC on a BioAccord LC-MS system (Waters, UK). Data was then screened against a database of known immunoglobulin heavy chain peptides to assess the presence of heavy chain peptides specific for each immunoglobulin isotype. Results In each sample tested, the EXENT solution identified at least one monoclonal light chain that was only seen in the total kappa or total lambda immunoprecipitations with no corresponding monoclonal peak(s) at the same mass(es) in the IgG, IgA or IgM specificities. This finding would be consistent with the presence of clonal plasma cells producing either monoclonal free light chains only, or IgD and IgE paraproteins. Subsequent LC-MS and LC-MSe (tandem MS) analysis of reduced, alkylated and tryptically digested eluates corresponding to these suspected IgD and IgE samples produced high quality peptide sequencing data. The data identified multiple IgD or IgE specific peptides in each sample and showed between 40% and 66% sequence coverage for IgD or IgE heavy-chain constant regions. Thus, confirming the presence of IgD or IgE in these samples which had been partially typed by the EXENT solution. Conclusion This data demonstrates that the EXENT (GAM) assay could potentially aid in detection of IgD and IgE paraproteins when combined with LC-MS proteomic techniques, as it allows efficient and facile confirmation of these rare heavy chain isotypes.

Abstract 6073: Distinct subtype of multiple myeloma revealed by whole genome and transcriptome sequencing

Abstract Background: Advanced sequencing technologies have contributed to identifying genomic and transcriptomic features of various types of tumors. Despite several sequencing data from multiple myeloma (MM) being generated, understanding various properties of MM remained insufficient. Methods: The patients confirmed with MM by bone marrow examination were analyzed in the study. Myeloma cells were enriched from the bone marrow aspirates of the patients using CD138. Whole genome sequencing (WGS) and whole transcriptome sequencing (WTS) were performed for isolated myeloma cells. Mutational signatures were analyzed using somatic mutations detected by WGS. Results: A total of 37 MM patients (median age 67) were enrolled in this study. WGS revealed somatic mutations of an average of 8872 single nucleotide variants (SNVs) and 934 insertions and deletions (Indels) from the patients, respectively. By the analysis of structural variants, 7 chromothripsis and 4 chromoplexy patients were identified. Mutational signature analysis showed that single base substitution (SBS) 9 signature largely varied between patients. SBS9 signature high patients were mostly diagnosed with non-IgG/non-IgA heavy chain and lambda light chain type myeloma. Notably, IgD myeloma patients were solely detected in the SBS9 signature high group compared to the low group (p = 0.001). Gene expression patterns obtained from WTS were well-divided into SBS9 signature high and low groups, and analysis of differentially expressed genes (DEG) between SBS9 signature high and low groups implied IgD myeloma features including high expression of IGHD. As a validation test, we tried mutational signature analysis on whole exome sequencing (WES) data of 784 MM patients from the MMRF database. Of the 38 patients with more than 500 exonic mutations, only the SBS9 signature high group had IgD myeloma candidates, whereas the SBS9 signature low group had no IgD myeloma candidate (p = 0.014). Conclusions: DNA and RNA sequencing of myeloma patients could classify specific subtypes of disease categories. Further study for SBS 9 signature high and IgD myeloma is needed to discover the underlying mechanism of distinct features and to find out their clinical implication. Citation Format: Sheehyun Kim, Hyundong Yoon, Youngil Koh, Sung-Soo Yoon. Distinct subtype of multiple myeloma revealed by whole genome and transcriptome sequencing. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6073.

Clinical characteristics and outcomes of IgD myeloma: experience across UK national trials

AbstractImmunoglobulin D (IgD) myeloma is a subtype often considered to have adverse features and inferior survival, but there is a paucity of data from large clinical studies. We compare the clinical characteristics and outcomes of patients with IgD myeloma from UK phase 3 myeloma trials analyzed in 2 groups: old (1980-2002) and recent (2002-2016) clinical trials, based on the time of adoption of novel myeloma therapies. Patients with IgD myeloma comprised 44 of 2789 (1.6%) and 70 of 5773 (1.2%) of the old and recent trials, respectively. Overall, IgD myeloma was associated with male predominance, low-level paraproteinemia (<10g/L), and λ light chain preference. The frequency of ultra-high-risk cytogenetics was similar in IgD myeloma compared with other subtypes (4.3% vs 5.3%, P > .99). Despite the old trial series being a younger group (median age: 59 vs 63 years, P = .015), there was a higher frequency of bone lesions, advanced stage at diagnosis, worse performance status, and severe renal impairment compared with the recent trials. Furthermore, the early mortality rate was significantly higher for the old trial series (20% vs 4%, P = .01). The overall response rate following induction therapy was significantly higher in the recent trials (89% vs 43%, P < .0001), and this was consistent with improved median overall survival (48 months; 95% confidence interval [CI] 35-67 months vs 22 months; 95% CI, 16-29 months). Survival outcomes for IgD myeloma have significantly improved and are now comparable to other myeloma types because of earlier diagnosis, novel therapies, and improved supportive care. This trial was registered at clinicaltrials.gov as # NCT01554852.

Criteria for Presumptive Diagnosis of IgD Multiple Myeloma

IgD myelomas constitute about 1% of myelomas, have worse prognosis, have higher association with lambda light chains, and are associated with excess free involved light chains. Standard immunofixation protocols stain only for IgG, IgM and IgA heavy chains. Proper attribution of a monoclonal gammopathy as having a delta heavy chain requires additional testing that is not available in most clinical laboratories. Retrospective review of protein electrophoresis and other laboratory results showed characteristic findings in IgD myelomas.

A novel protein encoded by circHNRNPU promotes multiple myeloma progression by regulating the bone marrow microenvironment and alternative splicing

BackgroudMultiple myeloma (MM) is an incurable plasma cell malignancy in the bone marrow (BM), while immunoglobulin D type of MM (IgD MM) is a very rare but most severe subtype in all MM cases. Therefore, systemic study on IgD MM is purposeful to disclose the recurrent and refractory features in both IgD and other types of MM, and beneficial to the development of potent therapeutic strategy on MM.MethodsAgilent SBC-ceRNA microarray chips were employed to examine 3 normal plasma cell samples (NPCs), 5 lgD MM samples and 5 lgG MM samples, respectively. Sanger sequencing, RNase R digestion and qPCR assays were used to detect the existence and expression of circHNRNPU. BaseScope™ RNA ISH assay was performed to test circHNRNPU levels in paraffin-embedded MM tissues. The protein encoded by circHNRNPU was identified by LC-MS/MS, which was named as circHNRNPU_603aa. The function of circHNRNPU_603aa on cellular proliferation and cell cycle was assessed by MTT test, colony formation assay, flow cytometry and MM xenograft mouse model in vivo. RIP-seq, RIP-PCR and WB analysis for ubiquitination were performed to explore the potential mechanism of circHNRNPU_603aa in MM. Exosomes were isolated from the culture supernatant of MM cells by ultracentrifugation and characterized by Transmission Electron Microscope and WB confirmation of exosomes markers Alix and CD9.ResultsCircHNRNPU was one of the top most abundant and differentially expressed circRNA in IgD MM relative to lgG and NPCs samples. Increased circHNRNPU was associated with poor outcomes in four independent MM patient cohorts. Intriguingly, MM cells secreted circHNRNPU, which encoded a protein named as circHNRNPU_603aa. Overexpressed circHNRNPU_603aa promoted MM cell proliferation in vitro and in vivo, in contrast knockdown of circHNRNPU_603aa by siRNA abrogated these effects. Due to circHNRNPU_603aa including RNA-binding RGG-box region, it regulated SKP2 exon skipping, thereby competitively inhibited c-Myc ubiquitin so as to stabilize c-Myc in MM. MM cells secreted circHNRNPU through exosomes to interfere with various cells in the BM microenvironment.ConclusionOur findings demonstrate that circHNRNPU_603aa is a promising diagnostic and therapeutic marker in both MM cells and BM niche.

IgD Myeloma: Clinical Features and Outcome from a Multicenter Retrospective Study in Chinese and Korean of 308 Patients from Asian Myeloma Network (AMN) Project

IgD myeloma is a rare hematologic malignancy for which clinical and biological features and patient outcomes have not been extensively studied. However, previous studies found 3.1% IgD myeloma prevalence in Asian myeloma patients, and with the high incidence of 6%, especially for younger than 50 years with 10.3% in Chinese myeloma patients (Kim K. et al. Am J Hematol. 2014, Lu J. et al. Drug Des Devel Ther. 2016). Therefore, to further assess the frequency and the specific characteristics and evaluate the outcome of patients with IgD myeloma, we carried out a multicenter retrospective study in Chinese and Korean patients from AMN project with diagnosis of IgD myeloma.A total of 308 patients from 22 centers were included in this analysis. The median age at diagnosis was 56 years with a male predominance (65.70%). Anemia and renal dysfunction were found in 86.7% and 46.2%, respectively. Renal failure is more common at presentation with an increase in serum creatinine (> 2 mg/dL) in more than 10% various series of IgD MM. The bias for λ light chain expression with a reversed light chain ratio is a characteristic feature of IgD MM, which showed 95.79% of patients with IgD λ light chain in Asian patients. DS stage 1, 2, and 3 were showed in 1.30%, 5.84%, and 92.86%, respectively. The chromosomal aberration accounted in 58.14% and t(11;14) was the most common cytogenetic finding (40.57%). Median overall survival (OS) was 39.2 months (95% CI 31.56-41.43). Higher International Staging System (ISS) stages III (62.62%) might be associated with worse survival (P = 0.02), while ISS stages I and II were seen in 16.39% and 20.98%. Patents received with stem cell transplantation showed better survival rates. New drugs including bortezomib, thalidomide, and lenalidomide were used in more than 60% of all patients and affected OS when used as a first-line treatment.In this multicenter retrospective study from Chinese and Korean IgD myeloma patients, we found that IgD MM more likely presented at advanced stage and showed a more aggressive clinical course. The underlying tumor biology responsible for these differences remains to be determined. DisclosuresNo relevant conflicts of interest to declare.

IgD Subtype But Not IgM or Non-Secretory Is a Prognostic Marker for Poor Survival Following Autologous Hematopoietic Cell Transplantation in Multiple Myeloma. Results From the EBMT CALM (Collaboration to Collect Autologous Transplant Outcomes in Lymphomas and Myeloma) Study

BackgroundThe Collaboration to Collect Autologous Transplant Outcomes in Lymphoma and Myeloma (CALM) study has provided an opportunity to evaluate the real-world outcomes of patients with myeloma. The aim of this study was to compare the outcome according to the different subtypes of myeloma using CALM data. PatientsThis study compared overall survival (OS), progression-free survival (PFS), and complete remission (CR) and the impact of novel versus non-novel drug containing induction regimens prior to autologous hematopoietic cell transplantation (HCT) of 2802 patients with “usual” and “rare” myelomas. ResultsOur data suggest that IgM and non-secretory myeloma have superior PFS and OS compared with IgD myeloma and outcomes comparable to those for usual myeloma. Patients who received novel agent induction had higher rates of CR prior to transplant. Non-novel induction regimens were associated with inferior PFS but no difference in OS. Although not the primary focus of this study, we show that poor mobilization status is associated with reduced PFS and OS, but these differences disappear in multivariate analysis suggesting that poor mobilization status is a surrogate for other indicators of poor prognosis. ConclusionWe confirm that IgD myeloma is associated with the worst prognosis and inferior outcomes compared with the other isotypes.

Light chain deposition disease involving kidney and liver in a patient with IgD myeloma

BackgroundIgD multiple myeloma (MM) is a rare subtype of MM and light chain deposition disease (LCDD) outside the kidney is also a rare and has scarcely been reported. We report herein the details of the first reported case of LCDD involving the kidney and liver co-occurring with IgD myeloma.Case presentationA 66-year-old female with IgD MM presented with rapidly progressive acute renal failure, ascites and pleural effusion. Immunofluorescent study of revealed the characteristic linear deposition of Igκ light chain along the glomerular and tubular basement membrane in kidney. Electron microscopy showed the powdery electron-dense deposits along the tubular and glomerular basement membrane consistent with the diagnosis of LCDD. Laser microdissection followed by mass spectrometry identified only Igκ light chain with more than 95% probability confirm the diagnosis of κ-LCDD but not heavy/light chain deposition disease. Liver biopsy with immunofluorescence study revealed the linear deposition of Igκ chain along the perisinusoidal space indicating the hepatic involvement of κ-LCDD. The patient was successfully treated with combination therapy with bortezomib, cyclophosphamide, dexamethasone, and daratumumab.ConclusionsThis report emphasizes that prompt biopsy of affected organs and initiation of clone directed therapy led to the correct diagnosis and favorable outcome in patient with LCDD who has extrarenal involvement.

A Rare Etiology of Chronic Polyradiculoneuropathy: IgD Multiple Myeloma

Introduction: Immunoglobulin D multiple myeloma (IgD MM) is a rare entity of multiple myeloma (2%), characterised by its clinical severity, renal presentation and poor prognosis. IgD myeloma remains an exceptional cause of chronic polyradiculoneuropathy. Observation: A 54-year-old patient, known to have type 2 diabetes since 2016, was admitted in December 2020 for non-febrile obnubilation associated with tetraparesis. The interrogation noted the occurrence of a motor deficit of the four limbs for 4 months in connection with a sensitivemotor polyradiculoneuropathy of the axon-myelin type of the four limbs. Glasgow’s score was 10. Blood pressure was 130/80 mmHg, pulse 116 beats/min, temperature 37°C, SaO2 92% on room air, low capillary blood glucose 1.08 and oliguria 70 cc/H. The physical examination revealed meningeal syndrome, tetraparesis, anaemia and renal oedema. Investigations revealed severe hypercalcaemia (140 mg/L), purulent meningitis (purulent liquid CSF, 12.38 g/L protein, 0.52 g/L glycorrhaphy, 14/mm3 leucocytes, 2000/mm3 red blood cells) and acute renal failure (74 mg/L creatinine, 5 mL/min/m3 GFR, 2.65 mg/L urea). Symptomatic IgD multiple myeloma was suspected on the basis of bone marrow plasmacytosis, bilateral frontal diploid lacunar osteolysis on CT scan and IgD positivity. Conclusion: Our observation illustrates the possible plurality of symptoms of IgD MM, particularly chronic polyradiculoneuropathy which is a rare neurological sign that should not be ignored in order to avoid diagnostic errors.

Immunoglobulin D Myeloma and Amyloidosis: Immunochemical and Structural Studies of Bence Jones and Amyloid Fibrillar Proteins

Urinary Bence Jones protein and amyloid fibril protein isolated from the subcutaneous tissue of a patient with IgD myeloma and associated amyloidosis were subjected to physicochemical and immunochemical identification. Peptide maps and amino-terminal tetrapeptide composition obtained from the two proteins were comparable. Immunochemical cross-reactivity between the two proteins, with other lambda-type amyloid and Bence Jones proteins, and with a serum component was demonstrated. The results suggest that the source of the amyloid fibril protein is an intact circulating light polypeptide chain as well as smaller amino-terminal fragments.

Light Chain Predominant Intact Immunoglobulin Monoclonal Gammopathy Disorders: Shorter Survival in Light Chain Predominant Multiple Myelomas.

A proportion of intact immunoglobulin (Ig)-producing multiple myelomas (MMs) was observed to secrete much higher amounts of free light chains (LCs) than usual. To determine the change point between usual and LC-predominant intact Ig-secreting MMs and other monoclonal gammopathic manifestations and the biological significance of the observation. We conducted retrospective examination of laboratory findings in 386 MM, 27 smoldering MM, and 179 monoclonal gammopathy of undetermined significance (MGUS) cases that secreted intact Igs. We recorded the highest levels of involved serum free LC, highest ratio of involved to uninvolved LC, highest concentration of involved LC per g of monoclonal Ig, and highest value for ratio of involved to uninvolved LCs divided by the monoclonal Ig concentration. Each data set was sorted into kappa- and lambda LC-associated lesions. Length of time, in months, between diagnosis and last contact with the patients having myeloma was recorded. Change point analysis of data revealed a subgroup of cases with distinctly higher levels of free LCs. In myelomas, including plasma cell leukemias, 16.4% of myelomas with kappa LCs and 22.3% of myelomas with lambda LCs, the LC secretion was distinctly higher than in the remaining cases, by a combination of 4 parameters, listed herein. Corresponding figures for smoldering myeloma (SMM) and monoclonal gammopathy of undetermined significance (MGUS) were 12.5, 27.3, 3.8, and 6.8, respectively. Ten of the 13 (77%) cases of plasma cell leukemia) and all cases of IgD myeloma (n = 4) showed excess secretion of serum free LCs. Among IgG and IgA myelomas, including plasma cell leukemias, the LC-predominant lesions had shorter survival, by an average of 22.5 months. In total, 18.4% of MMs, including plasma cell leukemias, secrete distinctly higher amounts of serum free LCs than other intact Ig-secreting myelomas and confer significantly lower survival. Quantification of monoclonal serum free LCs may be useful in this subgroup in monitoring progress and potentially in ascertaining minimal residual disease. The findings also stress the need for separate criteria for kappa and lambda LC associated monoclonal gammopathic manifestations. The significantly shorter survival of patients with LC-predominant myelomas warrants consideration in prospective trials of treatments.

Revisiting the Impact of Immunoglobulin Isotypes in Multiple Myeloma

Background Multiple Myeloma (MM) is a malignancy of terminally differentiated B lymphocytes (plasma cells, PCs) characterized by secretion of immunoglobulins and/or light chains (LCs). Association of immunoglobulin isotypes with survival in the context of contemporary therapies and accounting for modern prognostic factors has not been determined. Methods We utilized the Flatiron Health Electronic Health Record (EHR)-derived de-identified database to source patients (pts) with newly diagnosed MM from 01/2011 to 02/2020 with documented isotype data as part of the initial diagnostic work up. This nationwide database comprises de-identified, longitudinal patient-level demographic, clinical, and outcomes data curated via technology enabled abstraction. We used self-reported race and ethnicity and constructed a composite race/ethnicity variable as used by the National Cancer Institute. Similarly, we defined baseline labs (hemoglobin, serum creatinine, calcium, LDH) as those available within 90 days of diagnosis. We compared baseline characteristics using appropriate bivariate methods. Finally, we used Kaplan-Meier methods and Cox proportional hazard regression models to compare overall survival (OS), from the date of diagnosis, among the different isotypes (IgA, IgD, IgM, Light Chain (LC), others) with IgG MM after adjusting for known prognostic variables such as FISH abnormalities, ISS, renal function, age, sex, race/ethnicity, LDH, ECOG performance status, and treatment. Results We identified 8468 patients in the database who met the inclusion criteria. Patient with IgA MM (N=1688) were more likely to have ISS-III (IgA 21% vs. IgG 16%, p&amp;lt;0.001), anemia (IgA 41% vs. IgG 35%, p&amp;lt;0.001) and t(4;14) (IgA 8% vs. IgG 4%, p&amp;lt;0.001) than patients with IgG MM (N=4858). LC MM (N=1748) have more renal dysfunction (LC 21% vs. IgG 11%, p&amp;lt;0.001) and t(11;14) (LC 17% vs. IgG 8%, p&amp;lt;0.001). Patients with IgD MM (N=44) were younger, more likely to be male and non-Hispanic White, have ISS-III, high LDH, anemia and renal dysfunction and t(11;14). Patients with IgM MM (N=84) had higher incidence of hypercalcemia and lower proportion of patients with high LDH (Table). Across all groups 3106 (36.7%) patients received therapy containing a proteasome inhibitor (PI) and an immunomodulatory agent based triplet (IMiD), while 1458 (17.2%) received IMiD-based doublet, 2284 (27.0%) PI-based doublet, and 2109 (24.9%) received hematopoietic cell transplantation. Patients with IgA (mOS 4.7 vs 5.6 years, p&amp;lt;0.001) and LC MM (4.8 vs. IgG 5.6 years, p&amp;lt;0.001) patients have inferior OS (Figure). The adverse prognostic impact of IgA (HR 1.2, 95% CI 1.1-1.3, p&amp;lt;0.001) and LC isotypes (HR 1.2, 95% CI 1.1-1.3, p&amp;lt;0.001) on OS persisted even after adjustment for FISH abnormalities, ISS stage, renal function, age, sex, race/ethnicity, ECOG performance status, LDH, and treatment. Conclusion Using a contemporary "real world" dataset, we illustrate the distinct clinical features of MM with different immunoglobulin isotypes. Our findings suggest that IgA and LC MM are associated with poor survival suggestive of their unique biology beyond presence of high-risk FISH abnormalities and other adverse prognostic factors. Figure Disclosures Costa: Sanofi: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy; Genentech: Consultancy; BMS: Consultancy, Honoraria; Celgene: Consultancy, Honoraria.

AL Amyloidosis in a Patient with IgD Myeloma.

AL Amyloidosis in a Patient with IgD Myeloma.

Multiple myeloma with multiple neurological presentations

Multiple myeloma is a haematological malignancy with clonal plasma cell proliferation and production of monoclonal immunoglobulins. Its neurological complications are relatively common, caused by both the disease and the treatment....

Role of the clinical laboratory in myeloma IGD diagnosis: A case report

Role of the clinical laboratory in myeloma IGD diagnosis: A case report

Presentation Pattern, Diagnostic Markers, Management and Outcome of IgD Multiple Myeloma: A Systematic Review

Background:IgD multiple myeloma (MM) is a rare subtype contributing 2% of all multiple myeloma cases. Despite difficulty and delay in diagnosis, recent advances in the treatment of multiple myeloma in general also improved the outcomes for IgD myeloma subtype. The aim of this study is to summarize the data on presentation patterns, diagnosis, management approaches and outcomes for patients (pts) with IgD myeloma.Methods:A comprehensive literature search for articles published after December 2013 was performed using four databases: PubMed, Embase, Cochrane, and Clinicaltrials.gov. With initial search we identified 209 articles and after screening by two independent reviewers we included only 8 studies in the final analysis.Results:A total of 166 pts with IgD MM were included from 8 selected retrospective case series. Lambda (λ) was the predominant light chain sub-type in 136 patients (81.9%). Initial manifestations of IgD MM were Bence jones proteinuria (BJP>2 g/day-64.5%), renal dysfunction (63%), bone pain (55.9%), weakness, fatigue (34.2%) and extra medullary involvement (28.3%). Renal function was assessed by estimated glomerular filtration rate (eGFR<60 ml/min/1.73m2) in 54.3 % of patients and by serum creatinine level (Cr >2mg/dl) in 46.1% patients. Cytogenetic karyotype analysis in 56 pts using fluorescence in-situ hybridization (FISH) identified abnormal cytogenetics in 41 (73.2%) patients, cases were further classified as high risk (85.7%) and standard risk (14.3%). The patient characteristics and disease manifestations are mentioned in Table 1.Serum protein electrophoresis (SPEP) showed positive monoclonal spike (M) spike in 84% of the patients. The median M spike value for IgD MM was 9.42 g/l in a cohort of 17pts, (Djidjik et al.) which was lower as compared to IgG (median: 35 g/L) and IgA (median: 32 g/L) in this study. Abnormal serum free light chain ratio (sFLCR) was observed in 83% pts. Quantitative serum IgD levels were elevated only in 28% of the cases. Bone marrow (BM) plasmacytosis showing > 40% abnormal plasma cells was detected in 95.6% of the patients. N glycans are newly discovered biomarkers used for detecting abnormal protein glycosylation in MM patients. NG1(6)A2F and NG1(3)A2F were the two most significant N glycan markers for IgD MM patients with sensitivity of 95% & 95.2%, respectively and specificity of 95% & 78.6%, respectively. The prognostic significance of several other biomarkers studied in IgD MM is mentioned in Table 2.Treatment details were available for 149 patients and overall response rate (ORR) was seen in 125 (83.9%) patients while 24 (15.4%) patients had progressive or stable disease. The median overall survival (mOS) was between 9 - 62 months. Novel agents (NA) such as bortezomib, thalidomide and lenalidomide were given to 111 (74.4%) pts with the mOS between 15 - 38.6 months. Conventional agents (CA) such as melphalan, vinblastine, vincristine, epirubicin, and ifosfamide were given to 38 (25.5%) patients with mOS between 12.5 - 17 months. Data showed bortezomib based regimens resulted in a higher ORR (ORR=94%, CR=52%) compared to non bortezomib based regimens (ORR=77.8%, CR=27.7%) respectively. Stem cell transplant (SCT) was used in 37 (24.8%) patients with chemotherapy (NA=26, CA=11) which showed good response rate (ORR>90%,CR >60%). The comparison of response rate with different drugs is mentioned in the Table 3.Conclusion:N-glycan assay can overcome the limitations of SPEP and quantitative serum IgD assay in the diagnosis of IgD MM. This difficulty is posed by the lower concentrations of M spike ( SPEP) or lower-normal serum IgD value on quantitative serum assays, which can delay its diagnosis. Novel and conventional agents have good responses with ORR>90%, but mOS of conventional agents was lower when compared to novel agents. Bortezomib based regimens showed better responses when compared to non-bortezomib regimens. The best response (ORR=95%) was obtained with use of SCT in combination with novel agents. Serum free light chain levels, N glycan assay and serum IgD quantification were found to be the best prognostic markers for IgD MM. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

N-glycosylation of serum proteins for the assessment of patients with IgD multiple myeloma

BackgroundBecause glycosylation is one of the most common post-translational modifications of proteins and because changes in glycosylation have been shown to have a significant correlation with the development of many cancer types, we investigated the serum N-glycome used to diagnose, stage and evaluate the pathological outcomes in IgD multiple myeloma.MethodsSerum samples were available for 20 patients with IgD multiple myeloma, 41 patients with light chain multiple myeloma and 42 healthy control subjects. Serum N-glycans were released and analysed using DNA sequencer-assisted fluorophore-assisted capillary electrophoresis.ResultsCharacteristic changes were revealed in the serum N-glycome of IgD myeloma. In particular, three N-glycans (NG1(6)A2F, Peak3; NG1(3)A2F, Peak4; NA2FB, Peak7) showed increased clinical value. The best area under the ROC curve of NG1(6)A2F to diagnose IgD myeloma was 0.981, with a 95.0% sensitivity and 95.2% specificity, and that of NG1(3)A2F was 0.936, with a 95.0% sensitivity and 78.6% specificity. The best area under the ROC curve of NA2FB/NG1(3)A2F to differentially diagnose IgD myeloma versus light chain myeloma was 0.744, with a 95.3% sensitivity and 50.0% specificity. The level of NG1(3)A2F was correlated with the international staging system, while the higher abundance of NA2FB presented in IgD myeloma was predictive of a shorter progression-free survival.ConclusionsThe advent of serum N-glycan signatures may play a role in the diagnosis, staging and prognosis of IgD myeloma and will serve as the foundation for a precision medicine approach to this rare subtype of multiple myeloma.

Plasmapheresis が著効を奏した IgD-κ型 Myeloma の 1 症例

Plasmapheresis が著効を奏した IgD-κ型 Myeloma の 1 症例

Changes in Uninvolved Immunoglobulins during Multiple Myeloma Therapy

▪BackgroundSuppression of uninvolved immunoglobulins is a common finding in multiple myeloma and the preservation of uninvolved immunoglobulins at diagnosis is associated with improved progression-free and overall survival. However, little is known about the impact of myeloma treatment on levels of uninvolved immunoglobulins, and the link between changes in uninvolved immunoglobulins during therapy and treatment response, disease progression and survival.MethodsWe identified patients who received therapy for newly diagnosed multiple myeloma at our institution between 2001 and 2014, and who had data available on absolute lymphocyte count (ALC) and quantitative uninvolved immunoglobulins (Ig) before commencing treatment. The ALC and levels of uninvolved Ig after 4 cycles of therapy were abstracted from the electronic medical record; patients who switched or stopped treatment, or died, before this time point were excluded. To assess change in ALC, the percentage difference in ALC between baseline and 4 cycles was calculated; for uninvolved Ig, the average of the percentage difference between baseline and 4 cycles for each uninvolved Ig (IgA and IgM for IgG myeloma, IgG and IgM for IgA myeloma, IgG and IgA for IgM and IgD myeloma, and IgG, IgM and IgA for light-chain only myeloma) was calculated. Treatment response at 4 cycles was retrospectively assigned according to International Myeloma Working Group criteria. Time to treatment failure (TTF) was defined as time from start of initial therapy to start of next line of therapy or death (if no additional treatment was received). A landmark analysis was used to calculate overall survival (OS) from the date of follow-up after 4 cycles of therapy. The Kruskal-Wallis, Chi-Square, and log rank tests were used to detect differences in medians, proportions, and survival times respectively.ResultsA total of 421 patients were included in this analysis. The median age was 63 years (range 33-91), 254 patients (60.3%) were male and median follow-up was 6.5 years (95% CI 5.6-7.3); the vast majority of patients had IgG (n=247 [58.7%]), IgA (n=98 [23.3%]) or light-chain only myeloma (n=68 [16.2%]). First line therapy comprised of pulse-dose dexamethasone (DEX, n=92 [21.9%]), lenalidomide-dexamethasone (RD, n=176 [41.8%]), bortezomib-dexamethasone (VD, n=22 [5.2%]), bortezomib-cyclophosphamide-dexamethasone (VCD, n=84 [20.0%]), and bortezomib-lenalidomide-dexamethasone (VRD, n=47 [11.2%]).Across the entire cohort, the median change in ALC and uninvolved Ig after 4 cycles of treatment was -11.0% (range: -92.7 to +718.8) and +9.0% (-77.7 to +1094.4) respectively; treatment with VCD was associated with the greatest median declines in ALC (DEX: -0.1%; RD: -9.9%; VD: -20.8%; VCD: -40.9%; VRD: -15.3%) and uninvolved Ig (DEX: -0.5%; RD: +15.5%; VD: +44.0%; VCD: -14.0%; VRD: +76.0%, both p<0.001). Conversion from suppression to normalization of the primary uninvolved Ig (IgA in IgG myeloma, and IgG in all other myeloma types) after 4 cycles was seen more frequently with the use of RD (13.1%) and VRD (12.8%) compared to DEX (4.7%), VCD (1.3%), or VD (4.8%), χ2=21.8, p=0.040. When considering only patients in whom the primary uninvolved Ig remained suppressed between baseline and 4 cycles, a ≥25% reduction in the primary uninvolved Ig occurred more frequently with the use of DEX (51.5%) and VCD (34.5%) compared to RD (24.8%), VD (23.5%) or VRD (25.7%), χ2=15.1, p=0.005 (Table 1).Although an average reduction in uninvolved Ig between baseline and 4 cycles (ΔIg<0) was independently associated with a lower likelihood of achieving very good partial response (VGPR) of better on multivariate analysis adjusting for age, sex and treatment regimen (OR=0.40 [0.24-0.63], p<0.001), there were no differences in TTF (2.0yrs vs. 2.0yrs, p=0.783) or OS (8.0yrs vs. 8.0yrs, p=0.721) between patients with ΔIg<0 (n=169) and those with ΔIg≥0 (n=222).ConclusionsMyeloma treatments produce differential impacts on immune parameters, with VCD causing the greatest reduction in lymphocytes and uninvolved Ig, implying general targeting of plasma cells, in comparison to lenalidomide, which appeared to be more tumor-specific with relative sparing of lymphocytes and uninvolved Ig. While an average decrease in uninvolved Ig was an independent predictor of a lower likelihood of achieving VGPR or better after 4 cycles of therapy, it was not associated with a shorter TTF or poorer OS. [Display omitted] DisclosuresKumar:BMS: Consultancy; Glycomimetics: Consultancy; Onyx: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Kesios: Consultancy; Millennium: Consultancy, Research Funding; Noxxon Pharma: Consultancy, Research Funding; Array BioPharma: Consultancy, Research Funding; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; AbbVie: Research Funding. Dispenzieri:GSK: Membership on an entity's Board of Directors or advisory committees; Prothena: Membership on an entity's Board of Directors or advisory committees; pfizer: Research Funding; Jannsen: Research Funding; Alnylam: Research Funding; Celgene: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kapoor:Amgen: Research Funding; Celgene: Research Funding; Takeda: Research Funding. Bergsagel:Amgen, BMS, Novartis, Incyte: Consultancy; Novartis: Research Funding.