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Abstract 4030 Age is a major prognostic factor for the outcome of patients with multiple myeloma (MM), due to more intensive treatment in younger vs. older patients, comorbidities and toxicity, resulting in early discontinuation of treatment in older patients or even differences in disease characteristics. It is believed that the longer survival of patients ≤65 years is, to a large extent, due to the receipt of more lines of therapy and thus they can have an extended survival even after relapse to first line therapy. In order to decipher these differences in the outcome of MM patients of different ages, we analyzed 438 consecutive, unselected patients who were treated in a single center (Department of Clinical Therapeutics, University of Athens School of Medicine) from April 1994 to April 2012, and compared the characteristics and outcome of patients ≤65 years (166 patients), which are usually treated with more intensive therapies (including HDT), to that of patients 66–75 years (154 patients) and >75 years of age (118 patients). Some of these patients were included in clinical trials; however, even patients who were ineligible because of poor performance status, renal impairment or comorbidities were also included, thus, being more representative of the general myeloma population. Differences in the characteristics of patients of different age groups are depicted in the table. Younger patients presented less often with ISS-3, severe anemia, renal impairment or impaired PS than older patients. However, there was no difference in the detection of high risk cytogenetics. Response was higher and deeper in younger patients. Early deaths, within 2 months from initiation of therapy, occurred more often in older patients. Median PFS was longer in younger patients. Similar proportion of patients who relapsed have received 2nd line therapy (p=0.365). Post relapse survival (PRS) was 31 months for patients ≤65 years, 20 months for patients 66–75 years and 15 months for patients >75 years (p75 years was also significant (p=0.004). Median OS was 71 months for patients 75 years (p75 years (p=0.003). PRS for patients with a PFS75 years. Median OS was significantly better for patients who achieved CR or VGPR (58 months) vs. patients who achieved a PR (39 months) (p75 years (p75 years (p=0.092) were independently associated with improved survival. In conclusion, our data indicate that the survival of MM patients is distributed almost equally between the initial phase i.e. before relapse to first line therapy, and to subsequent phases of their disease i.e. post relapse survival. This is observed across all age groups, but in patients ≤65 years the duration of first response is significantly longer, perhaps due to more intensive therapies and to less frequent early deaths. In this unselected series of patients, the 10-year free of progression rate was 6.5%. Table ≤65 years 66–75 years >75 years p-value Males 60% 43.5% 51% 0.015 ISS-1 21% 18% 9% 0.02 ISS-2 50% 46% 47% ISS-3 29% 37% 45% Hb VGPR 56% 49% 34% 0.001 ≥PR 81% 79% 64% 0.003 Early deaths 2% 6% 12% 0.005 Median PFS (months) 34 19.5 15 0.001 Median PRS (months) 31 20 15 Disclosures: No relevant conflicts of interest to declare.

Abstract 3967 Multiple myeloma (MM) is characterized by the presence of osteolytic bone disease. Periostin, previously known as osteoblast-specific factor, is a matricellular protein, which is expressed in the periosteum after mechanical stress and is involved in bone formation. Periostin expression is up-regulated by several members of the TGF-β superfamily, including activin-A, which has been recently found to be elevated in MM by our group. Periostin expression and circulating levels were elevated in solid tumors with bone metastases, like breast cancer but there is no information for its role in MM. To address this issue we evaluated periostin in the supernatants of six myeloma cell lines (LR5, MR20, L363, U261, H929, and JJN3) and four ovarian cancer cell lines (A2780, C30, OVCA3 and SKOV3) before and after incubation for 24h and 48h with stromal cell line HS5. Furthermore, we measured periostin in the bone marrow plasma and the serum of 72 consecutive, newly diagnosed, patients with symptomatic MM (37M/35F, median age 70 years) before the administration of any kind of therapy and in the serum of 245 MM patients (106M/92F, median age 73 years) at different phases of the disease: 33 patients had asymptomatic myeloma (AMM) at diagnosis, 152 symptomatic MM at diagnosis (including the 72 with marrow plasma measurement), 30 “plateau” phase MM and 30 relapsed MM after previous response to therapy. Periostin was also measured in the bone marrow plasma and the serum of 23 patients with MGUS and in the serum of 30, gender- and age-matched, healthy controls. In all patients and controls, we also measured bone marrow plasma and serum activin-A, and serum C-telopeptide of collagen type-I (CTX, a bone resorption marker) and bone-specific alkaline phosphatase (bALP, a bone formation marker). Evidence of bone involvement in all patients was documented using plain radiographs and MRI of the spine. The periostin levels in the supernatants of the myeloma cell lines were higher than those found in the supernatants of the ovarian cancer cell lines (mean±SD: 17.2±6.14 ng/ml vs. 2.98±1.92 ng/ml; p=0.001; levels of periostin in the RPMI+FBS was 0.595 ng/ml). There was no difference regarding periostin concentrations among the different myeloma cell lines or among the different ovarian cancer cell lines. After incubation for 24h and 48h with stromal cell line HS5 (periostin level in the HS5 supernatant was 0.227 ng/ml), there was no alteration in the periostin levels of the supernatants of the myeloma cell lines. On the contrary, the ovarian cancer cell lines showed a dramatic increase in the periostin concentration after incubation with HS5 after 48h (18.3±16.3 ng/ml, p=0.023) but not after 24h (1.54±0.50 ng/ml). The mean periostin levels of the bone marrow plasma of the 72 patients were 3406 ng/ml (±5320 ng/ml) almost 5-fold higher that the respective values of MGUS patients (703±320 ng/ml; p Our data suggests that periostin is elevated in MM patients and correlates with bone fractures, diffuse MRI pattern, reduced bone formation and increased activin-A levels, supporting a significant role of this molecule into the biology of myeloma-related bone disease. Disclosures: No relevant conflicts of interest to declare.

Abstract 1819 Multiple myeloma (MM) is characterized by the presence of osteolytic lesions due to increased bone resorption and reduced osteoblast function. It has been recently reported that, during bone remodeling, osteoclasts express semaphorin 4D (Sema4D), previously shown to be an axon guidance molecule, which potently inhibits bone formation through the suppression of insulin-like growth factor-1 signaling and the modulation of osteoblast motility. Sema4D acts through its binding to its receptor plexin-B1. There is no information in the literature for the role of Sema4D/plexin-B1 signaling in myeloma-related bone disease. To address this issue we evaluated Sema4D and plexin-B1 in the supernatants of six myeloma cell lines (LR5, MR20, L363, U261, H929, and JJN3) and four ovarian cancer cell lines (A2780, C30, OVCA3 and SKOV3) before and after incubation for 24h and 48h with stromal cell line HS5. Furthermore, we measured Sema4D and plexin-B1 in the bone marrow plasma and serum of 72 newly diagnosed patients with MM (37M/35F, median age 70 years) before the administration of any kind of therapy, in 5 newly diagnosed patients with systemic amyloidosis (AL) and in healthy controls (bone marrow plasma, n=5; serum, n=20), gender- and age-matched. Sema4D and plexin-B1 levels were evaluated using ELISA methodology (USCN Life Science Inc., Wuhan, China). In all patients and controls, we also measured serum C-telopeptide of collagen type-I (a bone resorption marker) and bone-specific alkaline phosphatase (a bone formation marker). Evidence of bone involvement in all patients was documented using plain radiographs. Only one myeloma cell line produced high Sema4D (MR20: 104.45 ng/ml) compared to all others (mean±SD: 1.6±1.4 ng/ml), while there were undetectable Sema4D levels in the supernatants of all ovarian cancer cell lines. Regarding plexin-B1, two myeloma cells lines (H929: 25.3 ng/ml and JJN3: 30.8 ng/ml) and two ovarian cancer cell lines (OVCA3: 5125 ng/ml and SKOV3: 3516 ng/ml) produced high levels compared to the other myeloma (4±2.5 ng/ml) and ovarian cancer cell lines (27.6±3.8 ng/ml). The levels of Sema4D and plexin-B1 in the RPMI+FBS were not detectable. The plexin-B1 levels in the supernatants of the myeloma cell lines (76±140 ng/ml) were decreased compared to the respective levels of the ovarian cancer cell lines (963±1440 ng/ml, p=0.008). After incubation for 24h and 48h with stromal cell line HS5 (Sema4D and plexin-B1 level in the HS5 supernatant was not detectable and 464.4 ng/ml, respectively), there was no alteration in the Sema4D levels of the supernatants of both the myeloma and the ovarian cancer cell lines, while there was a 5- to 8- fold increase in the plexin-B1 levels in all studied cell lines. The mean Sema4D levels of the bone marrow plasma of the MM patients were 149 ng/ml (±112 ng/ml) and of the Al patients 232 ng/ml (±113 ng/ml), respectively; both dramatically elevated compared to controls (23±12 ng/ml, p Our data suggest that there are increased levels of Sema4D and its receptor plexin-B1 in both the bone marrow plasma and the serum of patients with symptomatic, newly-diagnosed MM. These high sema4D correlated with hypercalcemia and ISS stage and possibly contribute to osteolytic bone disease related to myeloma. Further studies with higher number of patients will reveal the exact role of Sema4D/plexin-B pathway in MM. Disclosures: No relevant conflicts of interest to declare.

Abstract 935 Lytic bone disease is a frequent complication of multiple myeloma (MM). Biochemical markers of bone metabolism provide information on bone dynamics and reflect activity in the bones. Several studies show that different bone markers are altered in myeloma patients, reflect the extent of bone disease and correlate with survival in the conventional chemotherapy era. Nevertheless, there is almost no information about their impact on the survival of myeloma patients who are treated upfront with novel agents. To address this issue we studied 122 consecutive, unselected, newly diagnosed patients with symptomatic MM (66M/56F, median age 71 years, range 36–88 years) who were diagnosed and treated in a single center (University of Athens, Greece). All patients received upfront novel agents: 75 patients IMiDs-based and 47 patients bortezomib-based regimens. The following bone remodeling markers were evaluated in the patients' serum before the administration of any kind of therapy: i) osteoclast regulators: sRANKL and osteoprotegerin (OPG); ii) osteoblast inhibitor dickkopf-1 (Dkk-1); iii) bone resorption markers: CTX and TRACP-5b; and iv) bone formation markers: bone-specific alkaline phosphatase (bALP) and osteocalcin. The above molecules were also measured in 36 gender- and age-matched, healthy controls. Evidence of bone involvement was documented using plain radiographs and MRI of the spine in all patients. Twenty-five (20%) patients had ISS-I disease, while 46 (37%) patients had ISS-II and 51 (41%) stage ISS-III disease. Fifty-eight (47%) patients had Hb2 mg/dl. The presence of lytic bone disease was documented in 76% of the patients. MRI evaluation of the spine revealed that 41% of the patients had focal, 38% diffuse, 19% normal, and 2% a variegated pattern of marrow involvement. At diagnosis, MM patients had increased serum concentrations of sRANKL (mean±SD: 0.4±0.5 pmol/L vs. 0.1±0.2 pmol/L; p225 U/L; p=0.011, and as continuous variable; p=0.019), ISS stage (p=0.02) and anemia (Hb225 U/L; p=0.038) were predictive for survival. Our study suggests that in the era of novel agents, only CTX, among 7 serum bone remodeling markers, correlated with survival. In particular, high CTX levels can distinguish a subset of patients who receive frontline IMiDs-based therapies and who have poor prognosis. This was not observed with bortezomib-based therapies, possibly due to the beneficial effect of bortezomib on bone metabolism. Disclosures: No relevant conflicts of interest to declare.