Mayo Clinic College of Medicine

Mayo Clinic Comprehensive Cancer Center

Multiple Myeloma 2016

Ayalew Tefferi

Professor of Medicine

Mayo Clinic

Slides were borrowed from

Vincent Rajkumar, MD

Myeloma expert Mayo Clinic, Rochester, MN

Disclosures

No conflicts to disclose

© Remstein E, Jevremovic D. 2010

NEW DIAGNOSTIC CRITERIA

• <10% BMPC AND

• <3gm/dL M protein AND

• No CRAB

• ≥10% BMPC OR

• ≥3 gm/dL M protein AND

• No CRAB

• Clonal PCPD

• CRAB

CRAB= Hypercalcemia, renal failure, anemia, or lytic bone lesions attributable to a clonal plasma cell disorder

MGUS SMM MM

Rajkumar SV. Cecil Textbook of Medicine, 24th Edition, 2012

Previous Disease Definitions

Bone Marrow Plasma Cell ≥60%

Rajkumar SV et al. N Engl J Med 2011; N Engl J Med 2011; 365:474-475

CT PET-CT

Rajkumar SV, Dispenzieri A. In: Niederhuber JE, et al, eds. Abeloff’s Clinical Oncology, 5th Edition; 2013.

Rajkumar SV. In: Goldman L and Schafer AI, eds. Goldman’s Cecil Medicine, 24th Edition. 2012.

©2012 MFMER | 3206302-8

Smoldering Multiple Myeloma

Low-risk SMM:

5%/yr risk of MM

High-Risk SMM

Ultra-High Risk 40%/yr risk of MM

= MM

25%/year risk of MM

• >60% BMPC

• FLCr >100

• >1 MRI focal

lesions

Mateos M et al. N Engl J Med 2013;369:438-447.

Len/Dex versus Observation in High Risk SMM: OS

• <10% BMPC AND

• <3 gm/dL M protein AND

• No MDE

• ≥10%-60% BMPC OR

• ≥3 gm/dL S. M protein OR

• ≥500 mg/24h Ur. M protein AND

• No MDE

• PCPD, AND

• 1 or more MDE

• CRAB

• ≥60% BMPC

• ≥100 FLC ratio

• >1 MRI focal lesion

MDE, myeloma-defining events

MGUS SMM MM

Revised IMWG Criteria

Rajkumar SV, Dimopoulos M, Palumbo A, et al. Lancet Oncol. 2014;15(12):e538-e548.

1961-70

1971-80

1981-90

1991-2000

2001-2010

Kumar S. Blood 2008;111: 2516 – 2520; Kumar S. Leukemia (2014) 28, 1122–1128.

Survival in Myeloma

Rajkumar SV et al. Blood 2011;118:3205-3211; Russell SJ et al. Lancet Oncology 2011

PROGNOSIS VARIES

MOLECULAR CLASSIFICATION

Myeloma Molecular Classification

t(14;16) (C-MAF)

t(14;20) (MAF-B)

Trisomies*

t(11;14) (CCND1)

t(6;14) (CCND3)

t(4;14) (FGFR3/

MMSET)

Standard-Risk ~75%

Intermediate-Risk ~10%

High-Risk ~15%

*10-15% have both trisomies and IgH translocation

Median survival <3 years Median survival 3-5 years Median survival 6-7 years

t(14;16) t(14;20) Del 17p

t(11;14)

t(6;14)

t(4;14)

High-Risk Intermediate-Risk Standard-Risk

msmart.org

CR appears critical Bortezomib Critical Excellent Outcome

*Presence of trisomies ameliorates high risk

Median survival <3 years Median survival 6-7 years

Trisomies

IMiDs

MM classification and Prognosis

Copyright ©2007 American Association for Cancer Research

Haessler, J. et al. Clin Cancer Res 2007;13:7073-7079

CR is critical in patients with high-risk myeloma

Low-Risk MM (87%) High-Risk MM (13%)

FIRST Trial: MPT vs Rd18 vs Rd till progression

Kaplan–Meier Estimates of Progression-free Survival and Overall Survival

Benboubker L et al. N Engl J Med 2014;371:906-917.

Bortezomib, Lenalidomide and Dexamethasone vs. Lenalidomide and Dexamethasone in Patients (Pts) with Previously Untreated Multiple

Myeloma Without an Intent for Immediate Autologous Stem Cell Transplant (ASCT): Results of the Randomized Phase III Trial SWOG

S0777

Brian G.M. Durie, MD, Antje Hoering, PhD, S. Vincent Rajkumar, MD, Muneer H. Abidi, MD, Joshua Epstein, DSc, Stephen P. Kahanic, MD, Mohan Thakuri, MD, Frederic Reu, MD, Christopher M. Reynolds, MD, Rachael Sexton, MS, Robert Z. Orlowski, MD, PhD, Bart Barlogie, MD, PhD, Angela Dispenzieri, MD

Overall Survival By Assigned Treatment

Arm

Log-rank P value = 0.0125 (one sided)*

HR = 0.709 (0.516, 0.973)*

19

*Stratified

Rajkumar SV. 2015

Initial Treatment of Myeloma

Not Transplant Candidate

VRd

Newly Diagnosed MM

Transplant Candidate

*Frailty Score; Palumbo A, Blood. 2015;125:2068-2074.

Rd (if frail, age ≥75)*

ROLE OF TRANSPLANT

Attal M. N Engl J Med 1996; 335:97; Child J. N Engl J Med 2003; 348:1875

54

42

Role of Autologous Transplantation

Fermand. Blood 1998; 92:3131; Barlogie JCO 2006;24:929-936

Upfront versus Delayed Transplantation

MAG study SWOG study

Rajkumar SV. 2015

Initial Treatment of Myeloma

Not Transplant Candidate

VRd

Newly Diagnosed MM

Transplant Candidate

VRd x 4 cycles

Auto SCT +/-

Maintenance

(Len for std risk;

bortez for high risk)

VRd x4 cycles

Len maintenance

Delayed Transplant

*Frailty Score; Palumbo A, Blood. 2015;125:2068-2074.

Rd (if frail, age ≥75)*

POST-TRANSPLANT MAINTENANCE

Lenalidomide Maintenance: CALGB

McCarthy et al. N. Engl. J. Med. 366, 1770–1781 (2012).

PFS OS

Bortezomib Maintenance

HOVON trial: OS according to Arm and del(17p)

Sonneveld P et al. JCO 2012;30:2946-2955

©2012 by American Society of Clinical Oncology

Post-Transplant Maintenance

Dispenzieri et al. Mayo Clin Proc 2007;82:323-341; Kumar et al. Mayo Clin Proc 2009 84:1095-1110; Mikhael et al. Mayo Clin

Proc 2013;88:360-376. v12

Standard-Risk Intermediate-Risk High-Risk

Autologous stem cell transplant

2 cycles of Len consolidation and observe;

or consider Lenalidomide maintenance

t(11;14), t(6;14), Trisomies Del 17p, t(14;16),

t(14;20)

t(4;14)

Bortezomib-based maintenance

Autologous stem cell transplant

a

b

b

a

b5

b1 b2 *

*

*

20S proteasome particle

b-subunit ring

Proteasome Inhibitor Comparison

IC50s (nM)

Carfilzomib Bortezomib

Chymotrypsin-

like 6 7

Caspase-like 2400 74

Trypsin-like 3600 4200

Biochemical mechanism and selectivity

Carfilzomib Bortezomib

Irreversible

(keto-epoxide tetrapeptide)

Slowly reversible

(boronic acid dipeptide)

Highly selective for chymotrypsin-like

active site within the proteasome

Inhibits both chymotrypsin-like and caspase-

like activities of the proteasome

Highly selective for proteasome

N-terminal threonine active sites Cross reactivity with serine proteases

* Three distinct N-terminal threonine protease active sites Stewart, ASCO 2007

Progression-free Survival.

Stewart AK, et al. N Engl J Med. 2015;372(2):142-152.

Carfilzomib-Rd vs Rd: Aspire Trial

RELAPSED MYELOMA

years from start of regimen 'i'

cu

mu

lati

ve p

rob

ab

ilit

y (

%)

0 2 4 6 8 10

0.0

0.2

0.4

0.6

0.8

1.0

Regimen 1

Regimen 2

Regimen 3

Regimen 4

Regimen 5

Regimen 6

Overall survival in Relapsed MM by regimen number

Kumar S. Mayo Clin Proc 2004;79:867-74

Pom-Dex vs Dex (PFS)

San Miguel J, et al. Lancet Oncol. 2013;14(11):1055-1066.

San Miguel JF, et al. Lancet Oncol. 2014;15(11):1195-1206.

Panobinostat-Vel vs Vel (PFS): Panorama 1 Trial

Treatment of Relapsed Myeloma

Alkylators Steroids Interferon Anthracyclines

Ixazomib Marizomib Daratumumab SAR650984

Dinaciclib Filanesib LGH447 ABT-199 Elotuzumab

Carfilzomib Pomalidomide

Panobinostat

Old Drugs Recently Approved

Drugs Future Drugs

Bortezomib Thalidomide Lenalidomide

Older Drugs

Rajkumar SV. 2015

Figure Response with increasing duration of therapy (A) and waterfall plot of best M-protein response (B) among 52

response-evaluable patients treated at the recommended phase 2 dose One patient in phase 2 was excluded from the

response-evaluable populati...

Kumar et al. The Lancet Oncology, Volume 15, Issue 13, 2014, 1503 - 1512

Ixazomib-Rd

Lonial S et al. N Engl J Med 2015. DOI: 10.1056/NEJMoa1505654

ELOQUENT 2: Elotuzumab Rd vs Rd

PFS

Daratumumab: Overall Response Rate in 106 refractory patients with MM

• ORR was 29% (95% CI, 21–39) in

patients receiving 16 mg/kg DARA

• The clinical benefit rate (ORR + MR)

was 34% (95% CI, 25–44)

• VGPR or better was achieved in 12%

(95% CI, 7–20) of patients including

sCR 3% (95% CI, 0.6–8.0)

0

5

10

15

20

25

30

35

16 mg/kg

Ove

rall

re

sp

on

se

ra

te, %

ORR = 29%

sCR

n = 3 (3%)

VGPR

n = 10 (9%)

PR

n = 18 (17%)

Lonial S et al. ASCO 2015

Active Drugs in Multiple Myeloma

Alkylators Steroids Interferon Anthracyclines

Oprozomib Marizomib

Isatuximab

Dinaciclib Filanesib LGH447 ABT-199

Carfilzomib Pomalidomide Panobinostat

Daratumumab Ixazomib Elotuzumab

Old Drugs Recently Approved

Drugs (2013-2015) Future Drugs

Bortezomib Thalidomide Lenalidomide Liposomal

doxorubicin

Older Drugs

(2003-2007)

Rajkumar SV. 2015