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We report feasibility and response results of a phase II study investigating prolonged weekly bortezomib and dexamethasone followed by thalidomide and dexamethasone as maintenance therapy after single autologous stem cell transplantation (ASCT) in patients with multiple myeloma. Within 4 to 8 weeks of ASCT, patients received weekly bortezomib and dexamethasone for six cycles, followed by thalidomide and dexamethasone for six more cycles. Thalidomide alone was continued until disease progression. Forty-five patients underwent ASCT. Forty patients started maintenance therapy; of these, 36 patients received four cycles, and 32 completed six cycles of maintenance bortezomib. Of these 40 patients, nine (22%) were in complete response (CR) before ASCT, 13 (32%) achieved CR after ASCT but before bortezomib maintenance therapy, and 21 (53%) achieved CR after bortezomib maintenance therapy. Nine patients not previously in CR (33%) upgraded their response to CR with bortezomib maintenance. At 1 year post-ASCT, 20 patients achieved CR, and two achieved very good partial response. Twenty-seven patients experienced peripheral neuropathy during bortezomib therapy, all grade 1 or 2. Our findings indicate that prolonged sequential weekly bortezomib, dexamethasone, and thalidomide maintenance therapy after single ASCT is feasible and well tolerated. Bortezomib maintenance treatment upgraded post-ASCT CR responses with no severe grade 3/4 peripheral neuropathy.

8089 Background: Increased immune responses post autologous HCT may be of benefit in long term disease control. Responses may be mediated by NK cell function and possibly other alternate pathways, including costimulatory molecule pathways. This pilot study assesses the expression of inhibitory (PD-1 and CTLA-4) and stimulatory (OX-40, ICOS, 4-1BB, and CD28) molecules on NK cells after auto-HCT in MM patients and evaluates the effect of lenalidomide treatment on these pathways. Methods: 17 patients with MM undergoing HCT, median age 56.7 years (36 – 67), were included in the study. Peripheral blood samples were taken 3 days prior to HCT and 14, 30, 60, 90, 180 days after HCT. At d180 post-HCT, 13/17 patients were receiving lenalidomide with d91 as median start date. NK cells and their costimulatory molecules were evaluated by flowcytometry using 2 six color panels of antibodies. One way ANOVA test and Kruskal-Wallis test (non-parametric) were applied to analyze the data using the Graphpad Software. Results: See table below. NK cell number was highest (median: 26% of total lymphocytes) at d14 (p: < 0.0001) compared to pre and post HCT levels. At d180, TNF-R OX40 expression was significantly increased in ≤PR group (n=5) (median: 9.5% of NK cells) compared to ≥VGPR (n=12) (0.8%; p=0.0084). In addition, NK cell number was higher in the lenalidomide group (n=13) (median: 15.15 % of total lymphocytes) compared to the no lenalidomide group (n=4) (6.74%; p=0.0108) at d180 post HCT. Significantly lower level of CTLA-4 expression was also found in the lenalidomide group (0.33% vs. 2.54%; p=0.0362). Conclusions: We observed NK cell recovery to baseline values at 60 days after HCT. At d180 post-HCT, OX-40 expression in NK cells was higher in ≤PR group than ≥VGPR group. Lenalidomide treatment was associated with higher NK cells number and decreased expression of CTLA-4. This observation could be a possible marker of enhanced host NK cell immune response against MM. Future clinical trials will explore therapies that increase NK cell responses. [Table: see text]

Abstract 5108 Introduction: Co-stimulatory signal is antigen non-specific and is provided by the interaction of costimulatory molecules expressed on the membranes of antigen presenting cells (APC) and T/NK cells. It plays as a complementary second signal to interaction of MHC molecules on APC and T cell receptors on T cells (first signal). Costimulatory molecules can be either inhibitory or stimulatory and may play a role in MM cell growth. Blockade of these pathways may provide a new therapeutic avenue. Background: Prior studies have shown up-regulation of inhibitory pathways such as CTLA-4 and down regulation of activating CD28 in MM patients, compared to healthy controls but there was no comprehensive characterization of costimulatory functions in MM patients. This is a pilot study assessing NK cell reconstitution and expression of inhibitory molecules (PD-1 and CTLA-4) and stimulatory molecules (ICOS, 4-1BB, CD28 and OX40) before and after autologous transplantation in MM patients. Methods: Twelve adult patients with MM undergoing auto-transplant who are able to provide written informed consent are included in the study. Median age is 56.5 years (range 36 – 67). Peripheral blood samples were taken on 3–21 days prior to autologous HCT, 14, 30, 60, 90, 180 and 360 days after HCT. At the time of the current analysis, all patients were followed up to 90 days after autotransplant conditioned with high dose melphalan. Median length of follow up is 90 days post autologous HCT. A Flowcytometry method was developed in 2 six color panels to identify NK & T cells (using antibodies to CD3, CD56 & CD16) and subsets of NK cells expressing different costimulatory molecules using specific antibodies to CD28, CD152(CTLA-4), CD278(ICOS), CD134 (OX-40), CD137 (4-1BB) and CD279 (PD-1). Each panel contained 200 ul of whole blood treated with RBC lysing buffer before staining with antibodies. Clinical data were collected for disease status before and after HCT as well as the presence of documented infections. One way ANOVA test and Kruskal-Wallis test (non-parametric) were used to analyze the data. Disease status for MM was defined as per International myeloma working group guidelines. Results: Very Good Partial Response or better (≥ VGPR) was seen in 5 patients before HCT and 8 patients after HCT (best response was taken if there are different disease status in a given patient after HCT). Partial Response or worse (≤ PR) was seen in 7 patients before HCT and 4 patients after HCT. One patient had a progressive disease. NK cell number was highest (20% of total lymphocytes) at d14 (p =0.011) compared to pre HCT, d60 and d90 levels and back to pre HCT level at d90 (Figure 1). No statistically significant difference in individual costimulatory molecule expression was noted between pre-HCT vs. post-HCT periods. NK cell numbers were higher in patients with ≥VGPR compared to patients with ≤PR at d30 (p =0.004) and d60 (p =0.028) (Figure. 2). There was no significant difference in individual costimulatory molecule expression between ≥ VGPR vs. ≤ PR groups. Higher number of NK cells were noted in patients with infections up to d90 (p=0.0081). In contrast, no significant difference in individual costimulatory molecule expression was seen between patients with infections vs. no infections. Conclusion: At present analysis, we can determine that NK cell recovery is shorter (60–90 days) as opposed to CD 4 + T cells which have been shown to take about 12 months to recover after autologous HCT. Higher NK cell number were seen in patients with better disease response. There were no differences in costimulatory molecule profiles pre and post HCT based on early disease response. However, we plan long term follow up to see if this is a predictor of relapse. Disclosures: Off Label Use: in administration of plerixafor. Krishnan:Celgene: Speakers Bureau; Millenium: Speakers Bureau.

Abstract 2399 The quality and depth of response particularly achievement of complete remission (CR) have been associated with significant improvement in progression free survival (PFS) and overall survival in multiple myeloma patients undergoing autologous stem cell transplant. Achievement of CR is considered a valid surrogate endpoint for survival in clinical trials for patients with multiple myeloma. We performed a phase II study investigating the role of sequential bortezomib/dexamethasone followed by thalidomide/dexamethasone as maintenance therapy post single autologous PSCT. The objectives were to examine the feasibility, toxicities, CR, PFS and overall survival rates. Within 4–8 weeks of autologous PSCT using melphalan 200mg/m2, pts received weekly bortezomib (bor) at 1.3mg/m2 /wk × 3 weeks with 1 week rest and dexamethasone (dex) at 40mg/d × 4 d for 6 months, followed by thalidomide (thal) at 50 –200mg/d and dexamethasone (dex) at 40mg/dx4 d for 6 more months. Single agent thalidomide was then continued until disease progression. Between March 2008 and June 2010, forty-five pts were enrolled. Median age was 54 years (29-71). Median time from diagnosis was 6.1 mo. (3.5 – 145.9). Disease stage at diagnosis; by Salmon-Durie (I/II/III 2/8/34/1 not available) and by ISS (I/II/III 18/14/8/ 5 not available). Pts received prior induction treatment with thal/dex (15), bortezomib based (27) and lenalidomide based regimens (10). Median B2M at enrollment was 1.8 mg/L (1.05 -5.3). Disease status at enrollment included complete remission (CR) (11), very good partial response (VGPR) (11), partial response (PR) (23). Six pts had chromosome 13 abnormalities (1 pt by karyotype and 5 pts by FISH), 2 pts had t 4;14 (one with concurrent ch 17 p del) and 3 pts had complex cytogenetic abnormalities. Results: Forty-five pts have been enrolled and undergone transplant. Five pts were unable to start planned maintenance therapy due to development of grade II or more neuro toxicities (4), and persistent thrombocytopenia (1) after PSCT. Thirty nine pts started maintenance bor/dex within 4–8 weeks of PSCT. One pt is too early for maintenance therapy. Twenty-five pts have completed the planned 6 months of bor/dex. Ten pts stopped bor/dex because of low WBC (2), PN (4), diagnosis of adrenal cancer (1), myocardial infarction (MI) (1), and relapse (2). Six pts are still receiving maintenance bortezomib. With a median F/U of 8.5 mo. (0.2 -24.0) twelve of 44 evaluable pts (27%) have achieved CR post PSCT and 17 of 33 evaluable pts (51%) have achieved CR after bor/dex on an intention to treat (ITT) analysis. Fifteen of 25 pts (60%) who have completed 6 months of bor/dex have achieved CR. Nine of 25 pts (36%) have upgraded their response with bor/dex. Eight pts (24%) could not complete bortezomib due to toxicities. At one year post PSCT fourteen of 28 evaluable pts (50%) remain in CR. Six pts have relapsed of whom 2 died of relapsed myeloma (leptomeningeal disease 1 pt). One pt experienced MI while receiving bortezomib (grade IV). Grade III toxicities have occurred in 17 pts; low platelet (1), asthenia (2), mood alteration (1), GI (severe constipation due to partial bowel obstruction on thalidomide) (1), skin rash (1), hyperglycemia (1), lymphopenia (10), sinus bradycardia (1), elevated triglyceride (1), DVT (1), low phosphate (3), leukopenia (1), edema (1). Sixteen pts had peripheral neuropathy (PN) grade I prior to start of bortezomib. Only 8 pts have developed new PN on the study and all are grade I-II. No patient has experienced grade III-IV PN. Median bortezomib dose is 1.3 mg /m2 per week. Conclusion: Prolonged weekly bortezomib maintenance therapy is well tolerated and can upgrade response post single autologous PSCT with no severe peripheral neuropathy. Fifty one percent of pts have achieved CR and 36% have upgraded their response after six months of bortezomib/dexamethasone therapy suggesting this is an active maintenance strategy post PSCT. Disclosures: No relevant conflicts of interest to declare.

Table S1. Identifying Best Fit Model for Longitudinal Analyses of BPI Worst Pain and FACT-P TOI Scores, Figure S1. Cohort plot of average BPI worst pain scores by missing data patterns and arm, Figure S2. Cohort plot of average FACT-P TOI scores by missing data patterns and arm. (DOCX 115Â kb)

Table S1. Identifying Best Fit Model for Longitudinal Analyses of BPI Worst Pain and FACT-P TOI Scores, Figure S1. Cohort plot of average BPI worst pain scores by missing data patterns and arm, Figure S2. Cohort plot of average FACT-P TOI scores by missing data patterns and arm. (DOCX 115Â kb)