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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. - PowerPoint PPT Presentation
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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
Defining Risk : ISS Stage
Stage 2m 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.
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
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)
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)
Hybrid Systems
t(4;14) or del(17p) & high 2 (n=42)
No del(13), t(4;14), or del(17p) & low 2 (n=155)
del(13) only & low 2 (n=110)
t(4;14) or del(17p) & low 2 (n=63)
del(13) & high 2 (n=69)
No del(13), ct(4;14),
or del(17p)& high 2
(n=74)
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
High LDH
Gkotzamanidou, M et al. Clin Lymphoma Myeloma Leuk. 11:409, 2011.
• High LDH predicts poor survival regardless of ISS stage
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
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
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
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-)
• 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
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 (?)
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
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.
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.
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.
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.
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.
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.
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 ?
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 will need to be craftier than the myeloma
Keats, JJ et al. Blood Epub, April 12, 2012.
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)
Study Design
StandardObservation
TreatmentCycles 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 ≥ 3.0Or
PC ≥ 10% or MP ≥ 3.0 and ≥ 95% aberrant immunophenotype +
immunoparesis
• 1o objective: TTP to symptomatic myeloma
TTP to Active DiseaseMedian 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
Pro
por
tion
of
pat
ien
ts a
live
50454035302520151050
1.0
0.8
0.6
0.4
0.2
0.0
TTP Excluding Early DiscontinuationMedian 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
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
Overall Survival from Inclusion
Len + Dex
No treatment
Lenalidomide + Dex: 93% at 3 yearsNo treatment: 76% at 3 years
Time from inclusion
Pro
port
ion
of p
atie
nts
ali
ve
p=0.04
50454035302520151050
1.0
0.8
0.6
0.4
0.2
0.0
Median follow-up: 32 months (range 12–49)
Overall Survival from Diagnosis
1009080706050403020100
1.0
0.8
0.6
0.4
0.2
0.0
Len + Dex
No treatment
Time from inclusion
Pro
port
ion
of p
atie
nts
ali
ve
HR: 5.01; 95% IC (1–22); p=0.03
Lenalidomide + Dex: 94% at 5 yrsNo treatment: 79% at 5 yrs
Median follow-up: 38months (range 14–96)
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