Presented at annual meeting of ASCO (American Society of Clinical Oncology), held in Chicago June 4-8, 2010.

1. HIGH-RISK MULTIPLE MYELOMA (MM): DISTINGUISHING EARLY FAILURES (EF) FROM SUSTAINED CONTROL (SC) B. Barlogie, J. D. Shaughnessy Jr, J. Haessler, A. Hoering, F. Van Rhee, E. J. Anaissie, J. Crowley University of Arkansas for Medical Sciences Little Rock, AR Cancer Research And Biostatistics Seattle, WA

3. TT2 (BOTH ARMS): CLINICAL OUTCOMES ACCORDING TO GEP-DEFINED RISK OVERALL SURVIVAL 0% 20% 40% 60% 80% 100% 0 2 4 6 8 10 Years from Start of Protocol Therapy Low Risk: 109/305 High Risk: 35/46 P < 0.0001 EVENT-FREE SURVIVAL 0% 20% 40% 60% 80% 100% 0 2 4 6 8 10 Years from Start of Protocol Therapy Low Risk: 186/305 High Risk: 39/46 P < 0.0001 2 distinct components in high-risk disease: early failure (EF) and sustained control (SC): breakpoint at 3 years EF SC EF SC

6. HIGHER FREQUENCY OF UNFAVORABLE GEP FEATURES IN EF vs SC MYELOMA Logistic Regression – OLD DEF 3 ( Not yet died or survived >= 3yrs post enrollment vs. rest ): SURVIVAL MODEL CR DUR MODEL VARIABLE EF (N=65) SC (N=58) P EF (N=38) SC (N=28) P B2M >=5.5mg/L 45% 50% 0.55 45% 32% 0.30 Albumin <3.5g/dL 49% 45% 0.63 50% 29% 0.08 LDH >= 190 U/L 60% 43% 0.06 66% 50% 0.20 CA 78% 67% 0.18 78% 79% 0.99 GEP >median score 60% 38% <0.02 68% 39% 0.02 GEP delTP53 22% 5% <0.01 18% 7% 0.28

7. MV LOGISTIC REGRESSION ANALYSIS OF VARIABLES LINKED TO EF vs SC Logistic Regression – OLD DEF 3 ( Not yet died or survived >= 3yrs post enrollment vs. rest ): * > MEDIAN IN HIGH-RISK MM % EF WITH FACTOR MODEL Variable N YES NO OR P SURVIVAL GEP delTP53 120 81% 48% 4.60 0.025 GEP very high risk* 120 64% 42% 2.41 0.022 CR DURATION GEP very high risk* 64 69% 41% 3.09 0.031

8. SHIFT TO HIGHER GEP RISK SCORE IN EF vs SC HIGH-RISK MYELOMA p-value=0.007 p-value=0.003 SURVIVAL MODEL CR DURATION MODEL SC EF

9. SURVIVAL MODEL-BASED GEP DIFFERENCES BETWEEN EF AND SC p-value=0.015 Most CD-1 is EF Shift to higher PI in EF vs SC p-value=0.348 60 40 30 10 20 50 Frequency 0.10 0.8 0.4 0.2 0 0.6 0.12 PR MY MS MF LB HY CD-2 CD-1

10. 14 GENES DISTINGUISH EF AND SC SUBGROUPS OF HIGH-RISK MYELOMA EF SC C20orf142 TP53INP ST6GAL1 235659_at YIPF6 MAN2A1 MEIS1 SPIB RNF43 SHISA SLC43A3 PLK1 RUNX2 PMAIP1 P < 0.0001 (FDR: 15.8%)

11. EXAMPLES OF EF-ASSOCIATED GENES Gene Description Chr SHISA WNT repressor and head inducer ; endoplasmic reticulum ; Wnt ligand signals through co-receptor on PM; single pass LRP5 and seven pass Frizzled (Fz); SHISA removes Frizzled receptor from PM via ER retention; NOTE: DKK1, head inducer; secreted; WNT repressor; removes LRP5/6 from PM thru endocytosis ; Supports role for Wnt suppression in MM pathogenesis 4p13 PLK1 S/K kinase ; nuclear; regulates centrosome maturation, spindle assembly, chromosome arm cohesions, APC/C inhibition, mitotic exit and cytokinesis; Interacts with EVI5, EVI5 is one of 19 in GEP70; may suppress EVI5? 16p12 SPIB Ets family transcription factor ; nuclear ; controls pDC and B-cell development; expressed in liver stem cells; linked to recent surge in liver mets?; Is EF disease a plasmacytoid dendritic cell neoplasm? 19q13 TP53INP1 TP53 inducible; nuclear ; concentrated in PML/POD/ND10 nuclear bodies; induces TP53-phosphorylation and TP53-mediated apoptosis 8q22 MAN2A1 Complex N-glycan biosynthesis; Golgi; Mutations causes SLE-like Dx in mice; inversely correlated with SHISA; Does Wnt suppression eliminate N-glycan modifications in MM cells? 5q21.2

13. Vel and VTDPACE PGx: Differential Sensitivity of TP53INP1 to Induction Chemo UP-REGULATION WITHIN 48HR OF TP53INP1 BY BORTEZOMIB AND AUGMENTED BY ADDED TDPACE RANKING TP53INP1 BASELINE VALUES FROM LOW TO HIGH, 48HR F/U POST-VEL & VTDPACE AS PART OF TOTAL THERAPY 3

14. TP53INP1 PGx Melphalan (10mg/m 2 x 48h) in Newly Diagnosed Disease TP53INP1 CAN BE UP-REGULATED BY TEST DOSE OF MELPHALAN 10MG/M 2 IN 48HR