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Background: Spinal anesthesia provides several benefits for patients undergoing total hip arthroplasty (THA) and total knee arthroplasty (TKA), but historically comes at the cost of slow and unpredictable return of lower-extremity motor function related to the use of long-acting local anesthetics. In this prospective, double-blinded, randomized clinical trial we sought to determine if an alternative local anesthetic, mepivacaine, would allow more consistent return of motor function compared with low-dose bupivacaine spinal anesthesia during primary THA and TKA. Methods: This trial was conducted at a single academic institution. Prior to trial initiation an internal pilot study determined that 154 patients were required to achieve 80% power. Patients were randomized in a 1:1 fashion with use of advanced computerized stratification based on procedure, age group, sex, and body mass index. Following the surgical procedure, motor function was assessed every 15 minutes in the nonoperative lower extremity according to the Bromage scale and discontinued once Bromage 0 was achieved (spontaneous movement at hip, knee, and ankle). Results: Return of lower-extremity function was more predictable in patients who received mepivacaine than in those who received low-dose bupivacaine. Among patients who received mepivacaine, 1% achieved motor function return beyond 5 hours compared with 11% of patients who received bupivacaine (p = 0.013). The mean time to return of lower-extremity motor function was 26 minutes quicker in patients who received mepivacaine (185 minutes; 95% confidence interval, 174 to 196 minutes) compared with low-dose bupivacaine (210 minutes; 95% confidence interval, 193 to 228 minutes) (p = 0.016). There were no significant differences in safety outcomes including pain scores, time to participation in physical therapy, incidence of orthostatic hypotension, urinary retention, or transient neurologic symptoms in patients receiving mepivacaine compared with low-dose bupivacaine. Conclusions: In patients undergoing primary THA and TKA, spinal anesthesia with mepivacaine allowed more consistent return of lower-extremity motor function compared with low-dose bupivacaine, without a concomitant increase in complications potentially associated with spinal anesthetics. This is particularly of value in an era of short-stay and outpatient surgical procedures. Level of Evidence: Therapeutic Level I . See Instructions for Authors for a complete description of levels of evidence.

Abstract Background: Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant plasma cell disorder that carries a 1% per year risk of progression to multiple myeloma (MM) or related malignancy. The prevalence and natural history of MGUS, in which by definition intact immunoglobulin heavy chain (IgH) is expressed, has been well described. However, up to 20% of myeloma (MM) is characterized by complete lack of IgH expression (Light-chain MM); the prevalence of a corresponding precursor entity, light chain MGUS (LC-MGUS) has not been determined. We report the first prevalence estimates of LC-MGUS in the general population from a large, well-defined geographic population using modern laboratory techniques. Methods: The cohort for this study was derived from one previously assembled by us to estimate the prevalence of MGUS (N Engl J Med2006;354:1362-9). The original cohort used to estimate the prevalence of MGUS consisted of 21,463 of the 28,038 enumerated residents aged 50 or over of Olmsted County Minnesota as of January 1, 1995. The sensitive serum free light chain (FLC) assay (The Binding Site Limited, Birmingham, U.K.) was performed on stored serum samples from these 21,463 persons. IgH expression was determined by immunofixation on all FLC results that had an abnormal kappa/lambda ratio (<0.26 or >1.65). LC-MGUS was defined as the presence of an abnormal FLC ratio and a negative immunofixation for IgH expression. Results: Adequate stored serum samples were available in 20,733 (97%) of the 21,463 persons. To date, the FLC assay has been performed and results were available for analysis on samples from 16,637 persons. An abnormal FLC ratio was observed in 572 persons. IgH expression was detected in 255 of these cases on immunofixation; these persons are considered as having MGUS, and were excluded from the estimation of LC-MGUS prevalence. This resulted in 317 persons out of 16,637 who had an abnormal FLC ratio without evidence of IgH expression, resulting in an estimated prevalence of LC- MGUS of 2%. Of the 317 cases of LC-MGUS identified in this study, 217 were kappa and 100 were lambda; in 35 cases the presence of the corresponding monoclonal light chain was apparent on immunofixation. The median age of the cohort of LC-MGUS was 62 years; males=151, females =166. The involved FLC level ranged from 0.118–270.0 mg/dL. The FLC ratio ranged from 0.014–0.253 (lambda) and 1.67–511.01 (kappa). So far, progression to multiple myeloma has occurred in 4 patients, a rate much higher than what is expected based on the prevalence of myeloma in the general population. Two additional patients have developed CLL. Conclusions: LC-MGUS is prevalent in 2% of the general population aged 50 years of age or older. The natural history of this disorder needs to be determined.

Abstract Due to the diagnostic sensitivity of serum free light chain quantitation for monoclonal light chain diseases, it has been suggested that urine assays no longer need be performed as part of the diagnostic algorithm for monoclonal proteins. We reviewed our experience to determine the relative diagnostic contribution of urine assays. Methods: Patients with a monoclonal gammopathy and monoclonal urinary protein at initial diagnosis who also had a serum immunofixation and serum free light chain quantitation within 30 days of diagnosis were identified (n = 428). The laboratory results for serum protein electrophoresis, serum immunofixation, serum free light chain, urine protein electrophoresis, and urine immunofixation were reviewed. Results: The patients in this cohort had diagnoses of multiple myeloma, primary amyloid, monoclonal gammopathy of undetermined significance, smoldering multiple myeloma, solitary plasmacytomas, and other less frequently detected monoclonal gammopathies. By definition of the cohort, all 428 had a monoclonal urine protein. 86% had an abnormal serum free light chain K/L ratio, 81% had an abnormal serum protein electrophoresis, and 94% had an abnormal serum immunofixation. In only 2 patients, however, were all 3 serum assays normal. Both of these were patients with monoclonal gammopathy of undetermined significance (idiopathic Bence Jones proteinuria). Conclusion: Discontinuation of urine studies and reliance on a diagnostic algorithm using solely serum studies (protein electrophoresis, immunofixation, and free light chain quantitation), missed 2 of the 428 monoclonal gammopathies (0.5 %) with urinary monoclonal proteins, and these 2 cases required no medical intervention.

Abstract Smoldering multiple myeloma (SMM) is characterized by a serum M protein ≥ 3g/dL and/or 10% or more of plasma cells in the bone marrow. However, the definition is not standardized, and it is not known whether both serum M protein levels and bone marrow plasma cell counts are necessary for diagnosis or if one parameter is sufficient. We reviewed the medical records and bone marrows of all patients from Mayo Clinic seen within 30 days of recognition of an IgG or IgA M protein ≥ 3g/dL or a bone marrow containing ≥ 10% plasma cells from 1970 to 1995. This allows for a minimum potential follow-up of 10 years. Patients with end-organ damage at baseline from plasma cell proliferation, including active multiple myeloma (MM) and primary amyloidosis (AL) and those who had received chemotherapy were excluded. A differential of the bone marrow aspirate coupled with the bone marrow biopsy morphology and immunohistochemistry using antibodies directed against CD138, MUM-1 and Cyclin D1 were evaluated in every case in order to estimate the plasma cell content. In all, 301 patients fulfilled either of the criteria for SMM. Their median age was 64 years and only 3% were less than 40 years of age; 60% were male. The median hemoglobin value was 12.9 g/dL; 7% were less than 10 g/dL, but the anemia was unrelated to plasma cell proliferation. IgG accounted for 75%, IgA 22%, and biclonal proteins were found in 3%. The serum light-chain was κ in 67% and λ in 33%. The median serum M spike was 2.9 g/dL; 11% were at least 4.0 g/dL. Uninvolved serum immunoglobulins were reduced in 81%; only 1 immunoglobulin was reduced in 31% and both were decreased in 50%. The urine contained a monoclonal κ protein in 36% and λ in 18% and 46% were negative. The median size of the urine M spike was 0.04 g/24h; only 5 (3%) were > 1 g/24h. The median bone marrow plasma cell content was 15 – 19%; 10% had less than 10% plasma cells, while 10% had at least 50% plasma cells in the bone marrow. Cyclin D-1 was expressed in 17%. Patients were categorized into 3 groups: Group 1, serum M protein ≥ 3g/dL and bone marrow containing ≥ 10% plasma cells (n= 113, 38%); Group 2, bone marrow plasma cells ≥ 10% but serum M protein < 3g/dL (n= 158, 52%); Group 3, serum M protein ≥ 3g/dL but bone marrow plasma cells < 10% (n= 30, 10%). During 2,204 cumulative years of follow-up 85% died (median follow-up of those still living 10.8 years), 155 (51%) developed MM, while 7 (2%) developed AL. The overall rate of progression at 10 years was 62%; median time to progression was 5.5 yrs. The median time to progression was 2.4, 9.2, and 19 years in groups 1, 2, and 3 respectively; correspondingly at 10 years, progression occurred in 76%, 59%, and 32% respectively. Significant risk factors for progression with univariate analysis were serum M spike ≥ 4g/dL (p < 0.001), presence of IgA (p = 0.003), presence of urine light chain (p = 0.006), presence of λ urinary light chain (p = 0.002), bone marrow plasma cells ≥ 20% (p < 0.001) and reduction of uninvolved immunoglobulins (p < 0.001). The hemoglobin value, gender, serum albumin, and expression of cyclin D-1 were not of prognostic importance. On multivariate analysis, the percentage of bone marrow plasma cells was the only significant factor predicting progression to MM or AL.

Abstract Background: Clonal cytogenetic aberrations define multiple myeloma (MM) into unique subsets of the disease each one with unique clinical and biologic features, associations with laboratory and pathologic markers and presumed differential influence on disease progression. While it is widely accepted that translocations represent primordial events in the pathogenesis of MM, it is controversial whether all translocations can be associated with disease stability and non-malignant behavior (i.e. in MGUS/SMM). We have found the translocations in cases of MGUS using dual fusion, cIg enhanced, interphase FISH, while others have found this translocation at lower prevalence using single fusion interphase FISH or the RT-PCR for IgH/MMSET. We thus sought to clarify by expanding the study of the t(4;14) among patients with MGUS and SMM. Materials and methods: We studied 210 patients who had the diagnosis of MGUS and SMM and entered into the Mayo Clinic Dysproteinemia database. Patients were excluded if they had active MM, extramedullary disease or plasmacytoma. Patients with isolated lytic bone lesions could be included if they had no overt evidence of progression. All studied patients had provided written informed consent for the collection of a research bone marrow aliquot that was collected at the time of routine bone marrow procurement. All patients had cytospin slides that were studied for a t(4;14) using cIg-FISH as previously described by us and using a double fusion FISH strategy. The importance of this is that the strategy will detect unbalanced t(4;14) with loss of der(14). Results: Twenty patients (9.5%) had evidence of the chromosome translocation. Detailed demographic data was available in 19; 14 were women (74%), 13 of 19 (68%) had SMM and there was no bias for heavy chain IgA (26%). Patients with t(4;14) were slightly younger than those without the abnormality (52 vs. 61 years), had similar hemoglobin concentrations, had slightly higher concentration of the serum M spike (2.0 vs 1.75 g/dl) and had overall slightly higher bone marrow plasmacytosis (median 23% vs 10%). Patients were followed since diagnosis for a median of 33 months (range 2–162 months). Three patients progressed to active MM at 12, 12 and 26 months after original diagnosis (all three originally having indolent/SMM). Conclusion: The t(4;14) can occur in patients with MGUS and SMM and without evidence of progression to MM. The prevalence is similar to that observed in MM, albeit slightly lower (9.5% versus 14%). In most “benign” plasma cell neoplasms the translocation is associated with greater plasmacytosis and thus enriched for in the smoldering MM category. It is also likely that the t(4;14) confers a higher risk of progression to MM given; a) its enrichment in SMM, b) the slightly higher prevalence of the translocation in MM as opposed to MGUS/SMM, and c) the well documented aggressive clinical course of MM with t(4;14).

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

Abstract Background: Monoclonal gammopathy of undetermined significance (MGUS) is a common pre-malignant plasma cell disorder associated with a 1% per year risk of progression to multiple myeloma or related malignancy. Since the risk factors for MGUS are poorly defined, the goal of the present study was to determine if the risk of MGUS is increased in first degree relatives of patients with known multiple myeloma (MM) or MGUS. Methods: MGUS probands (index cases) were recruited from a population-based prevalence study of MGUS in Olmsted County, MN while MM probands were recruited through the Mayo Clinic practice. Consenting probands were asked to provide contact information on all first-degree relatives ages 40 years and older. Serum samples were then collected from first-degree relatives with informed consent and subjected to agaraose-gel electrophoresis and immunofixation. The prevalence of MGUS in first-degree relatives of MM and MGUS probands was compared to population-based rates from Olmsted County using risk ratios (RR). For comparisons to the reference population, only cases detected by protein electrophoresis and confirmed by immunofixation were included so that the diagnostic strategy was identical in the two groups being compared. Results: Serum samples were obtained from 911 relatives of 329 unique families, including 493 siblings, 324 children and 94 parents of patients with MGUS or MM. Using protein electrophoresis, monoclonal protein was detected in the serum of 55 (6%) while immunofixation identified 28 additional relatives (3%), for an age- and sex-adjusted prevalence rate of 8.1% (95%CI: 6.3, 9.8). The age-specific prevalence of MGUS in first-degree relatives increased with age (1.9%, 6.9%, 11.6%, 14.6%, and 21.0% for ages 40–49, 50–59, 60–69, 70–79 and ≥80, respectively; P<0.001). Based on similar MGUS detection methodology as the reference population, there was a significantly higher risk of MGUS in first-degree relatives (age-adjusted RR, 2.6, 95%CI: 1.9, 3.4) compared to the reference population. The increased risk (P<0.001) was seen both in relatives of MM probands (RR, 2.0, 95%CI: 1.4, 2.8), as well as MGUS probands (RR, 3.3, 95%CI: 2.1, 4.8). This association was similar across age of proband, age and gender of relative, and relationship of the first-degree relative. When examining whether the increased risk of MGUS in relatives was specific to probands with a large monoclonal protein concentration or specific monoclonal immunoglobulin isotype (i.e. high-risk MGUS phenotype), there was suggestion of a greater risk for relatives of probands with a high (3 1.5 g/dL) M-protein (RR, 2.8, 95%CI: 2.0,3.8) compared to lower M-protein levels (RR, 1.8, 95%CI: 1.1,2.8) although the difference did not reach statistical significance (P=0.12). The risk of MGUS in relatives did not differ by proband’s isotype (IgG vs. other). Conclusions: First-degree relatives of patients with MM or MGUS have a greater than two-fold risk of MGUS compared to the general population, implying underlying genetic predisposition for these diseases and providing rationale for identifying genetic determinants of MGUS. This study also provides important baseline rates of MGUS in first-degree relatives that impact the clinical care of these patients.

Abstract Background: Traditionally response to therapy in multiple myeloma (MM) is based on changes in the serum and urine monoclonal protein by immunoelectrophoresis. Immunofixation allows for detection of small amounts of monoclonal protein that cannot be quantitated on immunoelectrophoresis. Serum immunoglobulin free light chain (FLC) assay allows for detection of unbound kappa and lambda free light chain and has allowed disease measurement in patients with oligosecretory myelomas and can potentially allow detection of low levels of tumor burden, below the threshold of the standard tests. We examined this hypothesis in patients who had obtained a negative immunofixation in serum and urine following treatment of their MM. Methods: For the purposes of the study, we included selected patients with MM who had measurable monoclonal (M) protein levels at baseline (defined as >1 gm/dL in the serum or >200 mg/24 hour in the urine or involved free light chain > 10 mg/dL) on protein electrophoresis; patients with non-secretory and oligo-secretory myeloma were excluded. We then identified patients who since 1995 had a negative immunofixation in the serum and urine, all done at the same time (within 30 days of each other). Baseline demographics and clinical characteristics; date of diagnosis, last follow up, and follow up status; serum and urine M protein levels at diagnosis; and results of serum and urine immunofixation, and serum free light chain (FLC) ratio within 30 days of the immunofixation were all collected from the existing databases. Results: Eighty-four patients met the criteria for the study, all of whom had measurable disease at baseline and subsequently achieved negative immunofixation in serum and urine. Among these, 46 patients (55%) also had a normal FLC ratio (K/L ratio; 0.26–1.65). Th median time from diagnosis to the documented immunofixation was 7.5 months (range, 1–157). The median overall survival from diagnosis among those with a normal FLC ratio along with negative immunofixation was not reached compared to 76 months for those with abnormal FLC ratio, P = 0.02. The median overall survival from the documentation of negative immunofixation was not reached for the group with normal FLC ratio compared to 46.5 months for those with an abnormal FLC, P = 0.03. Conclusion: Attainment of a normal FLC ratio at the time of serum and urine immunofixation negative status identifies a group of patients with better outcome. The presence of an abnormal FLC ratio likely represents persistence of the clonal population that is secreting none or very small amounts of monoclonal protein. The data presented here supports the inclusion of FLC measurements as part of response criteria for MM as has been done for the definition of stringent CR in the IMWG response criteria. Figure: Overall survival from diagnosis in patients with or with out a normal FLC ratio at the time of serum and urine immunofixation. Figure:. Overall survival from diagnosis in patients with or with out a normal FLC ratio at the time of serum and urine immunofixation.

Abstract Smoldering Waldenström’s Macroglobulinemia (SWM) is defined as a serum IgM monoclonal protein ≥3 g/dL and/or ≥10% bone marrow lymphoplasmacytic infiltration but no evidence of constitutional symptoms, symptomatic anemia, or hyperviscosity. Forty-eight patients with SWM were identified at Mayo Clinic from 1974 to 1995. Patients with a diagnosis of chronic lymphocytic leukemia or lymphoma or history of any antineoplastic therapy before diagnosis of SWM were excluded. The median age at diagnosis was 63 years (range 39–87 years). Only one patient (2%) was < 40 years of age, but 14 percent were < 50 years old. Thirty-two (67%) were men, and 16 (33%) were women. At diagnosis, hepatomegaly was noted in 10%, splenomegaly in 4%, and lymphadenopathy in 8%. The initial hemoglobin level ranged from 8.7 to 15.3 g/dL (median 11.8). The anemia in all 4 patients with an initial hemoglobin < 10 g/dL was due to other causes such as myelodysplastic syndrome, bronchopleural fistula, Barrett’s esophagus, and Coumadin administration. The initial leukocyte level ranged from 3.2 to 13.2 × 109/L (median 5.7), and platelets ranged from 101 to 578 × 109/L (median 285.5). Only one patient had a serum creatinine > 2.0 mg/dL and it was unrelated to SWM. The serum monoclonal protein level at the time of diagnosis ranged from 1.5 to 5.2 g/dL (median 3.3); 12 (25%) were < 3 g/dL, while 10 (21%) were ≥4 g/dL. IgM kappa accounted for 75%, IgM lambda 21%, and 2 (4%) were biclonal. Immunofixation of the urine was positive in 97% (kappa 80%, lambda 17%, indeterminate 3%) of those tested. The size of the urine M protein ranged from unmeasurable to 1.4 g/24h (median 0.04 g/24h). Serum albumin ranged from 2.5 to 4.3 g/dL (median 3.6). Five patients (10%) had an albumin value < 3 g/dL. Ten (26%) had a reduction of 1 uninvolved immunoglobulin, while 8 (21%) had a reduction of both IgG and IgA immunoglobulins. Lymphoplasmacytic infiltration of the bone marrow ranged from 3% to 80%, (median 30%). Three (6%) had less than 10% infiltration, while 13 (27%) had 50% or greater infiltration. The 48 patients were followed for a total of 292 (range 0.5 to 22.6 years; median 3.7) person-years, during which time 33 progressed to symptomatic WM and one to AL amyloidosis. The expected number of WM based on the SEER data was 0.004 cases. Thus, relative risk of progression to WM was increased 7,586-fold (95% CI, 5,083 to 10,373). The median time to progression was 4.6 years. The absolute risk of progression to WM was 6% at 1 year, 39% at 3 years, and 55% at 5 years. The median survival after progression to symptomatic WM was 5.1 years. Seventy-three percent of patients died, indicating a robust follow-up. We evaluated sex, hemoglobin level, size of serum M protein, reduction of uninvolved immunoglobulins, presence of urinary monoclonal light chains, serum albumin level, and the proportion of lymphoplasmacytic infiltration of the bone marrow as risk factors for progression. Significant risk factors for progression with univariate analysis included size of the serum M protein, hemoglobin level, reduction in uninvolved immunoglobulins, and degree of bone marrow lymphoplasmacytic cell infiltration. Multivariate modeling revealed that the size of the M protein and the degree of bone marrow infiltration were the most important risk factors. We conclude that smoldering WM is a distinct clinical entity that needs to be differentiated from IgM MGUS and symptomatic Waldenstrom’s Macroglobulinemia.