Larson, Dirk R.

Abstract Abstract 934 Background: An increased risk of developing myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) has been observed for over 40 years in patients with multiple myeloma (MM). While treatment for MM has been implicated as the cause of excess MDS/AML, the risk may also be related to the underlying plasma cell proliferative disease process or an inherent predisposition to other hematologic malignancies in patients with plasma cell disorders. A recent study found an increased risk of AML/MDS for patients with monoclonal gammopathy of undetermined significance (MGUS) where there is no confounding chemotherapy effect to consider (Mailankody S, Blood2011; 118:4086-92). However, that report is subject to detection bias (i.e. association is related to reason for electrophoretic testing rather than the result of the test) since the population was not uniformly screened for MGUS. The purpose of this study was to determine if there was an increased risk of AML/MDS and other acute leukemias in persons with MGUS in a large population-based cohort systematically screened for the presence or absence of MGUS. Methods: The study utilized the population-based cohort established to estimate the prevalence of MGUS in the general population (N Engl J Med 2006; 354:1362-9). Serum samples were collected from 21,463 of the 28,038 residents of Olmsted County, Minnesota age 50 years or older as of 1/1/1995. Serum electrophoresis and immunofixation were used to determine MGUS status by testing all serum samples for the presence of a monoclonal protein. MGUS status was then linked to diagnoses entered in the Mayo Clinic Medical Index from 1/1/1975 to last follow up or 5/31/2006. For any patient in whom the diagnosis of AML/MDS or acute lymphoblastic leukemia (ALL) was in doubt, the diagnosis was verified by medical record review. For MGUS patients who progressed to MM or related disorder, only diagnosis of leukemia made prior to progression was considered. Results: 17,315 patients who consented to serum analysis were included in this study; blinded patients included in the original cohort could not be evaluated. The final study cohort represents 435,021 person-years of follow-up. Mean follow up for patients with MGUS (n=605) was 24.64 years (range 0.11–30.57); controls (n=16,710) had a mean follow up of 25.14 years (range 0.01–31.40). MGUS patients had a significantly higher risk of developing acute leukemia (AML/ALL) or MDS compared to controls, risk ratio 2.20 (95% CI 1.23–3.92), p=0.008 (see Table). There was a higher risk of developing AML/MDS compared to controls, risk ratio 1.80 (95% CI .09-3.59), p=0.09. The risk of developing MDS was statistically significant (RR=2.10, p=0.049). MGUS patients had a 4.18-fold increased risk of developing ALL (p=0.010) and a 2.35-fold increased risk of developing any acute leukemia (p=0.050) over the general population. In subset analysis, patients with IgA/IgG MGUS had a 1.99-fold increased risk of developing MDS (p=0.108), while patients with an IgM M spike had a 2.81-fold increased risk of developing MDS over controls (p=0.152). Though MDS was observed in patients with IgA, IgG, and IgM M-spikes, AML was only observed only in patients with IgA or IgG isotypes (n=2/484). Conclusion: Our population-based study suggests MGUS is associated with a 1.8-fold increased risk of developing MDS/AML over the general population. The risk of AML/MDS is more modest than the 8-fold increased risk suggested in a previous report (Mailankody S, Blood2011; 118:4086-92). The smaller risk ratios in our study are likely related to our population-based cohort design that uniformly screened for the presence or absence of MGUS, and thereby minimized any amplification of risk that can occur in the presence of ascertainment bias. We also found a significant increase in the risk of ALL in persons with MGUS that requires further study. Our study supports the hypothesis that there may be an inherent increased risk of acute leukemia and MDS in patients with plasma cell disorders that is independent of myeloma therapy. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 3972 Background: The treatment paradigm for myeloma has undergone a dramatic shift in the past decade with the introduction of the novel agents and their application at every stage of the treatment. We and others had previously shown that survival of patients with myeloma had improved in the earlier half of the last decade and attributed this to a combination of novel therapies as well as increased use of stem cell transplant. It is not clear if this momentum in improving survival has been maintained. We examined the survival trends of patients with newly diagnosed myeloma seen within the past decade to examine this question. Patients and Methods: We studied 1056 patients with newly diagnosed myeloma, who were seen at Mayo Clinic between January 1, 2001 and December 31, 2010; who were seen within 30 days of their diagnosis. For examination of the time trends, we grouped the time interval into two five year periods, 2001–2005 and 2006–2010. Survival was estimated using Kaplan Meier method and survival curves were compared by log rank test. Impact of various prognostic factors was evaluated using Cox proportional hazards test. Results: The median age at diagnosis was 65 (range; 22–92), and 59% were male. The median estimated follow up for the entire cohort was 4.6 years (95% CI; 4.4, 4.9) and 57% of the patients were alive at last follow up. The median overall survival (OS) for the entire cohort was 5.4 years (95% CI; 5, 6.3). The overall survival for patients in the 2001–2005 group was 4.6 years compared with not reached for the 2006–2010 cohort (P< 0.001). The five-year estimated OS was 48% for the earlier group compared with 66% for the latter group. The estimated 1-year survival was 90% for the recent cohort compared with 83% for the earlier cohort, suggesting improvements in the early mortality. Interestingly, the improvement was predominantly seen in the older age group (>65 years; 49%). The 5-year survival of the older patients improved significantly from 31% (2001–2005) to 56% (2006–2010) (P<0.001). In contrast, among younger patients (≤65 years of age), the 5-year survival improved only marginally from 63% (2001–2005) to 73% (2006–2010) (P=NS). One or more novel agents (Lenalidomide, thalidomide or bortezomib) were used as part of initial therapy in 631 (62% of 1021 in whom treatment data was available). The OS among of this group was 7.3 years (95% CI; 5.9, NR) compared with 3.8 years (95% CI; 3.1, 4.6). In a multivariate model that included both use of novel agent and the year group, only the novel agent use was associated with improved survival suggesting that the improvement in the survival is related to the increased use of novel agents in the initial therapy. No significant differences were observed between the groups in terms of conventional prognostic factors. Conclusions: The current results confirm continued improvement in the overall survival of patients, even within the last 10 year period, and highlight the impact of initial therapy with novel agents. Most importantly, we demonstrate that the improved survival has primarily benefited older patients. Our study highlights that urgent need for additional new agents to provide further survival improvement for younger patients, and in order achieve a cure for this disease. Disclosures: Kumar: Merck: Consultancy, Honoraria; Celgene: Research Funding; Millennium: Research Funding; Novartis: Research Funding; Cephalon: Research Funding; Genzyme: Research Funding. Dispenzieri:Celgene: Research Funding; Millennium Pharmaceuticals, Inc.: Research Funding; Janssen Research & Development: Research Funding. Gertz:Binding Site: Honoraria.

Abstract Abstract 4000 Background: We have previously reported that there is an increased risk of monoclonal gammopathy of undetermined significance (MGUS) in first-degree relatives of patients with multiple myeloma (Vachon CM. Blood 2009 114: 785–790). There are several cytogenetic subtypes of myeloma, and there are no data on whether certain cytogenetic subtypes of myeloma are more frequently associated with familial MGUS. Methods: We studied patients with myeloma who participated in the familial MGUS study in whom presence or absence of MGUS in the first-degree relatives had been ascertained (Vachon CM. Blood 2009 114: 785–790). Probands were seen at the Mayo Clinic Hematology/Oncology practice (Rochester, MN, USA) between February 2006 and September 2007. Cytogenetic data was acquired via electronic medical record abstraction of fluorescence in-situ hybridization (FISH) lab reports, and used to categorize patients into one of nine cytogenetic subgroups: trisomy(ies), t(6;14), t(11;14), t(4;14), t(14;16), t(14;20), Mixed (those with trisomy(ies) and an IgH translocation), other cytogenetic abnormalities (in the absence of trisomy(ies) or IgH translocation), and normal (Kumar S. Blood 2012;119:2100–2105). We examined whether a difference in the distribution of the six primary cytogenetic categories of myeloma existed between probands with a family history of MGUS and/or myeloma and those without. Results and Conclusions: Of the 248 patients invited to participate, FISH data (with sufficient plasma cells) was available on 119 participants to establish the primary molecular cytogenetic classification of myeloma. All had available information regarding family history of MGUS and multiple myeloma. 27 had an affected first-degree relative with MGUS, and 92 did not. Distributions of cytogenetic subtypes in the two groups are shown in Table 1. IgH translocated MM was more common in myeloma patients who lacked an affected first-degree relative compared to those with familial MGUS (19% vs 30%, P=0.32) Interestingly, the t(11;14) subtype was more common in myeloma patients without familial MGUS compared to those with an first-degree relative with MGUS (19.6% vs 7.4%, P=0.24). The differences in Table 1 did not reach statistical significance, possibly due to the small numbers of individuals with a family history in this sample. However, the distribution (Table 1) suggests that the distribution of cytogenetic subtypes may be different in myeloma that is not associated with familial MGUS compared with myeloma in which a familial tendency is detected. IgH translocated MM appears to have a lower risk of familial tendency. Further investigation is needed to estimate the risk of familial MGUS within each cytogenetic subtype. Disclosures: Kumar: Merck: Consultancy, Honoraria; Millennium: Research Funding; Celgene: Consultancy, Research Funding; Novartis: Research Funding; Genzyme: Research Funding.

Abstract Abstract 1861 Idiopathic Bence Jones Proteinuria (Smoldering Monoclonal Light-Chain Proteinuria), first reported in 1982, is an asymptomatic plasma cell proliferative disorder associated with an elevated risk of progression to symptomatic MM or amyloidosis (AL). We defined it as the presence of a monoclonal light chain in the urine ≥200 mg/24h, absence of an intact immunoglobulin M protein (IGH expression) in the serum and no evidence of MM, AL or other related plasma cell proliferative disorders. Following approval by our Institutional Review Board, we searched a computerized database and reviewed the records of all patients seen at Mayo Clinic within 30 days of the recognition of a monoclonal light chain (Bence Jones protein) in the urine from January 1, 1960 through June 30, 2004. Patients with end-organ damage at diagnosis resulting from the plasma cell proliferative disorder (including MM or AL), or who had received chemotherapy or had a nephrotic syndrome were excluded. Follow-up included review of each patient's medical record at Mayo Clinic, as well as review of death certificates for patients who died. Patients were sent letters of inquiry if they had not visited Mayo Clinic in the preceding year. The risks of progression to MM and AL were compared to those expected on the basis of Surveillance, Epidemiology and End Results (SEER) rates for MM in Iowa and the incidence of AL in Olmsted County, Minnesota. One-hundred and one patients fulfilled the criteria for diagnosis during the 44-year period (1960–2004). The median age at diagnosis was 67 years (range 18–90 years), and only 2% were < 40 years old. Seventy-three percent were male. The urine M protein ranged from 200 mg/24h to 4.7 g/24h (median value, 500 mg/24h); 29% had > 1 g/24h. Kappa light chain accounted for 50% while the remaining 50% were lambda. Fifty-seven (56%) had a monoclonal light chain in the serum on immunofixation. Concentrations of uninvolved (normal, polyclonal or background) immunoglobulins were reduced in 62%. Eighty-eight percent of patients died during follow-up. During 900 person years of follow-up, 29 patients developed symptomatic MM (relative risk, 140.3; 95% CI, 93.9–201.5) and an additional 9 patients developed AL (relative risk, 104.4; 95% CI, 47.8–198.4). Four patients had both multiple myeloma and AL amyloidosis. The cumulative probability of progression to active MM or AL was 19% at 5 years, 31% at 10 years and 42% at 15 years. The factors associated with progression to MM or AL included size of urine M protein, percentage of bone marrow plasma cells, serum free light chain ratio < 1/100 or > 100, serum creatinine and reduction of all 3 uninvolved immunoglobulins. We conclude that patients with Idiopathic Bence Jones Proteinuria (Smoldering Monoclonal Light-Chain Proteinuria) are at risk for the development of MM or AL and must be followed indefinitely. Disclosures: No relevant conflicts of interest to declare.

Background: The variability of throwing metrics, particularly elbow torque and ball velocity, during structured long-toss programs is unknown. Hypotheses: (1) Elbow torque and ball velocity would increase as throwers progressed through a structured long-toss program and (2) intrathrower reliability would be high while interthrower reliability would be variable. Study Design: Descriptive laboratory study. Level of Evidence: Level 3. Methods: Sixty healthy high school and collegiate pitchers participated in a structured long-toss program while wearing a validated inertial measurement unit, which measured arm slot, arm velocity, shoulder rotation, and elbow varus torque. Ball velocity was assessed by radar gun. These metrics were compared within and between all pitchers at 90, 120, 150, and 180 ft and maximum effort mound pitching. Intra- and interthrower reliabilities were calculated for each metric at every stage of the program. Results: Ball velocity significantly changed at each progressive throwing distance, but elbow torque did not. Pitching from the mound did not place more torque on the elbow than long-toss throwing from 120 ft and beyond. Intrathrower reliability was excellent (intraclass correlation coefficient >0.75) throughout the progressive long-toss program, especially on the mound. Ninety-one percent of throwers had acceptable interthrower reliability (coefficient of variation <5%) for ball velocity, whereas only 79% of throwers had acceptable interthrower reliability for elbow torque. Conclusion: Based on trends in elbow torque, it may be practical to incorporate pitching from the mound earlier in the program (once a player is comfortable throwing from 120 ft). Ball velocity and elbow torque do not necessarily correlate with one another, so a degree of caution should be exercised when using radar guns to estimate elbow torque. Given the variability in elbow torque between throwers, some athletes would likely benefit from an individualized throwing program. Clinical Relevance: Increased ball velocity does not necessarily equate to increased elbow torque in long-toss. Some individuals would likely benefit from individualized long-toss programs for rehabilitation.

Objectives: The variability of throwing metrics, particularly elbow torque and ball velocity, during structured long-toss programs is yet to be fully elucidated. The primary aims of this study were to assess various throwing metrics through a structured long-toss program using wearable technology and to quantify the intra and inter thrower variability of these metrics at each stage of throwing. Methods: This was a descriptive laboratory study in which 60 high school and collegiate pitchers participated in a predetermined, structured, progressive long-toss program. All players wore a motusBASEBALL sleeve (Motus Global, Inc.; Rockville Centre, NY), which measured arm slot, arm velocity, shoulder rotation, and elbow varus torque. Radar guns were used to measure ball velocity. These metrics were compared within and between all pitchers at each of the following throwing distances: 90 ft, 120 ft, 150 ft, 180 ft, and maximum effort mound pitching. Intra- and inter- thrower reliabilities were calculated for each throwing metric at every stage of the program. Excellent intra-thrower reliability was defined by an Intra-class coefficient (ICC) >0.750. Acceptable inter-thrower reliability was defined by a Coefficient of Variation (CV) <5%. Results: Ball velocity significantly changed at each progressive throwing distance, but this did not consistently correlate with an increase in elbow torque. Pitching from the mound did not place more torque on the elbow than throwing from 120 ft and beyond. Intra-thrower reliability was excellent throughout the progressive long-toss program for each throwing metric. Ninety-one percent of throwers had acceptable inter-thrower reliability for ball velocity, whereas only 79% of throwers had acceptable inter-thrower reliability for elbow torque. Conclusion: Based on trends in elbow torque, it may be practical to incorporate pitching from the mound earlier in the program (once a player is comfortable throwing from 120 ft). Ball velocity and elbow torque do not necessarily correlate with one another, so a degree of caution should be exercised when using radar guns to estimate elbow torque. Given the variability in elbow torque between throwers, some athletes would likely benefit from an individualized throwing program.

Objectives: Progressive throwing programs are a mainstay of rehabilitating the throwing athlete after injury or surgery. Athletes are commonly asked to throw at reduced levels of effort (i.e. “50% effort”, ”75%,” etc) to minimize stress to healing tissues. However, it is unknown whether players’ perceived exertion matches actual exertion. The purpose of this study was to determine whether decreased effort correlates with decreased throwing metrics, whether metrics decrease to a predictable degree, and to quantify variability of these metrics within a given athlete when attempting to throw at sub-maximal effort. Methods: Sixty healthy, high school and collegiate baseball pitchers participated in a structured throwing program. After warming up, each pitcher was asked to throw five, max effort long toss throws at a distance of 120 feet. Afterwards, they were asked to give 5 throws at both 75% effort and 50% effort from the same distance. A motusBASEBALL sleeve (Motus Global, Inc.; Massapequa, NY) was worn by all players, which measured arm slot, velocity, shoulder rotation, and elbow varus torque (Nm). Ball velocity was measured in miles per hour (MPH) using a radar gun. The observed changes in throwing metrics were compared to one another across each of the throwing scenarios using a general estimating equation to control for multiple comparisons. They were also compared to the expected change to see if a decrease from 100% effort to 75%, and then to 50% resulted in proportional decreases in elbow torque and ball velocity. Intra-thrower variability was determined for each throwing metric at each degree of effort, and these results are reported using intra-class correlation coefficients (ICC) where an ICC > 0.75 was considered to represent excellent agreement. Results: Mean elbow torque decreased as players decreased their perceived effort from 100% (72.7 Nm) to 75% (67.3 Nm) to 50% (62.s Nm) (p<0.001). Mean ball velocity also decreased as they progressed from 100% effort (77.8 MPH) to 75% effort (66.5) to 50% effort (60.3 MPH) throws (p<0.001). However, these observed decreases in torque and velocity were much smaller in magnitude than the decreases in perceived effort. During the 75% effort throws, torque and velocity were not reduced to 75% of max. Instead, elbow torque was only reduced to 93.3% of max, and velocity dropped to 86.1% of max. Similarly, for the 50% effort throws, torque remained 86.5% of max effort torque, while velocity remained 78.1% of max. Accordingly, for every 25% decrease in perceived effort, torque only decreased 7%, and velocity only decreased 11%. These observed differences were all significantly different than the expected differences (p<0.001 for all). Intra-thrower reliability was considered excellent for all metrics within each throwing scenario: max effort, 75% effort, and 50% effort (ICC>0.75 for all). Conclusion: Measured effort was significantly greater than perceived effort during this standardized throwing program for all metrics tested. This is especially true for ball velocity and varus elbow torque. Ultimately, when players throw at what they perceive to be “reduced effort,” their actual throwing metrics do not decrease at the same rate as their perceived exertion. This has significant implications for throwers during the rehabilitation process as their elbows are likely experiencing more stress than desired. Clinicians and coaches must be aware and may want to consider transitioning to more objective measures of effort during rehabilition.

Background: During rehabilitation throwing programs, baseball players are commonly asked to throw at reduced levels of effort (ie, 50% effort, 75% effort, etc) to moderate stress to healing tissues. It is currently unknown how changes in players’ perceived exertion compares with changes in actual exertion during structured long-toss programs. Purpose: To determine whether decreased effort correlates with decreased throwing metrics, whether metrics decrease proportionally with reductions in perceived effort, and to quantify intrathrower variability. Study Design: Descriptive laboratory study. Methods: Sixty male high school and collegiate baseball pitchers participated in a structured throwing program. A motusBASEBALL sleeve was worn by all players, which measured elbow varus torque, arm velocity, arm slot, and shoulder rotation. Ball velocity was measured with a radar gun. Each pitcher threw 5 throws a distance of 120 ft with 3 efforts: maximum effort, 75% effort, and 50% effort. Throwing metrics were compared among the 3 levels of effort to see if each 25% decrease resulted in proportional decreases in elbow varus torque and ball velocity. Intrathrower variability was determined for each throwing metric at each degree of effort. Results: All throwing metrics decreased as players decreased their perceived effort ( P < .001). However, these observed decreases were much smaller in magnitude than the decreases in perceived effort. During the 75% effort throws, elbow varus torque was only reduced to 93% of maximum and velocity dropped to 86% of maximum. Similarly, for the 50% effort throws, elbow varus torque remained 87% of max effort torque, while velocity remained 78% of max. Intrathrower reliability was considered excellent for most metrics (intraclass correlation coefficient, >0.75). Conclusion: For every 25% decrease in perceived effort, elbow varus torque only decreased 7% and velocity only decreased 11%. Thus, when players throw at what they perceive to be reduced effort, their actual throwing metrics do not decrease at the same rate as their perceived exertion. Clinical Relevance: Measured effort decreased with decreasing perceived effort, but these were not proportional. This has significant implications for physical therapists, physicians, trainers, coaches, and athletes to understand and monitor elbow stress during the rehabilitation process.

Background: Periprosthetic joint infection (PJI) of the knee with concurrent disruption of the extensor mechanism is a devastating complication. Historically, knees with such complications have been salvaged with use of an arthrodesis or amputation. The purpose of this study was to assess the survival and functional outcomes of a 2-stage exchange arthroplasty combined with knitted monofilament polypropylene (Marlex; C.R. Bard) mesh reconstruction of the extensor mechanism. Methods: From 2000 to 2015, 16 patients underwent a 2-stage exchange arthroplasty and Marlex-mesh reconstruction for PJI with an extensor mechanism disruption. The study included 9 male patients and 7 female patients with a mean age at the time of reimplantation and mesh reconstruction of 64 years. The mean follow-up was 4 years. PJI was diagnosed on the basis of the Musculoskeletal Infection Society criteria. Clinical outcomes, including survivorship, Knee Society Score (KSS) results, and complications, were assessed. Results: Of 16 reconstructions, 13 were in place at the time of the latest follow-up. At 2 years, survivorship free of mesh failure was 86%, survivorship free of PJI was 87%, and survivorship free of PJI or mesh failure was 75%. The mean KSS improved from 48 prior to resection to 74 after mesh reconstruction and reimplantation. The mean extensor lag improved from 31° prior to resection to 3° after mesh reconstruction. Two patients required mesh revision, 1 patient required an above-the-knee amputation for complex wound complications related to reinfection, 1 patient developed a reinfection requiring irrigation and debridement, and 1 patient developed a superficial infection that required debridement. Conclusions: Two-stage exchange arthroplasty combined with Marlex-mesh reconstruction of the extensor mechanism is a viable alternative to knee arthrodesis or amputation. At 2 years, 75% of mesh reconstructions were in place and without evidence of PJI. Moreover, the functional outcomes were improved, with a negligible extensor lag. Level of Evidence: Therapeutic Level IV . See Instructions for Authors for a complete description of levels of evidence.