Optimizing the Treatment of Transplant- Eligible Patients in Multiple Myeloma

Transcription

1 Optimizing the Treatment of Transplant- Eligible Patients in Multiple Myeloma Wednesday, April 10 th, 2013 Chair: Dr. Ade Olujohungbe MD, FRCP, FRCPath Speaker: Dr. Joseph Mikhael MD, MEd, FRCPC, FACP To edit footers: "insert tab>header and footer" and apply to all 0

2 House Keeping

3 Steps in AUTOTRANSPLANTATION (ASCT)

4 Uptake of BMT in Patients Diagnosed with Multiple Myeloma in Manitoba Year Transplanted Not transplanted Total (7.69) 24 (92.31) 26 (8.23) (5.88) 16 (94.12) 17 (5.38) (5.26) 18 (94.74) 19 (6.01) (36.36) 7 (63.64) 11 (3.48) (33.33) 8 (66.67) 12 (3.80) (26.67) 11 (73.33) 15 (4.75) (31.82) 15 (68.18) 22 (6.96) (42.86) 12 (57.14) 21 (6.65) (57.89) 8 (42.11) 19 (6.01) (35.00) 13 (65.00) 20 (6.33) (50.00) 10 (50.00) 20 (6.33) (53.33) 7 (46.67) 15 (4.75) (52.38) 10 (47.62) 21 (6.65) (57.89) 8 (42.11) 19 (6.01) (42.86) 12 (57.14) 21 (6.65) (50.00) 9 (50.00) 18 (5.70) (45.00) 11 (55.00) 20 (6.33) Total 117 (37.03) 199 (62.97) 316 (100.00)

5 Overall survival of patients diagnosed with multiple myeloma, in Manitoba, between 1993 and 2009 Survival Probability Kaplan-Meier survival estimates Time (months) N= 316 entire cohort; median survival 90 s= months, 00 s =42.30 months. Log rank P value =

6 Joseph Mikhael, MD, MEd, FRCPC, FACP Consultant Hematologist and Associate Professor of Medicine Scottsdale clinic Arizona and Mayo college of Medicine. Specialist interest in plasma cell disorders, namely multiple myeloma, amyloidosis and Waldenstrom s macroglobulinemia. Principal investigator of many clinical trials,. Other interests pharmaco-economics, communication skills and supportive care in cancer. Medical school and internal medicine training at the University of Ottawa, Canada. Hematology training at the University of Toronto. Masters degree in education. Multiple Myeloma fellowship at Princess Margaret Hospital. Staff physician at the Princess Margaret Hospital and Toronto General Hospital when he moved to Arizona to work at the Mayo Clinic. Associate Chair of Education for the Department of Medicine. Vice-Chair of Education for the division of Hematology-Oncology. program director of the Hematology-Oncology Fellowship Training Program at Mayo Clinic Arizona. vice-chair of the Graduate Education Committee.

7 Canada s secret import to the USA.

8 Enjoyable program!

9 Learning Objectives Through a review of the most recent evidence and sharing of patient experience, this educational program will endeavor to: 1. Review current best practices in the treatment of patients with Multiple Myeloma prior to receiving a stem cell transplant 2. Explore the role of novel strategies post-transplant in achieving better patient outcomes to treatment 3. Discuss the management and optimal treatment sequencing for patients who have relapsed following a stem cell transplant

10 Please indicate your profession: a) Hematologist/Oncologist b) Nurse c) Pharmacist d) Industry e) Other

11 Please indicate your practice setting: a) Teaching/Academic based b) Community based c) Industry d) Other

12 How many Multiple Myeloma patients do you see in a month (average)? a) None b) 1 5 c) 6 10 d) e) More than

13 Over the past 12 months, what percentage of your newly diagnosed Multiple Myeloma patients received high dose chemotherapy followed by a stem cell transplant (SCT)? a) 0-25% b) 26-50% c) 51-75% d) %

14 What is the most important consideration when selecting an induction regimen for your frontline SCT eligible patients? a) Achieving a VGPR or better b) Stem-cell mobilization c) Overall survival (OS) d) Progression free survival (PFS) e) Tolerability

15 What induction regimen do you use/prefer for your front-line SCT eligible patients? a) Vel-Dex b) Vel-Rev-Dex c) CyBorD d) High dose Dex e) Other

16 Are you able to confidently describe the difference between consolidation and maintenance therapy, in the post-transplant setting? a) Yes b) No c) Not quite

17 What type of therapy are you currently using in your SCT eligible patients post-transplant? a) Consolidation alone b) Maintenance alone c) Consolidation followed by maintenance d) None

18 What regimen do you use/prefer for your SCT eligible patients for consolidation posttransplant? a) Thalidomide based b) Velcade based c) Revlimid based d) Other e) None

19 What regimen do you use/prefer for your SCT eligible patients for maintenance posttransplant? a) Thalidomide based b) Velcade based c) Revlimid based d) Other e) None

20 What is the main barrier to using some form of therapy post-transplant in your SCT eligible patients? a) Limited availability/coverage b) Not enough clinical data to support benefits c) Limited familiarity and/or comfort d) Tolerability issues e) Other

21 What is the most important consideration when selecting a treatment at 1 st relapse for your SCT eligible patients? a) Achieving a complete response (CR) b) Tolerability c) Overall survival (OS) d) Progression free survival (PFS) e) Duration of response to front-line treatment

22 Optimizing the Treatment of Transplant- Eligible Patients in Multiple Myeloma CBMTG Symposium April 10, 2013 Scottsdale, Arizona Rochester, Minnesota Jacksonville, Florida Joseph Mikhael, MD, MEd, FRCPC, FACP Staff Hematologist, Mayo Clinic Arizona

23 Objectives 1. Review current best practices in the treatment of patients with Multiple Myeloma prior to receiving a stem cell transplant 2. Explore the role of novel strategies posttransplant in achieving better patient outcomes to treatment 3. Discuss the management and optimal treatment sequencing for patients who have relapsed following a stem cell transplant

24 Treatment sequence NEW Thal/Dex VD Rev/Dex CyBorD VTD VRD SCT VD/VRD Nothing Thalidomide? Bortezomib? Lenalidomide? Bortezomib Lenalidomide Thalidomide Carlfilzomib Pomalidomide Elotuzumab HDAC Bendamustine Front line treatment Maintenance Relapsed Induction Consolidation Post consolidation Rescue OLD VAD DEX SCT Nothing Prednisone Thalidomide Few options

25 Survival probability Molecular Prognostic Model t(4;14) t(14;16) -17p13 All others including t(11;14) Months P<0.001 Poor Intermediate Good 24.7 mos 42.3 mos 51.0 mos Fonseca et al Blood 101:4569, 2003

26 msmart 2.0: Classification of Active MM High-Risk Intermediate-Risk* Standard-Risk* FISH Del 17p t(14;16) t(14;20) GEP High risk signature FISH t(4;14) Cytogenetic Deletion 13 or hypodiploidy PCLI >3% All others including: Hyperdiploid t(11;14)** t(6;14) Mikhael et al Mayo Clinic Proceedings April 2013

27 msmart 2.0: Classification of Active MM High-Risk 20% Intermediate-Risk 20% Standard-Risk 60% FISH Del 17p t(14;16) t(14;20) GEP High risk signature FISH t(4;14)* Cytogenetic Deletion 13 or hypodiploidy PCLI >3% All others including: Hyperdiploid t(11;14) t(6;14) 3 years 4-5 years 8-10 years

28 Case # 1 58 yo man with 4 month history of back pain Diagnosed with MM: 42% plasmacytosis t(11;14) and no high risk features IgG kappa (m spike 42) with elevated light chains (48 gm/dl) Anemic (Hb 102), ISS 2, Cr mildly elevated How will you treat him?

29 QUESTION #1 What would be your preferred option? 1. Bortezomib (1,4,8,11) and dexamethasone 2. Weekly Bortezomib and dexamethasone 3. CyBorD (Weekly Cyclophosphamide, bortezomib, dexamethasone) 4. Lenalidomide and dexamethasone 5. Bortezomib, lenalidomide, dexamethasone

30 High Risk msmart Off-Study Transplant Eligible Intermediate Risk Standard Risk VRD x 4 Induction with CyBorD 4 cycles of Rd a or CyBorD ASCT, especially if not in CR VRD maintenance for minimum of 1 year Autologous stem cell transplant (ASCT) Bortezomib based consolidation for minimum of 1 year Collect Stem Cells b Autologous stem cell transplant (ASCT) Continue Rd Consider Lenalidomide maintenance* Mikhael et al Mayo Clinic Proceedings April 2013

31 msmart Off-Study Transplant Ineligible High Risk Intermediate Risk Standard Risk* VRd* MP + weekly Bortezomib** or weekly CyBorD Rd b,c Bortezomib maintenance Observation Mikhael et al Mayo Clinic Proceedings April 2013

32 Randomized Phase 3 Trials Trial Rajkumar Regi men No. of pts ORR (%) CR plus VGPR (%) PFS - Median P value for PFS RD Rd year OS (%) Harousseau VAD VD Cavo TD VTD NR

33 Results RD vs. Rd RD Rd CR + PR 79% 68% 1 year OS 87% 96% Grade 3 or worse AE 52% 35% RD did not result in superior TTP, PFS, or OS compared to Rd OS at 1-year was significantly better with Rd than RD, resulting in early closure of the trial Rajkumar et al, 2010.

34 Once Versus Twice Weekly Bortezomib in CyBorD for Newly Diagnosed Myeloma

35 CyBorD Method 63 patients enrolled Cohort 1: (standard bortezomib dosing) (n=33) Cohort 2: (weekly bortezomib) (n=30) 1 st goal - 40%>VGPR 2 nd goal safety, survival, stem cell collection Newly diagnosed symptomatic MM ECOG < 2 Platelets > 100,000, ANC > 1,000, Cr < 3.5 Acyclovir, quinolone antibiotic

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37 Weekly versus Biweekly CYBOR-D as Induction Therapy Reeder C, et al. Leukemia 2009; 23: ; Reeder CB, et al. Blood 2010; 115:

38 Once Weekly Subcutanous Bortezomib with Cyclophosphamide and Dexamethasone Is Well Tolerated and Effective As Initial Treatment in Symptomatic Multiple Myeloma David Simpson, FRACP, FRCPA, MBChB, James Liang, MBChB, Ross Henderson, MBChB, PhD, FRACP, FRCPA, Merit Hanna, MBChB, FRCPA and Eileen Merriman, MBChB, FRACP, FRCPA Simpson D. et al. ASH 2012, A4049

39 Response After Each Cycle Weekly subcutaneous Bortezomib is well tolerated, and has high patient acceptance. Dose limiting neuropathy is rare, and responses are high when used in combination with CyBorD or VTD Simpson D. et al. ASH 2012, A4049

40 The NEW CyBorD All three drugs given weekly Cyclophosphamide 300mg/m2 PO Bortezomib 1.5 mg/m2 IV or SQ Dexamethasone 40mg PO We consider one cycle a 4 week course No week off Less neuropathy, more convenience, equal efficacy Always give viral prophylaxis Comment I see CyBorD as a slight modification to VMP

41 Novel Three- and Four-Drug Combination Regimens of Bortezomib, Dexamethasone, Cyclophosphamide, and Lenalidomide, for Previously Untreated Multiple Myeloma: Results From the Multi-Center, Randomized, Phase 2 EVOLUTION Study Shaji Kumar, MD, Ian W. Flinn, MD, PhD, Paul G Richardson, MD, Parameswaran Hari, MD, Natalie Scott Callander, MD, Stephen J. Noga, MD, PhD, A. Keith Stewart, MD, Jonathan Glass, MD, FACP, Robert M. Rifkin, MD, Jeffrey L Wolf, MD, Jose Estevam, BS, George Mulligan, PhD, Hongliang Shi, MS, Iain J. Webb, MD, FRCPC and S. Vincent Rajkumar, MD Kumar et al, ASH 2010 (Abstract 621)

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45 EVOLUTION Adverse Events VDCR n = 48 VDR n = 42 VDC n = 33 VDC-mod n = 17 Hematological AEs, n (%) Neutropenia 21 (44) 4 (10) 10 (30) 4 (24) Febrile neutropenia 4 (8) 1 (2) 2 (6) 0 Thrombocytopenia 7 (15) 5 (12) 4 (12) 0 Leukopenia 6 (13) 0 3 (9) 1 (6) Anemia 4 (8) 3 (7) 0 2 (12) Lymphopenia 4 (8) 1 (2) 4 (12) 0 Nonhematological AEs Pneumonia 2 (4) 2 (5) 0 1 (6) Neuropathy 6 (13) 7 (17) 3 (9) 3 (18) Fatigue 8 (17) 3 (7) 1 (3) 0 Diarrhea 3 (6) 1 (2) 1 (3) 1 (6) Nausea 0 1 (2) 0 0 Thromboembolism 1 (2) Constipation Hyperglycemia Summary At least one grade 3 or above AE 40 (83) 32 (76) 26 (79) 15 (88) At least one drug-related grade 3 or above AE 38 (79) 25 (60) 20 (61) 12 (71) At least one grade 3 or above hematological AE 28 (58) 11 (26) 17 (52) 5 (29) AE resulting in discontinuation 10 (21) 8 (19) 4 (12) 1 (6)

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48 Is there an evil side to treating with all drugs?

49 Dollar Cost of Regimens (BSA 2 m 2 ) per 28 days (per year) 1. VRD $23,000 (276K) 2. VTD $22,000 (264K) 3. PAD $14,400* (173K) 4. CyBorD (weekly) $ 9,200 (110K) 5. Rd $ 9,000 (108K) 6. TD $ 8,200 ( 98K)

50 Back to Case #1 Treated with weekly CyBorD After 4 cycles achieves PR (with m spike down from 42 to 12) You decide to send to ASCT Post ASCT at day 100, M spike now at 6 (just short of VGPR) What will you do?

51 QUESTION #2 What would you do post ASCT? 1. No further therapy, wait and watch 2. Second ASCT 3. Consolidation with more bortezomib 4. Maintenance therapy with lenalidomide 5. Maintenance therapy with bortezomib

52 1. Nada therapy 2. 2 nd ASCT Options now 3. Maintenance lenalidomide or bortezomib 4. Consolidation thalidomide/lenalidomide or bortezomib Remember the difference between them and the historical perspective

53 Phase 3: bortezomib consolidation versus no consolidation following ASCT Induction + single or double ASCT (n=404) Randomization (3 months post-asct) (n=392) Bortezomib (n=149) Observation (n=150) 1.3 mg/m 2 day 1, 4, 8, 11 for two 3-week cycles then day 1, 8, 15 for four 4-week cycles (total 20 injections over 21 weeks) Mellqvist et al. IMW 2011

54 Progression free survival 20 mo 27 mo bortezomib control p=0.037 Mellqvist et al. IMW 2011

55 Cavo et al. Blood 2012;120:9-19

56 Phase 3: VTD vs VD Efficacy VTD TD p After Induction > ncr 33.1% 13.7% < After Double ASCT > ncr 63.1% 54.7% After Consolidation > ncr 73.1% 60.9% Overall, the probability of upgrading from less than CR before consolidation therapy to CR after consolidation was significantly higher in patients receiving VTD (25 of 82 patients, 30.5%) than in those receiving TD (16 of 96 patients, 16.7%; p =.030). Most of the patients who improved to CR after VTD consolidation therapy were in ncr (44%) or VGPR (52%) before starting consolidation therapy. Cavo et al. Blood 2012;120:9-19

57 VTD VTD TD M.Cavo, Lancet 2010, 376,

58 Phase 3: VTD vs TD (GIMEMA study) Impact of VTD consolidation Per-protocol analysis: n=321, received entire treatment program VTD TD p CR post-consolidation 61% 47% Upgrade to CR post-consolidation 30.4% 16.6% Landmark analysis from start of consolidation (30 months median follow up) 3-yr probability of relapse or progression 38% 52% yr PFS 60% 48% Superior PFS with VTD vs TD consolidation retained across poor prognosis subgroups: t(4;14) and/or del(17q), del(13q) β 2 -M >3.5 mg/l, LDH >190 U/L, ISS stage 2 and 3 Cavo et al. Blood 2012;120:9-19

59 Clinical Impact of VTD Consolidation in VGPR Patients After ASCT Responses after ASCT VGPR 85% CR 15% Responses after VTD VGPR 49% CR 49% 15% 85% 49% 49% VGPR CR Ladetto et al. J Clin Oncol 2010;28:

60 Phase 3: VTD vs TD (GIMEMA study) Impact of VTD consolidation No OS difference between two groups Both treatments well tolerated Frequency of grade 3/4 AEs comparable in both groups 9.3% VTD, 8.6% TD PN with VTD: 0.6% Skin rash, DVT: 0.6% in each group Patients treated with VTD received 93% of planned doses of bortezomib and thal Cavo et al. ASH 2011 (Abstract 1871), oral presentation

61 Serious AEs and grade 3 or 4 AEs reported in at least 2% of patients during induction Cavo et al. Lancet 2010;376:

62 Phase 2: VRD induction, ASCT, VRD consolidation, lenalidomide maintenance (IFM 2008) Patients (n=31) % After VRD induction After ASCT After VRD consolidation After Len maintenance (3 cycles) (2 cycles) (12 months) scr CR VGPR Improvement in responses Consolidation: upgraded response in 26% Len maintenance: no improvement in response rate Roussel et al. ASH 2011 (Abstract 1872), poster presentation

63 HOVON-65/GMMG-HD4 Randomized Phase III Trial Comparing Bortezomib, Doxorubicin, Dexamethasone (PAD) Vs VAD Followed by High- Dose Melphalan (HDM) and Maintenance with Bortezomib or Thalidomide In Patients with Newly Diagnosed Multiple Myeloma (MM) Pieter Sonneveld, Ingo Schmidt-Wolf, Bronno van der Holt *, Laila el Jarari, Uta Bertsch, Hans Salwender, Sonja Zweegman, Edo Vellenga, Joerg Schubert, Igor Wolfgang Blau, Asiong Jie, Berna Beverloo, Dirk Hose, Anna Jauch, Helgi van de Velde, Martijn Schaafsma, Walter Lindemann, Marie Jose Kersten, Ulrich Duehrsen, MD, Michel Delforge, Katja Weisel, Sandra Croockewit, Hans Martin, Shulamit Wittebol, Christof Scheid, Gerard Bos, Marinus van Marwijk-Kooy, Pierre Wijermans, Henk Lokhorst and Hartmut Goldschmidt Sonneveld et al ASH 2010, (abstract 40) Oral presentation

64 ASH 2010 Phase III: PAD vs VAD induction, HDM and bortezomib or thalidomide maintenance HOVON 65 MM / GMMG-HD4 study MM Stage II or III, Age n=744, median age 57 Randomization n=373 3 x VAD CAD + GCSF 3 x PAD CAD + GCSF n=371 PAD: Bortezomib 1.3 mg/m 2 Doxorubicin 9 mg/m 2 Dex 40 mg MEL PBSCT MEL PBSCT Depending on local policy for patients PR MEL PBSCT Allogeneic Tx Depending on local policy for patients PR MEL PBSCT Thalidomide 50 mg/day for 2 years maintenance Bortezomib 1.3 mg/m 2 / 2 weeks for 2 years maintenance

65 ASH 2010 Response data VAD PAD P-value Response after induction (%) CR/nCR VGPR <0.001 PR < Response after HDM 1 (%) CR/nCR < VGPR <0.001 PR < Response on protocol (%) CR/nCR <0.001 VGPR PR

66 ASH 2010 Achievement of best response during maintenance therapy (%) Response after HDM (%) PR VGPR ncr Arm A (Thalidomide) Arm B (Bortezomib) Improvement of Response during Maintenance < PR PR 4 1 < VGPR VGPR < ncr ncr < CR CR 10 12

67 ASH 2010 Adverse effects during 2 years maintenance thalidomide (%) bortezomib (%) WHO CTC grade Infections GI Neurotoxicity (PN) Constitutional

68 ASH 2010 Feasibility of maintenance treatment VAD arm Thalidomide % PAD arm Bortezomib % Started M (n) At 6 months At 12 months At 18 months At 24 months 29 49

69 Progression-free and overall survival 100 (A) 100 (B) Cumulative percentage A: VAD B: PAD A: VAD B: PAD Cox LR At risk: N P= F (adj. ISS) B: PAD A: VAD months Cumulative percentage A: VAD B: PAD A: VAD B: PAD Cox LR At risk: N F P = B: PAD A: VAD mo (C) 100 Cumulative percentage A: VAD B: PAD A: VAD B: PAD Cox LR At risk: N D P = B: PAD A: VAD mo A: PFS all B: PFS censored for allo-sct C: OS Median follow up: 48 months

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73 Phase III Intergroup Study of Lenalidomide Vs Placebo Maintenance Therapy Following Single Autologous Hematopoietic Stem Cell Transplantation for MM: CALGB Registration Restaging Days Randomization S-D Stage 1-3, < 70 years >2 cycles of induction Attained SD or better 1 yr from start of therapy >2 x 10 6 CD34 cells/kg Mel 200 ASCT CR PR SD Placebo Lenalidomide* 10 mg/d with (5 15 mg) Patient stratification based on diagnostic β-2m and thalidomide and lenalidomide therapy during induction *provided by Celgene Corp, Summit, NJ McCarthy, P. L. et al. NEJM 2012

74 IFM : Study design Phase III randomized, placebo-controlled trial N= 614 patients, from 78 centers, enrolled between 7/2006 and 8/2008 Patients < 65 years, with non-progressive disease, 6 months after ASCT in first line Randomization: stratified according to Beta-2m, del13, VGPR Arm A= Placebo (N=307) Consolidation: Lenalidomide alone 25 mg/day p.o. days 1-21 of every 28 days for 2 months Arm B= Lenalidomide (N=307) until relapse mg/d until relapse Primary end-point: PFS. Secondary end-points: CR rate, TTP, OS, feasibility of long-term lenalidomide. ASCT = autologous stem cell transplant.

75 Efficacy of Maintenance CALGB trial Placebo Lenalidomide P- value TTP (months) < yr. OS (%) IFM trial PFS (months) < yr. OS (%) McCarthy et al. And Attal et al NEJM. May 10, 2012

76 Toxicity of Maintenance CALGB trial Placebo Lenalidomide P- value Grade III/IV hematological <0.001 SPM (n) 6 18 IFM trial Grade III/IV hematological <0.001 VTE SPM 1.2/100 PY 3.1/100 PY McCarthy et al. And Attal et al NEJM. May 10, 2012

77 Dr. Joe s Conclusions Lenalidomide maintenance does indeed prolong PFS but not OS PFS inadequate endpoint for maintenance study placebo vs active drug design Consider QOL, AEs, and COST! Len maintenance not yet proved to be superior to salvage Len One immature, (weakly) positive study does not change practice esp. if 2 nd more mature trial negative

78 Dr. Joe s Conclusions Contd. Somewhat biased to len responders However, this is an NCCN approved option The Second Primary Malignancy issue remains unclear, but likely less worrisome than first thought, and has a lot to do with melphalan risk grows at 2 years BUT, we must be vigilant to monitor Underscores the need of open communication with patient Many other maintenance options now being explored, esp with bortezomib

79 Maintenance Therapy - Practical Consider consolidation if responding Consider lenalidomide maintenance in standard risk patients not in VGPR or better Don t use maintenance therapy in patients with indolent myeloma (long standing MGUS/smoldering or slow growers We suggest bortezomib maintenance/consolidation in intermediate and high risk patients

80 Case #2 What if it were the same patient BUT: 1. They are in CR 2. They have t(4;14)

81 QUESTION #3 What would you do post ASCT if in CR? 1. No further therapy, wait and watch 2. Second ASCT 3. Consolidation with more bortezomib 4. Maintenance therapy with lenalidomide 5. Maintenance therapy with bortezomib

82 QUESTION #4 What would you post ASCT if t(4;14)? 1. No further therapy, wait and watch 2. Second ASCT 3. Consolidation with more bortezomib 4. Maintenance therapy with lenalidomide 5. Maintenance therapy with bortezomib

83 Case #3 Same original case of now 62 yo man with standard risk MM Had CyBorD with PR, ASCT then 4 more cycles of CyBorD achieving near complete remission Monitored for 3 years Now he is starting to relapse Initial thoughts? Ask yourself 10 questions

84 QUESTION #5 What would you do for relapse? 1. Go back to CyBorD 2. Class switch and use lenalidomide 3. Plan to go to 2 nd ASCT 4. 1 and and 3

85 RELAPSE With prolonged survival in most patients with myeloma, relapse therapy is more important than ever Approach must now take into account long term thinking Overall approach must be: Evidence based Rational Individualized to patient I don t really believe in standard second line therapy A strategy to choose the best therapy needs to address multiple issues Ask yourself the following 10 questions:

86 Question #1: Do I need to treat the patient? Spectrum of MGUS, Asymptomatic (smoldering) MM and true MM Recall the importance of Calcium Renal insufficiency Anemia Bone Disease Consider the pace of the relapse Other variables learned from newly dx MM (plasmacytosis >60% and FLC over 100)

87 Question #2: What did I use the last time? Depth of response How rapidly and successfully did it work CR, VGPR, PR, MR, SD Duration of Response How long did it last? If depth and duration reasonable, consider retreating with same regimen knowing it will be less effective Corollary is Class Switch

88 Question #3: How well tolerated was the previous therapy? Key areas of tolerability Neuropathy Cytopenias with sequelae Fatigue Other Did it lead to dose reductions or discontinuation? To what extent did it impair quality of life?

89 Question #4: Have I employed the Big Five? Hopefully sequentially Thal little cytopenias, ok in renal dz Neuropathy, fatigue, thrombosis, constipation Bortezomib manageable cytopenias, ok in renal dz Neuropathy, IV/SC administration (WEEKLY)

90 Question 4 contd. Lenalidomide little neuropathy Fatigue, may affect stem cell collection Concern of MDS or secondary malignancies Carfilzomib novel proteasome (FDA Approved July 2012) Must have had bortezomib + thal or len prior AND relapsing Issues include tumor lysis, SOB, possible cardiac issues

91 Question 4 contd. Pomalidomide (FDA approved February 2013) Similar toxicity profile to lenalidomide Slightly less myelosuppressive

92 Question #5: Is Salvage Transplant an Option? With increasing interest in novel agents, salvage ASCT may be forgotten Potential long term benefit (esp in standard risk) with long PFS and drug holiday Viable option as SECOND ASCT if: 1. Evidence of response first time 2. PFS of greater than 2 years 3. Well tolerated first time Repeat ASCT yields about 50-75% PFS of first

93 Question #6: Have I employed the Add On Agents? Several agents have demonstrated ability to amplify effect of the Big Three Steroids dexamethasone or prednisone (weekly or alt day) Cyclophosphamide orally, 300mg/m2 weekly very well tolerated Doxil usually with bortezomib PS: Don t forget Melphalan!

94 Question #7: Does Risk Stratification affect my choice? Please consider repeat marrow (with cytogenetics) at point of relapse High: likely combination and for prolonged period Intermediate: likely bortezomib based Standard: fewer drugs at once, more likely sequential

95 Question #8: What other patient factors influence choice? Several factors will sway choice: Age Renal insufficiency Aggressivity of relapse Cost Convenience Steroid status

96 Question #9: Should I consider multiple novel agent use? Potential use of an agent even if patients failed previously Defn: Progression on agent or within 60 days Usually in late or very aggressive relapse Most used combinations: VRD (bortezomib, lenalidomide, dex) VTD (bortezomib, thalidomide, dex) VDT-PACE (platinum, adriamycin, cyclophosphamide, etoposide)

97 Question #10: Is a Clinical Trial an Option? Depending on location and proximity, a host of options exist Over 160 trials listed on clinicaltrials.gov Initial therapy, transplant, relapse, supportive care, bone disease, phase 1. Most promising agents: novel proteasome inhibitors, monoclonal antibodies (esp daratumumab), KSP inhibitors and anti BAFF

98 60 Single-Agent Activity of 39 Drugs Tested in Multiple Myeloma 50 PR (%) Provided by Dr. Keith Stewart

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100 Implications 1. In high risk disease multiple genomic clones (combination chemotherapy a necessity) 2. In high risk disease genome is unstable (avoid DNA damaging agents?) 3. Re-Emergence of drug sensitive clones (Once resistant not always resistant)

101 Thank You! me anytime:

102 What is the most important consideration when selecting an induction regimen for your frontline SCT eligible patients? a) Achieving a VGPR or better b) Stem-cell mobilization c) Overall survival (OS) d) Progression free survival (PFS) e) Tolerability

103 Are you able to confidently describe the difference between consolidation and maintenance therapy, in the post-transplant setting? a) Yes b) No c) Not quite

104 If funding was available, what type of therapy would you consider using in your SCT eligible patients post-transplant? a) Consolidation alone b) Maintenance alone c) Consolidation followed by maintenance d) None e) Not sure

105 If funding was available, in which patients would you consider using consolidation therapy following transplant? a) All patients b) Selected patients c) None d) Not sure

106 If funding was available, in which patients would you consider using maintenance therapy following transplant? a) All patients b) Selected patients c) None d) Not sure

107 What is the most important consideration when selecting a treatment at 1 st relapse for your SCT eligible patients? a) Achieving a complete response (CR) b) Tolerability c) Overall survival (OS) d) Progression free survival (PFS) e) Duration of response to front-line treatment

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