Dispenzieri, Angela

Abstract Background: The combination of MPD and amyloidosis is rare, and this patient population's clinical outcome is not well studied. Methods: Pts with a MPD and amyloidosis were identified via an clinical note search engine that searches through the electronic medical records of patients seen at Mayo Clinic Rochester, Jacksonville, and Scottsdale between 1990 and 2016. Terms used included amyloid or amyloidosis, chronic myelogenous leukemia or CML, essential thrombocytopenia or ET, and polycythemia vera or PV. Demographic and clinical data were abstracted from the medical record. Pts with both disorders were analyzed and their mortality rates along with median time to death were calculated. Prevalences at the Mayo Clinic were calculated for the years 2014 and 2015. Results: Twenty-three pts diagnosed with both a MPD and amyloidosis were identified. Thirteen (56.5%) were male, 10 (43%) were female. Eleven (47.8%) were initially diagnosed at the Mayo Clinic. Types of amyloidosis were as follows: Eleven (47%) had immunoglobulin light-chain (AL), four had localized (17%), two (8.7%) had wild-type transthyretin (ATTR), one (4.3%) had mutant ATTR, and five (21.8%) were unknown. Types of MPD were as follows: Seven (30%) had polycythemia vera (PV), seven (30%) had chronic myelogenous leukemia (CML), five (22%) had myelofibrosis, and four (17%) had essential thrombocytosis (ET). Fifteen (65%) were initially diagnosed with a MPD. Median time to last follow-up from second diagnosis was 1.7 years, and median time to death following second diagnosis was 1.4 years. The mortality rate was 87% in the total population. The median time to death for AL and PV was 2.7 years, AL and CML 1.0 years, and AL and ET 1.17 years. Myelofibrosis did not occur with AL. The most common combination was AL and PV, which accounted for five (22%) of the cases. Treatment regimens for the patients with AL were varied. Multiple drugs were combined with dexamethasone including melphalan, velcade, pomalidomide, lenalidomide, doxorubicin, and revlimid. Cyclophosphamide, bortezomib, and dexamethasone (CyBorD) were used in two cases. The mean time to diagnosis of amyloidosis from symptom onset was 10.3 months. Prevalences of AL and a MPD in 2014 and 2015 at the Mayo Clinic were 2.8% and 1.5%, respectively. Conclusions: The mortality rate for the combined diagnoses is high. The most common combination of diagnoses was that of AL and PV, which was associated with a mean time to death of 2.7 years. Disclosures Al-Kali: Celgene: Research Funding; Onconova Therapeutics, Inc.: Research Funding.

Abstract Background: Pomalidomide has demonstrated excellent activity in patients with relapsed, lenalidomide refractory, multiple myeloma (MM). Between November 2007 and March 2012, we enrolled 285 patients with relapsed MM on 5 sequential phase 2 trials; patients received pomalidomide at 2mg or 4 mg daily with weekly dexamethasone (Pom/dex). The approved dose of pomalidomide is 4 mg for 21 of 28 days. We wished to compare efficacy, tolerability and long-term outcomes between cohorts treated with 2 mg or 4mg daily continuously and 4mg daily for 21/28 days. Methods: After excluding two ineligible patients, 283 patients with lenalidomide refractory, relapsed MM from 5 sequential cohorts were analyzed. These patients were divided into 3 groups: Group1 received Pom 2mg for 28/28 day cycle (N= 69), Group 2 received Pom 4 mg for 28/28 day cycle (N= 95) and Group 3 received Pom 4mg for 21/28 day cycle (N= 119). All patients received oral dexamethasone given 40 mg daily on days 1, 8, 15, and 22. Response was assessed by the IMWG Uniform Response criteria. All patients received aspirin 325 mg daily for DVT prophylaxis or full dose anticoagulation. Results: The median age was 63 years (32-85); 35% were female. The median time from diagnosis was 53 months and the median number of prior regimens was 4. 127 (46%) had high-risk molecular markers. Prior therapies (% received) included lenalidomide (100%), thalidomide (46%), bortezomib (78%), autologous stem cell transplant (71%), and allogeneic transplant (4%). The median follow-up is 16.4 months (3.2-64.4). Forty eight percent are alive and 26% remain progression free; 15 patients are continuing to receive treatment. Frequency of AEs by groups are shown in Table 1. The most notable difference is grade 3+ neutropenia seen in 39% of group 1 and 56% and 57% of groups 2 and 3. Confirmed responses of PR or better were seen in 29% (group1), 35% (group2) and 24% (group3). Median duration of response (DOR) was 14.1 months (group1), 14.5 months (group2) and 10.2 months (group3). Median PFS was 5.5 months (group1), 6.9 months (group2) and 4.3 months (group3). Although the dose level cohorts were sequential rather than randomized, we compared OS between the dose levels in an exploratory manner. There was no significant difference in OS between dose levels (p=0.26). Median overall survival (OS) was 16.6 months (group1), 21.9 months (group2) and 16.0 months (group3). Conclusions: Pom/dex is active and well tolerated even in heavily pretreated patients Responses are durable. Response rates and overall toxicity are similar between the 2 mg and 4 mg doses. Neutropenia is more common in those receiving doses of 4mg daily or for 21/28 days compared to those receiving 2 mg daily. Table 1. All Grades Grade 3+ 2mg 28 Day 4mg 28 Day 4mg 21 Day 2mg 28 Day 4mg 28 Day 4mg 21 Day Anemia 68% 58% 74% 14% 15% 27% Lymphopenia 22% 51% 11% 16% 32% 8% Neutropenia 71% 82% 77% 39% 57% 56% Thrombocytopenia 51% 61% 63% 10% 9% 23% Leukopenia 59% 77% 72% 26% 38% 39% Pneumonia 7% 11% 12% 6% 7% 11% Fatigue 51% 65% 60% 9% 5% 8% Neuropathy 28% 32% 28% 0% 3% 0% Elevated Blood Glucose 10% 21% 8% 4% 6% 3% Pneumonitis 3% 2% 3% 3% 1% 1% VTE (Thrombosis) 3% 3% 3% 1% 3% 3% Secondary Malignancy 0% 2% 1% 0% 2% 1% Figure1. Kaplan Meier Overall Survival Curves Figure1. Kaplan Meier Overall Survival Curves Disclosures Lacy: Celgene: Research Funding. Fonseca:Medtronic, Otsuka, Celgene, Genzyme, BMS, Lilly, Onyx, Binding Site, Millennium, AMGEN: Consultancy, patent for the prognostication of MM based on genetic categorization of the disease. He also has sponsored research from Cylene and Onyx Other, Research Funding. Bergsagel:Novartis: Research Funding; Constellation Pharmaceutical: Research Funding; OncoEthix: Research Funding; MundiPharma: Research Funding. Stewart:Novartis: Consultancy; Celgene: Consultancy; Bristol Myers Squibb: Consultancy; Array BioPharma: Consultancy; Sanofi: Consultancy; Takeda Pharmaceuticals International Co.: Research Funding. Reeder:Millennium, Celgene, Novartis: Research Funding. Mikhael:Onyx: Research Funding; Celgene: Research Funding; Sanofi: Research Funding; Novartis: Research Funding.

Abstract Background: Cytogenetic evaluation using fluorescence in situ hybridization (FISH) at the time of diagnosis is essential for initial risk stratification in multiple myeloma. Despite the absence of cytogenetic high-risk abnormalities a subset of patients does experience poor overall survival comparable high-risk disease (i.e. median overall survival less than three years after diagnosis). We aimed to identify demographic, clinical, and cytogenetic characteristics predicting poor three-year overall survival in patients with standard-risk cytogenetics. Methods: We studied 428 patients who were diagnosed with multiple myeloma between July 2004 and July 2014 at Mayo Clinic Rochester, underwent FISH evaluation within six months of diagnosis, and received treatment with novel agents (immunomodulator, proteasome-inhibitor, or a combination thereof). Patients with high- and intermediate-risk cytogenetics as well as patients lost to follow-up within three years were excluded. High-risk cytogenetics were defined as del(17p), t(14;16), and t(14;20). Intermediate-risk cytogenetics were defined as t(4;14) and gain(1q). 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 evaluating up to five potential partners (FGFR3, CCND1, CCND3, MAF, and MAFB). A multivariable-adjusted logistic regression model was used to assess the associations between the parameters of interest and three-year overall survival. Discrimination and calibration of the model were evaluated using the c-statistic and the Hosmer-Lemeshow test, respectively. The odds ratios of the identified predictors were rounded up to the next integer and assigned as points in a scoring system. Receiver operating characteristic analysis was used to determine the optimal cut-point and associated test performance characteristics. P-values below 0.05 were considered statistically significant. Results: The median age at diagnosis was 65 years (31 - 95), 259 (61%) of the patients were male. The median overall survival was 7.4 years (6.1 - 8.6) for the entire cohort (n = 428), 10.5 years (8.3 - NR) for those who survived at least three years (n = 327, 76%), and 1.6 years (1.2 - 1.7) for those who did not survive three years after diagnosis (n = 101, 24%). The factors associated with poor three-year overall survival and the derived scoring system are summarized in Table 1. Conclusions: Patients with multiple myeloma and standard-risk cytogenetics are a heterogeneous group. One fourth of the patients are experiencing less than three years of overall survival after diagnosis. Stage, age, extent of bone marrow involvement, karyotype, and platelet count at the time of diagnosis were helpful in identifying patients at risk for poor three-year overall survival. These findings emphasize the importance of further risk stratification in this patient population and warrant external validation. Disclosures Dispenzieri: Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jannsen: Research Funding; pfizer: Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Alnylam: Research Funding. Kapoor:Takeda: Research Funding; Amgen: Research Funding; Celgene: Research Funding. Kumar:AbbVie: Research Funding; BMS: Consultancy; Amgen: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Noxxon: Consultancy, Honoraria; Janssen: Research Funding; Skyline: Consultancy, Honoraria.

Abstract Background Systemic AL amyloidosis is a life-threatening disease with limited treatment options. Response criteria have been recently updated and retrospectively validated (Palladini et al, J Clin Oncol 2012). Hematologic response (suppression of FLCs) has been shown to predict for both organ response and survival (ibid). Preliminary results from the present phase 1 study (NCT01318902) regarding the safety, tolerability, and maximum tolerated dose (MTD) of ixazomib (the first oral PI to be investigated in the clinic) in RRAL were reported previously (Merlini et al, ASH 2012). At that time, 11 pts had received the MTD/RP3D of ixazomib - 4.0 mg. Here we update the safety data (primary objective) and report hematologic and organ responses, progression-free survival (PFS), and overall survival (OS) (secondary objectives) for the extended population of 22 pts receiving the RP3D. Methods Pts with RRAL after ≥1 prior therapy and with measureable heart/kidney involvement and cardiac biomarker stage I/II disease were eligible. Two expansion cohorts (PI-naïve and PI-exposed) were enrolled at the RP3D. Pts received oral ixazomib on days 1, 8, and 15 for up to 12 x 28-day cycles; continuation until disease progression was allowed. Pts with less than partial response (PR) after 3 cycles received added dexamethasone (Dex) 40 mg, days 1–4 from cycle 4 onwards. Adverse events (AEs) were graded by NCI-CTCAE v4.03. Responses were assessed per standard criteria (Palladini et al, J Clin Oncol 2012). Results At data cut-off (Dec 6, 2013), 27 pts had been enrolled, 22 at the RP3D of ixazomib 4.0 mg; the other 5 pts were enrolled at 5.5 mg and are not included in these analyses. In pts who received ixazomib 4.0 mg, median age was 64.5 yrs (range 54–78); 13 were male. Mayo cardiac biomarker risk stage was I/II/III in 11/10/1 pts, respectively. Median baseline FLC differential (dFLC) and NT-proBNP were 146 mg/L (range 40–734) and 849 pg/mL (range 51–5691). Major organ involvement included heart, kidney, or both in 9, 8, and 5 pts, with a median of 2 (range 1–6) organ systems involved. Pts had received a median of 3 prior therapies, including transplantation in 16 pts; 16 pts had received prior bortezomib (PI exposed) and 6 were PI naïve. Other prior therapies included melphalan (n=21), Dex (n=16), IMiDs (n=11), and cyclophosphamide (n=10). Best hematologic response to prior therapy was complete response (CR) in 3 pts, very good PR (VGPR) in 4, PR in 14, and stable disease (SD) in 1 pt; organ response was achieved by 5 pts, with 12 pts having no response. Exposure and outcome data by prior PI exposure are shown in the table. Pts discontinued due to disease progression (n=6), pt withdrawal, symptomatic deterioration (each n=3), or unsatisfactory response (n=2); 5 pts completed 12 cycles; 3 pts are ongoing. Overall hematologic response rate (ORR) was 52%. After a median follow-up of 16.9 mos, the 9 pts who achieved ≥VGPR, had a median PFS of 17.0 mos compared with 10.7 mos in pts who achieved a lesser response (p=0.03). Cardiac/renal response was observed in 50%/18% of pts (all ≥VGPR). The most common drug-related AEs included diarrhea, nausea (each n=7), fatigue, thrombocytopenia (each n=6), peripheral neuropathy, and pyrexia (each n=4). Drug-related grade 3 AEs (>1 pt) were thrombocytopenia (n=3), diarrhea, and maculo-papular rash (each n=2). Table.PI naïven=6PI exposed n=16TotalN=22Cycles received, median (range)12 (1–22)3.5 (1–16)5.5 (1–22)Dex added, n358Hematologic response-evaluable ptsn=5n=16N=21Response, n (%)ORR5 (100)6 (38)11 (52)CR2 (40)02 (10)VGPR3 (60)4 (25)7 (33)PR02 (13)2 (10)SD09 (56)9 (43)Cardiac response/heart evaluable, n/N (%)3/4 (75)3/8 (38)6/12 (50)Renal response/kidney evaluable, n/N (%)1/3 (33)1/8 (13)2/11 (18)1 yr hematologic PFS rate, %8341602 yr OS rate, %835157 Conclusions This is one of the first studies prospectively assessing hematologic and organ response according to the updated consensus criteria. These data suggest weekly oral ixazomib 4.0 mg is feasible and generally well tolerated in RRAL pts with vital organ dysfunction. High quality hematologic responses (≥VGPR) were observed in 43% of pts; these responses were sustained at 1 yr in 60% of this heavily-pretreated population. Achieving ≥VGPR was associated with cardiac response and extended PFS. These results warrant a phase 3 study of ixazomib plus Dex vs physician's choice of treatment, which is ongoing (NCT01659658). Disclosures Merlini: Pfizer: Honoraria; Millennium: the Takeda Oncology Company: Consultancy, Honoraria, Speakers Bureau. Off Label Use: Use of the investigational agent ixazomib, an oral proteasome inhibitor, in the treatment of relapsed or refractory light-chain amyloidosis. Sanchorawala:Celgene: Research Funding; Millennium: the Takeda Oncology Company: Research Funding; Onyx: Research Funding. Jeffrey:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees. Kukreti:Celgene: Consultancy, Honoraria. Schoenland:Celgene: Honoraria, Research Funding, Speakers Bureau; Janssen: Honoraria, Research Funding, Speakers Bureau. Jaccard:Celgene: Honoraria, Research Funding; Janssen: Honoraria. Dispenzieri:Millennium: the Takeda Oncology Company: Research Funding; Celgene: Research Funding; Pfizer: Research Funding; Janssen: Research Funding. Cohen:Onyx Pharmaceuticals: Advisory Board, Advisory Board Other; Bristol-Myers Squibb: Advisory Board, Advisory Board Other, Research Funding; Janssen: Advisory Board, Advisory Board Other; Celgene: Member, Independent Response Adjudication Committee Other. Berg:Takeda Pharmaceutical International Co.: Employment. Yuan:Takeda Pharmaceutical International Co.: Employment. Hui:Takeda Pharmaceutical International Co.: Employment. Comenzo:Millennium:the Takeda Oncology Company: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Teva: Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Abstract Introduction: A recent study revealed an antiproliferative and apoptotic effect of propranolol on multiple myeloma (MM) cells. Our previous small matched case-control study showed longer survival in patients with propranolol and other beta-blockers (BB) intake than those without. This larger scale study was conducted to confirm the positive association of BB and MM survival. Methods: We identified 1971 newly diagnosed pts seen at Mayo Clinic between 1995 and 2010. Cardiac medication usage after diagnosis of MM was extracted from patient records and categorized based on BB intake. Cause of death was collected with death due to MM as the primary interest event and death due to cardiac disease or other reasons as competing risk events. The primary outcomes were MM disease-specific survival (DSS) and overall survival (OS). Cumulative incidence functions and Kaplan-Meier method were used to estimate the 5-year cumulative incidence rate (CIR) of MM death and OS rate, respectively. DSS and OS were compared by Gray's test and log-rank test, respectively. Multivarable Cox proportional hazard models were used to estimate the adjusted cause-specific HR (HRCSadj.) and hazard ratio (HRadj.) for DSS and OS, respectively, adjusting for demographics, disease characteristics, diagnosis year, and various chemotherapies. Results: 930 (47.2%) of MM patients had no intake of any cardiac medications; 260 (13.2%) had BB only; 343 (17.4%) used both BB / non-BB cardiac medications; and 438 patients (22.2%) had non-BB cardiac drugs. Five-year CIR of MM death and OS rate were shown in table. Superior MM DSS was observed for BB only users, compared to patients without any cardiac drugs (HRCSadj., .53, 95% confidence interval [CI], .42-.67, padj.<.0001) and non-BB cardiac drugs users (HRCSadj., .49, 95% CI, .38-.63, padj.<.0001). Patients received both BB and other cardiac drugs also showed superior MM DSS than non-cardiac drugs users (HRCSadj.., .54, 95% CI, .44-.67, padj.<.0001) and non-BB cardiac drug users. (HRCSadj., .50, 95% CI, .40-.62, padj.<.0001). MM DSS does not differ between BB users with and without other cardiac drugs (padj.=0.90). Multivariable analysis showed the same pattern for OS. None of the MM therapies impacted the differences in DSS and OS among BB intake groups (interaction padj.>.60). Conclusion: MM patients with BB intake showed reduced risk of death due to MM and overall mortality compared to patients who used non-BB cardiac or never used cardiac drugs. The result warrants further investigation for anti-cancer effect of BB in MM. Disclosures Shi: Mayo Clinic: Employment. Kumar:Onyx: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Array BioPharma: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Research Funding; Glycomimetics: Consultancy; Janssen: Consultancy, Research Funding; Noxxon Pharma: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; BMS: Consultancy; Kesios: Consultancy. Gertz:NCI Frederick: Honoraria; Celgene: Honoraria; Med Learning Group: Honoraria, Speakers Bureau; Research to Practice: Honoraria, Speakers Bureau; Alnylam Pharmaceuticals: Research Funding; Novartis: Research Funding; Prothena Therapeutics: Research Funding; Ionis: Research Funding; Annexon Biosciences: Research Funding; GSK: Honoraria; Sandoz Inc: Honoraria. Kapoor:Celgene: Research Funding; Amgen: Research Funding; Takeda: Research Funding. Dispenzieri:pfizer: Research Funding; Celgene: Research Funding; Alnylam: Research Funding; Jannsen: Research Funding; GSK: Membership on an entity's Board of Directors or advisory committees; Prothena: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Abstract Background: Immunoglobulin light chain (AL) amyloidosis is a fatal complication of B-cell clonal proliferation. Currently, the best biomarker for treatment monitoring is serum free light chain (FLC) assay. Despite its higher sensitivity, it cannot distinguish clonality thus ultralow levels of monoclonal gammopathy can be missed. Urinary exosomes (UExs) are the smallest members of the extracellular vesicle family that are excreted in the urine. They exhibit different characteristics in patients with AL amyloidosis vs multiple myeloma. This study was undertaken to determine if urinary exosomes have different characteristics in patients AL amyloidosis who progress despite being in complete response (CR) vs those who have a renal response. Methods: UEx were extracted from 4 patients at different stages of AL (Table 1). Immunoglobin light chains (LC) were identified in the UEx using western blotting. Intact immunoglobulin light chains were identified in plasma, UEx, and kidney biopsy amyloid deposits using mass spectrometry (MS). cDNAs from bone marrow plasma cells (BMPC) collected at the time of diagnosis from patient 4 were sequened. Results: Oligomeric LC (250 kd) were identified in the UEx of patient 1 (newly diagnosed, Fig 1a) and 4 (renal progression in CR, Fig 1d) but only monomeric LC (25 kd) were detected in patient 2 (Fig 1b) and 3 (CR and renal response, Fig 1c). MS of the UEx and plasma of patient 4 detected 2 monoclonal λ LC. The mass of one of the LC was consistent with a lambda 6a LC which is also the most common cDNA (IGLV-6-57) found in the BMPC. Amino acid sequences derived from the tryptic digestion of the amyloid deposits matched the predicted sequence of the cDNA. The calculated weight of the peptide produced by the cDNA (23,304 Da ) was within margin of error of the mass of the lambda 6a LC (23,306 Da). The mass of the second LC (23,092 Da) was consistent with a λ4/λ5 LCs. A search of the amino acid and cDNA sequences failed to identify any similarity. The density ratio of the oligomeric LC to monomeric LC in the UEx was 0.47 which was similar to the intensity ratio by MS of the lambda 6a LC (23,306 Da) to the 23,092 Da LC in the blood (0.43). Discussion: Urinary EXs identified oligomeric LC in a patient with progressive renal disease despite achieving a CR. The mass one of the λ LC matched the predicted peptide product of the cDNA obtained from BMPC. The amino acid sequence predicted by the cDNA matched the trypsin digested sequences from the amyloid deposits. This strongly suggests the oligomeric LC represents the amyloidogenic λ6a LC detected in the blood which was being produced by the BMPC clone which is being deposited as amyloid in the kidney. The origin of the second λ LC is unknown but is likely a new monoclonal gammopathy of undetermined significance that developed after the initial bone marrow biopsy. The blood and urine samples were obtained 3 years after the BMPC. The development of a new monoclonal gammopathy in patients with plasma cell dyscrasia is not uncommon. Unfortunately, bone marrow biopsy collected at the time of the urine and blood sample had insufficient number of plasma cells (CR) for analysis. Conclusion: UEx can identify amyloidogenic LC even when current standard methods could not. The persistent presence of the amyloidogenic LC helps explain why patients can progress despite being in CR. The presence of a second λ LC which was not part of the amyloid deposit also has clinical implication. It may explain why some patients do well despite having a persistent monoclonal protein. If these results are confirmed, UEx may have a powerful role in the determination of organ and hematologic response in patients with AL amyloidosis. Disclosures Dispenzieri: Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees; Alnylam: Research Funding; GSK: Membership on an entity's Board of Directors or advisory committees; pfizer: Research Funding; Jannsen: Research Funding; Celgene: Research Funding.

Abstract Introduction: AL amyloidosis is a very heterogeneous disease. Prognosis is a function of organ tropism, extent of organ damage, and ability of tissues to heal, the last of which relates both to hematologic response and intrinsic toxicity of the light chain. Using mass spectroscopy (MS) technology, we are able to distinguish immunoglobulin light chain variable gene family (IGVL) usage on clinical samples. The goal of this study was to evaluate if IGVL usage impacts patient outcomes in patients with light chain amyloidosis (AL). Methods: IGVL usage was determined by mass spectroscopy (MS) of amyloid in clinical tissue specimens of Mayo Clinic patients. Specimens were from fat pad (n=257), bone marrow (n=172), myocardium (n=113), gastrointestinal (n=58), kidney (n=20), lung (n=15), and nerve (n=5). For those cases for which the IGVL could not be identified--not otherwise specified (NOS)—but constant region could be identified as lambda or kappa, we assume that the amyloid consisted primarily of immunoglobulin light chain gene constant regions or variable genes with somatic mutations making them uninterpretable to our matching algorithms. The medical records from these 700 patients were abstracted for relevant clinical and laboratory data. Results: The baseline characteristics of patients are shown in table 1. Three hundred and thirty-two patients have died with a median follow-up of surviving patients of 38 months. The estimated median survival for the entire population is 59 months. Out of 700 patients, 214 (31%) achieved a CR or a VGPR, 432 (62%) were not evaluable (NE) for hematologic or organ response, and 54 (8%) achieved a PR or did not respond (NR). The distribution of IGVL cases is shown in table 2. Overall survival (OS) for the whole group was not different across different IGVLs on univariate analysis, but when corrected for hematologic response, outcomes differed significantly based on IGVL. Patients could be further assembled into two groups, based on risk for death on univariate analyses: an IGVL high risk, which included KV1, LV1, LV2, LV3, and LV6; and low risk, which included all other cases (Figure). In a multivariate model that included level of hematologic response (CR/VGPR versus PR/NR/NE) and IGVL, IGVL family was independently associated with overall survival (RR=1.5 (95% CI 1.2-1.9, p=0.008). The risk ratio for CR/VGPR was 0.28 (95% CI 0.20-0.38, p<0.0001). This effect persisted when either the Mayo 2006 or the 2012 staging system was included in the multivariate. Conclusion: IGVL usage appears to have prognostic significance in patients who have not achieved VGPR or better to initial chemotherapy. Table 1. Baseline characteristics of patients N= 700 Age 63 (32-94) Male, (%) 447 (64%) Biopsy site Solid organ/Soft tissue 271 (39%) Fat pad 257 (37%) Bone Marrow 172 (25%) Organ involvement Cardiac 432 (62%) Renal 346 (49%) Gastrointestinal 168 (24%) Liver 56 (8%) Nerve 107 (15%) Lung 42 (6%) Soft Tissue 92 (13%) Organs involved 1 321 (46%) 2 228 (33%) ≥3 151 (22%) Laboratory characteristics NTBNP, pg/ml 2547 (11.3-70000) Troponin, ng/ml 0.03 (0.001-0.84) dFLC, mg/dl 26 (0.04-2330) Cardiac Stage 1 59 (18%) 2 125 (38%) 3 144 (44%) Table 2. Variable region family distribution. Light Chain N=700 N (%) KV1 107 (15%) KV2 3 (0.4%) KV3 17 (2%) KV4 25 (4%) KV6 1 (0.1%) LV1 85 (12%) LV2 64 (9%) LV3 118 (17%) LV4 3 (0.4%) LV6 97 (14%) LV8 1 (0.1%) LV9 1 (0.1%) Kappa NOS1 34 (4%) Lambda NOS1 140 (19%) Heavy chain amyloidosis 4 (0.6%) 1 No IGVL family could be identified Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Background: Autologous stem cell transplantation is an effective treatment modality for patients with multiple myeloma. While most of the patients relapse after ASCT with a median time to progression of 2 years, there is a significant heterogeneity in the duration of response. It has been hypothesized that the effect of high dose alkylator therapy used for conditioning may have a dual effect on the myeloma cells as well as marrow microenvironment. It is also known that hematopoiesis, especially thrombopoiesis, depends to some extent on signals form the marrow microenvironment. We examined if there was any relationship between delayed platelet engraftment and outcome after ASCT. Methods: We examined the outcomes in a group of patients undergoing ASCT for myeloma at our institution to compare the response duration to platelet engraftment kinetics. We studied 687 patients undergoing ASCT with melphalan conditioning followed by peripheral blood stem cell transplant. Results: Among the 687 patients undergoing ASCT, 200 pts (29%) achieved a platelet count of 50,000 by day 21 (early group) and the rest achieved this level after 21 days or never engrafted (late group). The median time to progression (TTP) among the late group was 24.8 months (95% CI; 19.6, 30 months) vs. 16.8 months (95% CI; 15.1, 18.6 months) for the late group (p < 0.001) (Figure). Patients in the late engraftment group were more likely to achieve a complete response compared to the early group; 39% vs. 30%, p = 0.02. In a multivariate analysis examining factors predicting for longer time to progression after ASCT, delayed platelet engraftment was independent of transplant within 12 months of diagnosis, CR with ASCT, absence of cytogenetic abnormalities, B2M < 3.5 mg/L and a plasma cell labeling index < 1% at the time of ASCT (Table). Conclusions: In this study, we have demonstrated for the first time a relationship between delayed platelet engraftment after ASCT and the duration of response following ASCT. This intriguing finding raises several hypotheses. It is possible that the delayed platelet engraftment is a marker of marrow microenvironment dysfunction secondary to high dose therapy, given the role of marrow microenvironment on thrombopoiesis. It is possible that this is a surrogate marker for the biological effectiveness of the melphalan dose, which can affect the other cells in the marrow microenvironment as well. It is likely a reflection of the marrow microenvironment dependence on the myeloma cells for its survival. These findings should be confirmed in other larger patient groups. Predictors of progression Variable Hazard Ratio P Platelet Engraftment > 21 days 0.80 (0.60, 0.96) 0.02 Late transplant (>12 months from diagnosis) 1.6 (1.3, 2.0) <0.01 Plasma cell labeling index > 1% 1.9 (1.5, 2.4) <0.01 Complete response 0.41 (0.33, 0.51) <0.01 Abnormal Cytogenetics 1.8 (1.4, 2.3) <0.01 B2M > 3.5 1.2 (0.96, 1.5) 0.12 Figure Figure

Abstract Background: Pomalidomide is an immunomodulatory agent (IMiD®) that has been approved for treatment of relapsed and refractory multiple myeloma (MM). Combinations of IMiDs and proteasome inhibitors offer the potential for deeper and more durable responses due to enhanced efficacy. Preliminary results of a phase 1 study of twice weekly bortezomib with pomalidomide have been reported with promising results (Richardson, ASH 2012). This phase I/II trial was designed to evaluate the maximum tolerated doses (MTD) as well as safety and efficacy of the combination of pomalidomide, once weekly bortezomib and dexamethasone (PVD) in patients with relapsed, lenalidomide refractory, MM. Patients and methods: We included patients with relapsed MM who had 1-4 prior lines of therapy and were resistant or refractory to lenalidomide. In the phase I portion of the trial, dose level 1 consisted of pomalidomide 4 mg days 1-21 PO, bortezomib 1.0mg/m2 days 1,8,15, and 22 IV or SQ and dexamethasone 40 mg days 1,8,15, and 22 PO, given every 28 days. Bortezomib was increased to 1.3mg/m2 for dose level 2 and and was adopted for the phase 2 portion. The primary aim of the phase I cohort was to determine the MTD of the combination, and for the phase II cohort was to evaluate the confirmed response rate (PR, VGPR, or CR) in relapsed refractory MM. Response was assessed by the IMWG criteria and toxicity was graded using the CTCAE v4.0. Results: 50 patients were accrued between March 2012 and July 2014 (dose level (DL)1: 3, DL 2: 6, Phase II: 41). We describe results in 47 patients treated at MTD and phase II. Median age was 66, 51% were female and median time from diagnosis to study was 46 months (15-142). Twenty five percent had mSMART defined high-risk status. Median number of prior regimens was 3. All patients had prior lenalidomide, 68% had stem cell transplant, 17% received thalidomide, 56% had alkylators and 57% had bortezomib. With median follow up of 9 months, 72% remain progression free, 96% are alive and 66% remain on treatment. The most common AEs at least possibly attributable to the combination were anemia, fatigue, leukopenia and thrombocytopenia; however, the majority of these were grade 1-2. Grade ≥3 AEs (regardless of attribution) that occurred in at least 3 patients included neutropenia (29), leukopenia (15), lung infection (6), lymphopenia (8) dyspnea (3) and syncope (3). DVT/PE occurred in one patient. Among the 42 patients who were evaluable, confirmed responses (PR, VGPR, or CR) were seen in 34 (81%) including sCR (3), CR (5), VGPR (8), PR (18). Confirmed responses were seen in 9 of 11( 82%) high risk patients. Median progression free survival was 17.7 months (95%CI: 9.5-NA). Conclusions: PVD is a highly effective combination in patients refractory to lenalidomide with confirmed responses in over 80%. Weekly administration of bortezomib enhanced the tolerability and convenience of this regimen. Toxicities are manageable, mostly consisting of mild cytopenias with no significant neuropathy or DVT. PVD is a highly attractive option in patients with relapsed and refractory MM. Disclosures Lacy: Celgene: Research Funding. Lust:Senesco: PI Other. Fonseca:Medtronic, Otsuka, Celgene, Genzyme, BMS, Lilly, Onyx, Binding Site, Millennium, AMGEN: Consultancy, patent for the prognostication of MM based on genetic categorization of the disease. He also has sponsored research from Cylene and Onyx Other, Research Funding. Stewart:Celgene: Consultancy; Novartis: Consultancy; Array BioPharma: Consultancy; BMS: Consultancy; Millenium: Research Funding. Reeder:Millennium, Celgene, Novartis: Research Funding. Mikhael:Onyx: Research Funding; Celgene: Research Funding; Sanofi: Research Funding; Novartis: Research Funding.

Abstract Background: The serum free light chain (FLC) ratio is a readily available laboratory test that has independent prognostic significance in monoclonal gammopathy of undetermined significance (MGUS) (Blood2005;106:812–17) and solitary plasmacytoma (Blood2006;108:1979–83). The purpose of this study was to determine if the FLC ratio will be of prognostic value in multiple myeloma (MM). Methods: We used a well characterized cohort of 1027 newly diagnosed MM patients seen at Mayo Clinic from January 1, 1985 to December 31, 1998 (Mayo Clin Proc2003;78:21–33) to ensure adequate follow up. Archived serum samples from blood drawn within 30 days of initial diagnosis were available on 790 of the 1027 patients. Quantitation of serum free κ and λ concentrations was performed on the archived sera by immunonephelometry, using specific antibodies on a BNII nephelometer. FLC ratio was calculated as κ /λ, i.e., free κ concentration divided by free λ, reference range 0.26–1.65. If the FLC ratio is >1.65, κ is considered to be the “involved” FLC and λ the “uninvolved” FLC, and vice versa if the ratio is less than 0.26. Incorporation of FLC into the International Staging System (ISS) was assessed in 576 of 790 patients (73%), in whom samples or data were available to estimate the ISS. Results: 790 patients (median age 66 years) were studied. The FLC ratio was outside the reference range in 95.1% of patients. The median involved κ and λ concentrations were 37.1 and 71.3 mg/dL, respectively. A cut-point κ /λ FLC ratio of <0.03 or >32 was chosen for further modeling analysis on the basis of its separation of the cohort into two roughly comparable parts. Overall survival was significantly inferior in patients with an FLC ratio <0.03 or >32 (n=479 patients) compared to those with an FLC ratio that was 0.03–32 (n=311 patients), with median survival of 30 versus 39 months, respectively, P<0.001 (hazard ratio 1.3, 95% CI 1.12–1.54). The FLC ratio (<0.03 or >32) retained independent significance after adjusting for the International Staging System (ISS) (P=0.03). The FLC ratio made the most significant contribution to predicting prognosis in patients with ISS Stage 2 (n=265 pts), separating this category of patients into those with 5 year survival rates of 20.5% (FLC ratio <0.03 or >32; n=152 pts) versus 35.2% (FLC ratio 0.03–32; n=113 pts), P=0.02. We studied the additional prognostic value of the serum FLC to the variables used in the ISS by defining FLC ratio <0.03 or >32, Sβ2M ≥3.5 g/L, and serum albumin <3.5 g/dL as three risk factors in a risk-stratification model. Patients with 0, 1, 2, or 3 risk factors had significantly different overall survival, with median overall survival times of 51, 39, 30 and 22 months, respectively, P<0.001. Conclusions: The serum FLC ratio at initial diagnosis is an important predictor of prognosis in myeloma. We show that the serum FLC ratio can be incorporated into the ISS, providing the greatest prognostic value in ISS Stage 2 patients, as well as providing a new risk-stratification model.