Starting Therapy for Low Risk Myeloma

1. Starting Therapy for Low Risk Myeloma Robert Z. Orlowski, Ph.D., M.D. Director, Myeloma Section Professor, Departments of Lymphoma/Myeloma & Experimental Therapeutics Principal Investigator, M. D. Anderson SPORE in Multiple Myeloma Chair, Southwest Oncology Group Myeloma Committee

2. Defining Risk : ISS Stage Greipp, PR et al. J Clin Oncol 23:3412, 2005.

3. ISS and Prognosis • Significant survival differences for three stages (P < 0.0001) • Better outcome predictor than the prior Durie-Salmon method • Still does not incorporate cytogenetics Greipp, PR et al. J. Clin. Oncol. 23:3412, 2005.

4. Molecular Staging : mSMART • Novel agents overcome del 13, t(4;14) http://msmart.org

5. Risk and FISH : t(4;14) • t(4;14) is a poor risk feature for both OS and PFS even in patients with ISS stage I • Also stage II and III OS – t(4;14) OS + t(4;14) PFS - t(4;14) PFS + t(4;14) Avet-Loiseau, H et al. Leukemia Epub Oct 3, 2012.

6. FISH Del 17p • Del 17p is another poor risk feature for both OS and PFS • t(14;16) • t(14;20) OS – del 17 OS + del 17 PFS - del 17 PFS + del 17 Avet-Loiseau, H et al. Leukemia Epub Oct 3, 2012.

7. Hybrid Systems No del(13), t(4;14), or del(17p) & low b2 (n=155) del(13) only & low b2 (n=110) No del(13), ct(4;14), or del(17p) & high b2 (n=74) del(13) & high b2 (n=69) t(4;14) or del(17p) & high b2 (n=42) t(4;14) or del(17p) & low b2 (n=63)

8. Primary Plasma Cell Leukemia • Outcomes have improved with novel agents for myeloma • This has not been the case for PPCL • PFS • OS Usmani, SZ et al. Leukemia Epub April 17, 2012.

9. High LDH • High LDH predicts poor survival regardless of ISS stage Gkotzamanidou, M et al. Clin Lymphoma Myeloma Leuk. 11:409, 2011.

10. Defining Risk : GEP70 • Expression profiling to identify high-risk patients • 30% of genes mapped to chr 1 • Independent predictor • HR 5.16, P < 0.001 Shaughnessy, JD Jr. et al. Blood 109:2276, 2007.

11. Useful at Diagnosis and at Relapse • GEP70 profiling is useful not just in newly diagnosed patients, but also at relapse Shaughnessy, JD Jr. et al. Blood 109:2276, 2007.

12. EMC-92 TT2 dataset TT3 dataset Kuiper, R et al. Leukemia Epub June 22, 2012.

13. Overlap Between Signatures 21 overlapping genes • If only a few genes are in common, do they all play a role in myeloma pathobiology, or do only some? Kuiper, R et al. Leukemia Epub June 22, 2012.

14. Do They Pass the Sniff Test? • ITPRIP, 10q25.1, Inositol 1,4,5-trisphosphate receptor interacting protein (Ca) • ALDOA, 16p11.2, Aldolase A, fructose-bisphosphate (glycolysis) • PSMD4, 1q21.3, Proteasome 26S subunit, non-ATPase, 4 (binds Ub-proteins) • EXOSC4, 8q24.3, Exosome component 4 (RNA processing) • AURKA, 20q13, Aurora kinase A (cell cycle progression; drugged !) • ASPM, 1q31.3, Abnormal spindle-like microcephaly-associated protein (Dros.) • CKS1B, 1q21.2, CDC28 protein kinase regulatory subunit 1B (cell cycle, p27) • LTBP1, 2p22.3, Latent transforming growth factor beta binding protein 1 (activation of TGF-b) • BIRC5, 17q25.3, Baculoviral IAP repeat containing 5 (apoptosis inhibitor; ?drugged) • FANC1, 15q26.1, Fanconi anemia, complementation group I (DNA repair) • ESPL1, 12q13.13, Extra spindle pole bodies homolog 1 (S. cerevisiae)(protease with role in chromosome segregation) http://www.genecards.org

15. Sniff Test Part II • MCM6, 2q21.3, Minichromosome maintenance complex component 6 (initiation of genome replication) • NCAPG, 4p15.31, Non-SMC condensin I complex, subunit G (conversion of interphase chromatin into mitotic-like condensed chromosomes) • SPAG5, 17q11.2, Sperm associated antigen 5 (chromosome segregation) • ZWINT, 10q21.1, ZW10 interactor (kinetochore formation and spindle checkpoint activity) • TMEM97, 17q11.2, Transmembrane protein 97 (cholesterol homeostasis) • MAGEA6, Xq28, Melanoma antigen family A, 6 (? Function; immunotherapy) • ITM2B, 13q14.2, Integral membrane protein 2B (protease inhibitor) • CDC2, 10q21.2, Cyclin-dependent kinase 1 (G1/S & G2/M checkpoints) • BUB1B, 15q15.1, Budding uninhibited by benzimidazoles 1 homolog beta (yeast)(spindle checkpoint function) • FAM49A, 2p24.2, Family with sequence similarity 49, member A (?) http://www.genecards.org

16. Which GEP Signature is Best? Kuiper, R et al. Leukemia Epub June 22, 2012.

17. GEP : Take Home Lessons • Among overlapping genes, most can be linked to a biological hypothesis • Replication/checkpoints/DNA repair • Validation of their roles as mediators of high risk is needed pre-clinically • Few have been drugged, and those that have were not studied in selected patients • Of the ones that haven’t been drugged, few look like they would be tumor-specific

18. Diagnostic Criteria : MGUS, AMM • The International Myeloma Working Group • MGUS • Serum monoclonal (M) protein <3.0 g/dL, AND • Marrow plasmacytosis <10% (if done), AND • No disease-related symptoms • Asymptomatic (smoldering) multiple myeloma • Serum M protein (IgG or IgA) ≥3.0 g/dL, AND/OR • Marrow plasmacytosis ≥10%, AND • No disease-related symptoms Dimopoulos, M et al. Blood 117:4701, 2010.

19. Risk of Progression • Approximately 1% per year for MGUS to myeloma or a related disorder • ~10%/year in the first 5 years for asymptomatic/smoldering myeloma Bladé, J et al. J Clin Oncol. 28:690, 2009.

20. Risk Stratifying MGUS • Low risk • M protein <1.5 g/dL, IgG type and normal FLC ratio • ✔ SPEP @ 6 mos., then q 2-3 years if stable and asymptomatic • Intermediate/High risk • M protein ≥1.5 g/dL, non-IgG type and abnormal FLC ratio • ✔ SPEP @ 6 mos., then annually Rajkumar, SV et al. Blood 106:812, 2005. Kyle, RA et al. Leukemia 24:1121, 2010.

21. Risk Stratifying AMM • Three groups • 1: M-protein ≥3 g/dL, marrow plasmacytosis ≥10% • 2: M-protein <3 g/dL, plasmacytosis ≥10% • 3: M-protein <3 g/dL, plasmacytosis <10% Bladé, J et al. J Clin Oncol. 28:690, 2009.

22. Risk Stratification with sFLCs • Three risk factors • Plasma cells ≥10% • Serum M-protein ≥3 g/dL • Serum free light chain ratio <0.125 or >8 • Groups 1 and 2 in both systems may be candidates for prevention trials Bladé, J et al. J Clin Oncol. 28:690, 2009.

23. Diagnostic Criteria : SMM • Symptomatic multiple myeloma • Clonal marrow plasmacytosis ≥10%, AND • Serum and/or urine M-protein (unless non-secretory), AND • Evidence of end-organ damage due to disease (CRAB) • HyperCalcemia (≥11.5 g/dL), or • Renal insufficiency (>2 mg/dL), or • Anemia (<10 g/dL or >2 g below nl), or • Bone lesions (lytic or osteopenic), or • Amyloidosis, or hyperviscosity, or frequent bacterial infections Dimopoulos, M et al. Blood 117:4701, 2010.

24. Impact of Genome Sequencing • Frequent mutations in genes involved in RNA processing, protein translation, and the unfolded protein response • How many can we target therapeutically ? Chapman, MA et al. Nature 471:467, 2011.

25. Other Gene Mutations • Do these involve micro RNAs and ncRNAs ? Chapman, MA et al. Nature 471:467, 2011.

26. Impact of Genome Sequencing • Ability to detect different myeloma clones that wax and wane in importance with time • We will need to be craftier than the myeloma Keats, JJ et al. Blood Epub, April 12, 2012.

27. 2010 ASH Abstract 991A Multicenter, Randomised, Open-label, Phase III Study of Lenalidomide/Dexamethasone versus Therapeutic Abstention in high-risk Smoldering MMMV Mateos, L López-Corral, MT Hernández, J de la Rubia, JJ Lahuerta, P Giraldo, J Bargay, L Rosiñol, A Oriol, J García-Laraña, l Palomera, F de Arriba, F Prósper, ML Martino, AI Teruel, J Hernández, G Estevez, M Mariz, A Alegre, JL Guzman, N Quintana, JL García, JF San Miguel.On behalf of Spanish Myeloma Group (PETHEMA/GEM)

28. Study Design • 1o objective: TTP to symptomatic myeloma Standard Observation Asymptomatic Myeloma Patients PC ≥ 10% + MP ≥ 3.0 Or PC ≥ 10% or MP ≥ 3.0 and ≥ 95% aberrant immunophenotype + immunoparesis Treatment Cycles 1-9: Lenalidomide 25 mg po days 1-21 of every 28-day cycle + dexamethasone 20 mg po on days 1-4 and 12-15 Later Cycles: Lenalidomide 10 mg po days 1-21 of every 2-month cycle

29. TTP to Active Disease Median follow-up: 32 months (range 12–49) Lenalidomide + dex Median TTP: NR 9 Progressions (15%) 5 pts:early disc followed by DP 4 pts:symptomatic DP Proportion of patients alive No treatment Median TTP: 23m 37 Progressions (59%) 20 patients: bone disease 7 patients: renal failure HR: 6.0; 95% IC (2.9–12.6); p < 0.0001 Time from inclusion

30. TTP Excluding Early Discontinuation Median follow-up: 32 months (range 12–49) Lenalidomide + dex Median TTP: NR 4 Progressions (7%) 4 pts:symptomatic PD No treatment Median TTP: 23m 37 Progressions (59%) 20 patients: bone disease 7 patients: renal failure HR: 12.3; 95% IC (4.4–34.7); p < 0.0001

31. Outcomes at Progression • At last f/u of maintenance therapy • 14 biological progressions • Dex was added according to the protocol • 2 pts: Improvement of response to PR • 10pts: Experienced stabilization of disease with dex • 8 remain stable after a median f/u of 19 m (4-31) • 2 pts: Progressed to active disease after 4 and 12 m • 1 pt: Progression to active disease before dex added • 1 pts: Withdrawal of informed consent

32. Overall Survival from Inclusion Median follow-up: 32 months (range 12–49) 1.0 Len + Dex 0.8 No treatment 0.6 Proportion of patients alive p=0.04 0.4 Lenalidomide + Dex: 93% at 3 years No treatment: 76% at 3 years 0.2 0.0 0 5 10 15 20 25 30 35 40 45 50 Time from inclusion

33. Overall Survival from Diagnosis Median follow-up: 38months (range 14–96) Len + Dex No treatment Proportion of patients alive HR: 5.01; 95% IC (1–22); p=0.03 Lenalidomide + Dex: 94% at 5 yrs No treatment: 79% at 5 yrs Time from inclusion

34. Conclusions • “Low risk” myeloma can be identified, but low risk ≠ no risk myeloma • Current data support treating patients earlier in the disease process, not later • An occasional patient with low risk myeloma may benefit from watchful waiting • Older patient with low disease burden • Vast majority of low risk patients should be urgently started on induction therapy