stem cell transplant in multiple myeloma - Louisiana Oncology Society

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stem cell transplant in multiple myeloma - Louisiana Oncology Society

STEM CELL TRANSPLANT IN

MULTIPLE MYELOMA

Bachir Farah, MD

Tulane University

New Orleans, LA

LOS/MOS Spring Meeting

April 12-13, 2013

Point Clear, AL


Number of Transplants

Indications for Hematopoietic Stem Cell Transplants in

the United States, 2010

5,500

5,000

4,500

Allogeneic (Total N=8,860)

Autogeneic (Total N=9,026)

4,000

3,500

3,000

2,500

2,000

1,500

1,000

500

0

Multiple

Myeloma

NHL AML ALL MDS/MPD HD CML Aplastic

Anemia

Other

Leuk

Non-

Malig

Disease

Other

Cancer


Mortality, %

100-day Mortality after

Autologous Transplants, 2010

50

40

30

Early Disease

Intermediate/Advance Disease

Sensitive

Resistant

Group

20

10

0

Acute Leukemia

Non-Hodgkin

Lymphoma

Hodgkin

Disease

Multiple

Myeloma


TREATMENT HISTORY

Melphalan

(N Blokhin)

HDT with

Melphalan

(T. J. McElwain

and R. L. Powles)

Thalidomide

(S. Singhal and B.

Barlogie)

Tandem HDT

+ autoPBSCT

(Attal)

Pomalidomide

1958

1962

1983

1996

1999

2002

2003

2012

2013

Corticosteroids

(R. E. Maas)

HDT + autoPBSCT

(Attal)

1- Bortezomib (R. Z.

Orlowski)

2- Lenalidomide (P. G.

Richardson and K. C.

Anderson

Carfilzomib


ASCT Vs. Conventional CT

Results of Randomized Studies

Author N Age CR/VGPR EFS OS

Attal et al, 1996 (IFM90) 200 ≤ 65 Yes Yes Yes

Fermand et al, 1998

(MAG91)

185 < 55 Yes Yes No

Child et al, 2003 (MRC7) 401 ≤ 65 Yes Yes Yes

Palumbo et al, 2004

(IMMSG)

Fermand et al, 2005

(MAG95)

195 < 70 Yes Yes Yes

190 55-65 Yes Yes No

Blade et al, 2005 (PETHEMA) 164


Time-Dependent Endpoints (TDE) as Predictors of Overall

Survival in Multiple Myeloma

Felix et al. BMC Cancer March 2013

• TDEs including: TTP, PFS and EFS

• Studies (excluding allogeneic transplantation) published from 1970 to

2011 were systematically searched (PubMed).

• Correlation coefficients of median TTP, PFS, and EFS with median OS were

0.51 (P=0.003), 0.75 (P


Median TDS vs. Median OS

EFS r 2 : 0.84

PFS r 2 : 0.75

Felix et al. BMC Cancer March 2013


Single vs. Tandem AutoSCT

• Barlogie et al in Arkansas reported that one

approach to increasing the CR was to repeat

intensive treatments.

• IFM 94 was the first randomized trial comparing

single and double ASCT

• Two planned autologous SCTs within 6 monhts

- Stem cells collected before the initial transplant

- Half of the stem cells used for each procedure


Single vs. Tandem AutoSCT

Age

Pat

(n)

EFS ρ OS ρ

Attal et al

NEJM 2003

IFM94

Single

Tandem


Overall Survival after Tandem SCT


Allogeneic Stem Cell transplant in MM

Myeloablative Allogeneic

SCT

Associated with high mortality rate (20% to 40%)

Reduced-Intensity

conditioning allogeneic SCT

(Mini-allo SCT)

Associated with a lower mortality rate (10% to 20%)

Acute GVHD: 30%

Chronic GVHD 50%

3 studies published with controversial results (Different inclusion criteria

and conditioning regimen)

TRM ranged from 10% to 16% in the 3 studies

Double autologous vs.

tandem auto/Allo-RIC

transplantation

French IFM study (IFM 99-03/IFM 99-04): No benefit in CR, EFS and OS

(Attal et al. Blood 2006)

The Italian group study: increase in CR rate and significant survival

advantage (Bruno et al. NEJM 2007)

The Spanish group PETHEMA study: no significant difference in EFS and OS

(Rosinol et al. Blood 2008)


Probability of Survival, %

Probability of Survival after Transplants

for Multiple Myeloma, 2000-2010

- By Donor Type -

100

90

80

Autologous (N27,979)

100

90

80

70

60

50

40

30

20

10

0

P < 0.0001

0 1 2 3 4 5

6

Years

Sibling Donor (N=892)

Unrelated donor (N=380)

70

60

50

40

30

20

10

0


Early vs. Delayed AutoSCT

70

60

50

40

30

Early

Delayed

20

10

0

Median OS Median EFS TWiSTT*

*Time Without Symptoms , Treatment and Toxicity

Fermand J et al. Blood. 1998; 92:3131


Early vs. Delayed AutoSCT

Early AutoSCT

Delayed AutoSCT

Longer TWiSTT indicates that

QOL improved

VS

Risk of procedure becoming

unfeasible due to:

1- Refractory disease

2- Deterioration of

performance status

3- Comorbidity

Only 77% of the patients of the late ASCT arm could actually receive the planned

intensification at the time of relapse

Fermand et al. . Blood. 1998; 92:3131


ASCT IN THE ERA OF NOVEL AGENTS

• Novel agents have improved the rate of complete

remission (CR) both before and after ASCT.

• The rate of VGPR increased from 15% with VAD in

1990’s to 70% using triplet Bortezomib-

Dexamethasone based combinations.

• The rate of VGPR are further upgraded with

Melphalan 200 mg/m 2 as the conditioning

regimen prior to ASCT


Response Rates to Novel Agent-Containing Induction Therapy

and Clinical Outcomes After HDT-ASCT in phase III Trials


Achievement of VGPR to induction therapy is an important

prognostic factor for longer PFS in the IFM 2005-01 trial

Moreau et al. Blood 2011


Transplantation for Myeloma in the ERA of Novel

Therapies

Enhanced

quality and

depth of

response

Higher CR

Improved

PFS

Novel agents and ASCT are

complementary rather then alternative

treatment approaches


“The paradox of response and survival in cancer

therapeutics”

Carol Ann Huff, William Matsui, B. Douglas Smith and Richard J. Jones; Blood 2006

“Cancer stem cells”: Small population of cells able to self-renew and responsible for

the tumor to sustain . Biologically distinct from the bulk of differentiated cancer

cells that characterize the disease.

Bortezomib/Novel

therapy

High Dose

Melpahlan

•Inhibit Myeloma cells in vitro

•Little activity against myeloma stem cells “in vitro”

Affects Myeloma

stem cells

•Dramatic responses on the bulk of differentiated

plasma cells

•Limited activity against myeloma stem cells

responsible for disease persistence and re-growth

Mechanisms of action of the Novel agents are different from HDT.

The 2 treatment steps should be considered complementary.

Large randomized prospective trial will answer this question.


Timing of Transplant for MM in the ERA of Novel Therapies

Upfront vs. Salvage

Lenalidomide, Bortezomib, and dexamethasone

combination therapy in patients with newly

diagnosed MM

Richardson et al. Blood 2010

Lenalidommide plus high-dose dexamethasone vs

lenalidomide plus low-dose dexamethasone as initial

therapy for newly diagnosed multiple myeloma: an

open-label randomized controlled trial (ECOG E4A03)

Rajkumar et al. Lancet 2010

-NON RANDOMIZED PHASE 2 TRIAL

-CHOICE OF PRECEDING TO HDT OR NOT WAS

BASED ON PHYSICIAN OR PATIENT PREFERENCE

-SMALL NUMBER OF PATIENT (N=66)

-ONLY 28 PATIENTS PROCEEDED TO MAINTENANCE

OR ASCT AFTER 8 CYCLES OF RVD

-NON RANDOMIZED FOR ASCT

-AFTER 4 CYCLES OF THERAPY, PATIENTS HAD THE

OPTION OF PROCEEDING TO ASCT OR CONTINUING

ON THE ASSIGNED THERAPY

Early vs delayed autologous transplantation after

immunomodulatory agents-based induction

therapy in patients with newly diagnosed multiple

myeloma

Kumar, Rajkumar et al. Cancer 2012

- RETROSPECTIVE STUDY


Outcome with lenalidomide plus dexamethasone followed by early

autologous stem cell tranplantation in the ECOG E4A03 randomized trial

D.S. Siegel, S. Jacobus, S.V. Rajkumar et al. Blood 2010 (abstract 38)

Post Hoc , retrospective analysis of OS at 3-yr for patients


Melphalan/prednisone/lenalidomide vs high-dose melpahlan and

autologous transplantation (MEL 200) in newly diagnosed MM

Palumbo, Boccadoro et al Blood 2011;118; Abstract (3069)

FIRST PROSPECTIVE RANDOMIZED STUDY

COMPARING CCT PLUS NOVEL AGENTS WITH

TANDEM HIGH-DOSE MELPHALAN AND ASCT

IN NEWLY DIAGNOSED MM PATIENTS


Melphalan/prednisone/lenalidomide vs high-dose melphalan and

autologous transplantation (MEL 200) in newly diagnosed MM

Palumbo, Boccadoro et al Blood 2011;118; Abstract (3069)


Melphalan/prednisone/lenalidomide vs high-dose melpahlan and

autologous transplantation (MEL 200) in newly diagnosed MM

Palumbo, Boccadoro et al Blood. 2011:118: Abstract (3069)

100%

90%

80%

70%

60%

50%

40%

30%

20%

10%

0%

CR (p=.55)

PFS @ 24 months

54% VS. 73%

(p=.0002)

OS @ 24 months

(p=.19)

MPR

MEL200


IFM/DFCI 2009 study


Randomized phase III Study to Compare VMP

With High Dose Melphalan Followed by VRD

Consolidation and Lenalidomide Maintenance

in Patients with Newly Diagnosed MM

(NCT01208766)


COST EFFECTIVENESS

What about

the cost, guys?

Cost of ASCT:

50,000$ to 100,000$

Average of 75,000$

National Bone Marrow Transplant Link

(nbmtLink)

Cost of Novel therapies:

Lenalidomide: 78,183$/yr/patient

Thalidomide: 53,295$/yr/patient

Velcade: 27,120$/yr/patient

Richard Cook: Economic and Clinical Impact of

Multiple Myeloma to Managed Care, J Manag Care

Pharm. 2008

What about 3 drugs combinations

such as VRD??

What about the cost of supportive

care??


What about QOL?

NO RANDOMIZED TRIAL DONE TO COMPARE QOL BETWEEN UPFRONT ASCT AND NOVEL

THERAPIES

Upfront ASCT

Novel therapies

Adverse Events:

Longer time without symptoms

(Fermand et al, Blood 1998)

Longer time without treatment

(Fermand et al, Blood 1998)

Longer time without treatment

toxicity

(Fermand et al, Blood 1998)

Neutropenia (V, R)

Thrombocytopenia (V, R)

Anemia (V, R)

Infection (V, T, R)

Neurotoxicity (V, T)

Cutaneous toxicity (T, R)

GI toxicity (V, T, R)

Thrombosis (T, R)

Renal toxicity ( R)


Conclusion

• ASCT is a cost-effective procedure with a low mortality rate

• ASCT remains the standard of care

• Timing of transplant in the era of novel agents will be answered with the

ongoing prospective randomized trials

• Future randomized trials should also focus on defining a risk-adapted

initial therapy

• Allogeneic transplantation as frontline therapy should largely be

considered investigational

• Tandem ASCT may be superior to single transplant in patients failing to

achieve a VGPR with the first ASCT


Roasted Bone Marrow with Parsley Salad


THANK YOU

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