Impact of achieving a complete response to initial therapy of multiple myeloma and predictors of subsequent outcome.

Achievement of a complete response (CR) in multiple myeloma (MM) correlates with improvement in survival outcomes; however, its impact on prognostic variables at baseline outside of clinical trial settings is not well described. We sought to determine the impact of achieving a CR within 2 years from diagnosis, its effect on the prognostic value of fluorescence in situ hybridization (FISH) and International Staging System (ISS) risk, and examined additional predictors of outcome among those achieving a CR in a routine clinical setting. We evaluated 1869 newly diagnosed MM patients who had ≥ 2 monoclonal protein immunofixation studies in the serum and urine available within 24 months from diagnosis, categorizing those with ≥ 2 negative serum and urine immunofixations as achieving CR. With a landmark at 24 months, median progression-free survival (PFS) for CR versus non-CR patients was 29.8 versus 20.9 months (p ≤ .0002); median overall survival (OS) was 104 versus 70 months (p < .0001). The impact of achieving a CR was retained after adjusting for FISH, ISS, sex, transplant status, and involved heavy chain. Baseline FISH and ISS stage were not associated with PFS or OS among patients achieving a CR. The following variables were found as predictors of inferior OS within the CR cohort: age > 75 years, male gender, hypoalbuminemia, and non-immunoglobulin G involved heavy chain. Our study confirms that achievement of CR within 2 years from diagnosis is associated with improvement in survival outcomes and neutralization of the impact of FISH and ISS risk, thereby confirming observations from the clinical trial setting among a clinical practice cohort.

MicroRNAs in urine as diagnostic biomarkers for multiple myeloma.

INTRODUCTION: Multiple myeloma (MM) is a hematological malignancy. It is of great clinical significance to screen microRNAs (miRNAs) in urine as noninvasive diagnostic biomarkers for MM. METHODS: Urinary miRNAs in MM were performed by Agilent Bioanalyzer 2100 and verified by quantitative real-time PCR (qRT-PCR). Receiver operator characteristic (ROC) was used to evaluate the diagnostic value of abnormal miRNAs for MM. Progression-free survival (PFS) of MM was calculated by Kaplan-Meier. RESULTS: In microarray analysis, twelve down-regulated miRNAs dysregulated in MM. The expression levels of miR-134-5p, miR-6500-5p, miR-548q, and miR-548y were validated. These miRNAs were significantly lower in MM (P < .05), but there was no significant difference between newly diagnosed, relapse, and remission group of MM (P> .05). ROC curve analysis showed that the sensitivity of miR-134-5p, miR-6500-5p, miR-548q, and miR-548y to MM was 91.7%, 100%, 100%, and 91.7%, and the specificity was 66.7%, 75.0%, 75.0%, and 100%, respectively. The four miRNAs were negatively correlated with the total urinary light chain (r = -0.427 P = .030, r = -0.461 P = .018, r = -0.469 P = .016, r = -0.493 P = .011). In addition, miR-134-5p, miR-6500-5p, and miR-548q were positively correlated with serum ALB (r = 0.518 P = .006, r = 0.400 P = .039,r = 0.492 P = .009). The expression level of miRNAs had no significant influence on PFS in MM patients (P> .05). CONCLUSION: The results show that miR-134-5p, miR-6500-5p, miR-548q, and miR-548y are potential noninvasive diagnostic biomarkers for MM.

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

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

Coincidental crystalline light chain cast nephropathy, light chain proximal tubulopathy, and urine crystallopathy: A case report and review of the literature
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Plasma cell dyscrasias, including multiple myeloma (MM), are associated with diverse forms of pathology in the kidney. Some pathologic lesions, including light chain (myeloma) cast nephropathy (LCCN), are relatively common, while others, such as light chain proximal tubulopathy (LCPT), are less so. Both LCCN and LCPT are associated with clinical manifestations of acute kidney injury. Rare instances of coincidental LCPT and LCCN have been reported, but none to our knowledge of coincidental crystalline forms of these diseases, with similar forms appearing in the urine. While LCPT is usually associated with intracytoplasmic deposition of crystallized light chains, the intraluminal light chain casts in LCCN are typically amorphous and do not form crystals. We report here the co-occurrence of these two monoclonal crystalline forms of acute kidney injury in a 66-year-old woman with known history of κ-restricted multiple myeloma. Additionally, forms suggestive of a crystalline morphology were observed in the urine sediment. Clinicians who observe similar crystalline structures on renal biopsy or in urine sediment should have a high index of suspicion for underlying multiple myeloma as a unifying diagnosis.

Epidemiological and immunochemical parameters of monoclonal plasma cell dyscrasias of 2121 cases in Algeria.

BACKGROUND: Plasma cell dyscrasias (PCD) are a heterogeneous group of diseases characterized by the expansion of monoclonal bone marrow plasma cells that produce a monoclonal immunoglobulin (M-component). PURPOSE: This is a retrospective study that describes the epidemiological, immunochemical features and etiology of monoclonal gammopathies diagnosed between 1998 and 2016 in the Teaching Hospital Beni-Messous of Algiers. PATIENTS AND METHODS: 2121 cases of monoclonal gammopathies (MG) were collected during this period. Serum/urine protein electrophoresis, serum/urine immunofixation and serum free light chain measurements were used to demonstrate M protein. RESULTS: The middle age of the patients at the time of the diagnosis were 62.96 ± 13.19 years with extremes ranging from 07 to 99 years. The study included 1013 (47, 76 %) men and 1108 (52, 23 %) women with a sex ratio 0,91. Isotypes repartition was: IgG (60.91 %), IgA (17.91 %), light chain (10.46 %), IgM (6.6 %), IgD (1.03 %) and IgE (0.09 %) of cases. The most frequent diagnosis was: Multiple Myeloma (55.20 %), followed by monoclonal gammopathy of undetermined significance (34.13 %). CONCLUSION: In our study, two particularities were noted. There is no male predominance in Algerian PCD patients. Moreover, we observed a higher frequency of light chain multiple myeloma and lower frequency of IgM isotype compared to western studies.

Is urine immunofixation electrophoresis necessary for monitoring myeloma patients who have undergone hematopoietic stem cell transplantation?

INTRODUCTION: To investigate the role of urine immunofixation electrophoresis in detecting relapse in patients with myeloma who have undergone autologous and allogeneic hematopoietic stem cell transplantation (HSCT). METHODS: The study included a total of 78 patients, comprising 49 males and 29 females, with progressive disease or relapse after HSCT. Serum protein electrophoresis (sPE), serum immunofixation electrophoresis (sIFE) and serum free light chain κ/λ ratio in addition to urine immunofixation (uIFE) were studied. RESULTS: sPE, sIFE and κ/λ ratio demonstrated relapse in 65.3%, 88.3% and 58.9% of the cases by theirselves respectively. The combination panel of sPE and sIFE demonstrated relapse in 88.3% of patients whereas sPE, sIFE and κ/λ ratio all together demonstrated relapse in 95.8% of the patients. In relapsed patients, urine immunofixation was found to be positive in 16.2% of the patients. No patients with relapsed disease were missed by omitting uIFE from serum studies (sPE, sIFE and sFLC). CONCLUSION: For evaluation of relapse in MM patients after HSCT, uIFE had no additional diagnostic capability compared to serum studies (sPE, sIFE, and sFLC). Therefore, urine studies should be performed more selectively.

Nanoporous silica coupled MALDI-TOF MS detection of Bence-Jones proteins in human urine for diagnosis of multiple myeloma.

Bence-Jones protein is a biomarker in urine for multiple myeloma. Traditional methods for urine Bence-Jones protein detection are either less-sensitive or laborious. Herein, we describe a new method for the detection of urine Bence-Jones protein using nanoporous materials and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). Macroporous ordered silica foams (MOSF) were used to enrich proteins in urine, and then the materials-proteins composites were analyzed by MALDI-TOF MS. Based on the presence of specific mass spectrometric signals, Bence-Jones protein can be detected for the diagnosis of multiple myeloma. Twenty-one clinical positive and twenty-seven clinical negative urine samples were analyzed by the method. High sensitivity (95.24%, 20/21) and specificity (100%, 27/27) for the diagnosis of multiple myeloma were achieved. Compared to other methods for multiple myeloma diagnosis, e.g. immunofixation electrophoresis and immunonephelometry, our approach is more rapid, economical and convenient, which can be a new choice for the clinical diagnosis of Bence-Jones protein related diseases.

Activin A: a novel urinary biomarker of renal impairment in multiple myeloma.

Renal impairment (RI) is a common complication of multiple myeloma (MM) that significantly affects treatment efficacy and mortality. However, no useful biomarkers for early detection of renal damage in MM exist. Reports indicate that activin A, a multifunctional cytokine of the TGF-ß superfamily, is involved in the development and progression of various kidney diseases. In the present study, we measured urinary activin A levels in patients with newly diagnosed MM (NDMM) (n=41), smoldering MM (SMM) (n=10), and monoclonal gammopathy of undetermined significance (MGUS) (n=28), including monoclonal gammopathy of renal significance (MGRS), and assessed the correlation between urinary activin A and several clinical parameters. Urinary activin A, undetectable in healthy volunteers, was significantly increased in NDMM patients but not in patients with SMM and MGUS (97.3, 25.0, and 6.61 mg/gCr, respectively, P<0.05). In all patients with NDMM, urinary activin A levels were significantly reduced after initial treatment regardless of the therapy regimen. There was a significant correlation of urinary activin A with spot urinary protein level (P<0.001) and serum M-protein (P=0.029) but not with estimated glomerular filtration rate (eGFR), serum creatinine (Cr), N-acetyl-glucosaminidase (NAG), and serum activin A level. Histological analysis using renal biopsy samples revealed that activin A, which was absent from normal kidneys, was detected in the renal tubular cells of patients with MGRS. These data suggest that urinary activin A reflects tubular injury in MM and might aid the early detection of RI in plasma cell neoplasms.

Role of urine immunofixation in the complete response assessment of MM patients other than light-chain-only disease.

Response criteria for multiple myeloma (MM) require monoclonal protein (M-protein)-negative status on both serum immunofixation electrophoresis (sIFE) and urine (uIFE) immunofixation electrophoresis for classification of complete response (CR). However, uIFE is not always performed for sIFE-negative patients. We analyzed M-protein evaluations from 384 MM patients (excluding those with light-chain-only disease) treated in the GEM2012MENOS65 (NCT01916252) trial to determine the uIFE-positive rate in patients who became sIFE-negative posttreatment and evaluate rates of minimal residual disease (MRD)-negative status and progression-free survival (PFS) among patients achieving CR, CR but without uIFE available (uncertain CR; uCR), or very good partial response (VGPR). Among 107 patients with M-protein exclusively in serum at diagnosis who became sIFE-negative posttreatment and who had uIFE available, the uIFE-positive rate was 0%. Among 161 patients with M-protein in both serum and urine at diagnosis who became sIFE-negative posttreatment, 3 (1.8%) were uIFE positive. Among patients achieving CR vs uCR, there were no significant differences in postconsolidation MRD-negative (<10-6; 76% vs 75%; P = .9) and 2-year PFS (85% vs 88%; P = .4) rates; rates were significantly lower among patients achieving VGPR. Our results suggest that uIFE is not necessary for defining CR in MM patients other than those with light-chain-only disease.

Laboratory assessment of multiple myeloma.

Laboratory testing plays an essential role in the diagnosis and management of patients with multiple myeloma. A variety of chemistry and molecular assays are routinely used to monitor patient progress, response to treatment and relapse. Here, we have reviewed current literature and core guidelines on the details of laboratory testing in myeloma-related investigations. This includes the use and value of protein electrophoresis, serum free light chain and cytogenetic testing. Furthermore, we discuss other traditional chemistry assays essential to myeloma investigation, and potential interferences that may arise due to the disease nature of myeloma, that is, the presence of a monoclonal immunoglobulin. Finally, we discuss the importance of communication in protein electrophoresis results, where laboratorians are required to relate clinically relevant myeloma-relevant information to the ordering physician on the background of a complex pattern of serum or urine proteins. Laboratory testing in myeloma-related investigation relies on several traditional chemistry assays. However, we anticipate new tests and technologies to become available in the future with improved analytical sensitivity, as well as improved clinical sensitivity in identifying patients who are at high risk of progression to multiple myeloma.

The FLC dimer with lambda type may false-migrate to the position of "albumin" band by urine protein electrophoresis on Sebia agarose gel-based detection system.

BACKGROUND: Monoclonal free light chains (FLC) commonly exist in monomeric or dimeric forms but rarely as larger molecules. Little is known about whether polymeric molecules can affect urine protein electrophoresis (UPE) results. METHODS: Urine samples were collected from 72 multiple myeloma (MM) patients with Bence Jones protein (BJP). Urine protein and immunofixation electrophoresis were analyzed on Sebia SDS "agarose" gel electrophoresis system (SDS-AGE), and immunoglobulin free light chains were measured on the BNII nephelometric assay. RESULTS: A type of disulfide-bound FLC dimer shows a pattern shift to the position of the "albumin" band in urine protein electrophoresis in multiple myeloma (MM) patients according to the Sebia agarose gel-based detection system, which was validated by immunofixation, SDS-PAGE, and mass spectrometric methods. Similar cases were found in 21 (29.17%) of 72 MM patients with BJP, and 19 (90.5%) of 21 patients were the lambda type. CONCLUSIONS: These results indicate that BJP with lambda type has a strong tendency to abnormally migrate, which may increase the risk of misinterpretation of protein electrophoresis in clinics. Thus, when the urine protein electrophoresis is inconsistent with the result by nephelometric method, urine protein electrophoresis needs to be repeated on the deduced condition to confirm the essence of the originally identified "albumin."

Concentrations of Serum Free Light Chains in Kappa and Lambda Lesions in Light-Chain Myelomas.

BACKGROUND: Concentration of serum free light chains has been promoted as an assay in the evaluation of monoclonal gammopathic manifestations. A high false-positive rate in patients without monoclonal gammopathic manifestations and a high false-negative rate in patients with those manifestations have been reported. The false-negative rate for lambda chain-associated lesions is higher than that for kappa chain-associated lesions. OBJECTIVE: To assess the serum free light chains in light-chain myelomas. METHODS: Concentrations of involved and uninvolved serum free light chains were retrospectively reviewed in patients with light-chain myelomas. RESULTS: The highest recorded levels of involved light chains in kappa-chain myelomas and lambda-chain myelomas were comparable. The levels of uninvolved light chains were higher, although not statistically significantly, in lambda-chain lesions. CONCLUSIONS: The results of serum free light chains in light-chain myelomas support the clinical usefulness of the assay in monitoring patients with light chain myeloma.

Serum free light chain measurements to reduce 24-h urine monitoring in patients with multiple myeloma with measurable urine monoclonal protein.

Detection of myeloma progression (PD) relies on serial 24-h urinary M protein measurements in patients without measurable serum M spike. We examined whether serial difference free light chain (dFLC) levels could be used as a surrogate for serial 24-h urine M protein measurements in monitoring for PD in patients with baseline measurable urine M protein. We studied 122 patients who had serial measurement of urine M protein and serum FLC and had demonstrated PD. The median increase in dFLC with progression as defined by urine M spike was 110% (IQR: 55-312) and median absolute increase was 74 mg/dL; while 89% of patients had dFLC increase ≥ 25%, 94% had absolute increase in dFLC > 10 mg/dL, and 98% met at least 1 of these 2 criteria at PD. In patients with baseline measurable serum FLC (n = 118), 89% had increase in dFLC ≥ 25%, 97% had dFLC increase of > 10 mg/dL, and 98% had 1 of the 2. We conclude that serial dFLC assessments can be used in place of serial 24-h urine protein assessments during myeloma surveillance to monitor for PD. Once patients have an absolute increase in dFLC of >10 mg/dL from the nadir, a 24-h urine collection can then be assessed to document PD as per the International Myeloma Working Group criteria.

Light Chain Cast Nephropathy: Practical Considerations in the Management of Myeloma Kidney-What We Know and What the Future May Hold.

PURPOSE OF REVIEW: To update and evaluate the current knowledge on pathogenesis and management of light chain cast nephropathy. Light chain cast nephropathy (LCCN) is the leading cause of acute renal failure in patients with multiple myeloma and is currently recognized as a myeloma defining event. RECENT FINDINGS: The immunoglobulin free light chain plays an integral role in the pathogenesis of LCCN. The level of free light chain (FLC) in the blood and urine is directly associated with the risk of developing LCCN. Recovery of renal function is related to the speed and degree of the serum FLC reduction. Recently, two randomized trials using high cutoff dialyzer for the removal of serum FLC produced different results in terms of renal recovery. FLC plays a key role in the development and resolution of LCCN. Future therapies will aim to rapidly reduce its concentration or interrupt its interaction with Tamm-Horsfall protein.

Population Pharmacokinetics of Lenalidomide in Healthy Volunteers and Patients With Hematologic Malignancies.

A population pharmacokinetic (PopPK) model of lenalidomide was developed using data pooled from 13 clinical studies (dose range, 5-400 mg) in participants who were considered to have adequate capability for renal excretion of lenalidomide (creatinine clearance [CrCl] > 50 mL/min). The analysis population included 305 healthy volunteers and 83 patients with multiple myeloma or myelodysplastic syndromes. A 1-compartment model with linear absorption and elimination described well the observed data for both healthy volunteers and patients. Covariate analysis suggested lenalidomide apparent clearance was positively correlated with CrCl, and lenalidomide volume of distribution was positively correlated with body weight. Both pharmacokinetic parameters were reduced by 29% in patients, independent of the effect of CrCl or body weight. Despite their statistical significance, effects of study population and body weight are considered clinically unimportant in adult patients with CrCl > 50 mL. After accounting for the above effects, body weight had no significant effect on CL/F, whereas age, sex, race, and mild hepatic impairment had no significant effect on either lenalidomide parameter. The PopPK model should be useful for future modeling of lenalidomide pharmacokinetics in the pediatric population and for further comparison of pharmacokinetic properties among structurally similar immunomodulatory drugs.

Concurrent structural and biophysical traits link with immunoglobulin light chains amyloid propensity.

Light chain amyloidosis (AL), the most common systemic amyloidosis, is caused by the overproduction and the aggregation of monoclonal immunoglobulin light chains (LC) in target organs. Due to genetic rearrangement and somatic hypermutation, virtually, each AL patient presents a different amyloidogenic LC. Because of such complexity, the fine molecular determinants of LC aggregation propensity and proteotoxicity are, to date, unclear; significantly, their decoding requires investigating large sets of cases. Aiming to achieve generalizable observations, we systematically characterised a pool of thirteen sequence-diverse full length LCs. Eight amyloidogenic LCs were selected as responsible for severe cardiac symptoms in patients; five non-amyloidogenic LCs were isolated from patients affected by multiple myeloma. Our comprehensive approach (consisting of spectroscopic techniques, limited proteolysis, and X-ray crystallography) shows that low fold stability and high protein dynamics correlate with amyloidogenic LCs, while hydrophobicity, structural rearrangements and nature of the LC dimeric association interface (as observed in seven crystal structures here presented) do not appear to play a significant role in defining amyloid propensity. Based on the structural and biophysical data, our results highlight shared properties driving LC amyloid propensity, and these data will be instrumental for the design of synthetic inhibitors of LC aggregation.