Managing Multiple Myeloma

Multiple MyelomaResearch Foundation

Powerful thinking advances the cure1

Management of Multiple Myeloma:

Stem Cell Transplant

David H. Vesole, MD, PhD

Co-‐Director, Myeloma Division

Director, Myeloma Research

John Theurer Cancer Center

Hackensack University Medical Center



3 Multiple MyelomaResearch Foundation

Powerful thinking advances the cure

Stem Cell Transplantation

• Myeloma and normal cells are killed by high-dose chemotherapy (eg, melphalan)

• Stem cells are ‘bone marrow-like cells’ harvested from the peripheral blood

• Sources of stem cells: – Autologous—cells collected from the patient – Allogeneic—cells collected from a donor

• Related or unrelated donors: blood stem cells or bone marrow

• Umbilical cord



Rationale for Stem Cell Transplant in the Treatment of MM

• HDC is more effective than conventional dose chemotherapy against myeloma –  “More is better”

• Autologous or allogeneic (donor) stem cells can restore (eg, “rescue”) marrow function in patients after high dose chemotherapy

• Allogeneic BM or PBSC can provide an additional immune “graft vs. myeloma” effect and eliminates graft contamination by myeloma cells

• Offers opportunity for durable remissions



Autologous Stem Cell Transplant • Considered standard therapy worldwide • Patients must have acceptable liver, renal, pulmonary,

and cardiac function to be eligible for ASCT • High response rate (results confirmed the value of CR,

nCR, and VGPR on survival) • No overt age limitation • Low mortality (< 1%) (higher mortality in patients > 70

yrs; ~3%) • No donor limitation • Documented survival benefit • Still not curative for most patients • Double transplants are beneficial for some patients

Bensinger, 2009; Kumar, 2009; NCCN, 2010. CR = complete response; nCR = near complete response; VGPR = very good partial response.



Autologous Stem Cell Transplant

High Dose

Chemotherapy Autologous

Stem Cells

Autologous Stem Cells

-190oC Freezer

Mobilization and

Leukapheresis of Patient

Stem Cells

Cryopreservation of Patient Stem

Cells

Autologous Stem Cells

Thawing and infusion of patient stem cells





Stem Cell Collection

• Harvesting sufficient stem cells is necessary for engraftment

• Most centers collect sufficient cells for two transplants

• Stem cell mobilization options – Growth factors

• Neupogen® (G-CSF), Neulasta®

• Mozobil®

– Chemotherapy • Cytoxan (cyclophosphamide) • Combination chemotherapy (DCEP, VDT-PACE, CDE)

• Bone marrow RARELY collected (except for donor transplant)



Stewart et al, 2001.

Randomized Trial of Stem Cell “Purging” by CD34 Selection of PBSC for Myeloma



Autologous Stem Cell Transplant: Conventional Chemotherapy vs High-Dose + ASCT

• Two large trials • IFM 90: 200 patients • MRC VII: 400 patients

• Both reported: –  Higher response rates, longer remission

duration, improved overall survival by 1-2 yrs

• Current trials show approximately 30% of patients in continuous remission beyond 10 years



Progression-Free and Overall Survival with novel induction followed by transplant

Regimen PFS OS

Bort/Dex 55% 3y 81% 3y

VAD 45% 3y 77% 3y

Bort/Thal/Dex 70% 3y 86% 3y##

Thal/Dex 55% 3y 84% 3y##

Len/Dex -> Transplant 92% 3y nr

Len/Dex No Transplant* 79% 3y nr

## Tandem Tx + consolidation nr not randomized



N = 849

Impact of Response on Outcome: OS After 1 or 2 Transplants

p = .0002 CR

VGPR

PR

< PR

0 1 2 3 4 5 6 7 8 0.00

0.25

0.50

0.75

1.00

Median FU

Harousseau et al, 2006. PR = partial response; FU = follow-up.





Single Vs. Double Autografts for MM • Attainment of a CR/nCR is important for

survival benefit

• Patients in CR/VGPR after 1 autograft do not benefit from second autograft –  Confirmed in 2 trials –  Large US trial (BMT CTN 0702) re-

addressing one versus two transplants

• Only patients with PR/SD currently receiving a second transplant (outside of a clinical trial)

Bensinger, 2009. SD = stable disease; CTN = Clinical Trials Network.



First Randomized Trial in MM: 1962

•  A controlled trial of urethane treatment in multiple myeloma.

•  Randomized 83 patients

with treated or untreated multiple myeloma to receive urethane or a placebo consisting of a cherry- and cola-flavoured syrup.

•  No difference was seen in

objective improvement or in survival in the two treatment groups. In fact, the urethane-treated patients died earlier Blood 1966; 27: 328-342

Blood. 1966;27:328-42







Lenalidomide + Low- or High-Dose Dex ECOG E4A03

1:1

Lenalidomide

High-Dose Dexamethasone

(LD)

Lenalidomide

Low-Dose Dexamethasone

(Ld)

Newly Diagnosed

Multiple Myeloma

N = 445

1:1

SCT or Continue Off Study

Lenalidomide: 25 mg daily, days 1-‐21 in a 28-‐day cycle High-‐dose Dex: 40 mg, d1-‐4, 9-‐12, 17-‐20 (total 480 mg) Low-‐dose Dex: 40 mg, d1, 8, 15, 22 (total 160 mg) Aspirin: 325 mg

Primary Endpoint Response at 4 months

Rajkumar SV, et al. Lancet Oncology, 11: 29 - 37, 2010

Continue On Study



Landmark Analysis

431 patients alive! at 4 cycles!

Off therapy !at 4 cycles!

N = 183!

Primary therapy !beyond 4 cycles!

N = 248!

!No transplant!

N = 93 !(median age: 69)!

!

Transplant !N = 90 !

(median age: 57)!

!Rd!

N = 140!(median age: 66)!

!

RD!N = 108!

(median age: 65)!

Rajkumar et al, 2010.



E4A03: OS According to Transplant or No Further Treatment at 4 Cycles

ASCT after 4 cycles LD or Ld

P=NS

92% 3-yr OS rate

Ld

LD

Surv

ival

Pro

babi

lity

0

20

40

60

80

100

Time (mo) 0 6 12 18 24 30 36

P=NS

79% 3-yr OS rate

Ld

LD

Surv

ival

Pro

babi

lity

0

20

40

60

80

100

Time (mo) 0 6 12 18 24 30 36

E4A03: Primary Therapy Beyond 4 Cycles

Response ≥ PR, % 91

CR (IF-, serum/urine), % 22 CR + VGPR, % 56



Outcomes in pts Age <65

Progression Free Survival Overall Survival



Survival: ASCT vs Ld/LD

No Early SCT: Early SCT

Overall 0.94 (0.91, 0.96) 0.99 (0.97, 1.00)

Age <65 0.94 (0.90, 0.98) 0.99 (0.96, 1.00)

65≤ Age <70 0.96 (0.91, 1.00) 0.94 (0.83, 1.00)

Age ≥70 0.92 (0.88, 0.97) 1.00 (1.00, 1.00)

1-yr mortality

Siegel et al Blood 2010



Response, n (%) All pts (N=66) Phase II (N=35) CR 19 (29) 13(37) nCR 7 (11) 7 (20) VGPR 18 (27) 6 (17) PR 22 (33) 9 (26) CR+nCR 26 (39) 20 (57) (90% CI) (29, 50) (42, 71)

CR+nCR+VGPR 44 (67) 26 (74) (90% CI) (56, 76) (59, 86)

At least PR 66 (100) 35 (100) (90% CI) (96, 100) (92, 100)

•  Response improvement seen in 42/56 pts (75%) from C4–8 and 20/38 pts (53%) beyond C8

•  Median (range time to best overall response) was 2.1(0.6,20) mo •  31 pts (47%) have proceeded to ASCT





Upfront Regimens for Multiple Myeloma

Regimen ORR VGPR CR Reference

Len/Dex 91 56 22 Rajkumar

VRD 100 74 44 Richardson

VCD 91 60 39 Reeder

VTD 90 62 19 Cavo

VCRD 96 39 32 Kumar Note: some of these are a-er induc3on followed by transplant and others maximal response.

ORR=overall response rate. VGPR=very good par3al response. CR=complete response. VRD=bortezomib/lenalidomide/dexamethasone.

VCD=bortezomib/cyclophosphamide/dexamethasone. VTD=bortezomib/thalidomide/dexamethasone. VCRD=bortezomib/cyclophosphamide/lenalidomide/dexamethasone.



C:\Users\David\Pictures\My Pictures\London 2011\IMG_1279.JPG



MEL 200

MEL 200

MEL 200

MEL 200

VRD x 4

BMT CTN 0702

Lenalidomide

Lenalidomide

Lenalidomide



IFM/DFCI 2009 Study Newly Diagnosed MM Pts (SCT candidates)

VRDx3

VRD x 2

VRD x 5

Lenalidomide 12 mos

Melphalan 200mg/m2* +

ASCT

Induction

Consolidation

Maintenance

CY (3g/m2) MOBILIZATION Goal: 5 x106 cells/kg

VRDx3

CY (3g/m2) MOBILIZATION Goal: 5 x106 cells/kg

Randomize, stratification ISS & FISH

Collection

Lenalidomide 12 mos SCT at relapse

MEL 200 mg/m2 if <65 yrs , >65 yrs 140mg/m2



Role of ASCT in the Era of Novel Therapies

• Up-front ASCT has been the treatment of choice for eligible patients

• Addition of novel agents has improved outcomes with ASCT

• Best CR/VGPR and PFS rates are obtained with novel agents before and/or after ASCT





MAINTENANCE AFTER TRANSPLANT THERAPY



Why Maintenance Therapy?

• Can maintenance therapy: – prevent or delay disease progression? – convert partial responses to complete

responses? – improve overall survival?



Thalidomide as Post-transplantation Maintenance Therapy

•  Thalidomide is effective as maintenance therapy –  Longer progression-free survival (PFS) –  Significant benefits only in patients with

–  < 90% response at randomization –  No Chr 13 deletion –  Either β2M > 3 mg/L or < 3 mg/L

Response No

Maintenance Pamidronate Pamidronate

+ Thalidomide P Value

CR or VGPR, % 55 57 67 0.001 3-year EFS, % 36 37 52 0.009 OS at 4-year, % 77 74 87 <0.04

Bone events, % 24 21 18 0.4

Attal et al. Blood. 108:3289, 2006





!Lenalidomide Maintenance after Autologous Transplantation for Myeloma:!

Final analysis of a prospective randomized study of the Intergroupe Francophone du Myélome !

(IFM 2005-02 trial) !!!!!Michel Attal, Valerie Cances Lauwers , Gerald Marit, Denis Caillot, Thierry Facon, Cyrille Hulin, Philippe Moreau, , Claire Mathiot, Murielle Roussel, Catherine Payen, Hervé Avet-Loiseau, and Jean-Luc Harousseau for the IFM.!

CALGB 100104

A Phase III Randomized, Double-Blind Study of Maintenance Therapy With Lenalidomide (CC 5013) or Placebo Following Autologous Stem Cell

Transplantation for Multiple Myeloma

McCarthy et al







Efficacy Data from Newly Diagnosed Multiple Myeloma Studies

Median PFS/TTP Lenalidomide Arm vs

Control

Disease Progression

Risk Reduction

IFM 2005/021 42 vs 24 months 50% (p<0.00000001)

CALGB 1001042 42 vs 22 months 61% (p<0.0001)

1.  Attal et al. ASH 2010 2.  McCarthy et al. ASH 2010



ASH Data on Second Malignancies IFM1 CALGB2

Revlimid

Placebo

Revlimid

Placebo

N 307 307 231 229 Solid 6(2.0%) 1(0.3%) 10(4.3%) 5(2.2%) Hematological 11(3.5%) 2(0.7%) 5(2.2%) 1(0.4%) Total 17(5.5%) 3(1.0%) 15(6.5%) 6(2.6%)

•  Among 845 ndMM patients treated with Revlimid there were 45 second malignancies (5.4%), which is within the expected background incidence

•  Among 689 ndMM patients treated with placebo there were 11 second malignancies (1.6%), which is below the expected background incidence

1.  Attal et al. ASH 2010 2.  McCarthy et al. ASH 2010



Median age, y (no. of pa3ents)

Induc3on therapy

Maintenance dose, dura3on of treatment

Improvement in quality of response

EFS or PFS* OS* Tolerance

HOVON/GMMG: Sonneveld et al46 (2010)

57 (N = 613) PAD

Bortezomib 1.3 mg/m2, biweekly, for 2 y; thalidomide 50 mg/d for 2 y

(A) CR/nCR 50% 3-‐y PFS 3-‐y OS G3 and G4

PNP

≥ VGPR 65% (A) 48% (A) 78% (A) 16%

VAD (B) CR/nCR 38% (B) 42% (B) 71% (B) 7%

≥ VGPR 61% P = .047 P = .048

Maintenance and consolidation studies with bortezomib in combination with thalidomide or prednisone



Drug Dose/regimen Dura3on of therapy

Impact on

Risk groups Tolerance Level of evidence/

rade of recommenda3on

Comments Quality of response PFS OS

Thalidomide 50* (100) mg/d

Up to 1 y,† no correla3on between dura3on and outcome‡

Yes Yes

Yes, preferen3ally if not part of the induc3on regimen; yes, in meta-‐analysis

No benefit In FISH defined high-‐risk pa3ents§ Possible benefit in pa3ents with abnormal metaphase cytogene3cs and GEP-‐defined high risk

PNP, fa3gue and other limi3ng dose and dura3on of therapy

I/A

Poor tolerance in some (par3cularly elderly) pa3ents; not recommended for pa3ents with FISH defined high-‐risk profile

Lenalidomide

10‖ (5-‐15) mg/d con3nuously or days 1-‐21, every 28 d

Un3l PD or intolerance Yes Yes

Presently shown in one-‐third of studies

Does not overcome nega3ve impact of FISH-‐defined unfavorable cytogene3cs

Few discon3nua3ons because of AEs

I/A

Unprecedented extension of PFS, increase in OS in 1 of 3 studies; usually well tolerated, increased risk for secondary primary malignancies

Bortezomib‖ 1.3 mg biweekly 2 y or un3l PD or intolerance Yes¶ Yes¶ Yes¶

Ac3ve in pa3ents with renal failure and cytogene3c risk groups

PNP grades 3 or 4: 16% (based on intravenous administra3on)

Not applicable

Only comparison between PAD-‐ASCT bortezomib with VAD-‐ASCTthalidoavailable

Summary of benefits and limitations of maintenance therapy with novel drugs for clinical decision making



Whether lenalidomide maintenance therapy should be routinely offered to patients is controversial among experts. Some consider the marked gain in PFS and the survival advantage observed in one of the 2 studies in younger patients as a strong argument for therapy, whereas others weigh the increased incidence of SPMs as an important risk and so prefer to wait for more mature survival data before making specific recommendations.

IMWG consensus on maintenance therapy in multiple myeloma

Ludwig et al Blood. 2012;119:3003-3015.





Allogeneic Stem Cell Transplantation

• High response rate • Graft-versus-myeloma immune effect • High mortality

– 10-20% with non-myeloablative transplants – 20-40% with ablative transplants

• Age limitation (Medicare does not pay for alloTx)

• Donor limitation • Documented long-term survival-20% ? CURE • Limited number of allogeneic SCTs still

performed in US





Tandem Autologous or Autologous è Non-Ablative Allograft for MM

N = 80

N = 82

Intent to Treat

Bruno et al, 2007.



1st Autologous Transplant

N=710

No Sibling Donor

Auto-Auto N=484

Sibling Donor Auto-Allo N=226

High Risk N=48

Standard Risk

N=189

Standard Risk

N=436

High Risk N=37

Main groups compared

BMT CTN 0102 Study Schema



Progression-free Survival Overall Survival

Prob

abilit

y, %

100

0

20

40

60

80

90

10

30

50

70

Mp10_5.ppt

Auto/Allo, 43% @ 3yr

Auto/Auto, 46% @ 3yr

p-value = 0.67 p-value = 0.19

Auto/Allo, 77% @ 3yr

Auto/Auto, 80% @ 3yr 100

0

20

40

60

80

90

10

30

50

70

0 6 12 18 24 30 36 42 48 436 424 406 395 370 348 305 107 79 189 183 167 160 156 143 124 43 27

Survival Outcomes after the First Transplant: Auto-Auto vs. Auto-Allo: Intent-to-treat analysis

Months 0 6 12 18 24 30 36 42 48

# at risk: Auto/Auto 436 395 348 292 242 213 178 54

42 Auto/Allo 189 165 138 117 105 89 71 23

16



Intermediate Risk

Kumar SK, et al. Mayo Clin Proc. 2009;84:1095-‐1110 (revised and updated, June 2010).

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

GEP •  High risk signature

FISH •  t (4;14)†

Cytogen3c dele3on 13 or hypodiploidy

PCLI ≥3%

All others including • Hyperdiploidy •  t (11;14)§ •  t (6;14)

High Risk Standard Risk*‡

*Note that a subset of pa3ents with these factors will be classified as high risk by GEP. †Prognosis is worse when associated with high beta-‐2 M and anemia. ‡LDH >ULN and beta-‐2 M >5.5 may indicate worse prognosis. §t (11; 14) may be associated with plasma cell leukemia.

mSMART 2.0: Classification of Multiple Myeloma

mSMART=Stra3fica3on for Myeloma And Risk-‐adapted Therapy. FISH=Fluorescence in situ hybridiza3on. GEP=gene expression profiling. PCLI=Plasma cell labeling index.





Bortezomib Administration: Impact on del(17p13) on PFS and OS.

Neben K et al. Blood 2012;119:940-948

For all patients with del(17p13), the median PFS times (A) and 3-year OS rates (B) in the bortezomib-based treatment arm B were better compared with the standard arm A.



Clinical Trials of Interest in US involving SCT with or without maintenance

Phase Sponsor Regimen

3 CTN0702 Single Autologous Transplant With or Without Consolidation Therapy Versus Tandem Autologous Transplant With Revlimid Maintenance

2 CTN Revlimid as Maintenance Therapy Post Allogeneic Hematopoietic Cell Transplantation for High-risk Multiple Myeloma

3 DFCI IFM Velcade Revlimid, Dexamethasone induction, consolidation, with or without autologous transplant followed by Revlimid maintenance

2 UCLA Autologous Peripheral Blood Progenitor Cell Transplantation With Velcade Maintenance as Treatment for Intermediate- and Advanced-Stage Multiple Myeloma

3 MSK Revlimid Plus Low-dose Dexamethasone (Rd x 4 Cycles) Then Stem Cell Collection Followed by Randomization to Continued Rd or Stem Cell Transplantation (SCT) Plus Maintenance Revlimid

2 COH Tandem High-Dose Therapy With Melphalan and Total Marrow Irradiation (TMI) With Peripheral Blood Progenitor Cell Support and Revlimid Maintenance

2 FHCRC Tandem Autologous HCT / Nonmyeloablative Allogeneic HCT From HLA-Matched Related and Unrelated Donors Followed by Velcade Maintenance Therapy for Patients With High-Risk Multiple Myeloma

2 FHCRC Velcade and Zolinza as Maintenance Therapy After Autologous Stem Cell Transplant



Conclusions • Autologous transplant remains a standard of care

(maintenance may be beneficial)

• New drug combinations for frontline therapy are under evaluation

– Bortezomib, lenalidomide, steroids, liposomal doxorubicin, cyclophosphamide • Improved EFS with transplant • Effect on OS with or without transplant are

unknown

• Allogeneic transplants are still investigational but may be a reasonable option for high-risk or relapsed young patients

EFS = event-free survival.



Health & Medicine

Managing Multiple Myeloma