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

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 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

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 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 (?)

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/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