Citations

Abstract The current definition of complete response in multiple myeloma includes a requirement for a bone marrow (BM) examination showing less than 5% plasma cells in addition to negative serum and urine immunofixation. There have been suggestions to eliminate the need for BM examinations when defining complete response. We evaluated 92 patients with multiple myeloma who achieved negative immunofixation in the serum and urine after therapy and found that 14% had BM plasma cells more than or equal to 5%. Adding a requirement for normalization of the serum-free light chain ratio to negative immunofixation studies did not negate the need for BM studies; 10% with a normal serum-free light chain ratio had BM plasma cells more than or equal to 5%. We also found that, on achieving immunofixation-negative status, patients with less than 5% plasma cells in the BM had improved overall survival compared with those with 5% or more BM plasma cells (6.2 years vs 2.3 years, respectively; P = .01).

Abstract Background: The repertoire of serologic tests for identifying a monoclonal gammopathy includes serum and urine protein electrophoresis (PEL), serum and urine immunofixation electrophoresis (IFE), and quantitative serum free light chain (FLC). Although there are several reports on the relative diagnostic contribution of these assays, none has looked at the tests singly and in combination for the various plasma cell proliferative disorders (PCPDs). Methods: Patients with a PCPD and all 5 assays performed within 30 days of diagnosis were included (n = 1877). The diagnoses were multiple myeloma (MM) (n = 467), smoldering multiple myeloma (SMM) (n = 191), monoclonal gammopathy of undetermined significance (MGUS) (n = 524), plasmacytoma (n = 29), extramedullary plasmacytoma (n = 10), Waldenström macroglobulinemia (WM) (n = 26), primary amyloidosis (AL) (n = 581), light chain deposition disease (LCDD) (n = 18), and POEMS syndrome (n = 31). Results: Of the 1877 patients, 26 were negative in all assays. Omitting urine from the panel lost an additional 23 patients (15 MGUS, 6 AL, 1 plasmacytoma, 1 LCDD), whereas the omission of FLC lost 30 patients (6 MM, 23 AL, and 1 LCDD). The omission of serum IFE as well as urine lost an additional 58 patients (44 MGUS, 7 POEMS, 5 AL, 1 SMM, and 1 plasmacytoma). Conclusions: The major impact of using a simplified screening panel of serum PEL plus FLC rather than PEL, IFE, and FLC is an 8% reduction in sensitivity for MGUS, 23% for POEMS (7 patients), 4% for plasmacytoma (1 patient), 1% for AL, and 0.5% for SMM. There is no diminution in sensitivity for detecting MM, macroglobulinemia, and LCDD.

Abstract The outcome of patients with multiple myeloma is dictated primarily by cytogenetic abnormalities and proliferative capacity of plasma cells. We studied the outcome after initial therapy with lenalidomide-dexamethasone among 100 newly diagnosed patients, risk-stratified by genetic abnormalities and plasma cell labeling index. A total of 16% had high-risk multiple myeloma, defined by the presence of hypodiploidy, del(13q) by metaphase cytogenetics, del(17p), IgH translocations [t(4;14), or t(14;16)] or plasma cell labeling index more than or equal to 3%. Response rates were 81% vs 89% in the high-risk and standard-risk groups, respectively. The median progression-free survival was shorter in the high-risk group (18.5 vs 36.5 months, P < .001), but overall survival was comparable. Because of unavailability of all tests for every patient, we separately analyzed 55 stringently classified patients, and the results were similar. In conclusion, high-risk patients achieve less durable responses with lenalidomide-dexamethasone compared with standard-risk patients; no significant differences in overall survival are apparent so far. These results need confirmation in larger, prospectively designed studies.

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

Abstract We examined whether monoclonal gammopathy of undetermined significance (MGUS) is increased in first-degree relatives of multiple myeloma (MM) or MGUS patients. Probands were recruited from a population-based prevalence study (MGUS) and the Mayo Clinic (MM). Serum samples were collected from first-degree relatives older than 40 years and subjected to electrophoresis and immunofixation. The prevalence of MGUS in relatives was compared with population-based rates. Nine-hundred eleven relatives of 232 MM and 97 MGUS probands were studied. By electrophoresis, MGUS was detected in 55 (6%) relatives, and immunofixation identified 28 additional relatives for an age- and sex-adjusted prevalence of 8.1% (95% CI, 6.3 to 9.8). The prevalence of MGUS in relatives increased with age (1.9%, 6.9%, 11.6%, 14.6%, 21.0% for ages 40-49, 50-59, 60-69, 70-79, ≥ 80 years, respectively; P < .001). Using similar MGUS detection methods, there was a higher risk of MGUS in relatives (age-adjusted risk ratio [RR], 2.6; 95% CI, 1.9 to 3.4) compared with the reference population. The increased risk was seen among relatives of MM (RR, 2.0; 95% CI, 1.4 to 2.8) and MGUS probands (RR, 3.3; 95% CI, 2.1 to 4.8). The increased risk of MGUS in first-degree relatives of MGUS or MM patients implies shared environment and/or genetics.

AbstractPrimary systemic amyloidosis (AL) is a rare monoclonal plasma cell (PC) disorder characterized by the deposition of misfolded immunoglobulin (Ig) light chains (LC) in vital organs throughout the body. To our knowledge, no cell lines have ever been established from AL patients. Here we describe the establishment of the ALMC-1 and ALMC-2 cell lines from an AL patient. Both cell lines exhibit a PC phenotype and display cytokine-dependent growth. Using a comprehensive genetic approach, we established the genetic relationship between the cell lines and the primary patient cells, and we were also able to identify new genetic changes accompanying tumor progression that may explain the natural history of this patient's disease. Importantly, we demonstrate that free lambda LC secreted by both cell lines contained a beta structure and formed amyloid fibrils. Despite absolute Ig LC variable gene sequence identity, the proteins show differences in amyloid formation kinetics that are abolished by the presence of Na2SO4. The formation of amyloid fibrils from these naturally secreting human LC cell lines is unprecedented. Moreover, these cell lines will provide an invaluable tool to better understand AL, from the combined perspectives of amyloidogenic protein structure and amyloid formation, genetics, and cell biology.

AbstractThe immunoglobulin free light chain (FLC) assay is an invaluable tool for following patients with oligosecretory plasma cell dyscrasia. Baseline values have also been shown to be prognostic in all plasma cell disorders tested. A looming question, however, is the role it should play in following myeloma patients with disease that is measurable using serum and urine electrophoresis. We used the data and stored samples from a mature Eastern Cooperative Oncology Group clinical trial (E9486) to assess serum levels of FLC at baseline and after 2 months of alkylator-based therapy. For serial determinations, the absolute level of involved serum FLC or the difference of the involved and uninvolved FLC is preferred over the ratio of involved to uninvolved FLC. FLC response after 2 months of therapy was superior to early M-protein measurement to predict overall response. The ideal cut-point for FLC change appears to be between 40% and 50% reduction. The correlation between serial measurements of serum FLC and urine M-protein is inadequate to abolish the serial 24-hour urine protein. Although baseline values of FLC are prognostic in newly diagnosed myeloma patients, serial measurements do not appear to have added value in patients who have M-proteins measurable by electrophoresis.

Abstract The Multiple Myeloma Research Consortium has established a tissue bank for the deposition of bone marrow samples from patients with multiple myeloma to be mailed and processed under good laboratory practices. To date, over 1,000 samples have been collected. At this time, limited information is available on shipped bone marrow aspirates in regards to cell viability, yield, purity, and subsequent RNA yield and quality. To test these determinants, we did a pilot study on behalf of the Multiple Myeloma Research Consortium where samples were drawn at Mayo Clinic Rochester (MCR) pooled and split into two equal aliquots. One-half of each sample was processed following good laboratory practices compliant standard operating procedures, immediately after sample procurement, at MCR. The CD138+ cells were stored at -80°C as a Trizol lysate. The other half of the aspirate was sent overnight to Mayo Clinic Scottsdale where they were processed using identical standard operating procedures. The RNA was extracted and analyzed in a single batch at MCR. At both locations, samples were assayed for the following quality determinants: Viability was assessed using a three-color flow cytometric method (CD45, CD38, and 7-AAD). Cell counts were done to determine plasma cell recovery and post-sort purity determined by means of a slide-based immunofluorescent assay. RNA recovery and integrity was assessed using the Agilent Bioanalyzer. Lastly, gene expression profiles were compared to determine the signature emanating from the shipment of samples. Despite minor differences, our results suggest that shipment of samples did not significantly affect these quality determinants in aggregate. (Cancer Epidemiol Biomarkers Prev 2008;17(3):666–73)