Module 3: Multiple Myeloma Induction and Transplant Strategies Treatment Planning Challenge Question: Role of Autologous Stem Cell Transplant Which of the following is true about eligibility for high-dose therapy/autologous stem cell transplant? A. Advanced age is an absolute contraindication B. The patient s social network and support system should not impact eligibility C. Renal insufficiency renders one ineligible D. Comorbidities affect the benefit:risk ratio for autologous stem cell transplant 1
Challenge Question: The Value of Autologous Transplant Which of the following is true about autologous transplant regimens in multiple myeloma? A. Clinical trials have largely shown the benefit of autologous stem cell transplant in response rates, progression-free survival, and in some studies, overall survival B. The current body of data on autologous stem cell transplant was largely generated using older induction regimens (ie, not with novel therapies) C. Autologous stem cell transplant is still considered an important and relevant treatment option D. All of the above Challenge Question: Induction Regimens Which of the following regimens would not be appropriate for front-line therapy in a transplant-eligible patient? A. Bortezomib-dex B. Lenalidomide-dex C. VMP D. VTD 2
Challenge Question: Maintenance Regimens Which of the following is true about maintenance regimens for high-dose therapy/autologous stem cell transplant? A. Interferon remains the gold-standard maintenance regimen in myeloma B. Trials of thalidomide maintenance have shown consistently positive results C. None of the induction trials to date have included a maintenance therapy component D. There are several important ongoing clinical trials that address maintenance therapy in myeloma Learning Objectives 1. Define the role of HDT/autologous transplant in MM in the era of novel agents 2. Describe the evidence supporting the use of CR as an important response criterion in transplant-eligible MM patients 3. Define the current understanding of the impact of high-risk cytogenetic features on the response to therapy in MM patients 4. List the benefits and risks of allogeneic SCT in MM 5. Describe the evidence behind induction regimens containing novel agents 6. Identify key induction and maintenance trials in transplanteligible patients 3
Performance Goals For this core activity and the cases that follow 1. Avoid use of an induction regimen that compromises stem cell harvest in transplant-eligible patients For the cases that follow 1. Adopt an evidence-based definition of CR 2. Use CR as a surrogate marker 3. Choose a regimen with a high response rate 4. Use an evidence-based diagnostic workup (checklist) 5. Consider risk-factor assessment in evaluating the patient and choosing a regimen 6. Enroll patients in appropriate clinical trials Faculty William Bensinger, MD Director of the Autologous Stem Cell Transplant Program Fred Hutchinson Cancer Center Professor of Medicine University of Washington Seattle, Washington Neal Christiansen, MD Medical Oncologist South Carolina Oncology Associates Columbia, South Carolina Sagar Lonial, MD Associate Professor of Hematology and Oncology Director, Translational Research B-cell Malignancy Program The Winship Cancer Institute Emory University Atlanta, Georgia 4
Part 1 The Evolving Role of High-Dose Therapy/Autologous Stem Cell Transplant: What s Best? Patient Factors and HDT-SCT Eligibility Age Physiologic age more important than chronologic Benefit of transplant not as established in the really old (most studies had upper age limit cutoffs) Comorbidities affect the benefit:risk ratio COPD Cardiac disease Renal dysfunction alone is not an absolute contraindication for HDT-SCT* Patient s expressed wishes/support structure are important *NCCN guidelines stipulate that eligible patients should have sufficient liver, renal, pulmonary, and cardiac function. NCCN Clinical Practice Guidelines in Oncology v2.2008. Available at www.nccn.org/professionals/physician_gls/pdf/myeloma.pdf. Accessed July 27, 2008. Personal communication William Bensinger, MD. 5
IFM Analysis of Cytogenetics/β 2 -M on Survival After Tandem Autologous Transplant 1.0 FISH-, β 2 -M <4 Proportion Surviving 0.75 0.50 0.25 del13, β 2 -M <4 FISH-, β 2 -M >4 del13, β 2 -M >4 4;14,17p, β 2 -M <4 4;14,17p, β 2 -M >4 0.0 0 10 20 30 40 50 60 70 Months BLOOD by Avet-Loiseau. Copyright 2007 by American Society of Hematology (ASH). Reproduced with permission of American Society of Hematology (ASH) in the format Copy via Copyright Clearance Center. Avet-Loiseau H, Attal M, Moreau P et al. Blood. 2007;109:3489-3495. Evolution of CR Definitions Defining Group SWOG Criteria (1970s) 1 EBMT/IBMTR & ABMTR (1990s) 2 IMWG (2006) 3 Definition No definition for CR (too few patients achieved high level response) Objective response based on serum M protein synthetic rate, urine protein, clinical profile Absence of original monoclonal protein in the serum and urine (using immunofixation) for 6 weeks AND <5% normal plasma cells in bone marrow AND No increase in size or number of lytic bone lesions AND Disappearance of any soft tissue plasmacytomas Negative immunofixation on the serum and urine AND Disappearance of any soft tissue plasmacytomas AND 5% plasma cells in bone marrow 1. Alexanian R et al. Cancer. 1972;30:382-389. 2. Bladé J et al. Br J Haematol.1998;102:1115-1123. 3. Durie BGM et al. Leukemia. 2006;20:1467-1473. 6
Working Definitions of CR CR Classification Definition Traditional CR Stringent CR (not yet validated) Requires undetectable serum or urine monoclonal protein levels by sensitive assays, usually immunofixation, together with stable or improved bone disease, and no monoclonal plasma cells detectable in marrow Above definition plus a normal FLC ratio and absence of clonal cells in the marrow by immunohistochemistry or immunofluorescence Flow/Molecular CR (research tool) Absence of clonal myeloma cells in bone marrow as determined by (1)flow cytometry for myeloma-specific markers (eg, CD 38, CD138, CD45, kappa/lambda expression) (2)PCR for myeloma-specific molecular markers (ie, immunoglobulin gene rearrangements) Bensinger W. J Clin Oncol. 2008; 26:480-492. Durie BGM et al. Leukemia. 2006;20:1467-1473. Bladé J et al. Br J Haematol.1998;102:1115-1123. Cavo M et al. Blood. 2000;96:355-357. NCCN Clinical Practice Guidelines in Oncology. v2.2008. Available at www.nccn.org/professionals/physician_gls/pdf/myeloma.pdf. Accessed July 27, 2008. Zhao X et al. Am J Clin Pathol. 2006;125:895-904. Rawstron AC et al. Haematologica. 2008;93:431-4358. Value of CR Wang (ASH 2006) robust analysis: Reviewed the effect of response in 721 patients with newly diagnosed MM (up-front [induction] therapy +/- HDT-ASCT) Median survival With CR: 9-14 y With PR: 5.9 y Prolonged survival evident when intensive therapy induced a major response, especially CR Wang M et al. Blood;2006;108:123a-124a abstract 403. 7
Improving CR Criteria Value of defining minimal residual disease via PCR Small study post allogeneic transplant 1 Relapse rates: PCR negative: 0%; PCR mixed: 33%; PCR positive: 100% Need a more precise definition of CR? 2 Serum FLC assay More precise flow cytometry of marrow Improved molecular monitoring Novel imaging (ie, MRI) Measuring progression: challenges in interpreting immunofixation patterns 3 1. Corradini P et al. Blood. 2003;102:1927-1929. 2. Bensinger W. J Clin Oncol. 2008;26:480-492. 3. Lonial S, Gertz MA. Blood. 2008;111:3297-3298. Role for Tandem Transplant: Current Thinking CR or ncr: important marker of response from first transplant Patient who attains CR or ncr does not benefit from a second transplant Patients who achieve PR or stable disease with the first autologous transplant benefit from a second autologous transplant Maintenance therapy with thalidomide after the first autologous transplant (with second transplant reserved for relapse or progression) is more effective than tandem transplant NCCN Clinical Practice Guidelines in Oncology. v2.2008. Available at www.nccn.org/professionals/physician_gls/pdf/myeloma.pdf. Accessed July 27, 2008. Abdelkefi A et al. Blood. 2008;111:1805-1810. 8
Role for Allogeneic Transplant Positives High CR rates and improved survival Benefit of graft-versus-tumor effect Best chance for a cure Benefits in some high-risk cytogenetic groups who do not respond to autografts Negatives Only a limited number of patients eligible High treatment-related mortality (TRM) Reduced intensity conditioning (RIC) considered to reduce TRM, but it does not provide same response level Current recommendation: only use allogeneic transplant for MM patients in the context of a clinical trial. Bensinger WI. Leukemia. 2006;20:1683-1689. Kröger N. Leukemia. 2007;21:1851-1858. Garban F et al. Blood.2007;107:3474-3480. High-Risk Cytogenetic Features: Role for Allogeneic Transplant? Schilling and colleagues analyzed the most frequent genetic abnormalities in patients undergoing HDT/allogeneic transplant after melphalan/fludarabine Patients with del(17p): smaller percentage achieved CR (7% vs 56%; P=.001) and shorter EFS Only del(13) (HR: 2.34, P=.03) and del(17p) (HR: 2.24; P=.04) significantly influenced the incidence of relapse Major finding: t(4;14) did not even show a trend for less CRs or worse EFS or OS. Conclusions Del(17p) is a negative prognostic factor for achieving CR as well as for EFS after allogeneic HSCT Translocation t(4;14) might be overcome by allogeneic HSCT Schilling G et al. Leukemia. 2008;22:1250-1255. 9
Conclusions Autologous transplant is an important therapeutic option to consider for eligible MM patients While the ultimate goal of MM therapy is improved survival, attainment of a major response, such as CR, is an acceptable endpoint in the short-term for evaluating therapies in trials and in the clinic CR definitions have evolved over the years and have become more stringent A second autologous transplant does not add benefit when patients are still in a major response from the first autologous transplant Allogeneic transplant offers the chance for cure but is challenged by high TRM. Reduced intensity allografts hold promise, and allogeneic transplant may overcome some cytogenetic abnormalities that autologous transplant cannot Rechallenge Question: Role of Autologous Stem Cell Transplant Which of the following is true about eligibility for high-dose therapy/autologous stem cell transplant? A. Advanced age is an absolute contraindication B. The patient s social network and support system should not impact eligibility C. Renal insufficiency renders one ineligible D. Comorbidities affect the benefit-risk ratio for autologous stem-cell transplant 10
Rechallenge Question: The Value of Autologous Transplant Which of the following is true about autologous transplant regimens in multiple myeloma? A. Clinical trials have largely shown the benefit of autologous stem cell transplant in response rates, progression-free survival, and in some studies, overall survival B. The current body of data on autologous stem cell transplant was largely generated using older induction regimens (ie, not with novel therapies) C. Autologous stem cell transplant is still considered an important and relevant treatment option D. All of the above Thank you. Please continue to Section 2. 11