Successfully reported this slideshow.
We use your LinkedIn profile and activity data to personalize ads and to show you more relevant ads. You can change your ad preferences anytime.
Starting Therapy for Low
Risk Myeloma
Robert Z. Orlowski, Ph.D., M.D.
Director, Myeloma Section
Professor, Departments of ...
Defining Risk : ISS Stage
Stage β2m Albumin N Median
Survival
(mos.)
P value
I <3.5 ≥3.5 2401 62 <0.0001
II <3.5
≥3.5 -<5....
Greipp, PR et al. J. Clin. Oncol. 23:3412, 2005.
ISS and Prognosis
• Significant survival
differences for three
stages (P ...
Molecular Staging : mSMART
http://msmart.org
• Novel agents overcome del 13, t(4;14)
Risk and FISH : t(4;14)
Avet-Loiseau, H et al. Leukemia Epub Oct 3, 2012.
• t(4;14) is a
poor risk
feature for
both OS and...
FISH Del 17p
Avet-Loiseau, H et al. Leukemia Epub Oct 3, 2012.
OS – del 17
OS + del 17
PFS + del 17
PFS - del 17
• Del 17p...
Hybrid Systems
t(4;14) or del(17p)
& high β2 (n=42)
No del(13), t(4;14), or del(17p)
& low β2 (n=155)
del(13) only & low
β...
Primary Plasma Cell Leukemia
Usmani, SZ et al. Leukemia Epub April 17, 2012.
• Outcomes
have improved
with novel
agents fo...
High LDH
Gkotzamanidou, M et al. Clin Lymphoma Myeloma Leuk. 11:409, 2011.
• High LDH
predicts poor
survival
regardless of...
Defining Risk : GEP70
Shaughnessy, JD Jr. et al. Blood 109:2276, 2007.
• Expression
profiling to identify
high-risk patien...
Useful at Diagnosis and at Relapse
Shaughnessy, JD Jr. et al. Blood 109:2276, 2007.
• GEP70
profiling is
useful not just
i...
EMC-92
Kuiper, R et al. Leukemia Epub June 22, 2012.
TT2 dataset TT3 dataset
Overlap Between Signatures
Kuiper, R et al. Leukemia Epub June 22, 2012.
• If only a few genes are in common, do they all ...
Do They Pass the Sniff Test?
• ITPRIP, 10q25.1, Inositol 1,4,5-trisphosphate receptor interacting protein (Ca)
• ALDOA, 16...
Sniff Test Part II
http://www.genecards.org
• MCM6, 2q21.3, Minichromosome maintenance complex component 6
(initiation of ...
Which GEP Signature is Best?
Kuiper, R et al. Leukemia Epub June 22, 2012.
GEP : Take Home Lessons
• Among overlapping genes, most can be linked
to a biological hypothesis
• Replication/checkpoints...
Diagnostic Criteria : MGUS, AMM
• The International Myeloma Working Group
• MGUS
– Serum monoclonal (M) protein <3.0 g/dL,...
Risk of Progression
• Approximately 1%
per year for MGUS
to myeloma or a
related disorder
• ~10%/year in the
first 5 years...
Risk Stratifying MGUS
• Low risk
– M protein <1.5g/dL, IgG type 
and normal FLC ratio
✔ SPEP @ 6 mos., then q 2-3
years if...
Risk Stratifying AMM
• Three groups
– 1: M-protein 3 g/dL,≥
marrow
plasmacytosis 10%≥
– 2: M-protein <3 g/dL,
plasmacytosi...
Risk Stratification with sFLCs
• Three risk factors
– Plasma cells 10%≥
– Serum M-protein 3≥
g/dL
– Serum free light chain...
Diagnostic Criteria : SMM
• Symptomatic multiple myeloma
– Clonal marrow plasmacytosis 10%, AND≥
– Serum and/or urine M-pr...
Impact of Genome Sequencing
Chapman, MA et al. Nature 471:467, 2011.
• Frequent mutations in genes involved in RNA
process...
Other Gene Mutations
Chapman, MA et al. Nature 471:467, 2011.
• Do these involve micro RNAs and ncRNAs ?
Impact of Genome Sequencing
• Ability to detect
different myeloma
clones that wax and
wane in importance
with time
• We wi...
2010 ASH Abstract 991
A Multicenter, Randomised, Open-label, Phase III
Study of Lenalidomide/Dexamethasone versus
Therapeu...
Study Design
Standard
Observation
Treatment
Cycles 1-9: Lenalidomide 25 mg po
days 1-21 of every 28-day cycle +
dexamethas...
TTP to Active Disease
Median follow-up: 32 months (range 12–49)
Lenalidomide + dex
Median TTP: NR
9 Progressions (15%)
5 p...
TTP Excluding Early Discontinuation
Median follow-up: 32 months (range 12–49)
Lenalidomide + dex
Median TTP: NR
4 Progress...
Outcomes at Progression
At last f/u of maintenance therapy
14 biological progressions
Dex was added according to the proto...
Overall Survival from Inclusion
Len + Dex
No treatment
Lenalidomide + Dex: 93% at 3 years
No treatment: 76% at 3 years
Tim...
Overall Survival from Diagnosis
1009080706050403020100
1.0
0.8
0.6
0.4
0.2
0.0
Len + Dex
No treatment
Time from inclusion
...
Conclusions
• “Low risk” myeloma can be identified, but
low risk no risk myeloma≠
• Current data support treating patients...
Upcoming SlideShare
Loading in …5
×

Starting Therapy for Low Risk Myeloma

669 views

Published on

Published in: Technology, Health & Medicine
  • Be the first to comment

  • Be the first to like this

Starting Therapy for Low Risk Myeloma

  1. 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. 2. Defining Risk : ISS Stage Stage β2m Albumin N Median Survival (mos.) P value I <3.5 ≥3.5 2401 62 <0.0001 II <3.5 ≥3.5 -<5.5 <3.5 OR 3278 44 <0.0001 III ≥5.5 2770 29 <0.0001 Greipp, PR et al. J Clin Oncol 23:3412, 2005.
  3. 3. Greipp, PR et al. J. Clin. Oncol. 23:3412, 2005. 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
  4. 4. Molecular Staging : mSMART http://msmart.org • Novel agents overcome del 13, t(4;14)
  5. 5. Risk and FISH : t(4;14) Avet-Loiseau, H et al. Leukemia Epub Oct 3, 2012. • 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)
  6. 6. FISH Del 17p Avet-Loiseau, H et al. Leukemia Epub Oct 3, 2012. OS – del 17 OS + del 17 PFS + del 17 PFS - del 17 • Del 17p is another poor risk feature for both OS and PFS • t(14;16) • t(14;20)
  7. 7. Hybrid Systems t(4;14) or del(17p) & high β2 (n=42) No del(13), t(4;14), or del(17p) & low β2 (n=155) del(13) only & low β2 (n=110) t(4;14) or del(17p) & low β2 (n=63) del(13) & high β2 (n=69) No del(13), ct(4;14), or del(17p) & high β2 (n=74)
  8. 8. Primary Plasma Cell Leukemia Usmani, SZ et al. Leukemia Epub April 17, 2012. • Outcomes have improved with novel agents for myeloma • This has not been the case for PPCL – PFS – OS
  9. 9. High LDH Gkotzamanidou, M et al. Clin Lymphoma Myeloma Leuk. 11:409, 2011. • High LDH predicts poor survival regardless of ISS stage
  10. 10. Defining Risk : GEP70 Shaughnessy, JD Jr. et al. Blood 109:2276, 2007. • Expression profiling to identify high-risk patients • 30% of genes mapped to chr 1 • Independent predictor – HR 5.16, P < 0.001
  11. 11. Useful at Diagnosis and at Relapse Shaughnessy, JD Jr. et al. Blood 109:2276, 2007. • GEP70 profiling is useful not just in newly diagnosed patients, but also at relapse
  12. 12. EMC-92 Kuiper, R et al. Leukemia Epub June 22, 2012. TT2 dataset TT3 dataset
  13. 13. Overlap Between Signatures Kuiper, R et al. Leukemia Epub June 22, 2012. • If only a few genes are in common, do they all play a role in myeloma pathobiology, or do only some? 21 overlapping genes
  14. 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-β) • 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. 15. Sniff Test Part II http://www.genecards.org • 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 (?)
  16. 16. Which GEP Signature is Best? Kuiper, R et al. Leukemia Epub June 22, 2012.
  17. 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. 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. 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/smol dering myeloma Bladé, J et al. J Clin Oncol. 28:690, 2009.
  20. 20. Risk Stratifying MGUS • Low risk – M protein <1.5g/dL, IgG type  and normal FLC ratio ✔ SPEP @ 6 mos., then q 2-3 years if stable and asymptomatic • Intermediate/High risk – M protein 1.5g/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. 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. 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. 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. 24. Impact of Genome Sequencing Chapman, MA et al. Nature 471:467, 2011. • Frequent mutations in genes involved in RNA processing, protein translation, and the unfolded protein response • How many can we target therapeutically ?
  25. 25. Other Gene Mutations Chapman, MA et al. Nature 471:467, 2011. • Do these involve micro RNAs and ncRNAs ?
  26. 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. 27. 2010 ASH Abstract 991 A Multicenter, Randomised, Open-label, Phase III Study of Lenalidomide/Dexamethasone versus Therapeutic Abstention in high-risk Smoldering MM MV 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. 28. Study Design Standard Observation 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 Asymptomatic Myeloma Patients PC 10% + MP 3.0≥ ≥ Or PC 10% or MP 3.0≥ ≥ and 95% aberrant≥ immunophenotype + immunoparesis • 1o objective: TTP to symptomatic myeloma
  29. 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 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 Proportionofpatientsalive 50454035302520151050 1.0 0.8 0.6 0.4 0.2 0.0
  30. 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 50454035302520151050 1.0 0.8 0.6 0.4 0.2 0.0
  31. 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. 32. Overall Survival from Inclusion Len + Dex No treatment Lenalidomide + Dex: 93% at 3 years No treatment: 76% at 3 years Time from inclusion Proportionofpatientsalive p=0.04 50454035302520151050 1.0 0.8 0.6 0.4 0.2 0.0 Median follow-up: 32 months (range 12–49)
  33. 33. Overall Survival from Diagnosis 1009080706050403020100 1.0 0.8 0.6 0.4 0.2 0.0 Len + Dex No treatment Time from inclusion Proportionofpatientsalive HR: 5.01; 95% IC (1–22); p=0.03 Lenalidomide + Dex: 94% at 5 yrs No treatment: 79% at 5 yrs Median follow-up: 38months (range 14–96)
  34. 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

×