Treatment of Multiple Myeloma with Stem Cell Transplantation (SCT)

Görgün Akpek, MD, MHS

Director, SCT and Cellular Therapy Program

Adjunct Associate Professor of Medicine

University of Texas MD Anderson Cancer Center

GAkpek@mdanderson.org

MULTIPLE MYELOMAA plasma cell neoplasm

Malignant plasma cell proliferation in the BMMonoclonal Immunoglobulin (or light chain) in serum + urine

Multiple MyelomaPresenting Features

98% >40 years old

61% Males

79% Skeletal X-ray abnormalities

68% Bone pain

62% Anemia

55% Renal Insufficiency

30% Hypercalcemia

88% Proteinuria

49% Bence Jones Proteinuria

21% Hepatomegaly

5% Splenomegaly

Kyle RA, Mayo Clin Proc 1975:50:29

Life expectancy is doubled in myeloma Now, average 7 years after diagnosis

Kumar S K et al. Blood 2008;111:2516-20

Longer survival is directly related to depth of response to therapy

• Complete response (CR): No detectable disease

• Partial response (PR): Still detectable disease

• No response: Poor outcome

2.5 years

4 years

5 years

Improvement in survival of patients with myeloma is multifactorial

• Initial (Induction) Therapy (2-4 months)• Stem Cell Transplantation (Highest CR rate)• Post-transplant Consolidation and Maintenance (Some

additional benefit)• Supportive Care (Critical)• Treatment of Relapsed Disease (Clinical trials)

Hematopoietic Stem Cell (CD34+ cells)

Stem Cell Donor Selection

• Autologous (from patients)• Matched Sibling/Related Donor (MRD)• Matched Unrelated Donor (MUD)• Cord Blood Unit (>4/6 match with adequate cell dose)• Mismatched Related/Unrelated (MMURD)• Haploidentical (parent or child)

• Source of Stem Cells– Peripheral Blood Stem cells

• Shorter time to engraftment

– Bone Marrow Stem Cells• Less chronic GVH

How do we perform Stem Cell Transplantation?

Patients are initially treated to reduce myeloma cells in BM Stem cells are

mobilized from bone marrow into blood collected by apheresis processed & frozen in vaporized liquid nitrogen containers (-200 C)

Patients are treated with high dose Melphalan chemotherapy Stem cells are thawed at the bedside and infused like a blood

transfusion (Day 0) Stem cells grow in the empty marrow and produce new blood

cells within 2 weeks Patients are discharged home and followed in the clinic

Appelbaum F. N Engl J Med 2007;357:1472-1475

History of Hematopoietic Stem Cell Transplantation

Indications for Hematopoietic Stem Cell Transplants in the United States, 2009

Num

ber

of

Transp

lants

0

500

1,000

1,500

2,000

2,500

3,000

3,500

4,000

4,500

5,000

5,500

MultipleMyeloma

NHL AML HD ALL MDS/MPD AplasticAnemia

CML OtherLeuk

Non-Malig

Disease

OtherCancer

Allogeneic (Total N=7,012)

Autologous (Total N=9,778)

<65

Blood 2005

Stem cell transplant adds one more year to patient survival

Why Stem Cell Transplant in the Era of Novel Therapy?

• Safer than before – Deaths due to transplant 1-2% (was 3-5%)

• Improves outcome when combined with newer agents– Doubles CR rate 30-35% (Harousseau J, JCO 2010, Cavo M,

Lancet 2010)– More durable responses (remission of disease)

– Probably still longer overall survival with SCT

• Longer duration of remission and better Quality of Life with upfront (early) Stem Cell Transplant

• Cumulative cost of SCT is similar to novel agents x 6 mos

Why early SCT is recommended?

Chemotherapy or Novel agent therapy alone (No transplant)

Early transplantR RR R

RR RR

R = Recurrence of Myeloma

65%

35%

R R

How can we further improve transplant outcomes?

• Planned Tandem (double) transplants– Select cases

• Consolidation therapy after initial transplant– Controversial

• Maintenance therapy– Cost/benefit ratio is high

• Reduced intensity allogeneic transplantation– Benefit in select cases

• New Preparative Regimens– Needed

4643

Higher CR rate and longer EFS with double transplant but survival benefit is less clear

The study was not statistically powered to evaluate this difference

We probably don’t need to do second transplant in all patients

Post-transplant Consolidation Therapy

• Short-term multiagent treatment after auto-HCT to improve the depth of response

• It is associated with– Improvement in CR– Improvement in PFS

• Cavo M et al. Blood 2012

• Consider in select high risk cases who have less than CR after auto-SCT and not eligible to undergo tandem SCT (Medicare patients).

Maintenance Therapy after Transplant

• Thalidomide– Attal et al. Blood 2006 (597 patients)

• Observation vs. Pamidronate vs. Thalidomide• 3-year EFS: 38, 39 and 51%• 4-year OS: 77, 74 and 87%

– Spencer et al. JCO 2009 (269 patients)• Prednisolone vs. Thalidomide + Prednisolone• 3-year PFS: 23 vs. 42%• 3-year OS: 75 vs. 86%

– 1 trial (MRC IX) showed improvement in PFS but not OS• Morgan GI et al. Blood 2012

Maintenance Therapy after Transplant

• Lenalidomide vs. Placebo

– Attal et al. IFM Trial. NEJM 2012• 614 patients• Median EFS: 40 vs. 23 months• No survival benefit

– McCarthy et al. CALGB trial. NEJM 2012• 568 patients• Median TTP: 46 vs. 27 months• OS: p=0.03

– Lenalidomide was associated with:• Neutropenia• Blood clots • Increased second cancers?

The Improved Outcome in Myeloma is Not Seen in High-Risk Patients

Life expectancy: – Standard Risk Disease : 8-9 years– High Risk Disease: 2-3 years

Investigations for Risk Stratification

• Conventional studies– Conventional Karyotyping (Cytogenetics)– Fluorescent in-situ hybridization (FISH)

• Newer Studies– Comparative Genomic Hybridization (CGH) Array– Single Nucleotide Polymorphism (SNP) array– Gene expression profiling (GEP)– Positron Emission Tomography (PET)

• >3 FDG-avid lesions Poor– Magnetic Resonance Imaging (MRI)

• CR on MRI correlates with superior outcome

Risk Stratification of Myeloma(IMWG)

• High-Risk– By conventional karyotyping

• del 13 or 13q• t(4;14)• del 17p

– By FISH• t(4;14)• t(14;16)• Del 17p

• Standard-Risk– All others

Standard-risk (70%)

•  Hyperdiploidy

•  t (11;14)

•  t (6;14)

Intermediate-risk (10-15%)

•  t (4;14)

•  Deletion 13 or hypodiploidy by conventional karyotyping

High-risk (15% of all cases)

•  17p deletion

•  t (14;16)

•  t (14;20)

• High-risk gene expression profiling signature• Plasma cell leukemia• Multiple extramedullary plasmacytomas

Risk Stratification of Myeloma(Mayo Clinic)

Treatment Goal in High-Risk MM

• Achievement and maintenance of CR with more intense treatment strategies– Rajkumar SV AJH 2012; Haessler J, Clin Cancer Res 2007

• Bortezomib should be part of treatment in all phases in patients with t(4;14)

• Thalidomide or Lenalidomide do not improve outcome in t (4;14) or del 17p

Multiple myeloma: Update on diagnosis, risk‐stratification, and management

Blood 2011; 87: 78-88

Randomized Phase II Trial Of CD3/CD28 Activated Id-KLH Primed Autologous Lymphocytes In Patients With Myeloma Undergoing Autologous Transplant

Phase II Study of the combination of MLN 9708 with Lenalidomide as Maintenance Therapy post Autologous Stem Cell Transplant in Patients with Multiple Myeloma

Allogeneic Hematopoietic Stem Cell Transplantation for High-Risk Myeloma

Advances in Cellular Therapy in MyelomaUniversity of Texas

MD Anderson Cancer Center

Idiotype Vaccine Preparation

Activated T Cell Production Ex Vivo

1. Leukapheresis, enrich, deplete, or isolate cells of interest

3. Large scale cell expansion

Reinfuse cells

4. Remove beads, wash and concentrate cells

2. Stimulate cells with aAPC

5. Quality Control

J Immunol 1997; 159: 5921 Science 1997; 276: 273Immunol. Rev. 1997; 160: 43Mol. Ther. 2004; 9; 902Exp. Opin. Biol. Ther. 2008; 8: 475

Anti-CD3Anti-CD3Anti-CD28Anti-CD28

Artificial APC: Bead Artificial APC: Bead

Signal 1Signal 1

Growth

CD28 CTLA4 CD28 CTLA4TcR/CD4TcR/CD4

Signal 2Signal 2

Activated T Cell Production with Artificial APCsCellular and Vaccine Production Facility CVPF

MLN9708 (Ixazomib)

• Second generation small molecule proteosome inhibitor.

• Orally bioavailable.

• Longer survival time in mice vs. bortezomib.

• Less risk of neuropathy.

• Several trials have demonstrated efficacy in relapsed/refractory myeloma.

Chauhan et al. CCR 2011

Allogeneic SCT for Multiple Myeloma

• Only therapy with a potential to cure the disease

• Graft-versus-myeloma effect – Usually associated with GVHD– Not effective in extramedullary myeloma

• Treatment-related mortality remains a major obstacle– GVHD, regimen related toxicity, and infection.

Allogeneic SCT is potentially curative in myeloma

Barlogie et al. JCO 2006

TRM has decreased with RIC regimens

Crawley et al. Blood 2007

FM100 vs. FM140(Protocol # ID01-518)

41 vs. 24% @ 2-yrP=0.12

63 vs. 45% @ 2-yrP=0.38

Bashir et al MDACC. Submitted 2013

Bortezomib With Tacrolimus And Methotrexate Reduces The Risk Of GVHD In Mismatched Transplantation

Koreth et al. JCO 2012

Conclusions

• Patients with standard-risk myeloma highly benefit from stem cell transplantation and incorporation of novel agents in their treatment plans

• High-risk myeloma has significantly worse outcome even in the era of novel agents and tandem transplants

• New anti-myeloma agents and novel cellular therapies targeting common myeloma antigens are likely to change the poor outlook in high-risk myeloma.

Stem Cell Transplantation Program Jan 14, 2014 (First year)

Additional Slides

Adoptive T Cell Therapy

• Adoptive transfer comprises of the infusion of immunocompetent cells for the treatment of cancer or infectious disease

• Adoptively transferred T cells can persist for at least a decade in humans

• T cells produce effector and central memory subsets that have extensive replicative capacity and stem cell like qualities

• Dr. June’s laboratory has developed a novel “prime-and-boost” strategy by collecting T lymphocytes from patients that have been vaccine-primed in vivo

• These cells are activated and expanded ex vivo with anti-CD3/CD28 coated magnetic beads (artificial antigen -presenting cells), and reinfused after lymphocytotoxic chemotherapy

• Adoptive T-cell transfer can facilitate both humoral and cellular immune responses to vaccination despite cytotoxic therapy

100

10

1

0.1

0.01

T cell expansion

ex vivoCancerVaccine

“Thresholdfor cure”% Tumor

specificT cells in

vivo

Hypothesis

Combining Active and Passive Immunotherapy