Kyle, Robert A.

Abstract We studied the prognostic significance of plasmablastic (PB) multiple myeloma (MM) in Eastern Cooperative Oncology Group Phase III trial E9486. Two reviewers independently reviewed 453 cases. They agreed on 37 PB (8.2%) cases and 416 non-PB cases, achieving an 85% concordance (P < .0001). These PB cases had significantly lower hemoglobin and serum albumin levels, higher calcium and β 2-microglobuin levels, and higher percentage BM plasma cells (PC) by immunofluorescence. They had higher bone marrow PC labeling indices, higher serum soluble interleukin-6 receptor (sIL-6R) levels, and a higher probability of ras mutations. Three treatment regimens were used: vincristine, bis-chloro-ethyl nitrosourea (BCNU) melphalan, cyclophosphamide, and prednisone (VBMCP) alone; VBMCP with added cyclophosphamide (HiCy); or recombinant interferon α 2 (rIFNα2). Although the numbers are low, patients with PB had a significantly lower response rate versus non-PB MM when treated with VBMCP (treated, 47.1% v nontreated, 66.5% [P = .015]). Patients with nonresponding PB had a significantly higher progression rate than non-PB cases (30.6%v 11.8% [P < .0001]), especially with VBMCP alone (35.3% v 15.8% [P = .002]), and with added HiCy (37.5% v 9.8% [P < .0001]), but not with added rIFNα2. Event-free and overall survival of PB MM was shorter (median years, 1.1 v 2.7 and 1.9 v 3.7, respectively [P < .0001 for both]). In multivariate analysis, PB classification was also highly prognostic. There is no survival difference between the patients who were classified as PB by both reviewers versus patients classified as PB by only one reviewer. We conclude that PB MM is a discrete entity associated with more aggressive disease and shortened survival. Tumor cell rasmutations and increased sIL-6R may contribute to a higher proliferation rate and reduced survival. There were significant improvements in response and progression with the addition of HiCy and rIFNα2 to VBMCP, but the numbers were small and improved survival could not be shown.

Introduction With the introduction of novel agents, survival in multiple myeloma has successively increased in the past decade. This improved survival increases the risk for late complications. Patients continue to receive melphalan therapy as a standard induction for those over the age of 65. Lenalidomide is considered a standard component of induction therapy in the United States for patients who are transplant candidates. Stem cell transplantation remains the standard of care for patients eligible to receive it. As a consequence of exposure to lenalidomide, stem cell transplant, and melphalan, the risk of late myelodysplasia and acute leukemia remains significant. We reviewed the Mayo Clinic experience with therapy-induced myelodysplasia beginning with the advent of novel agents. Patients and Methods All patients that carry the diagnosis of multiple myeloma between January 1, 2000, and September 1, 2011, were included. Patients with a synchronous diagnosis of a myeloproliferative or a myelodysplastic disorder or those who developed the myelodysplastic disorder within 15 months of first chemotherapy exposure were excluded. The date of diagnosis for the purpose of this abstract was based on first exposure to chemotherapy and not first detection of a monoclonal protein or smoldering multiple myeloma. All patients had to have morphologic verification in the bone marrow of dysplastic change consistent with therapy-related myelodysplasia. Results Of 3111 patients who had a myeloma diagnosis and first treatment after January 1, 2000, through September 1, 2011, 22 patients were identified to fulfill the criteria of myelodysplasia. There were 13 men and 9 women with a median age of 67 (46 to 82). At the time of this report, 17 have died. Prior to the development of myelodysplasia, exposure to an alkylating agent, lenalidomide, or an auto stem cell transplant was seen in 13, 15, and 10, respectively. Only one patient had been exposed to lenalidomide alone. Eighteen patients were classified as myelodysplasia. Four had acute non-lymphocytic leukemia. Metaphase cytogenetics was available in 19 and only one was normal. Twelve were hypodiploid. Trisomy 8 or abnormalities of chromosome 5 and 7 were present in 13. Seven patients received a hypomethylating agent with no clear evidence of response in any. Four patients had an allotransplant to manage the MDS/AML and only one survives 487 days after a matched-related donor allogeneic transplant. The median time from initial therapy of multiple myeloma to recognition of MDS or AML was 50.9 months (range: 15.2-146.5 months) fig 1. The median overall survival of the 22 patients is 6.5 months. Fig 2 Six of the 22 had active myeloma at the diagnosis of MDS/AML. Conclusion Myelodysplasia during the era of novel agents is a devastating complication of therapy with a very short survival and low response rate. As a time-dependent complication, the overall risk cannot be accurately estimated but has occurred in <1% of our patient population to date. Hypomethylating agents were ineffective in the seven that received it. One of four allotransplant patients remains alive. Ongoing surveillance for MDS/AML in this population is warranted and more effective therapies are needed. Disclosures: Kumar: Onyx: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Celgene: Consultancy, Research Funding.

Abstract Abstract 2887 Introduction: Cardiac involvement is the major cause of death in patients with immunoglobulin light chain amyloidosis (AL). Detection of cardiac involvement and risk stratification has been facilitated by cardiac biomarkers like troponin T (cTnT) and N-terminal brain natriuretic peptide (NT-proBNP). A novel high sensitivity cTnT (hs-cTnT) assay has been developed, and we evaluated its diagnostic use with three questions in mind: 1) How do the cTnT and hs-cTnT perform in the AL amyloid staging system? 2) Does higher sensitivity add significant additional value in terms of prognosticating outcomes for patients with AL amyloidosis? 3) Can the current AL amyloidosis staging system be further improved upon? Methods: Stored serum samples (-20°C) from 224 pts with AL were analyzed for concentrations of hsTnT, TnT, and NT-proBNP on the E170 Modular analyzer (Roche Diagnostics, Penzberg, Germany). 99th percentile reference limits were <0.014 and <0.010 mcg/L for hsTnT and TnT, respectively. Results: Median values for hsTnT, TnT, and NT-proBNP were 38 ng/L (range 0–075.4), 0.017 mcg/L (<0.0–0.904), and 1230 ng/L (0–32, 226), respectively. The correlation coefficient between hsTnT and TnT was 0.972. Those classified by echocardiographic parameters as having (n=143) or not having (n=81) cardiac involvement had TnT concentrations of 0.04 and 0.01 mcg/L and hsTnT levels of 52.2 and 15.6 ng/L, respectively. The direct numeric result from the hs-cTnT result CANNOT merely be substituted for a cTnT result in the Mayo AL staging system since 14% of patients would be misclassified. The performance of the receiver operation curve derived hs-cTnT cut-point of 54 ng/L is a slight improvement over the direct substitution of 35 ng/L if replacement of one assay for another is required. An alternate staging option using hs-cTnT alone—using the two thresholds14 ng/L and 54 ng/L (figure)—performs as well as either the original Mayo AL staging system or a derivative system incorporating hs-cTnT with respective relative risks of death (95%CI) of 3.6 (2.3, 5.7), 3.8 (2.5, 5.9), and 3.3 (2.2, .50). On multivariate analysis, our newly described alternate 3 level, hs-cTnT alone staging system is independent of other factors including period of diagnosis, type of therapy, and NT-proBNP value, the last of which dropped out of the model. Alternate models using NT-proBNP and cTnT were explored, but none performed better than the original staging system or the new hs-cTnT system. Conclusion: The direct numeric result from the hs-cTnT result cannot merely be substituted for a cTnT result in the Mayo amyloid staging system. Consideration could be made for AL staging systems using hs-cTnT alone and relegating the NT-proBNP for measuring cardiac response. Disclosures: Jaffe: Roche: Consultancy.

Abstract Background While patients with monoclonal gammopathy of undetermined significance (MGUS) are known to be at an increased risk of developing multiple myeloma, Waldenström macroglobulinemia, and primary amyloidosis, the risk of developing non-hematologic malignancies is less clear. A recent report suggested that MGUS patients have a 1.56-fold increased risk of developing nonhematologic malignancies. An excess risk of developing nonmelanoma skin (RR = 2.04), endocrine (RR = 3.34), breast (RR = 1.32), kidney and urinary tract (1.58), respiratory (RR = 1.42), male reproductive system (RR = 1.32), and GI cancers (RR = 1.25) has been reported for people with MGUS (Blood Oct 13 2011;118(15):4086-4092). This study constructed a cohort by discovering MGUS status through medical workup. Therefore, associations discovered might be related to the reason the test was performed more than the result of the test. This study aimed to determine if there was an increased risk of solid malignancies in persons with MGUS using a large, population-based, systematically screened cohort. Methods The population-based cohort established to estimate the prevalence of MGUS was examined for this study (N Engl J Med 2006; 354:1362-1369). Of the 28,038 residents of Olmsted County, Minnesota age 50 years or older as of January 1, 1995, 21,463 individuals' serum samples were collected. All samples were evaluated with serum electrophoresis and immunofixation to determine MGUS status. The Mayo Clinic Medical Index from 1/1/1975 to last follow up or 5/31/2006 was used to link MGUS status to other diagnoses. All patients diagnosed with a solid malignancy were identified, and disease prevalence was determined for cases and controls. For MGUS patients who progressed to MM or related disorder, only solid malignancy diagnoses made prior to progression was considered. A second analysis was performed in which only malignancies that developed after the MGUS screening or diagnosis date were considered. Results 17,315 patients with 435,021 person-years of follow-up were included in the study. Any patient who was blinded in the initial cohort could not be included. Patients with MGUS (n=605) had a mean follow up of 24.64 years (range 0.11 to 30.57) while controls (n=16,710) had a mean of 25.14 years (range 0.01 to 31.40) of follow up. The risk ratio for developing any solid tumor was 1.08 (95% CI 0.94 to 1.25). Persons with MGUS had a 1.61-fold increased risk of developing respiratory tumors over controls. MGUS patients did not have a significantly increased risk of developing cancer in any other anatomical position studied, including bone, brain, breast, endocrine, eye, gastrointestinal, kidney, skin (melanoma or non-melanoma), oral/nasal/pharyngeal, reproductive, or salivary gland. MGUS patients were not found to be at increased risk of developing tumors with a specific pathology over controls. The second analysis, which considered only tumors that developed after the MGUS screening or diagnosis date, showed that MGUS patients were not at an increased risk of respiratory tumors (RR 1.28, p=0.21). According to this analysis, MGUS patients are at decreased risk of developing non-melanoma skin cancer (RR 0.76, p=0.003). No statistically significant increased risk of any solid tumor was identified through this analysis. Conclusion This study used a systematically screened population-based cohort to determine if patients with MGUS are at an increased risk of developing solid tumors. The analysis suggests that patients with MGUS have a significantly increased risk of developing respiratory malignancies (RR 1.61, p=0.01). However, when only tumors diagnosed after MGUS screening or diagnosis date were considered, this risk was no longer significant (RR 1.28, p=0.21). Contrary to previous reports, we did not find patients with MGUS to be at an increased risk of developing other solid malignancies. The discrepancy between these findings and previously reported increased risk may be related to the elimination of ascertainment bias in this population-based cohort universally screened for the presence or absence of MGUS. Accurately understanding the risks associated with MGUS, a condition affecting 3% percent of the population over 50 years of age, may allow for more informed recommendations for screening and counseling for these patients. Disclosures: Kumar: Celgene: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Onyx: Consultancy, Research Funding.

Abstract 5079 Introduction: IgD monoclonal proteins are rare. They are not seen as a MGUS and are present in 1% to 2% of patients with myeloma. In light chain amyloidosis (AL), IgD monoclonal proteins are rare. When an IgD protein is found, amyloidosis is often omitted from the differential diagnosis. An IgD protein in amyloidosis has been reported in single cases but never as a patient series. We report IgD AL in 53. Patients & Methods: Clinical and demographic data for patients were retrieved from the patient records. Factors of interest were compared between patients who did and did not have an IgD protein. Results: Among 3,955 patients with AL amyloidosis seen, 53 patients (1.3%) had a serum IgD monoclonal protein. (Table 1) A serum monoclonal protein peak was visible on SPE in only 14, and only 5 had an M spike greater than 1 g/dL. On immunofixation of the serum, the IgD light chain was k in 11, λ in 35, and uncertain in 6; 1 patient had a biclonal D λ and G k protein. A urine monoclonal protein was detected in 43 of 51 patients; urinary immunofixation detected a λ light chain in 33 and a k light chain in 10. Biopsy of tissues showed amyloid deposits in the bone marrow in 47% and in the fat aspirate in 73%. Six patients (age 47–63 years) underwent autologous SCT. Four had renal & two had cardiac AL. All 6 had hematologic PR, 4 CR, and 4 had organ response. One patient had relapse of disease and is now on dialysis, and another had relapse and is alive with salvage chemotherapy. One patient had disease relapse and died of progressive GI amyloidosis at 22 months. The other 5 are alive at a median of 68 months (range, 7.5–83.5 months). We compared the 53 patients with IgD amyloidosis with 144 patients with non-IgD amyloidosis. (Table 2) Findings that were significantly different between groups included a lower frequency of renal amyloidosis (P=.005) and a lower prevalence of cardiac amyloidosis (P=.047). There was a higher serum albumin level (P=.04) related to the lower level of proteinuria. No difference in survival was seen between the groups. (Figure). Variables that might affect survival—liver size, performance status, septal thickness, serum creatinine level, and β2-microglobulin level—were not different between groups. Conclusions: IgD AL patients have a lower frequency of renal involvement and possibly also of cardiac involvement. The overall survival of these patients does not appear to be different from that of patients who have AL associated with another monoclonal protein. IgD monoclonal proteins are so closely linked to the diagnosis of multiple myeloma in the mind of a clinician that the possibility of amyloidosis may be overlooked. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 2950 Background: The median age of patients diagnosed with MM is approximately 70 years, and it is a relatively uncommon disease in the younger population. Both conventional chemotherapy and stem cell transplantation (SCT) have favorably impacted the overall survival (OS) of young MM patients. The median survival of patients < 40 years of age, diagnosed prior to 1993 was reportedly 54 months at our institution. However, the impact of novel agents in this patient population is not well known. We studied the outcome of young patients presenting to our institution over the last decade. Methods: Records of 1538 patients presenting between 01/99 to12/08 were reviewed. The demographics, features and therapeutic interventions in patients up to 45 years of age at diagnosis were analyzed using descriptive statistics. The survival outcome of this group was compared with the remainder of the cohort using the Kaplan-Meier method. Results: One-hundred (6.5%) out of 1538 newly diagnosed MM patients were ≤ 45 years of age at diagnosis. The median follow-up of this group of young patients was 86 months. The disease and patient characteristics are outlined in table 1. A median of 5 regimens (range 1–14) was administered, and 85% patients had received high-dose therapy. 15 patients underwent allogeneic SCT after at least one prior autologous SCT. Novel agents were used both in the front-line and relapsed setting (lenalidomide 60%, thalidomide 56%, pomalidomide 9% and bortezomib 49%), and 45% of initial regimens were novel agent based. The 5 and 7-year OS from diagnosis was 69% and 59%, respectively and the median OS was 93 months. In contrast, the median OS of patients >45 years diagnosed during this period was 53 months (P=0.001, figure 1). Conclusion: A marked improvement in OS of young patients with MM diagnosed in the novel agent era is noted in comparison to the historical control of similar age group. In addition, the age associated survival benefit in the younger patient population prevails in the era of novel therapies. Disclosures: Gertz: Celgene: Honoraria. Lacy:Celgene: Research Funding. Dispenzieri:Binding site: Honoraria; Celgene: Research Funding. Kyle:Millennium: Consultancy; Binding Site: Honoraria. Kumar:Millennium Pharmaceuticals, Inc.: Research Funding; Celgene: Consultancy, Research Funding; Genzyme: Research Funding; Novartis: Research Funding; Merck: Consultancy, Honoraria.

Abstract Background Multiple myeloma (MM) is uncommon in patients below 40 years of age. Between 1960 and 1992 when stem cell transplantation (SCT) was rarely performed and novel agents were unavailable, overall survival (OS) was reported to be 54 months in the Mayo Clinic series of patients with MM below forty years of age. The impact of novel agents or SCT in this population is unclear. Herein, we report the outcomes of patients under 40 years of age who were evaluated over a span of more than five decades with a focus on the periods contemporaneous with the introduction of SCT and novel agents, the major therapeutic milestones in the management of MM. Methods We analyzed the medical records of patients with MM under 40 years of age who were evaluated at Mayo Clinic, Rochester, MN between 1/1/1960 and 12/31/2011. SCT and novel agents were utilized infrequently prior to the years 1990 and 2000, respectively. Patients were therefore divided into three cohorts by the year of diagnosis of MM: Group A (1960 -1979), Group B (1980 to 1999) and Group C (2000 –2011) to assess the impact of major therapeutic advances (i.e. Increased utilization of SCT and novel agents compared to conventional chemotherapy). OS was calculated by the Kaplan -Meier method. Results Out of 8063 unique MM patients seen at our institution during this period, 174 (2%) patients were under 40 years of age at diagnosis. The median age at diagnosis was 36 years (range: 19-39). The estimated median follow-up of the entire cohort was 179 months (95% CI: 149-196 months). The median OS of the entire cohort was 76 months (95% CI: 45-80 months) from diagnosis. The median OS of patients in Groups A (n=29, 17%), B (n=93, 53%), and C (n=52, 30% ) was 44 months (95% CI: 20- 76), 79 months (95% CI: 46-97), and 92 months (95% CI: 42-NR), respectively (p=0.005). No significant OS difference was noted between Groups B and C (Figure). Sixty-six (38%) patients underwent at least one SCT (autologous: 56 patients and allogeneic 10 patients). The utilization of SCT increased over the three time periods from Group A 0%, Group B 39% and Group C 58% (p<0.001). Of 153 patients in whom front-line therapy-related data were available 118 (77%) received conventional and 35(23%) received novel agents. The median OS of patients who underwent transplantation (n=66) was 93 months compared to 46 months for those who did not (n=108, p=.01). In the 66 patients who underwent SCT, the median OS was 93 months for conventional agents-based induction (95% CI: 73-143) versus 97 months (95% CI: 41-187) for novel agent based induction (p=.4). Sixty-eight (40%) patients received novel agents at some point during the course of their disease [bortezomib 35 (54%), thalidomide 44 (67%), lenalidomide 47 (71%) and pomalidomide 7(11%)]. The median survival of these patients was 131 (95% CI: 88-161) months versus to 46 (CI: 37-74) months for those (n=106) receiving conventional agents only (p=0.0002). Conclusions OS of patients with MM under 40 years of age in the pre-transplant era (Group A) was significantly shorter than that of patients diagnosed in the era of SCT (Group B) and SCT plus novel agents (Group C). Although improvement of survival outcomes is evident with utilization of novel agents, similar outcomes of Groups B and C indicate lack of incremental benefit over SCT with utilization of novel agents. Maximal survival gain coincides with the introduction of SCT in this unique patient cohort. Disclosures: Kumar: Celgene: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Onyx: Consultancy, Research Funding.

Abstract Background: Monoclonal gammopathy of undetermined significance (MGUS) affects 3% of persons age 50 yrs or greater. Reliable predictors of progression of MGUS to myeloma or related malignancy are needed. We hypothesized that the presence of monoclonal unbound (free) kappa or lambda immunoglobulin light chains in MGUS, as detected by an abnormal serum kappa/lambda free light chain (FLC) ratio would indicate clonal evolution in the neoplastic plasma cell and increase risk of progression to malignancy. Methods: Patients (pts) from Southeastern Minnesota with MGUS seen at the Mayo Clinic from Jan 1, 1960 through Dec 31, 1994 who had baseline serum samples collected and stored at the time MGUS was first recognized were studied. Free kappa and lambda chains were measured using the serum FLC assay (FREELITETM, The Binding Site Ltd). Results: Of 1384 pts with MGUS during the defined time period, baseline serum samples obtained within 30 days of diagnosis of MGUS were available in 1148 pts. At a median follow-up of 15 yrs, malignant progression has occurred in 87 (7.6%) pts: myeloma (53 pts), IgM lymphoma (17), primary amyloidosis (6), macroglobulinemia (6), chronic lymphocytic leukemia (3) and plasmacytoma (2). An abnormal kappa/lamda FLC ratio (kappa/lambda ratio <0.26 or >1.65) indicating presence of monoclonal FLC was detected in 379 (33%) pts. In a Cox proportional hazards model, the risk of progression in pts with an abnormal kappa/lamda FLC ratio was significantly higher (hazard ratio 3.5, 95% CI 2.3–5.5; p<0.001) compared to pts with a normal ratio. After adjusting for the size of the serum monoclonal (M) protein by multivariate analysis, the hazard ratio was only slightly reduced to 2.8, p<0.001. The risk of progression to myeloma or related malignancy at 10 years was 17% with an abnormal kappa/lambda FLC ratio versus 5% with a normal ratio; corresponding rates at 20 years were 35%, and 13%, respectively. MGUS pts with both an abnormal serum FLC ratio and high serum M protein had a risk of progression at 20 years of 46% (high-risk), versus 26% with one of two risk factors (intermediate-risk) and 7% with no risk factors (low-risk) (Table). The true life-time (28 year) risk of myeloma or related malignancy in the low-risk group was only 5.3% when other competing causes of death were taken into account. Conclusions: Presence of monoclonal FLC in the serum as detected by an abnormal kappa/lamda FLC ratio is a major independent risk factor for progression of MGUS to myeloma or a related malignancy. The new risk-stratification identifies a low-risk subset with a remarkably small life-time risk of progression, a finding of significant importance for the management of MGUS. Risk-stratification of MGUS using the size of the serum M spike and free light chain ratio Risk Group No. of patients Hazard ratio Absolute risk of progression at 20 years Low-risk (Serum M protein <1.5 gm/dL and normal FLC ratio [0.26–1.65]) 606 1 7% Intermediate-risk (Either risk factor present) 373 3.5 26% High-risk (Serum M protein >/=1.5 gm/dL and abnormal FLC ratio [<0.26 or >1.65]) 169 6.8 46%

Abstract Background: Multiple myeloma (MM) is a heterogeneous disease with very divergent outcomes that are dictated in a large part by specific cytogenetic abnormalities, as well as other prognostic factors such as the proliferative rate of marrow plasma cells. Prognostic systems incorporating these factors have shown clinical utility in identifying high-risk patients, and are increasingly being utilized for treatment decision-making. However, the prognostic relevance of these factors may change with the application of novel therapies. The objective of this study was to determine the impact of risk-stratification (incorporating plasma cell metaphase cytogenetics, interphase fluorescent in-situ hybridization (FISH) and the slide-based plasma cell labeling index (PCLI)) in a cohort of patients with newly diagnosed MM treated initially with lenalidomide + dexamethasone (Rev-Dex). Methods: From March 2004 to November 2007, 100 consecutive patients treated with Rev (25mg/day) on days 1 through 21 of a 4-week cycle in combination with dexamethasone as initial therapy for newly diagnosed myeloma, were identified. High-risk MM was defined as presence of any one or more of the following: hypodiploidy, monoallelic loss of chromosome 13 or its long arm (by metaphase cytogenetics only), deletion of p53 (locus 17p13) or PCLI ≥ 3% or immunoglobulin heavy chain (IgH) translocations, t(4;14) (p16.3;q32) or t(14;16)(q32;q23) on FISH. PFS and OS survival estimates were created using the Kaplan Meier method, and compared by log-rank tests. Results: The median estimated follow-up of the entire cohort (N=100) was 36 months. The median PFS was 31 months; the median OS has not been reached. The 2- and 3-year OS estimates were 93% and 83%, respectively. 16% patients were deemed high-risk by at least one of the 3 tests (cytogenetics, FISH or PCLI). Response rates (PR or better) were 81% versus 89% in the high-risk and standard risk groups, respectively, P=NS; corresponding values for CR plus VGPR rates were 38% and 45% respectively. The median PFS was 18.5 months in high-risk patients compared to 37 months in the standard-risk patients (n=84), P<0.001(Figure). Corresponding values for TTP were 18.5 months and 36.5 months, respectively, P=<0.001. OS was not statistically significant between the two groups; 92% 2-year OS was noted in both the groups. Overall, 95 patients had at least one of the 3 tests to determine risk, while 55 patients could be adequately stratified based on the availability of all the 3 tests, or at least one test result that led to their inclusion in the high-risk category. The significant difference in PFS persisted even when the analysis was restricted to the 55 patients classified using this stringent criterion; 18.5 months vs. 36.5 months in the high-risk and standard- risk groups respectively; P<0.001. In a separate analysis, patients who underwent SCT before the disease progression were censored on the date of SCT to negate its effect, and PFS was still inferior in the high-risk group (p=0.002). Conclusion: The TTP and PFS of high-risk MM patients are inferior to that of the standard-risk patients treated with Rev-Dex, indicating that the current genetic and proliferation-based risk-stratification model remains prognostic with novel therapy. However, the TTP, PFS, and OS obtained in high-risk patients treated with Rev-Dex in this study is comparable to overall results in all myeloma patients reported in recent phase III trials. In addition, no significant impact of high-risk features on OS is apparent so far. Longer follow-up is needed to determine the impact of risk stratification on the OS of patients treated with Rev-Dex. Figure Figure

Abstract Abstract 4867 Introduction Both multiple myeloma (MM) and (AL) amyloidosis are clonal plasma cell proliferative disorders. While AL rarely “progresses” to MM, probably due to the shorter survival of AL patients, patients with MM have been reported to develop overt AL at a higher frequency. We conducted this study to identify and describe the clinical features, diagnosis, treatment patterns and response, and outcome among patients diagnosed with AL following an initial diagnosis of MM. Patients and Methods Of the 354 patients identified from a prospectively maintained database who carried a diagnosis of both MM and AL during the interval between January 1990 and December 2008, 44 patients had a histologic diagnosis of AL, at least 6 months after the diagnosis of MM. The organ involvement and treatment response (organ and hematologic) for AL as well as MM response to treatment were assessed according to conventional criteria. Results The median age at diagnosis of MM and AL was 63 years (range, 42-82) and 68 years (range, 45-86), respectively; 27 (61%) were males. The median time to AL diagnosis after MM diagnosis was 41 months (range, 7.6-134). The estimated median follow up from diagnosis of MM and AL is 15.5 years and 10 years, respectively and 39 (89%) patients have died. The median overall survival (OS) from diagnosis of MM and AL was 68.6 months and 9.1 months, respectively. At the time of AL diagnosis, 33 (75%) patients had developed typical features suggestive of AL [heart failure (12), paresthesias (11), nephrotic range proteinuria (9), elevated alkaline phosphatase and hepatomegaly (2), fatigue (7), weight loss (5), macroglossia (4) and periorbital ecchymoses (1)]; while others developed atypical features (3) (7%) or had an incidental finding of AL (8) (18%) [autopsy (2), unexplained cytopenia (2), mild proteinuria (1) and no symptoms (3)]. Cumulatively, amyloid deposits were revealed by biopsy of: bone marrow (23) (52%), subcutaneous abdominal fat (17) (39%), organ (10) (23%) and carpal tunnel tissue (6) (14%). Organ involvement, treatment response and hematologic status of MM at AL diagnosis were assessed for the evaluable patients. None, 1 and >1 organ involvement occurred in 5 (11%), 28 (64%) and 9 (20%) patients, respectively at AL diagnosis or follow up; while AL as the cause of neuropathy was questionable in 2. The organs involved were: heart (14, including 8 with >1 organ involvement), nerves (11), kidney (10), soft tissue (6), lung (5), GI (1) and liver (1). The hematologic status of MM at AL diagnosis included SD (22), progression (10), PR (3), VGPR (3) and not evaluable (6). The subsequent hematologic and organ response did not differ significantly among those who had a treatment change or started (20) (45%) compared with those who did not have a treatment change (20) (45%) at AL diagnosis [excluding those lost to follow up (2) or diagnosed at autopsy (2)]; although more patients (8/10) who had biochemically progressive MM belonged to the former group. The best hematologic response to treatment(s) after AL diagnosis (28) (64%) was: SD (17), PR (3), VGPR (6), CR (1), and progression (1); and not evaluable in others. The organ response (excluding patients with carpal tunnel surgery) to treatment(s) (18) (41%) was: progression (11), stable (4) and organ improvement (3). More patients with an improved (2/3) and stable (1/4) organ response had hematologic PR or better than those with progression (0/11) of organ disease. Five (11%) patients were alive at last follow up; and had either isolated kidney (3) and soft tissue (macroglossia) (1) or no organ involvement (1). All patients with an organ improvement, and 2/5 patients alive, had received PBSCT after AL diagnosis. Fewer patients with >1 organ involvement (1/9) underwent PBSCT compared with those without organ involvement (2/5); and achieved (0) PR versus (3) VGPR (to any treatment), respectively. Only 1/8 patient with an incidental discovery of AL developed symptomatic (cardiac) AL after 108 months of MM diagnosis and died; the remaining are either alive (1) or died from MM and its complications (3), infection (1), or were diagnosed at autopsy (2). Conclusion The recognition of AL (especially cardiac and multiorgan involvement) is critical in MM patients in order to determine prognosis and influence treatment. A high index of suspicion is required for the prompt recognition of AL to ensure timely institution of therapy with a goal of achieving hematologic and organ response. Disclosures No relevant conflicts of interest to declare.