Treatment of Multiple Myeloma with Stem Cell Transplantation (SCT) Görgün Akpek, MD, MHS Director, SCT and Cellular Therapy Program Banner MD Anderson Cancer Center GAkpek@mdanderson.org
MULTIPLE MYELOMA Plasma cell neoplasm Malignant plasma cell proliferation in the BM Monoclonal Immunoglobulin (or light chain) in serum + urine
Multiple Myeloma Presenting 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
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 (Possible but expensive)
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 to the patients like a blood transfusion (Day 0) Stem cells grow in the empty but intact marrow and give rise new blood cells within 2 weeks Patients are discharged home and followed in the clinic
History of Hematopoietic Stem Cell Transplantation Appelbaum F. N Engl J Med 2007;357:1472-1475
Indications for Hematopoietic Stem Cell Transplants in the United States, 2009 Number of Transplants 5,500 5,000 4,500 4,000 3,500 3,000 2,500 2,000 1,500 Allogeneic (Total N=7,012) Autologous (Total N=9,778) 1,000 500 0 Multiple Myeloma NHL AML HD ALL MDS/MPD Aplastic Anemia CML Other Leuk Non- Malig Disease Other Cancer
<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 transplant R R R R 65% 35% R R R R R R R = Recurrence of Myeloma
How can we further improve transplant outcomes? Planned Tandem (double) transplants Select cases Consolidation therapy after initial transplant Some centers Maintenance therapy Cost/benefit ratio is high Reduced intensity allogeneic transplantation Benefit in select cases New Preparative Regimens Needed
46 43 Somewhat higher CR rate and questionable survival benefit with double SCT
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 McCarthy et al. CALGB trial. NEJM 2012 568 patients Median TTP: 46 vs. 27 months OS: p=0.03 Lenalidomide was associated with: Neutropenia Immunosuppression 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
Risk Stratification of Myeloma (Mayo Clinic) 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
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
Advances in Cellular Therapy in Myeloma University of Texas MD Anderson Cancer Center 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
Idiotype Vaccine Preparation
Activated T Cell Production Ex Vivo 1. Leukapheresis, enrich, deplete, or isolate cells of interest 5. Quality Control Reinfuse cells 4. Remove beads, wash and concentrate cells 3. Large scale cell expansion 2. Stimulate cells with aapc
Activated T Cell Production with Artificial APCs Cellular and Vaccine Production Facility CVPF Artificial APC: Bead Anti-CD3 Anti-CD28 TcR/CD4 Signal 1 CD28 CTLA4 Signal 2 J Immunol 1997; 159: 5921 Science 1997; 276: 273 Immunol. Rev. 1997; 160: 43 Mol. Ther. 2004; 9; 902 Exp. Opin. Biol. Ther. 2008; 8: 475
MLN9708 (Ixazomib) Second generation small molecule proteasome 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-yr P=0.12 63 vs. 45% @ 2-yr P=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 benefit from advances in stem cell transplantation and incorporation of novel agents in 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 prognosis 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
Combining Active and Passive Immunotherapy 100 % Tumor specific T cells in vivo 10 1 0.1 0.01 Hypothesis Threshold for cure Cancer Vaccine T cell expansion ex vivo