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

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

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

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. 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. 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. 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/smol
dering myeloma
Bladé, J et al. J Clin Oncol. 28:690, 2009.

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

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 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. 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. 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. 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. 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
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. 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. 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