getting clear answers to complex treatment …ºs f. san-miguel, md, phd only on a clinical trial,...

Friday, December 8, 2017Atlanta, Georgia

Getting Clear Answers to Complex Treatment Challenges in Multiple Myeloma: Case Discussions

Friday Satellite Symposium preceding the 59th ASH Annual Meeting & Exposition.

This activity is supported by educational grants from Amgen, Celgene Corporation, Janssen, Karyopharm, Takeda Oncology, and The Binding Site.

Image: Copyright©2017 DNA Illustrations. All Rights Reserved

Discussion 1Accurately Diagnosing MM: When Should

Systemic Myeloma Treatment Be Initiated?

Presented by Bruno Paiva, PhD

Bruno Paiva, PhDDepartment of Hematology and ImmunologyFlow Cytometry Core - CIMA LAB DiagnosticsUniversity of NavarraPamplona, Spain

Bruno Paiva, PhD, has disclosed that he has received consulting fees from Celgene, Janssen, Merck, Novartis, and Takeda, funds for contracted research from Celgene, EngMab and Sanofi, and fees for non-CME/CE services from Amgen, Celgene, Janssen, and Takeda.

Presenting Faculty

Program Director

Brian G.M. Durie, MDCo-Chair Myeloma Committee, SWOG Chairman, International Myeloma FoundationSpecialist in Multiple Myeloma and Related Disorders Cedars-Sinai Outpatient Cancer CenterLos Angeles, California

Brian G.M. Durie, MD, has disclosed that he has received consulting fees from Celgene, Johnson & Johnson, Amgen, and Takeda.

Patient Case 1 A 52-yr-old asymptomatic male has elevated total serum protein (10.2 g/dL) with

normal albumin during a routine analysis

Labs show hemoglobin 14 g/dL and creatinine 0.8 mg/dL, with normal calcium levels and liver function

IgG-Kappa M-protein was detected (3.5 g/dL) with hypogammaglobulinemia

Serum kappa/lambda free light chain (sFLC) ratio is 85

Skeletal survey, PET/CT, MRI show no lytic lesions, increased uptake, or focal lesions

12% plasma cell bone marrow infiltration, 97% are abnormal by flow

FISH shows del(17p)

Would you consider this patient a candidate for treatment?

Expert RecommendationBrian G.M. Durie, MD Only on a clinical trial, because the patient has high-

risk smoldering myeloma

Philippe Moreau, MD Only on a clinical trial, because the patient has high-risk smoldering myeloma

Bruno Paiva, PhD Only on a clinical trial, because the patient has high-risk smoldering myeloma

S. Vincent Rajkumar, MD Only on a clinical trial, because the patient has high-risk smoldering myeloma

Jesús F. San-Miguel, MD, PhD Only on a clinical trial, because the patient has high-risk smoldering myeloma

Patient Case 1, Continued A 52-yr-old asymptomatic male has elevated total serum protein (10.2 g/dL) with

normal albumin during a routine analysis

Labs show hemoglobin 14 g/dL and creatinine 0.8 mg/dL, with normal calcium levels and liver function

IgG-Kappa M-protein was detected (3.5 g/dL) with hypogammaglobulinemia

Serum kappa/lambda free light chain (sFLC) ratio is 85

Skeletal survey, PET/CT, MRI show no lytic lesions, increased uptake, or focal lesions

12% plasma cell bone marrow infiltration, 97% are abnormal by flow

FISH shows del(17p)

After 1 yr, his M-protein increases 15%, his sFLC ratio increases up to 100, hemoglobin levels decrease by 1 g/dL, and bone marrow plasma cell infiltration increases up to 20% (100% clonality by flow)

Now, would you consider this patient a candidate for treatment?

Expert RecommendationBrian G.M. Durie, MD Yes, the patient has active myeloma

Philippe Moreau, MD Yes, the patient has active myeloma

Bruno Paiva, PhD Yes, the patient has active myeloma

S. Vincent Rajkumar, MD Yes, the patient has active myeloma

Jesús F. San-Miguel, MD, PhD Yes, the patient has active myeloma

Bruno PaivaHematology and Immunology Departments. Clinica Universidad de Navarra

Flow Cytometry Core - CIMA LAB DiagnosticsUniversidad de NavarraEuroFlow Consortium

Spanish Myeloma Group (GEM)

Accurately Diagnosing MM: When Should Systemic Myeloma Treatment Be Initiated?

MGUS to Myeloma: A Continuum

Dhodapkar MV. Blood. 2016;128:2599-2606.

NormalTUMORInter- and intra-clonal heterogeneity

Genomic instability

Secondary eventsSub-clonal evolution

? Polyclonal Pre-MGUS MGUS SMM Myeloma

? Big bang? Clonal evolution

?

MICROENVIRONMENTImmune cellsBone cellsNiche-derived signals

Others

Growth restricting signals

Growth permissive signals

Risk of Progression Is Not the Same for All Smoldering Myeloma Patients

Kyle R, et al. N Engl J Med. 2007;356:2582-2590.

100

80

60

40

20

00 5 10 15 20 25

Prob

abili

ty o

f Pro

gres

sion

(%)

51

6673 78

4 1016 21

MGUS

Smoldering MM

Yrs Since Diagnosis

Standard-Risk SMM (60%): 5% per yr risk of MM

High-Risk SMM (25%):25% per yr risk of MM

Ultra-high-risk SMM (15%):40% per yr risk of MM• ≥ 60% BMPC• FLCr ≥ 100• > 1 MRI focal lesions

Smoldering Multiple Myeloma

MDE, myeloma-defining events

• < 10% BMPC AND• < 3 g/dL M protein AND• No MDE

• ≥ 10% to 60% BMPC OR• ≥ 3 g/dL serum M protein OR• ≥ 500 mg/24 hr urine M protein AND• No MDE

• PCPD, AND• 1 or more MDEo CRABo ≥ 60% BMPCo ≥ 100 FLC ratioo > 1 MRI focal lesion

MGUS SMM MM

No MDE MDE

Rajkumar SV, et al. Lancet Oncol. 2014;15:e538-e548.

IMWG Updated Criteria forthe Diagnosis of Multiple Myeloma

• Biomarker validated in three independent series 1-3

≥ 60% Plasma Cells in Bone Marrow- Myeloma Defining Event -

BMPC ≥ 60% (n = 21); median TTP: 7 months

BMPC < 60% (N = 634)

1. Rajkumar SV, et al. N Engl J Med. 2011;365:474-75.2. Kastritis E, et al. Leukemia. 2013;27:947-953.3. Waxman AJ, et al. J Leukemia. 2015;29:751-753.

1. Larsen JT, et al. Leukemia. 2013;27:941-946.2. Kastritis E, et al. Leukemia. 2013;27:947-953.3. Waxman AJ, et al. J Leukemia. 2015;29:751-753.

Free-Light Chain (FLC) Ratio ≥ 100- Myeloma Defining Event -

• Biomarker validated in three independent series 1-3

FLC ratio ≥ 100 or ≤ 1/100; median TTP: 13 months

FLC ratio < 100 or > 1/100; median TTP: 75 months

Median TTP: 13 mos

Median TTP: NRPr

ogre

ssio

n-Fr

ee S

urvi

val

Mos Since MRI Treatment

1.0

60 1812 3024 4236 5448 60

0.8

0.6

0.4

0.2

0

> 1 focal lesion

Log-rank P<.001

≤ 1 focal lesion

1. Hillengass J, et al. J Clin Oncol. 2010;28:1606-1610.2. Kastritis E, et al. Leukemia. 2013;27:947-953.

> 1 Focal Lesion by MRI- Myeloma Defining Event -

• Biomarker validated in two independent series 1,2

Before 2014 After 2014

U-HR15% HR

25%SR

60%

HR15%

SR85%

Smoldering Multiple Myeloma

High-risk model Risk of progression to active MM

Mayo Clinic≥10% BMPC infiltration≥3 g/dL of serum M-proteinsFLC ratio between <0.125 or >8

1.9-year median TTP

PETHEMA ≥95% of aberrant PCs by MFCImmunoparesis 1.9-year median TTP

Heidelberg T-mass (Mayo) high + t(4;14), del17p, or þ1q 3-year TTP, 55%

SWOGSerum M-protein ≥2 g/dLInvolved FLC >25 mg/dLGEP risk score >0.26

2-year TTP, 71%

Penn≥40% clonal BMPC infiltration sFLC ratio ≥50 Albumin ≤3.5 mg/dL

2-year TTP, 81%

Japanese Beta 2-macroglobulin ≥2.5 mg/LM-protein increment rate >1 mg/dL/d 2-year TTP, 67.5%

Czech and HeidelbergImmunoparesisSerum M-protein ≥2.3 g/dLInvolved/uninvolved sFLC >30

2-year TTP, 81%

BarcelonaEvolving patternSerum M-protein ≥3 g/dL Immunoparesis

2-year TTP, 80%

Mayo Clinic evolving modeleM-proteineHemoglobin≥20% PCs

1-year median TTP

Danish Serum M-protein ≥3 g/dL Immunoparesis 2-year TTP, 50%

Biomarkers Currently Used to Identify Patients with High-Risk Smoldering MM (50% Risk at 2y)

Proteins

Cells

Dissemination

Partial overall regarding myeloma biology

Complementary information on

patients’ outcome

7. Ravi P. Blood Cancer J. 2016;6(7):e4548. Paiva B. Leukemia. 2013;27(10):2056-20619. Bianchi G. Leukemia. 2013;27(3):680-68510. Gonsalves WI. Leukemia. 2017;31(1):130-13511. Neben K. J Clin Oncol. 2013;31(34):4325-433212. Rajkumar SV. Leukemia. 2013;27(8):1738-1744

13. Dhodapkar MV. Blood. 2014;123(1):78-8514. Khan R. Haematologica. 2015;100(9):1214-122115. Merz M. Leukemia. 2014;28(9):1902-190816. Siontis B. Blood Cancer J. 2015;5:e36417. Zamagni E, et al. Leukemia. 2016;30(2):417-422

BiomarkerM protein concentration 1,2

BJ proteinuria 3,4

M protein type 1,3

Immune paresis 1-3

Serum FLC ratio 5

Evolving M protein 6,7

BMPCs on microscope 1

Phenotyping of BMPCs 2,8

Circulating tumor cells 9,10

Cytogenetics 11,12

Gene expression profiling 13,14

MRI 15

PET/CT 16,17


1. Kyle RA. N Engl J Med 2007; 356:2582-25902. Pérez-Persona E. Blood. 2007;110:2586-25923. Kyle RA. Lancet Haematol. 2014;1(1):e28-e364. Gonzalez V. Leukemia. 2016;30(10):2026-20315. Dispenzieri A. Blood. 2008;111(2):785-7896. Rosiñol L. Mayo Clin Proc. 2007;82(4):428-434


Biomarker Interpretation Standardization AutomationM protein concentration 1,2 Semi-informatic No (total proteins, yes) YesBJ proteinuria 3,4 Visual No YesM protein type 1,3 Visual No YesImmune paresis 1-3 Informatic Yes YesSerum FLC ratio 5 Informatic No YesEvolving M protein 6,7 Semi-informatic No (total proteins, yes) YesBMPCs on microscope 1 Visual No NoPhenotyping of BMPCs 2,8 Visual No NoCirculating tumor cells 9,10 Visual No NoCytogenetics 11,12 Visual No NoGene expression profiling 13,14 Bioinformatic No YesMRI 15 Visual No NoPET/CT 16,17 Visual No No


13. Dhodapkar MV. Blood. 2014;123(1):78-8514. Khan R. Haematologica. 2015;100(9):1214-122115. Merz M. Leukemia. 2014;28(9):1902-190816. Siontis B. Blood Cancer J. 2015;5:e36417. Zamagni E, et al. Leukemia. 2016;30(2):417-422




13. Dhodapkar MV,. Blood. 2014;123(1):78-8514. Khan R. Haematologica. 2015;100(9):1214-122115. Merz M. Leukemia. 2014;28(9):1902-190816. Siontis B. Blood Cancer J. 2015;5:e36417. Zamagni E, et al. Leukemia. 2016;30(2):417-422

Risk-stratification

Risk-stratification Recalibration of risk Recalibration of risk

Invasive

Minimally invasive

M protein concentration1,2, BJ proteinuria3,4, M protein type1,3, Immune paresis1-3, Serum FLC ratio5, Evolving M protein6,7, Circulating tumor cells 9,10, MRI15, PET/CT16,17

BMPCs on microscope1, Phenotyping of BMPCs2,8, Cytogenetics11,12, Gene expression profiling13,14


Rd vs Observation in Patients with High-Risk SMM (QuiRedex): Long-Term Follow-Up*

* Median follow-up for surviving patients was 75 months (IQR 67–85)

Mateos MV, et al. Lancet Oncol. 2016;17:1127-1136.

Mailankody S, et al. Blood Advances. 2017;1:1911-1918.Median potential follow-up was 43.3 months.

Clinical Outcomes in Patients with High-Risk SMM After 8 Cycles of KRd and 2 Years of Lenalidomide Maintenance

++++++++++ + +

++ +

PFS OS1.0

0.8

0.6

0.4

0.2

0.0

18 18 17 13 5 0

0 10 20 30 40 50Biochemical PFS, monthsPts at risk, n

Censored+

Surv

ival

Pro

babi

lity

+ +++++++++ +++ +1.0

0.8

0.6

0.4

0.2

0.0

18 18 17 15 5 1

0 10 20 30 40 50OS, monthsPts at risk, n

Censored+

Surv

ival

Pro

babi

lity

+

Clinical trials being presented at EHA & ASH 2017 Monotherapy Combination therapy

Siltuximab(Brighton. Abst 3155)

Pembrolizumab(Manasanch. Abst 3089)

Daratumumab(Hofmeister. Abst 510)

Elotuzumab-Rd(Ghobrial. Abst S779)

CESAR (KRd)(Mateos. Abst 402)

DesignRandomized, double-blind, placebo-controlled Phase II trial

Pilot study Open-label Phase II trial; 3 treatment arms Phase II double-arm Phase II single-arm

Patients 74 high-risk(including ultra-HR)

12 intermediate & high-risk (including ultra-HR)

123 intermediate & high-risk (excluding ultra-HR)

50 high-risk (excluding ultra-HR)

90 high-risk SMM < 70y(including ultra-HR)

Treatment Until disease progression

8 cycles (24 cycles if≥ MR at Cycle 8)

20 cycles (2 arms) or 1 cycle (1 arm)

Until disease progression

KRd x 6, HDT/ASCT, KRd x 2, Rd for 2y

TEAEs (N)

Infections (N=5) and renal/urinary disorders (N=1)

G2 elevation in LFT (N=2), G3 myalgia (N=1), and G3 acute kidney injury (N=2); there were no G4/5

Hematologic were < 10% & G3/4 infection ≤ 5% in all arms. IRR occurred in 56%, 37%, and 55% of pts (but G3 < 3%)

G3 hypophosphatemia (30%), neutropenia (14%), infection (12%), anemia (2%), pulmonary embolism (2%), rash (4%), and diarrhea (2%). G4 thrombocytopenia (2%), neutropenia (2%) and one instance of cholecystitis (2%)

G3/4 infections (N=9),skin rash (N=7), neutropenia (N=4) and thrombocytopenia (N=2) during induction

CR (%) NR 1/12 (8%) 1/122 (0.8%) 2/31 (7%) 20/43 (46%) after induction

Outcome 84.5% PFS at 1-Yr NR 89-98% PFS at 1-Yr 100% PFS at 1-Yr 98% PFS at 1-Yr

Induction 6 cycles of KRd

ASCT (melphalan 200)

Consolidation (2 cycles of KRd)

Maintenance (Len-dex for 2yrs)

MRD

MRD

MRD

MRD

Disease Control vs Curative Strategy for High-Risk Smoldering Multiple Myeloma

“The depth of response improved along with the duration of treatment, achieving up to 85% of ≥ CR in patients who completed induction, ASCT, and consolidation, with an acceptable safety profile.”Mateos, et al. ASH 2017. Abstract 402. Sunday, Dec 10 at 9:30 AM-11:00 AM

CESAR ASCENT

KRd + DARA x 4 cycles

MEL 200ASCT



KR – DARA x 1 year

MRD at

CR

NCT03289299.

• Better understanding of myeloma biology and development of sensitive biomarkers

have contributed to accurately diagnosing myelomao Initiate treatment in the presence of CRAB and/or MDE

• Goals by initiating treatment earlier:o Prevent development of CRAB (MDE)

o Prevent transformation to malignant states that remain mostly incurable (eg: R-ISS-3)

Disease control (eg, monotherapy)

Disease eradication (eg, intensive combination therapy)

• IMWG guidelines to standardize biomarkers (invasive and minimally invasive) to

identify patients with high-risk SMM candidates to be enrolled in clinical trials

Summary

Go Online for More CCO Coverage of Myeloma!

On-demand Webcast of this event at myeloma.org

Capsule Summaries of all the key data for ASH 2017

Additional CME-certified slideset on myeloma with expert faculty commentary

Online treatment decision aid with recommendations from5 experts for your individual patients with myeloma

ashsymposium2017.myeloma.org

clinicaloptions.com/oncology

clinicaloptions.com/MyelomaTool

getting clear answers to complex treatment …ºs f. san-miguel, md, phd only on a clinical trial,...

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