starting therapy for low risk myeloma
DESCRIPTION
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 PresentationTRANSCRIPT
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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 TherapeuticsPrincipal Investigator, M. D. Anderson SPORE in Multiple Myeloma
Chair, Southwest Oncology Group Myeloma Committee
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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.
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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
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Molecular Staging : mSMART
http://msmart.org
• Novel agents overcome del 13, t(4;14)
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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)
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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)
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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)
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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
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High LDH
Gkotzamanidou, M et al. Clin Lymphoma Myeloma Leuk. 11:409, 2011.
• High LDH predicts poor survival regardless of ISS stage
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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
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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
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EMC-92
Kuiper, R et al. Leukemia Epub June 22, 2012.
TT2 dataset TT3 dataset
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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
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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
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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 (?)
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Which GEP Signature is Best?
Kuiper, R et al. Leukemia Epub June 22, 2012.
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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
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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.
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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.
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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.
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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.
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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.
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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.
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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 ?
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Other Gene Mutations
Chapman, MA et al. Nature 471:467, 2011.
• Do these involve micro RNAs and ncRNAs ?
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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.
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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)
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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
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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 failureHR: 6.0; 95% IC (2.9–12.6); p < 0.0001
Time from inclusion
Prop
ortio
n of
pat
ient
s aliv
e
50454035302520151050
1.0
0.8
0.6
0.4
0.2
0.0
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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
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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
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Overall Survival from Inclusion
Len + Dex
No treatment
Lenalidomide + Dex: 93% at 3 yearsNo treatment: 76% at 3 years
Time from inclusion
Prop
ortio
n of
pat
ient
s aliv
e
p=0.04
50454035302520151050
1.0
0.8
0.6
0.4
0.2
0.0
Median follow-up: 32 months (range 12–49)
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Overall Survival from Diagnosis
1009080706050403020100
1.0
0.8
0.6
0.4
0.2
0.0
Len + DexNo treatment
Time from inclusion
Prop
ortio
n of
pat
ient
s aliv
e
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)
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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