Treatment of Multiple Myeloma with Stem Cell Transplantation (SCT)
Görgün Akpek, MD, MHSDirector, SCT and Cellular Therapy Program
Adjunct Associate Professor of MedicineUniversity of Texas MD Anderson Cancer Center
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 old61% Males79% Skeletal X-ray abnormalities68% Bone pain62% Anemia55% Renal Insufficiency30% Hypercalcemia88% Proteinuria49% Bence Jones Proteinuria21% Hepatomegaly5% 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 o
f Tra
nspl
ants
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 2005Stem 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 differenceWe 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
karyotypingHigh-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-CD28
Artificial APC: Bead
Signal 1
Growth
CD28 CTLA4TcR/CD4
Signal 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
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T cell expansion
ex vivoCancerVaccine
“Thresholdfor cure”% Tumor
specificT cells in
vivo
Hypothesis
Combining Active and Passive Immunotherapy