Elisabet Manasanch M.D., M.H.Sc.

Assistant Professor, Department of Lymphoma/Myeloma Division of Cancer Medicine

Best approach to newly diagnosed multiple

myeloma

Disclosures

Nothing to disclose

Overview

Fit patients

Unfit patients

High risk multiple myeloma

Outline

Overview103,826 new cases72,453 deaths

Kihyun Kim et al. Clinical profiles of multiple myeloma in Asia – An Asian Myeloma Network Study. 2014. AJH.JH Lee et al. Multiple myeloma in Korea: past, present, and future perspectives. 2010. Int J Hematol.

worldwide

Incidence rate3-5/100,000

Blacks

Age 70 years

Incidence rate0.5-3/100,000

Age 62 years

Plasma cell malignancy – molecular heterogeneityNatural history progression from MGUS/SMM

Evidence of end-organ damage

Overview

GROUPS Associated translocations

7 -> MF t(14;16) and t(14;20)

6 -> CD-2CCND1/CCND3

t(11;14) and t(6;14) activating Cyclin D 1 and Cyclin D3

5 -> CD-1CCND1/CCND3

t(11;14) and t(6;14) activating Cyclin D 1 and Cyclin D3

4 -> HY Hyperdiploidy

3 -> MS t(4;14), activation of FGFR3 and MMSET

2 -> LBLow Bone

Underexpression of DKK1

1 -> PRPRoliferation

Increased proliferation index

Zhan et al. The molecular classification of multiple myeloma. Blood. 2006 / Lohr et al. Widespread genetic heterogeneity in multiple myeloma:Implications for targeted therapy. Cancer Cell. 2014.

Treatment History

1958 1962 1983-86 1996 20031999 2006 2012

Melphalan/prednisone

HD dexamethasoneVAD

HD melphalanAutologous BM

transplants

High-dose therapy with autologous stem cell

support

LenalidomideThalidomide

Bortezomib

Carfilzomib

Pomalidomide

Elotuzumab

Daratumumab

Dex VAD Thal+Dex CTD VD PAD Rd VTD RVD CRd0

102030405060708090

100

Pati

en

ts w

ith

≥ V

GP

R

(%)

S Kumar et al. Cancer Treatment Reviews 2010; Korde et al. ASH 2013.

Sarcolysine

DIAGNOSTIC APPROACH

Blood CBC with differentialComplete chemistriesLDHSerum quantitative immunoglobulinsSPEP/IFESerum β2-M and albuminSerum free light chain assay

Urine 24 hour UPEP/IFE

Pathology/Molecular

Bone marrow biopsy (core and aspirate – unilateral)Metaphase cytogeneticsFISHBM aspirate flow cytometryGene expression profiling*

Imaging Skeletal surveyMRI/PETCT

Overview

RA Kyle and SV Rajkumar. Criteria for diagnosis, staging, risk stratification and response assessment of multiple myeloma. Leukemia. 2009. Manasanch et al. Flow cytometric sensitivity and characteristics of plasma cells in patients with multiple myeloma or its precursor disease: influence of biopsy site and anticoagulation method. Leukemia and Lymphoma. 2014. In press.

Overview

Fit patients

Unfit patients

High risk multiple myeloma

Outline

Fit patients

IFM 2005/01 GIMEMA HOVON-GMMG PETHEMA/GEM

HarousseauVD vs VAD

(n= 240 vs 242) JCO 2010

CavoVTD vs TD(n=241 vs

239)Blood 2012

Sonneveld

PAD vs VAD

(n=417 vs 416)

JCO 2012

Rosinol

VTD vs VBCMP/VBAD+V

vs TD

(n=130 vs 129 vs 127)

Blood 2012

Results post-ASCT

CR (nCR+sCR)

40% vs 18.4%73.1% vs

60.9%31% vs 15% 46% vs 38% vs 24%

PFS (months) 36 vs 29.7 (S) NR vs 32 35 vs 28 (S) 56.2 vs 35.5 vs 28.2 (S)

OS (months)Not reached (32 months follow

up)

90% vs 88% at 3 years

Not reached (66 months follow up)

74% vs 70% vs 65% (4 years) (NS)

Absence of comorbidities, even if advanced ageMost patients are treated with ASCT

Phase III trials with bortezomib induction regimens

Combinations novel agents

Richardson et al. Lenalidomide, bortezomib and dexamethasone combination therapy in patients with newly diagnosed mutiple myeloma. Blood. 2010. / Reeder et al. Cyclophosphamide, bortezomib and dexamethasone induction for newly diagnosedMultiple myeloma: high response rates in a phase II clinical trial. Leukemia. 2009.

VRD

CyBorD

Phase II studies with small numbers of patients

Combinations novel agentsRandomized phase II study EVOLUTION (140 patients)

8 x 3 week cycles initial therapy followed by 6-week cycles of bortezomib maintenance

S Kumar et al. Randomized, multicenter, phase 2 study(EVOLUTION). Blood. 2012

Small numbers of patients PFS at one year: 86 vs 83 vs 93 vs 100 (%)OS at one year: 94% vs 100% in all other arms

CRd in newly diagnosed MMJakubowiak et al

(Phase I/II, n = 53)Korde et al

(Phase II, n = 45)

Combination therapy

CRd (Phase II Cfz 20/36 mg/m2) 8 cycles

CRd (Cfz 20/36 mg/m2) 8 cycles

Extended dosing

CRd (Cfz every other week) 16 cycles, off-protocol Ln at last tolerated dose

d1-21 after 16 cycles

Ln 10 mg d1-21, 24 cycles

Transplant ≥PR stem cell collection, HDM optional Stem cell collection

A Jakubowiak et al. A phase ½ study of carfilzomib in combination with lenalidomide and low-dose dexamethasone as a frontline treatment for multiple myeloma. Blood. 2012 / N Korde et al. Phase II Clinical and Correlative Study of Carfilzomib, Lenalidomide, and Dexamethasone Followed by Lenalidomide Extended Dosing (CRD-R) Induces High Rates of MRD Negativity in Newly Diagnosed Multiple Myeloma (MM) Patients. ASH abstract 538. 2013.

Jakubowiak et al(Phase I/II, n = 53)

Korde et al(Phase II, n = 45)

ORR 62% nCR/CR, 81% VGPR, 98% PR after 12 cycles

51% CR/nCR, all MRD negative (without ASCT)

PFS 92% (at 24 months) 97% (at 12 months)

New agents in NDMM

RANDOMIZED PHASE 3 STUDIES

1.- IFM/DFCI: RVD with upfront or delayed autologous stem cell transplant2.- RVD vs CRd

EARLY PHASE TRIALS

1.- Carfilzomib, cyclophosphamide, dexamethasone2.- Carfilzomib, bendamustine, dexamethasone3.- Ixazomib, lenalidomide, dexamethasone 4.- Ixazomib, cyclophosphamide, dexamethasone5.- RVD+ panabinostat6.- Cyclophosphamide, lenalidomide, dexamethasone

Overview

Fit patients

Unfit patients

High risk multiple myeloma

Outline

Velcade as initial treatment in newly diagnosed myeloma not eligible for

transplantRandomized, international, phase III trial of VMP vs MP in 682 previously untreated patients with symptomatic MM who were not candidates for HDT-ASCT due to age (≥65 yrs) or co-morbid conditions

VMPCycles 1–4Bortezomib 1.3 mg/m2 IV: d 1,4,8,11,22,25,29,32Melphalan 9 mg/m2 and prednisone 60 mg/m2: d 1–4

Cycles 5–9Bortezomib 1.3 mg/m2 IV: d 1,8,22,29Melphalan 9 mg/m2 and prednisone 60 mg/m2: d 1–4

MPCycles 1–9 Melphalan 9 mg/m2 and prednisone 60 mg/m2: d 1–4

RANDOMIZE

9 x 6-week cycles (54 weeks) in both arms

• Primary end point: TTP

• Secondary end points: CR rate, ORR, time to response

J San Miguel et al. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. NEJM. 2008

VISTA trial

VMP: 24.0 monthsMP: 16.6 monthsP < .000001

0

20

40

60

80

100VMPMP

Time (months)

Median follow-up: 25.9 months3-year OS: VMP: 72% MP: 59%P = .0032

VMPMP

Time (months)0 3 6 9 12 15 18 21 24 27

0

20

40

60

80

100

0 4 8 12 16 20 24 28 32 36 40

Time to progression Overall survival

682 patientsRR: 71% VMP versus 35% MPRate of CR: 30% VMP versus 4% MP

J San Miguel et al. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. NEJM. 2008

HD vs LD lenalidomide. ECOG E4A03

1-yr OS 2-yr OS

HD/lenalidomide 87% 75%

LD/lenallidomide 96% 87%

Four 28-day cycles

Transplant-eligible patients can

proceed to SCT

Continue therapy until disease progression

Lenalidomide + High-Dose Dexamethasone (RD)a

Len: 25 mg/day, days 1-21

Dex: 40 mg/day, days 1-4, 9-12, 17-20 (n = 223)

Lenalidomide + Low-Dose Dexamethasone (Rd)

Len: 25 mg/day, days 1-21

Dex: 40 mg/day, days 1, 8, 15, 22 (n = 222)

Rajkumar et al. Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label randomised controlled trial. Lancet Oncol. 2010.

Mateos MV et al. Proc ASH 2013;Abstract 403.

Progression Free Survival

FIRST trial

Overall Survival

T. Facon et al. ASH 2013. Abstract 2.

Overview

Fit patients

Unfit patients

High risk multiple myeloma

Outline

High risk MMGenomic abnormalities

FISH - del 17p - t(14:16) - t(14:20)

GEP - High risk signature

Laboratory abnormalities

Renal failureCirculating plasma cellsIncreased LDH or B2M

Moreau et al. Combination of International Scoring System 3, High Lactate Dehydrogenase, and t(4;14)and/or del(17p) Identifies Patients With Multiple Myeloma (MM) Treated With Front-Line Autologous Stem-Cell Transplantation at High Risk of Early MM Progression–Related Death. JCO. 2014

High risk MM* Bortezomib containing regimens as initial

treatment

* Use of bortezomib consolidation/maintenance

* Use of ASCT as consolidation

* Explore tandem ASCT

* Enroll in clinical trials if this is a possibilityAK Nooka et al. Consolidation and maintenance therapy with lenalidomide,bortezomib and dexamethasone (RVD) in high-risk myeloma patients. Leukemia. 2014.

Conclusions* Fit patients:

*3 drug combination as initial therapy.

*Stem cell collection and evaluation for ASCT.

* Unfit patients:

*VMP (other MPR, MPT)

*Rd continuous treatment

* High risk patients:

*Refer for clinical trials

*Use bortezomib (proteasome inhibitors) in consolidation/maintenance

*Evaluate for ASCT/tandem ASCT

Dr. Robert Orlowski

Dr. Jatin Shah

Dr. Donna Weber

Dr. Sheeba Thomas

Dr. Michael Wang

Dr. Parmar

Dr. Qazilbash

Dr. Shah

Dr. Bashir

Stem Cell Transplant Department

Support staff, nurses, coordinators

Patients

MDACC Myeloma Center