Citations

Abstract Amyloid fibrils consist in part of immunoglobulin light chains. Because light chains are synthesized by plasma cells, it seems reasonable to treat patients with amyloidosis with alkylating agents. Two patients who had primary amyloidosis and were treated with melphalan subsequently developed a rapidly fatal acute leukemia. Since melphalan may play a significant role in the development of acute leukemia, we suggest that alkylating agents not be used in the treatment of patients with amyloidosis without full consideration of risks involved, particularly until it has been proved that these drugs are beneficial.

Abstract Background Bendamustine/rituximab (BR) and dexamethasone/rituximab/cyclophosphamide (DRC) combination therapy are acceptable options for the treatment of WM, both in the frontline or salvage setting. Prospective data, however, are only available in treatment-naïve (TN) WM patients, and no direct comparison between BR and DRC has been reported. We compared outcomes of BR and DRC in relapsed/refractory (R/R) and TN WM patients seen at a single institution. Methods Records of WM patients seen consecutively at Mayo Clinic from 01/2007 to 12/2014 were reviewed. The MYD88L265P status, as assessed by AS-PCR, was recorded when available. The data obtained from symptomatic patients treated with DRC or BR were analyzed. The time-to-event analyses were performed from DRC or BR therapy using the Kaplan-Meier method. We used the Consensus criteria (6th International Workshop) for response assessment. Results Of 160 WM patients, 60 patients received BR (73% in R/R setting) and 100 patients received DRC (50% in R/R setting). In the R/R population, BR was the 2nd line (range 2-11) therapy in 47% of patients, while DRC was 2nd line (range 2-8) in 58% of patients. Rituximab monotherapy was the only prior line of therapy in 8 (20%) patients in the BR group and 20 (40%) in the DRC group (p=0.66). Baseline characteristics were similar in patients treated with BR or DRC (Table 1). Six patients received both BR and DRC during their disease course and overlapped between the 2 cohorts. Among the previous untreated patients, the median IgM levels decreased from 3,785 mg/dL to 724 mg/dL (p=0.0001) at best response with BR, while it decreased from 4,130 mg/dL to 1,250 mg/dL (p=0.001) with DRC. The median time to best response was 6.1 (1-25) months in the BR group and 11 (0.5-47) months in the DRC group (p=0.13). For patients treated with BR, the overall response rate (ORR) was 93% [VGPR 29% (n=4), PR 57% (n=8), MR 7% (n=1)]. One patient (7%) had progressive disease. For patients treated with DRC, ORR was 96% [VGPR 17% (n=8), PR 70% (n=32), MR 9% (n=4)]. One patient (4%) achieved SD. Median follow up in the BR and DRC groups were similar (30 months). The 2-year progression-free survival (PFS) was 88% and 61% in the BR and DRC groups, respectively (p=0.08). The 2-year time-to-next therapy (TTNT) was 88% and 76% in the BR and DRC groups, respectively (p=0.35). Median PFS, TTNT and disease specific survival (DSS) were not reached with either regimen. In the R/R setting, the median IgM levels decreased from 3,880 mg/dL to 659 mg/dL (p=0.0001) at best response with BR, and from 3,870 mg/dL to 1,846 mg/dL (p=0.001) with DRC. The median time to best response was similar [7 (1-39) months with BR and 7 (0.5-28) months with DRC (p=0.77)]. For patients treated with BR, ORR was 95% [CR 3% (n=1), VGPR 38% (n=14), PR 41% (n=15), MR 13% (n=5)]. Two patients (5%) had progressive disease. With DRC, the ORR was 87% [VGPR 4% (n=2), PR 64% (n=30), MR 19% (n=9)]. Four patients (9%) achieved SD and 2 patients (4%) had progressive disease. Median follow up from BR was 32 months and 51 months from DRC (p=0.24). The 2-year PFS was 66% and 53% in the BR and DRC groups, respectively (p=0.08). The 2-year TTNT was 75% and 68% in the BR and DRC groups, respectively (p=0.24). The median DSS in the BR group was 69 months (95% CI: 65-69) and NR (95% CI: NR-NR) in the DRC group (p=0.57). The proportion of patients with R/R disease was significantly higher in the BR cohort (Table 1). In a bivariate analysis of the entire cohort for PFS, incorporating the setting (TN vs. RR) and the regimen involved (BR vs. DRC), the latter emerged as a significant factor (hazard ratio 0.52, p=0.019) in favor of BR. Time-to-event outcomes and response rates were similar in the MYD88L265P and MYD88WT patients. Grade ≥ 3 adverse events were neutropenia (12%), infections (7%) and nausea/vomiting (2%) with BR, and neutropenia (20%), thrombocytopenia (7%) and infections (3%) with DRC. Conclusions Although both DRC and BR regimens show activity and comparable toxicities, BR regimen shows a trend for superior PFS in WM patients, both in the TN and R/R setting. No difference was seen in TTNT. MYD88 L265P mutation status does not appear to impact activity of BR or DRC. Randomized controlled trial(s) are needed to confirm our findings. Disclosures Ailawadhi: Pharmacyclics: Consultancy; Novartis: Consultancy; Amgen Inc: Consultancy; Takeda Oncology: Consultancy. Ansell:BMS, Seattle Genetics, Merck, Celldex and Affimed: Research Funding. Reeder:Millennium: Research Funding; BMS: Research Funding; Novartis: Research Funding; Celgene: Research Funding. Dispenzieri:Jannsen: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; pfizer: Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Alnylam: Research Funding; GSK: Membership on an entity's Board of Directors or advisory committees. Kumar:Sanofi: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; AbbVie: Research Funding; Array BioPharma: Consultancy, Research Funding; BMS: Consultancy; Kesios: Consultancy; Glycomimetics: Consultancy; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Noxxon Pharma: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Onyx: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Kapoor:Celgene: Research Funding; Takeda: Research Funding; Amgen: Research Funding.

Abstract A patient with symptomatic primary cryoglobulinemia was followed for 9 yr and was found at autopsy to have generalized amyloidosis. There was a monoclonal serum protein spike of IgG kappa type that was cryoglobulin. The cryoglobulin was further characterized as IgG2 kappa Gm (n-). This case constitutes, to our knowledge, the first example of amyloidosis associated with monoclonal IgG cryoglobulinemia, with characterization of the monoclonal serum cryoglobulin, and also the first reported case of successful symptomatic treatment of cryoglobulinemia by plasmapheresis.

Abstract BACKGROUND: Necrobiotic Xanthogranuloma (NXG) is a rare chronic granulomatous disorder of the skin associated with monoclonal gammopathies (MG). Due to its rarity, data on response to various therapies are largely limited to single case reports or small case series. Hence, we described the clinical features in patients with NXG and MG as well as their subsequent disease course and response to treatment. METHODS: This was a retrospective study evaluating 35 patients with NXG and coexisting MG from 1994-2015 who were evaluated in the Hematology Outpatient Clinic at the Mayo Clinic, Rochester. All patients had a biopsy proven diagnosis of NXG with the concurrent presence of a serum monoclonal gammopathy. RESULTS: The median age at diagnosis was 56 years (range: 26-88). Most patients had a plasma cell dyscrasia (28 MGUS; 5 Smoldering myeloma) while 2 had chronic lymphocytic leukemia. Themost common monoclonal (M) protein was IgG kappa (60%). The median M-spike was 1.1 g/dL (range: 0-3). The most common site of NXG was periocular (66%). All patients received treatment, with over half requiring >3 different lines of treatment. The treatments were heterogeneous and included excision, intra-lesional injection, radiotherapy as well as systemic treatment. The types of systemic treatment used and clinical response are reported in Table 1. The median follow up was 46 months (range: 4-234) and the median survival was not reached but at the time of analysis 80% were still alive. At last follow-up, 80% of patients had signs of either clinical improvement or stable skin disease. Eight patients (23%) had disease progression to multiple myeloma at a median of 67 months (Range: 21 - 107). CONCLUSIONS: We report the clinical findings and treatment outcomes of one of the largest series of patients with NXG associated with MG. The clinical course is generally indolent but malignant transformation is not uncommon. Cutaneous objective responses can be achieved with various systemic agents used in the treatment of lymphoproliferative malignancies. Table 1. Treatment Types and Clinical Response Rates Treatment No of patientsA Clinical Benefit Rate B Response rateC Chemotherapy - Chlorambucil +/- Steroids - Melphalan/Steroids - Cytoxan/Steroids - Cladribine - Vincristine/doxorubicin/dexamethasone - High dose therapy with stem cell rescue - Fludarabine/cyclophosphamide/rituximab 5 3 4 3 2 3 1 2/5 (40%) 0/3 (0%) 1/4 (25%) 1/3 (33%) 1/2 (50%) 2/3 (67%) 1/1 (100%) 1/5 (20%) 0/3 (0%) 0/4 (0%) 1/3 (33%) 0/2 (0%) 2/3 (67%) 1/1 (100%) Novel agents - Thalidomide +/- Steroids - Lenalidomide +/- Steroids - Bortezomib +/- Steroids - Bortezomib/Lenalidomide/Dexamethasone 11 14 4 1 5/11 (45%) 10/14 (71%) 2/4 (50%) 1/1 (100%) 4/11 (36%) 7/14 (50%) 1/4 (25%) 1/1 (100%) Intravenous immunoglobulin 4 3/4 (75%) 2/4 (50%) Systemic steroids alone 11 4/11 (36%) 4/11 (36%) Rituximab 6 2/6 (33%) 1/6 (17%) AntibioticsD 3 0/3 (0%) 0/3 (0%) ImmunosuppressantsE 6 1/6 (17%) 0/6 (0%) ANo of patients who underwent a particular therapy amongst the 35 patients in the study cohort. BClinical Benefit: Improvement or stable skin disease CResponse: Improvement in skin disease DAntibiotics: Fluoroquinolones, Tetracycline EImmunosuppressants: Cyclosporine, Methotrexate, Plaquenil Disclosures Kumar: Celgene, Millennium, Onyx, Novartis, Janssen, Sanofi: Research Funding; Celgene, Millennium, Onyx, Janssen, Noxxon, Sanofi, BMS, Skyline: Consultancy; Skyline, Noxxon: Honoraria.

Abstract Multiple myeloma was diagnosed in six residents of Thief River Falls, Minn. in 1968 (a rate of 84/100,000). A survey of the normal population for monoclonal serum protein peaks was undertaken in 1969. Serum from 1200 residents of the city, who were 50 yr of age or older, was collected. Fifteen (1.25%) had monoclonal serum protein peaks: IgG in 11, IgA in one, and IgM in three, with kappa in 11 and lambda in four. No clinical, laboratory, or roentgenographic evidence of myeloma or macroglobulinemia was found in any of the patients. The incidence of monoclonal serum protein peaks is similar to that reported from Sweden. It was concluded that there was no significant increase in monoclonal proteins in the population of Thief River Falls. The 1968 socalled epidemic of multiple myeloma in Thief River Falls remains unexplained.

Abstract All cases of multiple myeloma diagnosed in bona fide residents of Olmsted County, Minnesota, during the years 1945 through 1964 were identified and reviewed. Pathologic material was available for reconfirmation of the diagnosis in 33 of the 35 cases reported. In the remaining two cases the diagnosis was based on roentgenologic findings and protein abnormalities as well as a typical clinical picture. The incidence rate for males was 1.9 times that for females. During the 20 year period covered in this study the average annual incidence rate in the total population has remained about 3/100,000 and when computed for persons 30 years of age and over, it is 6.3/100,000. Incidence figures by place of residence did not reveal a significant difference in the urban-rural rates. Myeloma was listed as a cause of death in 74 per cent of the death certificates. The mean survival time from onset in all cases was about 2 years, with a median survival of approximately 1 year. The age-specific rate increased with age, the highest rates being among male residents 80 years of age and older.

Abstract Bone marrow studies of multiple myeloma revealed, in some cases, a conspicuous proliferation of "lymphoid" cells, virtually indistinguishable by light microscopy from those seen in lympho-proliferative disorders. Electron microscopy demonstrated a variety of cells ranging from typical lymphocytes to cells with plasmocytoid features. Between these two types of elements there were cells with intermediate characteristics. In addition, in several cases of myeloma the presence of fixed reticuloendothelial cells and "reticular" plasma cells (or reticulum cells with plasmocytic features) was frequently noted. The presence of reticulum cells and lymphocytes and of cells apparently "intermediate" between these cellular elements and plasma cells, as judged from electron microscopic observations, is suggestive morphologic evidence of a phenomenon of cell transformation and evidence of a mixed cell proliferation in certain cases of multiple myeloma.

Abstract 1. A group of 64 myeloma patients was given a loading dose of Melphalan, 0.15 mg./Kg./Dx7. This was followed by a rest period to allow bone marrow recovery to occur, after which maintenance therapy with a maximum of 0.05 mg./Kg./D was started. 2. To obtain good results, drug doses were required which produced significant bone marrow depression. 3. Subjective improvement was noticed in about 65 per cent of patients; objective improvement, in 78 per cent. 4. Fifty-five per cent of the patients had a response as defined in this study. 5. No difference in survival was found between males and females, nor between patients with Bence Jones proteinuria and those without. 6. Patients who have been on treatment for 3 months and were then found to be responders lived longer than similarly treated patients classified as nonresponders.

Abstract Background: Cytogenetic evaluation, especially using fluorescence in situ hybridization (FISH), at the time of diagnosis is essential for initial risk stratification and the employment of risk-adapted treatment strategies in multiple myeloma. Little is known about the occurrence and prognostic significance of cytogenetic evolution during follow up. Methods: We studied 433 patients who were diagnosed with multiple myeloma between January 2000 and December 2011 and had at least two FISH evaluations at Mayo Clinic Rochester, including the diagnostic specimen. Bone marrow aspirates were evaluated for deletions, monosomies, trisomies, and tetrasomies using chromosome- or centromere-specific FISH probes. IGH rearrangements were evaluated using an IGH break-apart probe and up to five potential partners (FGFR3, CCND1, CCND3, MAF, and MAFB). Cytogenetic evolution was defined as a new deletion, monosomy, trisomy, tetrasomy, or translocation during follow up. Multivariable-adjusted logistic regression models were used to assess the associations between the parameters of interest and the presence of cytogenetic evolution in follow-up specimens. Multivariable-adjusted Cox proportional hazards models were used to assess the effect of cytogenetic evolution on overall survival. All models were adjusted for sex, age, the presence of high-risk FISH abnormalities, and the number of abnormalities at the time of diagnosis. Likelihood ratio tests were used to assess the goodness of fit of nested models. The χ2 or Fisher's exact test was used to assess the distribution of cytogenetic abnormalities in subgroups. Results: The median age at diagnosis was 60 years (32 - 82), 264 (61%) of the patients were male. The median overall survival for the entire cohort was 7.0 years (6.2 - 7.8). At the time of diagnosis, 150 (35%) and 57 (13%) of the 433 patients presented with a hyperdiploid karyotype and cytogenetic high-risk abnormalities, respectively. Independent of each other, the presence of a translocation at the time of diagnosis was associated with decreased odds of cytogenetic evolution during follow up (OR 0.39, 95% CI 0.24 - 0.63, p < 0.001) while the presence of at least one trisomy or tetrasomy at the time of diagnosis was associated with increased odds (OR 2.53, 95% CI 1.37 - 4.70, p = 0.003). A greater proportion of patients presenting with a hyperdiploid karyotype experienced cytogenetic evolution during follow up. Those patients more frequently evolved additional trisomies and tetrasomies, while translocations were more common in those presenting with a non-hyperdiploid karyotype (Table 1). The development of additional abnormalities during the three years following diagnosis (compared to no new abnormalities) was associated with increased subsequent mortality in those who survived at least three years (HR 3.22, 95% CI 1.82 - 5.68, p < 0.001). Including the time between first and last cytogenetic evaluation as a covariate did not significantly change the parameter estimates or improve model fit (p = 0.727). Conclusions: Demographics, risk profile, and overall survival of this cohort reflect the fact that patients had to survive long enough to undergo repeated cytogenetic evaluation. Hyperdiploid and non-hyperdiploid genotypes were associated with distinct behavior regarding cytogenetic evolution during follow up. The identification of cytogenetic evolution was an adverse prognostic factor in those who survived at least three years after diagnosis. These findings emphasize the importance of the dynamics of the underlying clonal disease process for accurate risk assessment and suggest that selected subgroups of patients may benefit from risk stratification during follow up. Table 1. Cytogenetic evolution during follow up in 433 patients with multiple myeloma stratified by karyotype at the time of diagnosis Hyperdiploid (n = 150) Non-hyperdiploid (n = 283) p New abnormality 76 (51%) 108 (38%) 0.012 New monosomy 8 (5%) 24 (8%) 0.243 New trisomy 48 (32%) 55 (19%) 0.004 New tetrasomy 37 (25%) 27 (10%) < 0.001 New deletion 17 (11%) 27 (10%) 0.557 New translocation 1 (1%) 11 (4%) 0.065 Most common new abnormality [type (percent of type in each group)] Monosomy mono(13) (75%) mono(13) (62%) Trisomy tri(11) (22%) tri(3) (22%) Tetrasomy tetra(15) (48%) tetra(15) (30%) Deletion del(17p) (79%) del(17p) (63%) Translocation t(11;14) (100%) t(11;14) (36%) Data are given as count (percent) unless denoted otherwise. Disclosures Binder: American Society of Hematology: Research Funding. Kumar:AbbVie: Research Funding; Onyx: Research Funding; Sanofi: Research Funding; Celgene, Millenium, Sanofi, Skyline, BMS, Onyx, Noxxon,: Other: Consultant, no compensation,; Skyline, Noxxon: Honoraria; Millenium/Takeda: Research Funding; Janssen: Research Funding; Celgene: Research Funding.

Abstract Abstract 1893 Background: Recent data has shown that the level of immunoglobulin free light chain (FLC) is a prognostic factor for patients with AL amyloidosis. Approximately 25% of patients with AL amyloidosis have coexistent multiple myeloma (MM) with myeloma-related end-organ damage and patients may also present with 310% plasma cells (PC) in the bone marrow (BM) in the absence of any MM features. The goal of this study was to determine the effect of increased BM plasmacytosis in the absence of MM end-organ damage on early mortality. Methods: We performed a retrospective study of 263 consecutive patients with AL amyloidosis seen at Mayo Clinic within 30 days of diagnosis from July 2002 – April 2009, to compare the effect of PC burden among those who died within 90 days of diagnosis (n=88) and those who survived more than 90 days after diagnosis (n=175). Only those patients with documented BM PC were included in this study. MM end-organ damage was defined according to the CRAB criteria. Results: In those who died <90 days after diagnosis and patients who lived beyond 90 days, the proportion of patients with 310% BM PC were 57% and 55%, respectively. Overall survival (OS) was significantly shorter in the early mortality group when there was 310% BM PC present at diagnosis (25 vs. 54 days, p=0.006), but this was not observed in the group who survived beyond 90 days (Figure 1). In patients with 310% BM PC, troponin-T, ejection fraction (EF), and hemoglobin (Hgb) were significantly worse in the early mortality cohort but patients who survived beyond 90 days had significant increase in intraventricular septal (IVS) thickness and beta-2 microglobulin (Table 1). As expected, patients with 310% BM PC in both cohorts had significantly higher serum M-spike and involved FLC (Table). The same cohort of patients were analyzed substituting MM-related end-organ damage for 310% BM PC and similar results were observed with the exception of uric acid and calcium being significantly higher in the early mortality cohort with MM (results not shown). Conclusion: This study demonstrated that an excess of early—but not late—deaths occur in AL amyloidosis patients with 310% BM PC at diagnosis. In our cohort, this finding can be attributed to higher troponin-T levels, indicating more severe cardiac involvement as observed by worse cardiac function. These findings warrant additional investigation. Disclosures: Lacy: Celgene: Research Funding. Kumar:Celgene: Consultancy, Research Funding; Millennium: Research Funding; Merck: Consultancy, Research Funding; Novartis: Research Funding; Genzyme: Consultancy, Research Funding; Cephalon: Research Funding. Dispenzieri:Celgene: Honoraria, Research Funding; Binding Site: Honoraria.