Gertz, Morie A.

8581 Background: Autologous stem cell transplant (ASCT) improves survival in patients with multiple myeloma (MM). Recent studies have elucidated the relationship in ASCT between absolute lymphocyte count (ALC) recovery and improved survival, highlighting the importance of immune recovery. We conducted a retrospective analysis of patients with multiple myeloma to observe the impact of different measures of immune recovery at day 100 post-ASCT on outcome. Methods: Retrospective analysis of data from the existing clinical databases identified 1184 patients with multiple myeloma that underwent ASCT at Mayo Clinic between 1987-2011. Markers of immune recovery analyzed on day 100 status-post ASCT included ALC, monocyte count, and immunoglobulin levels. Kaplan Meier analysis was performed to determine progression free survival (PFS) and overall survival (OS). Results: Among the 1184 patients, median age at diagnosis of multiple myeloma was 57 (range, 23-75 yr), and median age at time of transplantation was 59 (range, 24-75 yr); 59% were male. The median OS and PFS post-transplant were 80 months and 34 months respectively. 62% of patients were alive 5-years post-transplant. The median OS was not improved with normal vs. abnormal IgG levels at day 100 (p=.298). In contrast, monocyte recovery was a significant predictor of OS. Patients with normal monocyte counts of greater than 0.3 x 10⁹ cells/L at day 100 showed superior survival (65 vs. 37 months, p= .001). Similarly, patients with normal monocyte recovery at day 15 post-transplant showed a significant survival benefit (68 vs. 50 months, p=.007). Early ALC recovery, which has been shown to be a positive prognostic indicator at day 15 post-transplant, was not prognostic at day 100 (p= .960). Conclusions: The present study further elucidates prognostic indicators after ASCT for MM highlighting the importance of various markers of immune recovery. Immunoglobulin recovery was not associated with superior survival, while monocyte recovery at day 15 and day 100 post-transplant translated to an improved survival and requires further study. It may be hypothesized that early immune system reconstitution may have a positive effect against disease post-transplant.

8541 Background: Achievement of a complete response (CR) to treatment is an important predictor of outcome for patients (pts) with myeloma (MM). The goal of the current study was to assess whether the treatment that resulted in CR has any impact on the outcomes. Methods: We identified 462 pts with MM, who fulfilled the IMWG criteria for CR, seen at Mayo Clinic between 1991 and 2011. The treatment was classified into groups by the regimen that led to CR (Table), and also based on whether an autologous stem cell transplant (ASCT) was part of the regimen. The remaining 21 pts had a variety of regimens and are not included in the Table. Results: The median age at diagnosis was 58.5 yrs (27.1–82.3 yrs) with 56% males. The overall survival (OS) from diagnosis for the entire cohort was 10.7 yrs (95% CI; 9.3, NR). The median interval from diagnosis to the recorded CR was 10.3 mos (range 1- 170), with 272 (58.4%) and 385 (82.7%) obtaining a CR in <12 mos and <24 months from diagnosis. We first compared the outcomes based on whether ASCT was part of the regimen; 328 had an ASCT while 117 pts received only chemotherapy. Median time to progression (TTP) following a CR was 5.1 yrs for the ASCT group compared with 5.5 yrs for the rest (P=0.3). Median OS from CR was 9.1 yrs for the ASCT group and 7.5 yrs for the rest (P=0.5) and OS from diagnosis was 10.1 yrs for the ASCT group and 12.6 for the rest (P=0.5). Examining the outcomes based on the regimen utilized showed that the TTP and OS from CR as well as OS from diagnosis were similar for all the groups (Table). Among pts who had a CR within a year of diagnosis, there were no differences in terms of the TTP or OS from the onset of CR or from diagnosis between the ASCT vs. chemotherapy groups or between the different regimens (P=NS for all comparisons). Conclusions: The current study highlights an important message regarding CR in MM. The results suggest that the prognostic value of CR is independent of the nature of therapy, and likely reflects the contribution of disease biology to obtaining a CR. [Table: see text]

8516 Background: There is consensus that light chain amyloidosis (AL) patients with CRAB criteria (abnormal calcium or renal function, anemia or lytic bone lesions) also have multiple myeloma (MM). These patients are typically excluded from AL trials; however, AL patients with >= 10% bone marrow plasma cells (BMPC) in the absence of CRAB are included in trials along with AL with < 10% BMPC. We postulated that the currently used dichotomy may be incorrect and examined the spectrum of AL with and without MM. Methods: We identified 1,272 patients with AL seen within 90 days of diagnosis, between January 1, 2000, and December 31, 2010. We defined the population of patients with coexisting MM based on the existence of CRAB (AL-CRAB-MM). Patients without CRAB were divided into two groups, AL-only (<10% BMPC) and AL-PC-MM (>=10% BMPC). Results: Among the 1,272 patients, 117 (9%) had AL-CRAB-MM, 476 (37%) had AL-PC-MM, and 679 (53%) had AL only. Their respective median overall survivals (OS) were 16.2, 15.8, and 28.4 months (p<0.0001). Autologous stem cell transplant (ASCT) was performed in 203 (30%), 138 (29%) and 23 (20%) patients respectively. Since the outcomes of AL-CRAB-MM and AL-PC-MM were similar, they were pooled for univariate and multivariate analyses. On multivariate analysis, AL-CRAB-MM and AL-PC-MM retained negative prognostic value independent of age, cardiac stage, prior autologous stem cell transplant (ASCT), beta 2 microglobulin, and dFLC. We next considered whether patients received ASCT as part of their treatment. For those patients who never received ASCT, the 5-year OS were 19%, 14%, and 31%, p<0.001, for AL-CRAB-MM, AL-PC-MM, and AL only respectively. In contrast, for those patients who received ASCT, the respective 5-year OS were 46%, 56%, and 73%, p<0.001. Conclusions: AL patients with >=10% BMPCs have a poor prognosis similar to patients with AL-CRAB-MM and should therefore be considered as AL with MM.

TPS8116 Background: Eukaryotic translation initiation Factor 5A (eIF5A) has been implicated in the regulation of apoptosis and is the only known protein to be modified by hypusination. Hypusinated eIF5A is the predominant form of eIF5A in cancer cells. However, in its unhypusinated form, eIF5A is pro-apoptotic. SNS01-T, designed to treat myeloma, consists of two components: a plasmid DNA expressing eIF5AK50R (human eIF5A containing a lysine to arginine substitution at position 50) which remains pro-apoptotic because it cannot be hypusinated, and an siRNA against an untranslated region of native eIF5A mRNA. When these two components are combined with linear polyethyleneimine (PEI), the nucleic acids are condensed into nanoparticles for protection from degradation in the blood and enhanced delivery to tissues. The eIF5AK50R transgene is under the control of the B29 promoter and enhancer, which restricts expression to B cells. The mode of action of SNS01-T is to use an eIF5A-specific siRNA to deplete the pool of hypusinated eIF5A in myeloma cells while simultaneously adding pro-apoptotic eIF5AK50R. In vitro cell studies and in vivo xenograft studies have demonstrated the efficacy of this approach. Methods: Eligible patients are enrolled sequentially into four cohorts of increasingly higher doses. Each cohort will receive SNS01-T by intravenous infusion twice weekly for 6 consecutive weeks and then be observed every 4 weeks during a 24-week follow-up period. Eligible patients must have been diagnosed with multiple myeloma according to IMWG criteria, have measurable disease, have relapsed disease after two or more prior treatment regimens, have a life expectancy of at least 3 months, and not be eligible to receive any other standard therapy known to extend life expectancy. The primary objective is to evaluate the safety and tolerability of multiple escalating doses of SNS01-T. Secondary objectives include pharmacokinetics, immunogenicity studies, proinflammatory cytokine quantitation, and therapeutic efficacy. Two of the planned 15 patients have been enrolled. (Clinical Trials.gov Identifier: NCT01435720.)

8105 Background: Tumor stage migration can artifactually inflate cancer survival rates and overestimate benefits of newer therapies. We have previously shown a favorable impact of widely used novel agents in MM patients. However, it is not known whether use of well tolerated and easily administrable novel agents results in their introduction at lower levels of MM burden (and therefore add to improved outcome). Our goal was to assess for stage migration in newly diagnosed active MM patients. Methods: We reviewed records of 1,467 patients with active MM at Mayo Clinic, at initiation of therapy from 3 consecutive 5-year intervals: 01/1996-12/2000 (Group 1), 01/2001-12/2005 (Group 2), 01/2006- 12/2010 (Group 3). These intervals reflect the practice changing approaches at our center transitioning from the use of alkylator-based to novel agent-based initial therapy. Traditional parameters and staging systems were used to estimate tumor burden. We performed one way analysis of variance (ANOVA) to assess for differences in these parameters among the groups. A p-value of <0.05 was considered significant. Results: Group 3 shows an upward trend for hemoglobin (Hgb), and lower creatinine and bone marrow plasma cell (BMPC) percent. Compared to other groups, a greater proportion of Group 3 patients are assigned to lower Durie Salmon (DS) stages (Table) suggesting reduced tumor burden at therapy initiation. In contrast, the International Staging System (ISS) which is not used for decisions regarding therapy initiation divides cohorts in similar proportions. Conclusions: Stage migration is evident in our cohort of active MM patients presenting in the time periods of evolving initial therapeutic strategies. Future studies should take into account the bias introduced by this phenomenon in interpreting survival analysis of MM patients. [Table: see text]

8092 Background: High dose therapy and autologous stem cell transplant (SCT) remain an integral part of the treatment of multiple myeloma (MM). Despite the introduction of several new drugs, disease relapse remains inevitable and a second SCT often allows continued disease control. Methods: We examined the outcomes in 105 patients (pts) undergoing a second SCT (SCT2) for relapsed MM, from among 1033 pts receiving initial transplant between 1994 and 2009. Patients receiving an allogeneic SCT post SCT2 were not included in the survival analysis. Results: Median (range) age at SCT2 was 60 yrs (35-74) and the time between SCTs was 46 mos (10-130). The median follow-up was 5 yrs from SCT2. The median (range) number of regimens between the two SCTs and from diagnosis was 2 (0-7) and 3 (1-11), respectively. Conditioning regimen was Mel 200 in 85 (81%) pts. Median (range) CD34 cells infused was 4.6 (2.5-25 million/kg). Hospitalization was required for 53 pts (50%), median hospital stay was 7 days.. Median time to ANC of 500 and platelets of 50,000 were 13 and 16 days, respectively. Treatment related mortality was seen in 5 (5%) pts. A partial response or better was seen in 95 (90%) pts, including a stringent CR in 10%, CR in 19%, and VGPR in 21%. Stable disease or progression was seen in 7 pts and 3 pts died prior to disease assessment. The median (95% CI) PFS and OS after SCT2 were 10.4 (8, 14) and 33 (28, 51) mos, respectively. The median OS was not reached and 33 mos respectively, for those obtained a CR and those with <CR, P=0.03. FISH pre-SCT2 was available for 73 pts; the PFS and OS were not affected by the presence of high-risk MM. In multivariate analyses, shorter duration of response to SCT1, higher plasma cell (PC) labeling index at SCT2, more regimens used prior to SCT2 all predicted shorter PFS and OS post SCT2. Lack of CR to SCT2 was also significantly associated with shorter PFS. Conclusions: Second SCT is an effective therapy for eligible pts relapsing after other treatments. It provides a meaningful duration of response and appears to be well tolerated. Pts with longer duration of response to first transplant and those achieving a CR appear to have maximum benefit.

8043 Background: The mammalian target of rapamycin (mTOR) signal pathway controls cell proliferation and survival. The trial's goal was to determine the anti-tumor activity and safety of single-agent everolimus (TORC1 inhibitor) in patients with relapsed/refractory Waldenstrom macroglobulinemia (WM). Methods: Eligible patients had measurable disease (IgM monoclonal protein >1000 mg/dL with >10% marrow involvement or nodal masses >2 cm), a platelet count ≥75,000 x 106/L, a neutrophil count ≥1,000 x 106/L. Patients received everolimus 10 mg PO daily. Tumor response was assessed after cycles 2 and 6 and then every 3 cycles until progression. Results: 60 pts were treated. The median age was 64 years (range, 43-85). The median number of prior therapies was 3 (range, 1-11). All but two patients (97%) had received prior rituximab based therapy and 64% of patients had received prior alkylator based therapies. The overall response rate (complete response CR+ partial response PR+ minimal response MR) was 73% (95% CI: 60-84%), with a PR of 50% and 23% MR. The median time to progression (TTP), progression-free survival (PFS), and overall survival (OS) for the entire study population is 28 months (mos), (95% CI: 18-not reached (NR)), 22 mos (95% CI: 12 0-NR), and 55 mos (95% CI: 55-NR), respectively. The estimated PFS at 12 and 24 months is 62% (95%CI: 51-75%), and 48% (95%CI: 37-63%), respectively. The 30 patients who achieved a PR responded after a median of 2 months (range, 1-26) of treatment. The median duration of response (DR) for these patients has not yet been reached and 19 of these patients remain in response after a median follow up of 31 months (range, 3-54). All but two patients had a decrease in their serum IgM. Grade 3 or higher related toxicities were observed in 67% of patients. The most common were hematological toxicities with cytopenias. Pulmonary toxicity occurred in 5% of patients. Dose reductions due to toxicity occurred in 63% of patients. Conclusions: Everolimus has high single-agent activity with an overall response rate of 73% and manageable toxicity in patients with relapsed WM, and offers a potential new therapeutic strategy for this patient population.

8096 Background: The combination of lenalidomide and dexamethasone (Len-Dex) is a commonly used initial therapy for newly diagnosed multiple myeloma. While the short-term outcomes with respect to response and toxicity is well-known, long-term outcome with this combination as initial therapy is not well described. Methods: We studied 286 consecutive patients with newly diagnosed MM seen at our institution, who received initial therapy with Len-Dex, and who had complete follow up records. Data regarding the clinical course was obtained from medical records. Results: The median (range) age at diagnosis was 63 (28-92) yrs; 166 (58% were ≤ 65 yrs and175 (61%) were male. The median estimated follow-up was 3.9 yrs (95% CI, 3.4, 4.2) and 203 (71%) pts were alive at the time of last follow up. The median estimated duration on Len-Dex was 5.3 mos (95% CI, 4.6, 6.4). The best overall response (≥PR) was 72%, including 26% with VGPR or better and 14 (5%) not being evaluable for a response. At last follow up, 41 (14%) patients were continuing on therapy. There were 93 pts (32%) who stayed on therapy for 12 months or more. Among these patients, the ORR was 86%, including 45% with VGPR or better. The median overall survival (OS) for the entire cohort from diagnosis was 7.4 yrs (95% CI; 5.8, NR) and the estimated 5-yr survival was 67%. There were 16 (5.5%) pts who died within a year of diagnosis. The median time to first disease progression, irrespective of transplant status, was 30.2 mos (95% CI, 25, 42). Overall, 143 (50%) of the patients have gone to stem cell transplant. Censoring those patients who proceeded to SCT prior to relapse at the time of BMT, the median TTP was 25.5 mos (95% CI, 22, 29). The median OS was 7.4 yrs for those ≤65 yrs, compared with 6.2 yrs for the older patients (P=0.01). The 5-yr OS estimate for patients in ISS stage 1, 2 and 3 were 82, 65, and 44 months respectively. Conclusions: The current study provides long-term estimates of responses and survival in a series of patients treated initially with lenalidomide and dexamethasone. The median survival of nearly 8 years reflects the efficacy of the novel agents both at diagnosis and at relapse and confirms the survival improvements seen in MM in the last decade.

7621 Background: Thalidomide (Thal) in combination with dexamethasone (Dex) is an effective therapy for myeloma (MM). Though initially evaluated in MM because of its anti-angiogenic properties, it is not clear how much this contribute to its anti-MM effects. We examined whether the degree of angiogenesis influences response to Thal + Dex, as well as effect of therapy on marrow angiogenesis. We also examined whether expression of angiogenic cytokines by MM cells affect response to therapy. Methods: A total of 207 pts with newly diagnosed MM were randomized on the ECOG phase III trial (E1A00) to either Thal-Dex or Dex alone. Bone marrow microvessel density (MVD) was determined on 88 pts at diagnosis and at 4 mos after therapy in 25 pts. Expression of fibroblast growth factor (FGF) and vascular endothelial growth factor (VEGF) by MM cells was determined by RTPCR on 60 pts at diagnosis and on 22 pts at 4 mos. In addition, the percentage of marrow PCs in apoptosis was determined at diagnosis and 4 mos in 43 pts. A decrease in the serum M protein by 50% or in its absence, a decrease in urine M protein by 50% was considered a response. Results: The median BM MVD at diagnosis was 33 (3–118), and was similar in the pts responding to therapy (36.4) and in the non responders (45.4). We also separately looked at those receiving the combination vs. Dex alone, and did not find any correlation. The expression of FGF and VEGF in the PCs did not predict response to therapy with either the combination or Dex. Among the 17 responding pts, MVD decreased by a mean of 12 compared to an increase in the mean MVD of 3 among the non responders (P = NS). There was no significant correlation between the level of FGF or VEGF expression and the marrow MVD. There was no correlation between the percentage of myeloma cells in apoptosis at baseline and response to therapy. Conclusion: While the anti-angiogenic activity of Thal may play a role in its anti-myeloma effect, baseline MVD or tumor cell expression of angiogenic cytokines do not predict resistance or response to Thal-Dex or Dex alone. The findings here confirm previous observations that marrow angiogenesis is not related to the degree of secretion of angiogenic cytokines by individual cells, but rather the cumulative effect of the tumor mass. No significant financial relationships to disclose.