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Considerations for Optimizing Transplant in Multiple Myeloma Patient Management

Considerations for Optimizing Transplant in Multiple Myeloma Patient Management. PARAMESWARAN HARI MD MEDICAL COLLEGE OF WISCONSIN. Support Acknowledgement. This activity has been made possible through an unrestricted educational grant from Spectrum Pharmaceuticals.

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Considerations for Optimizing Transplant in Multiple Myeloma Patient Management

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  1. Considerations for Optimizing Transplant in Multiple Myeloma Patient Management PARAMESWARAN HARI MD MEDICAL COLLEGE OF WISCONSIN

  2. Support Acknowledgement This activity has been made possible through an unrestricted educational grant from Spectrum Pharmaceuticals

  3. Accreditation Information • Physician Accreditation Statement: This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint-sponsorship of Medical Education Resources (MER) and PleXus Communications. MER is accredited by the ACCME to provide continuing medical education for physicians. Credit Designation: Medical Education Resources designates this live activity for a maximum of 1.0 AMA PRA Category 1 Credit(s). Physicians should only claim credit commensurate with the extent of their participation in the activity.   • Nursing Accreditation: Medical Education Resources is an approved provider of continuing education by the Colorado Nurses Association, an accredited approver by the American Nurses Credentialing Center's Commission on Accreditation. This CE activity provides 1.0 contact hours of continuing nursing education. Medical Education Resources is a provider of continuing nursing education by the California Board of Registered Nursing, Provider #CEP 12299, for 1.0 contact hour. • Pharmacists: Educational Review Systems is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education. This program is approved for 1hour (0.1 CEUs) of continuing pharmacy education credit.  Proof of participation will be posted to your NABP CPE profile within 4 to 6 weeks to participants who have successfully completed the post-test. Participants must participate in the entire presentation and complete the course evaluation to receive continuing pharmacy education credit. UAN  # 0761-9999-16-015-L01-P Certificates will be mailed to participants in 4-6 weeks

  4. Faculty Disclosure Faculty: Disclosures:

  5. Learning Objectives After completing this program, participants should be able to: • Identify factors that might determine eligibility for and timing of high-dose chemotherapy (HDT) followed by autologous stem cell transplant (ASCT) in patients with multiple myeloma (MM) • Differentiate treatment strategies for patients with newly diagnosed multiple myeloma who are eligible for HDT/ASCT • Identify barriers in access to HDT/ASCT for MM • Review the rationale for conditioning regimens in patients with multiple myeloma who are eligible for HDT/ASCT • Compare and contrast pertinent data regarding a new formulation of melphalan

  6. Myeloma Overview

  7. Revised International Staging System (R-ISS) for MM • R-ISS I (n = 871) • Including ISS stage I (serum β2-microglobulin level < 3.5 mg/L and serum albumin level ≥ 3.5 g/dL) • No high-risk CA [del(17p) and/or t(4;14) and/or t(14;16)] • Normal LDH level (less than the upper limit of normal range) • R-ISS III (n = 295) • Including ISS stage III (serum β2-microglobulin level > 5.5 mg/L) • High-risk CA or high LDH level • R-ISS II (n = 1,894) • Including all the other possible combinations *At a median follow-up of 46 months Palumbo, et al. JCO. 2015;33(26):2863-2869.

  8. Indications for Considering Treatment (IMWG Consensus Guidelines) • At least one of the CRAB Criteria (evidence of end organ damage) • ≥60% clonal bone marrow plasma cells • Serum involved/uninvolved free light chain ratio ≥100 • >1 Focal bone lesion (≥5mm) on MRI • “Clinical judgement” Rajkumar, et al. Lancet Oncology. 2014;15(12):e538-48.

  9. Available Therapies and Phases of Treatment for MM Initial Therapy Consolidation / Maintenance Treatment ofRelapsed Disease ASCT if eligible* Supportive Care *Transplant eligibility may impact initial treatment decisions

  10. Treatment Goals for MM • Disease Response and Survival • Rapid cytoreduction to relieve symptoms • Minimize treatment-related toxicity • Prolong survival – Overall Survival • Symptom Control • Ameliorate pain and other disease-related symptoms • Prevent further organ damage • Preserve performance status and quality of life

  11. AUTOLOGOUS TRANSPLANTATIONTransplant Vs Conventional Therapy

  12. Meta-analysis of PFS: Standard Chemotherapy vs Autologous SCT Favors HDT Favors SDT PFS (95%CI) IFM90 MAG90* MAG91 MRC7 S9321 PETHEMA* HOVON* M97G* IFM9906*† Combined Sensitivity/Sub-group Analyses Excluding Non-Standard RCTs RCTs preferring PBSCs RCTs with Longer Follow-up RCTs with Lower Crossover ‡ 0.61 (0.42, 0.89) 0.42 (0.30, 0.58) 0.76 (0.57, 1.02) 0.68 (0.54, 0.85) 0.87 (0.72, 1.06) 0.85 (0.60, 1.22) 0.85 (0.63, 1.14) 0.48 (0.34, 0.66) 1.80 (1.30, 2.50) 0.75 (0.59, 0.96) 0.75 (0.65, 0.87) 0.77 (0.59, 1.00) 0.70 (0.51, 0.96) 0.72 (0.62, 0.83) .1 .5 10 1 5 Hazard Ratio of Progression • *Nonstandard study • † Patients aged >65 years • ‡ Two negative studies (HOVON, IFM9906) with missing crossover information were omitted from this analysis. • Figure from: Koreth J, et al. Biol Blood Marrow Transplant. 2007;13:183-196.

  13. AHCT Has Changed Natural History of MM: Population-level Data Changes in MM relative survival ratio in the Netherlands ≤ 65 years > 65 years Figure from Schaapveld M, et al. Eur J Cancer . 2009;46:160.

  14. High-dose Melphalan + ASCT vs Chemotherapy + Lenalidomide Followed by Lenalidomide + Prednisone vs Lenalidomide Maintenance in MM Induction Four 28-day cycles of lenalidomide (25 mg on days 1–21) and dexamethasone (40 mg on days 1, 8, 15, and 22) Induction CY (3g/m2) MOBILIZATION CY (3g/m2) MOBILIZATION Collection Cyclophosphamide, Lenalidomide, Dexamethasone High-dose Melphalan + ASCT Consolidation Lenalidomide Lenalidomide + Prednisone Lenalidomide Lenalidomide+ Prednisone Maintenance Gay, et al. Lancet Oncol. 2015;16:1617-1629.

  15. Longer PFS with High-dose Melphalan + ASCT vs Chemotherapy + Lenalidomide • Median follow-up was 52.0 months • Median PFS with consolidation therapy • High-dose melphalan + ASCT: 43.3 months • Chemotherapy + lenalidomide: 28.6 months (HR for the first 24 months = 2.51, P < .0001) • Median PFS with maintenance therapy • Lenalidomide + prednisone: 37.5 months • Lenalidomide: 28.5 months (HR = 0.84, P = .34). • 4-year OS • High-dose melphalan + ASCT: 86% • Chemotherapy + lenalidomide: 73% (HR = 2.40, P = .004). Gay, et al. Lancet Oncol. 2015;16:1617-1629.

  16. Phase 3MPR Consolidation vs Tandem MEL200 Lenalidomide + low-dose Dexamethasone Induction 4 cycles (N = 402) MPR 6 cycles (n = 202) MEL 200 (n = 200) Lenalidomide Maintenance 10 mg, d 1-21 (n = 98) Lenalidomide Maintenance 10 mg, d 1-21 (n = 100) No Maintenance (n = 104) No Maintenance (n = 100) MPR: melphalan, prednisone, lenalidomide Palumbo, et al. N Engl J Med. 2014;371:895-905.

  17. Tandem MEL-200 Improves OS Progression Free Survival Survival Tandem Transplant + Len Tandem Transplant, NO Len NO Transplant + NO Len Tandem Transplant + Len 63% of relapsed non transplant pts received ASCT Palumbo, et al. N Engl J Med. 2014;371:895-905.

  18. Mel200-ASCT vs Chemotherapy + Lenalidomide: PFS Median Follow-up from Randomization: 4 Years 1.00 0.75 0.50 0.25 0 PFS (% of patients) Mel200-ASCT: PFS 41 months CC + R: PFS 26 months HR, .55; 95% CI, .45-.69; P < .0001 0 10 20 30 40 50 60 70 80 Months Gay, et al. Blood. 2014;124:Abstract 198.

  19. Mel200-ASCT vs Chemotherapy + Lenalidomide: OS Median Follow-up from Randomization: 4 Years 1.00 0.75 0.50 0.25 0 Mel200-ASCT: OS 84% OS (% of patients) CC + R: OS 71% HR, .59; 95% CI, .40-.87; P = .008 0 10 20 30 40 50 60 70 80 Months Gay, et al. Blood. 2014;124:Abstract 198.

  20. 100 100 90 90 80 80 70 70 60 60 50 50 40 40 30 30 20 20 10 10 0 0 Transplant Outcomes Improving Over Time 2005-2010 (n=2,223) 2000-2004 (n=1,464) Probability, % 1995-1999 (n=686) * vs. 1995-1999, P<0.05 # vs. 2000-2004, P<0.05 Years1995-99 72% 47%2000-04 81%* 55%*2005-10 86%*# 57%* 3 4 0 1 2 5 Costa LJ et al. BiolBlood Marrow Transplant. 2013 Nov;19(11):1615-24

  21. Bortezomib-based vs Non-bortezomib—based Induction Treatment Before ASCT Sonneveld. J Clin Oncol. 2013;31(26):3279-87.

  22. Bortezomib-based vs Non-bortezomib—based Induction Treatment Before ASCT Median TTP 37.5 months vs 31.3 months; P< 0.0001 Sonneveld, et al. J Clin Oncol. 2013;31:3279-3287.

  23. Earlier Phase Studies: Induction Regimens for Transplantation-Eligible Pts 100 81 80 67 68 60 58 60 Pts Achieving ≥ VGPR (%) 40 20 0 RVD[1] KRd[2] KTd[4]] CyBorD[5] Ixazomib/RD[7] [1]Richardson, PG et al. Blood. 2010;116:679-686. [2]Jakubowiak A, et al. Blood. 2012;120:1801-1809. [3] Jasielec J, et al. ASH 2013. Abstract 3220. [4] Sonneveld P, et al. Blood. 2015;125:449-456. [5]Reeder CB, et al. Blood. 2010;115:3416-3417. [6]Reeder CB, et al. ASH 2013. Abstract 3192. [7]Kumar SK, et al. Lancet Oncol. 2014;15:1503-1512.

  24. Autologous transplantationEarly vs Late HCT

  25. Early vs Late SCT: Ongoing Phase 3 Study in Newly Diagnosed MM SCT Candidates (IFM/DFCI 2009) Randomize RVDx3 Induction RVDx3 CY (3g/m2) MOBILIZATION Goal: 5 x106 cells/kg CY (3g/m2) MOBILIZATION Goal: 5 x106 cells/kg Collection Melphalan 200 AHCT + RVD x 2 Consolidation RVD x 5 Lenalidomide Maintenance Lenalidomide RVD: lenalidomide, bortezomib and dexamethasone AHCT at relapse ClinicalTrials.gov Identifier: NCT01208662

  26. IFM 2009: Best Response. Attal M et al Blood 2015 126:391

  27. IFM 2009: PFS (9/2015) Attal M et al Blood 2015 126:391

  28. IFM/DFCI 2009: PFS according to MRD (FCM) post consolidation (9/2015). RVD Arm Transplant Arm Attal M et al Blood 2015 126:391

  29. AUTOLOGOUS transplantWho, When and How?

  30. Transplant Ineligible vs Transplant Eligible Transplant Ineligible Transplant Eligible Good performance status Adequate organ function Compensated comorbidities Social economic factors Adequate care givers Adequate support for transport to and from transplant center Ability to comply with peritransplant follow-up care Willing to proceed • Poor performance status • Elderly and frail • Unable to perform activities of daily living • Decompensated comorbidity • Social economic factors • Patient choice • Very low-risk disease • Asymptomatic myeloma • Solitary plasmacytoma • Age should not be considered an absolute contraindication for SCT Rajkumar SV, et al. Mayo Clin Proc. 2005;80(10):1371-1382. Harousseau JL, et al. N Engl J Med. 2009;360(25):2645-2654.

  31. Influence of Response After Induction: Superior Outcome When CR is Achieved Before ASCT CR vs nCR: P = .1 CR vs PR: P = .07 CR vs SD: P = .02 nCR vs PR vs SD: P = .9 CR vs nCR: P = .1 CR vs PR: P = .05 nCR vs PR: P = .9 1.0 0.9 1.0 0.8 0.9 0.7 0.8 0.6 0.7 OS (Probability) EFS (Probability) 0.5 0.6 0.4 0.5 0.3 0.4 0.2 0.3 0.1 0.2 0 0.1 0 12 24 36 48 60 72 84 96 12 24 36 48 60 72 84 96 0 Mos Mos 0 CR (n = 101) nCR (n = 96) PR (n = 346) SD (n = 63) PD (n = 26) Lahuerta JJ, et al. J Clin Oncol. 2008;26:5775-5782.

  32. 100 100 90 90 80 80 70 70 60 60 50 50 40 40 30 30 20 20 10 10 0 0 Outcomes with/without Pre-ASCT Salvage PFS OS P = .3470 P = .2622 NO SALVAGE (n=251) SALVAGE (n=324) SALVAGE (n=324) NO SALVAGE (n=251) P = NS P = NS 0 0 2 2 4 4 6 6 8 8 10 10 Years Years Vij, et al. Blood. 2012;120(21): Abstract 597

  33. International Myeloma Working Group (IMWG) Consensus Recommendations for Cell Doses • Is there an optimum CD34+ cell dose to be infused? • Cell doses > 3 × 106 CD34+ cells/kg associated with better outcomes[1-3] • Studies primarily retrospective • Recommendation: the issue of optimal CD34+ cell dosing in aHSCT for MM requires a prospective clinical trial • Is there an optimal dose of CD34+ cells to be collected? • Recommendations[1] • Minimum target of 4 × 106 CD34+ cells/kg should be collected • If feasible an average of 8-10 × 106 CD34+ cells/kg should be collected • These targets allow most patients to undergo at least 2 aHSCT, each with an optimal cell dose aHSCT, autologous hematopoietic stem cell transplantation; MM, multiple myeloma. [1]Desikan JR, et al. Br J Haematol. 2001;112:242-247. [2]Bensinger W, et al. J Clin Oncol. 1995;13:2547-2555. [3] Weaver CH, et al. Blood. 1995;86:3961-3969. [4] Giralt S, et al. Leukemia. 2009;23:1904-1912

  34. Myeloma X: High-dose Melphalan + Salvage ASCT vs Cyclophosphamide in R/R MM Randomized 1:1 Melphalan 200mg/m2IV + ASCT (n = 89) R/R MM; >18 mos after prior ASCT (N = 293) PAD induction 2-4 cycles Cyclophosphamide 400mg/m2 PO/wk x12 cycles (n = 85) • PAD induction therapy:Bortezomib + Doxorubicin + Dexamethasone 2-4 cycles • PBSC mobilization and harvesting if applicable • Removed from study if PD orCD34+ cells <2x106/kg • Primary endpoint: time to disease progression • Secondary endpoints: OR, PFS, OS, toxicity, safety, pain, QoL Cook G, et al. Lancel Oncol. 2014;15:874-885.

  35. Myeloma X: Response Rates with High-dose Melphalan/2nd ASCT vs Cyclophosphamide PFS 39.3% 22.4% P = .012 • ≥ VGPR rate: 59.5% after salvage ASCT vs 47.1% after cyclophosphamide (OR: 0.38 [95% CI: 0.2-0.7]; P = .0036) Cook G, et al. Lancet Oncol. 2014;15:874-885.

  36. Barriers to Autologous Transplant Access SOCIAL Age Ethnicity and race Language Culture Health literacyPatient/family attitudesCaregiver availability ECONOMIC Socioeconomic status EducationNumber of wage earners Employment status Insurance coverage Place of residenceTransportation ACCESS TO TRANSPLANT HEALTH CARE SYSTEM Limited number of HCT centers Workforce shortageCapacity limitationsInfrastructure issues PROVIDER Physician referralProvider attitudes/biases Provider expertiseProvider diversity Adapted from: Majhail NS, et al. Biol Blood Marrow Transplant. 2010;16(8):1070-1075.

  37. Elderly Patients and Black Patients Are Less Likely to Obtain HCT Referral CI, confidence interval; OR, odds ratio. Survey of hematologists/oncologists in the United States about HCT referral practices The odds of not receiving HCT are listed in the table Pidala J, et al. Bone Marrow Transplant. 2013;48:63–67.

  38. Factors to be Considered in the Treatment of Elderly Patients • Lower functional capacity (performance status, activities of daily living [ADL score], cognitive function) • Comorbidities(renal, pulmonary, hepatic, cardiac, bone marrow) • Disability • Frailty(weakness, poor endurance, weight loss, low physical activity, slow gait speed) • Ahigher prevalence of unfavorable prognostic factors (β2-microglobulin ≥3.5 μg/mL, albumin <3.5 g/dL, hemoblobin <10 g/dL, International Staging System [ISS] stage III) • Polypharmacy • Lower capacity to tolerate toxicity • Therapy should be adjusted according to risk groups defined by age, comorbidity, organ function, disability, and frailty Ludwig, et al.Oncologist. 2012;17: 592–606

  39. Role of Maintenance Therapy

  40. Maintenance in Myeloma • PFS advantage[1-3] • OS improvements?[2] • Toxicities of treatment • Myelosuppression[3] • Second primary malignancies[3,4] • Quality of life • Unclear whether all patients benefit from maintenance • Unclear which agent and duration of therapy [1]Attal M, et al. ASH 2013. Abstract 406. [2] McCarthy PL, et al. N Engl J Med. 2012;366:1770-1781. [3] Attal M, et al. N Engl J Med. 2012;366:1782-1791. [4] Palumbo A, et al. Lancet Oncol. 2014;15:333-342.

  41. The Deeper the Response, the Longer PFS Figure from: Bruno Paiva et al. Blood . 2015;125:3059-3068

  42. MM MRD Testing by Flow Cytometry: U.S. in 2015 53 year old female with myeloma Abnormal plasma cells at diagnosis: CD19-, CD45-, CD38 dim, CD20-, CD56+, CD81, CD27 dim Now MRD work-up post therapy 1 Million cells 3 Million cells 500,000 cells 100,000 cells No abnormal plasma cells 6 abnormal plasma cells 12 abnormal plasma cells 30 abnormal plasma cells Mailankody et al. Nature Reviews. 2015;12:286–295

  43. Features of Currently Available Techniques to Monitor MRD in MM Table from: Bruno Paiva et al. Blood . 2015;125:3059-3068

  44. Imaging of Residual Disease in MM • PET may be useful for some, but not all, patients • Variability in PET approaches across different studies and institutions PET/CT[1,2] PFS (CR Pts After First-line Therapy) 1.0 PET CRmedian: 90 mos 0.8 0.6 PFS (Proportion) 0.4 NO PET CRmedian: 50 mos 0.2 P = .010 0 Mos 0 12 24 36 48 60 72 [1]Zamagni E, et al. Blood. 2011;118:5989-95. [2]Zamagni E, et al. ASH 2013. Abstract 1936.

  45. Awaited Phase 3 Upfront Transplant Study: BMT CTN 0702 Lenalidomide Maintenance Register and Randomize Lenalidomide Maintenance MEL 200mg/m2 RVD x 4 MEL 200mg/m2 Lenalidomide Maintenance Primary End Point PFS RVD: lenalidomide, bortezomib and dexamethasone ClinicalTrials.gov Identifier: NCT01109004

  46. Can We CHANGE Conditioning?

  47. Conditioning Regimens for MM • Anti Myeloma activity • Standard • MELPHALAN; TBI (total body radiation) • Investigational • TOXICITY • Mortality (TRM) – very low for MEL 200 mg/m2 • GI toxicity – dose limiting toxicity • Pulmonary Syndrome • Arrhythmias • COST • Days in Hospital • Cost of procurement • Timely availability – e.g TBI / Thiotepa in the USA

  48. High-dose Melphalan is the Most Frequently Used Conditioning Regimen CIMBTR 2010

  49. Melphalan Dose for Transplant • MEL 200 mg/m2 is standard • MEL 200 – popularized by Royal Marsden , UK (Cunningham, et al) • IFM 90 randomized trial (Attal, et al) established ASCT as standard of care • Used MEL 140 + 8 Gy TBI as conditioning • Retrospective EBMT study (Bjorkstrand, et al) • OS and PFS better for MEL over MEL TBI • IFM 95-02 Randomized study of MEL 200 vs MEL 140 + TBI ( total body irradiation)

  50. High-dose Melphalan (200 mg/m2) is the Proven Conditioning Regimen for MM Survival 100 90 80 70 60 50 40 30 20 10 0 MEL 200 Overall Survival Rate TBI + MEL 140 P = 0.05 0 10 20 30 40 50 Months Moreau, P. et al. Blood;2002;99:731-735.

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