Optimizing the Treatment of Transplant- Eligible Patients in Multiple Myeloma

Optimizing the Treatment of Transplant-Eligible Patients in Multiple Myeloma

Chair: Dr. Ade Olujohungbe MD, FRCP, FRCPath

Speaker: Dr. Joseph Mikhael MD, MEd, FRCPC, FACP

Wednesday, April 10th_{, 2013}

0 To edit footers: "insert tab>header and footer" and apply to all

Uptake of BMT in Patients Diagnosed with Multiple Myeloma in Manitoba Year 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 Total Transplanted 2 (7.69) 1 (5.88) 1 (5.26) 4 (36.36) 4 (33.33) 4 (26.67) 7 (31.82) 9 (42.86) 11 (57.89) 7 (35.00) 10 (50.00) 8 (53.33) 11 (52.38) 11 (57.89) 9 (42.86) 9 (50.00) 9 (45.00) 117 (37.03) Not transplanted 24 (92.31) 16 (94.12) 18 (94.74) 7 (63.64) 8 (66.67) 11 (73.33) 15 (68.18) 12 (57.14) 8 (42.11) 13 (65.00) 10 (50.00) 7 (46.67) 10 (47.62) 8 (42.11) 12 (57.14) 9 (50.00) 11 (55.00) 199 (62.97) Total 26 (8.23) 17 (5.38) 19 (6.01) 11 (3.48) 12 (3.80) 15 (4.75) 22 (6.96) 21 (6.65) 19 (6.01) 20 (6.33) 20 (6.33) 15 (4.75) 21 (6.65) 19 (6.01) 21 (6.65) 18 (5.70) 20 (6.33) 316 (100.00)

Overall survival of patients diagnosed with multiple myeloma, in Manitoba, between 1993 and 2009

0 .0 0 0 .2 5 0 .5 0 0 .7 5 1 .0 0 S u rv iv a l P ro b a b ili ty 0 25 50 75 100 125 Time (months) 1993-1999 2000-2009

Kaplan-Meier survival estimates

N= 316 entire cohort; median survival 90’s= 33.72 months, 00’s =42.30 months. Log rank P value = 0.0519.

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 2004 - 2008 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.

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

8 06.03.2010

Please indicate your profession: a) Hematologist/Oncologist b) Nurse c) Pharmacist d) Industry e) Other 06.03.2010 9

Please indicate your practice setting: a) Teaching/Academic based b) Community based c) Industry d) Other 06.03.2010 10

How many Multiple Myeloma patients do you see in a month (average)? a) None b) 1 – 5 c) 6 – 10 d) 11 – 15 e) More than 15 06.03.2010 11

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) 76-100%

What is the most important consideration when selecting an induction regimen for your front-line SCT eligible patients?

a) Achieving a VGPR or better b) Stem-cell mobilization

c) Overall survival (OS)

d) Progression free survival (PFS) e) Tolerability

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

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

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

What regimen do you use/prefer for your SCT eligible patients for consolidation

post-transplant? a) Thalidomide based b) Velcade based c) Revlimid based d) Other e) None 06.03.2010 17

What regimen do you use/prefer for your SCT eligible patients for maintenance

post-transplant? a) Thalidomide based b) Velcade based c) Revlimid based d) Other e) None 06.03.2010 18

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

What is the most important consideration when selecting a treatment at 1st _{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

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

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 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

•

Treatment sequence

Induction Consolidation

Front line treatment

Post consolidation Maintenance Rescue Relapsed OLD VAD DEX SCT Nothing Prednisone Thalidomide Few options NEW Thal/Dex VD Rev/Dex CyBorD VTD VRD SCT VD/VRD Nothing Thalidomide? Bortezomib? Lenalidomide? Bortezomib Lenalidomide Thalidomide Carlfilzomib Pomalidomide Elotuzumab HDAC Bendamustine

0.0 0.2 0.4 0.6 0.8 1.0 0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 S u rv iv a l p ro b a b il it y S u rv iv a l p ro b a b il it y Months Months P<0.001 P<0.001 t(4;14) t(14;16) -17p13 t(4;14) t(14;16) -17p13 ∆ ∆ ∆ ∆13 ∆ ∆ ∆ ∆13

All others including All others including All others including All others including t(11;14)

t(11;14) t(11;14) t(11;14)

All others including All others including All others including All others including t(11;14) t(11;14) t(11;14) t(11;14) Poor 24.7 mos Intermediate 42.3 mos Good 51.0 mos Poor 24.7 mos Intermediate 42.3 mos Good 51.0 mos Fonseca et al Blood 101:4569, 2003

Molecular Prognostic Model

Molecular Prognostic Model

mSMART 2.0: Classification of Active MM FISH Del 17p t(14;16) t(14;20) GEP High risk signature

All others including:

Hyperdiploid t(11;14)** t(6;14) FISH t(4;14)G Cytogenetic Deletion 13 or hypodiploidy PCLI >3%

High-Risk Intermediate-Risk* Standard-Risk*†

mSMART 2.0: Classification of Active MM FISH Del 17p t(14;16) t(14;20) GEP High risk signature

All others including:

Hyperdiploid t(11;14) t(6;14) FISH t(4;14)* Cytogenetic Deletion 13 or hypodiploidy PCLI >3%

High-Risk 20% Intermediate-Risk 20% Standard-Risk 60%

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

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

mSMART – Off-Study

Transplant Eligible

Mikhael et al Mayo Clinic Proceedings April 2013

Standard Risk

Autologous stem cell transplant (ASCT)

Consider Lenalidomide maintenance*

4 cycles of Rda _{or CyBorD}

Collect Stem Cellsb

Continue Rd† High Risk

VRD x 4

Intermediate Risk

Autologous stem cell transplant (ASCT)

Bortezomib based consolidation for minimum of 1 year

Induction with CyBorD

ASCT, especially if not in CR

VRD maintenance for minimum of 1 year

mSMART – Off-Study

Transplant Ineligible

Observation Intermediate Risk Standard Risk*

MP + weekly Bortezomib** or weekly CyBorD

Bortezomib maintenance

Rdb,c

Mikhael et al Mayo Clinic Proceedings April 2013

High Risk

Randomized Phase 3 Trials Trial Regi men No. of pts ORR (%) CR plus VGPR (%) PFS -Median P value for PFS 3 year OS (%) Rajkumar RD 223 81 50 19.1 75 Rd 222 70 40 25.3 0.026 74 Harousseau VAD 242 63 15 30 77 VD 240 79 38 36 0.06 81 Cavo TD 238 79 28 40 84 VTD 236 93 62 NR 0.006 86

Results

RD vs. Rd

Rajkumar et al, 2010. 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,

Once Versus Twice Weekly Bortezomib in CyBorD for Newly Diagnosed Myeloma

CyBorD Method

• 63 patients enrolled

– Cohort 1: (standard bortezomib dosing) (n=33)

– Cohort 2: (weekly bortezomib) (n=30)

• 1st _{goal - 40%>VGPR}

• 2nd _{goal – safety, survival, stem cell collection}

• Newly diagnosed symptomatic MM

– ECOG < 2

– Platelets > 100,000, ANC > 1,000, Cr < 3.5

Weekly versus Biweekly CYBOR-D

as Induction Therapy

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

Response After Each Cycle

Simpson D. et al. ASH 2012, A4049

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

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

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

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) 0 0 0 Constipation 0 0 0 0 Hyperglycemia 0 0 0 0 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)

Dollar Cost of Regimens (BSA 2 m2₎

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)

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

6T (just short of VGPR)

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

Options now

1.

Nada therapy

2.

2nd _ASCT

3.

Maintenance – lenalidomide or bortezomib

4.

Consolidation – thalidomide/lenalidomide or bortezomib

Remember the “difference” between them and the historical perspective

Phase 3: bortezomib consolidation versus no consolidation following ASCT

Mellqvist et al. IMW 2011 Induction + single or double ASCT (n=404)

Randomization (3 months post-ASCT) (n=392)

Bortezomib (n=149) 1.3 mg/m2

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)

Progression free survival

bortezomib control p=0.037 27 mo 20 mo Mellqvist et al. IMW 2011

Phase 3: VTD vs VD

Efficacy VTD TD p

After Induction

> nCR 33.1% 13.7% <0.0001

After Double ASCT

> nCR 63.1% 54.7% 0.123

After Consolidation

> nCR 73.1% 60.9% 0.020

• 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.

VTD

VTD TD

Phase 3: VTD vs TD (GIMEMA study) Impact of VTD consolidation

VTD TD p

CR post-consolidation 61% 47% 0.012

Upgrade to CR post-consolidation 30.4% 16.6% 0.030 Landmark analysis from start of consolidation (30 months median follow up)

3-yr probability of relapse or progression 38% 52% 0.039

3-yr PFS 60% 48% 0.025

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

Per-protocol analysis: n=321, received entire treatment program

• Superior PFS with VTD vs TD consolidation retained across poor prognosis subgroups:

– t(4;14) and/or del(17q), del(13q)

Responses after ASCT VGPR 85% CR 15% Responses after VTD VGPR 49% CR 49%

Ladetto et al. J Clin Oncol 2010;28:2077-84.

VGPR CR

85% 15%

49% 49%

Clinical Impact of VTD Consolidation in VGPR Patients After ASCT

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

Serious AEs and grade 3 or 4 AEs reported in at least 2% of patients during induction

Phase 2: VRD induction, ASCT, VRD consolidation, lenalidomide maintenance (IFM 2008) • Patients (n=31) % After VRD induction (3 cycles)

After ASCT After VRD consolidation (2 cycles) After Len maintenance (12 months) sCR 17 36 39 38 CR 6 6 9 10 VGPR 39 26 36 28

Roussel et al. ASH 2011 (Abstract 1872), poster presentation

• Improvement in responses

• Consolidation: upgraded response in 26%

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

Randomization

MM Stage II or III, Age 18–65

CAD + GCSF 3 x VAD CAD + GCSF 3 x PAD MEL 200 + PBSCT Depending on local policy for patients ≥≥≥≥PR

MEL 200 + PBSCT

MEL 200 + PBSCT

Depending on local policy for patients ≥≥≥≥PR

MEL 200 + PBSCT Thalidomide 50 mg/day for 2 years maintenance Allogeneic Tx Bortezomib 1.3 mg/m2 _{/ 2 weeks for} 2 years maintenance

Phase III: PAD vs VAD induction, HDM and bortezomib or thalidomide maintenance

HOVON 65 MM / GMMG-HD4 study n=371 n=373 n=744, median age 57 PAD: Bortezomib 1.3 mg/m2 Doxorubicin 9 mg/m2 Dex 40 mg ASH 2010

VAD PAD P-value

Response after induction (%)

CR/nCR 5 11 0.002 ≥VGPR 15 42 <0.001 ≥PR 55 78 < 0.001 Response after HDM 1 (%) CR/nCR 15 30 < 0.001 ≥VGPR 36 61 <0.001 ≥PR 77 88 < 0.001 Response on protocol (%) CR/nCR 34 49 <0.001 ≥VGPR 55 76 0.001 ≥PR 83 91 0.003 Response data ASH 2010

Arm A (Thalidomide) Arm B (Bortezomib) Response after HDM (%) ≥ PR ≥ VGPR ≥ nCR 77 36 15 88 61 33

Improvement of Response during Maintenance

< PR → PR 4 1

< VGPR → VGPR 13 11

< nCR → nCR 12 13

< CR → CR 10 12

Achievement of best response during maintenance therapy (%)

thalidomide (%) bortezomib (%) WHO CTC grade 2 3-4 2 3-4 Infections 35 18 40 24 GI 10 7 19 4 Neurotoxicity (PN) 26 15 14 9 Constitutional 24 2 14 2

Adverse effects during 2 years maintenance

Feasibility of maintenance treatment VAD arm Thalidomide % PAD arm Bortezomib % Started M (n) 239 205 At 6 months 77 90 At 12 months 55 76 At 18 months 39 64 At 24 months 29 49 ASH 2010

Progression-free and overall survival

Median follow up: 48 months

A: VAD B: PAD Cox LR N 414 413 P=0.002 F 255 222 (adj. ISS) A: VAD B: PAD At risk: 414 413 292327 202241 106133 3648 69 A: VAD B: PAD 0 25 50 75 100 months 0 12 24 36 48 60 C u m u la ti v e p e rc e n ta g e (A) A: VAD B: PAD Cox LR N 414 413 F 273 242 P =0.008 A: VAD B: PAD At risk: 414 413 325356 227261 120140 4451 89 A: VAD B: PAD 0 25 50 75 100 mo 0 12 24 36 48 60 C u m u la ti v e p e rc e n ta g e (B) A: VAD B: PAD Cox LR N 414 413 D 130 109 P =0.07 A: VAD B: PAD At risk: 414 413 361 374 327 338 200 224 86 104 16 19 A: VAD B: PAD 0 25 50 75 100 mo 0 12 24 36 48 60 C u m u la ti v e p e rc e n ta g e (C) A: PFS all

B: PFS censored for allo-SCT C: OS

S-D Stage 1-3, < 70 years > 2 cycles of induction Attained SD or better

≤ 1 yr from start of therapy > 2 x 106 _{CD34 cells/kg} Placebo Lenalidomide* 10 mg/d with ↑↓ (5–15 mg) Restaging Days 90–100 Registration

Phase III Intergroup Study of Lenalidomide Vs Placebo Maintenance Therapy Following Single Autologous Hematopoietic Stem Cell

Transplantation for MM: CALGB 100104

CR PR SD

Patient stratification based on diagnostic β-2M and

thalidomide and lenalidomide therapy during induction

Mel 200 ASCT

*provided by Celgene Corp, Summit, NJ Randomization

IFM 2005-02: Study design

Arm A= Placebo

(N=307) until relapse

Patients < 65 years, with non-progressive disease, ≤≤≤≤ 6 months after ASCT in first line

Arm B= Lenalidomide (N=307) 10-15 mg/d until relapse Primary end-point: PFS.

Secondary end-points: CR rate, TTP, OS, feasibility of long-term lenalidomideL. Phase III randomized, placebo-controlled trial

N= 614 patients, from 78 centers, enrolled between 7/2006 and 8/2008

ASCT = autologous stem cell transplant.

Consolidation:

Lenalidomide alone 25 mg/day p.o.

days 1-21 of every 28 days for 2 months

Efficacy of Maintenance

CALGB trial

Placebo Lenalidomide P- value

TTP (months) 21 39 <0.001 3 yr. OS (%) 80 88 0.03 IFM trial PFS (months) 23 41 <0.001 3yr. OS (%) 80 84 0.29

Toxicity of Maintenance

CALGB trial

Placebo Lenalidomide P- value Grade III/IV hematological 17 48 <0.001 SPM (n) 6 18 IFM trial Grade III/IV hematological 22 58 <0.001 VTE 2 6 0.01 SPM 1.2/100 PY 3.1/100 PY 0.002

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 2nd _more

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 melphalanTrisk 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

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

Case #2

•

What if it were the same patient BUT:

1.

They are in CR

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

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

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 relapseT

•

Initial thoughts?

QUESTION #5

What would you do for relapse?

1.

Go back to CyBorD

2.

Class switch and use lenalidomide

3.

Plan to go to 2nd _ASCT

4.

1 and 3

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

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)

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

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?

Question #4: Have I employed the Big Five?

•

Hopefully sequentiallyT

•

Thal – little cytopenias, ok in renal dz

•

Neuropathy, fatigue, thrombosis,

constipation

•

Bortezomib – manageable cytopenias, ok in

renal dz

•

Neuropathy, IV/SC administration

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,

Question 4 contd.

•

Pomalidomide (FDA approved

February 2013)

•

Similar toxicity profile to lenalidomide

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

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

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

Question #8: What other patient factors influence choice?

•

Several factors will sway choice:

•

Age

•

Renal insufficiency

•

Aggressivity of relapse

•

Cost

•

Convenience

•

Steroid ““““status””””

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,

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 1T.

•

Most promising agents: novel proteasome

inhibitors, monoclonal antibodies (esp daratumumab), KSP inhibitors and anti BAFF

Single-Agent Activity of 39 Drugs Tested in Multiple Myeloma

≥ P R ( % ) 60 50 40 30 20 10 0

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

Thank You!

•

Email me anytime:

What is the most important consideration when selecting an induction regimen for your front-line SCT eligible patients?

a) Achieving a VGPR or better b) Stem-cell mobilization

c) Overall survival (OS)

d) Progression free survival (PFS) e) Tolerability

06.03.2010 10 1

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 06.03.2010 10 2

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

06.03.2010 10 3

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 06.03.2010 10 4

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 06.03.2010 10 5

What is the most important consideration when selecting a treatment at 1st _{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

06.03.2010 10 6

10 7 06.03.2010