Case 2: Transplant-eligible patient with newly diagnosed myeloma – would you recommend transplant, and if so, what induction regimen?

1

Tomer M. MarkDepartment of Medicine, Division of Hematology /

OncologyWeill-Cornell Medical College /

New York Presbyterian Hospital, New York, NY, USA

Lymphoma & Myeloma 2013

Disclosures

Research Funding: Celgene Inc.; Onyx Inc.

Speakers Bureau: Celgene Corp; Millennium Inc.; Onyx Inc.

Membership on an entity's advisory committees: Celgene Corp., Millennium Inc.

Off-label usage of bortezomib, lenalidomide, and carfilzomib are discussed

Case History

• A 45 year-old male with a history of obesity and type-2 diabetes, “diet-controlled”, develops back pain after moving furniture

• When the back pain doesn’t relent after 3 weeks, he sees his PMD who advises NSAID use

• There is minimal relief after taking 800mg ibuprofen TID. He sees his PMD again the following week and a plain film of the spine is ordered

History

• Multiple lytic lesions of the lumbar spine are noted

• The PMD refers to an oncologist who orders bloodwork, a 24 hour urine, skeletal survey, and performs a bone marrow biopsy.

Medical History

PMHx:• Diet-controlled diabetes• Episode of Legionella

pneumoniaMed:• Ibuprofen 800mg prn

SHx:• Works as a hospital

administrator• Former tobacco use: 10 pack

years, quit 15 years ago• Social EtOH, no illicit drug use

FHx:• Mother: Crohn’s disease• Sister: breast cancer• Uncle: colon cancer

ROS:• +back painPE

GEN: middle-aged male, NADHEENT: PERRL, EOMI, anicteric scleraeNECK: no masses, nl carotid upstrokeCV: nl S1/S2, RRR, no m/r/gPULM: CTABABD: soft, NT/ND, +bowel soundsEXT: no c/c/eMSK: no spinal tenderness on palpation, he lies down on the exam table with greatdifficulty.

Diagnostic Tests

• Skeletal survey: multiple lytic lesions in the T, L-spine, cranium, pelvis, and R prox femur

• Bone Marrow Aspirate: 86% plasma cells with atypical features, kappa-light chain restricted

• Karyotype: 46 XY• FISH: 2/20 cells + del13q

Diagnostic Tests

Laboratory Results:

8.39.8

29.4 236

1403.7

11319

221.4

131

Albumin: 3.6Calcium 8.9T. Bili: 0.8Alk Phos: 57AST: 38ALT: 35LDH: 1902M: 3.8CRP: 0.54

Serum Protein Electrophoresis:Decreased amounts of gamma globulins with a monoclonal spike- 3.2 g/dL

Immunofixation / Quantitative Immunoglobulins:IgM: <4 mg/dL; IgA: 12 mg/dL; IgG: 4300 mg/dL

24 hr Urine Electropheresis and Immunofixation:Total Protein: 2.08g/day10% albumin90% kappa free light chain

Serum Free Light Chain Assay:Kappa FLC: 1540 mg/dLLambda 0.67: mg/dLKappa/Lambda: 2300

Summary

• 45 year-old male with history of hyperglycemia and newly diagnosed SD Stage 3a, ISS Stage 2, IgG-kappa MM, with extensive skeletal involvement and mild renal insufficiency.

Is a Stem Cell Transplant Recommended?

• Stem cell transplant has a OS benefit– Caveat: data is old

• Stem cell transplant deepens treatment response– Does a deeper response post-transplant lead to longer

OS?– What if pt is in CR prior to transplant?

ASCT vs. Conventional Chemotherapy

Study Tx N CR (%) Median OS (mo)

Attal el al (IFM 90)1VMCP/BVAP 100 5 44§

VMCP/BVAP->MEL-140/TBI-8 100 22 57§

Fermand et al2VMCP 91 -- 50

VAMP->Bu/MEL-140 or MEL-200 94 -- 55

Bladé et al3VMCP/VBAD 83 11 64

VBMVP/VBAD->MEL-200 81 30 72

Child et al4ABCM 200 8 42§

VAMPC->MEL-200 or MEL-140/TBI 201 44 54§

1. Attal M et al. N Engl J Med. 1996;335:91.2. Fermand J et al. Blood. 1998;92:3131.3. Bladé et al. Hematol J. 2001;2:2724. Child JA et al. N Engl J Med. 2003;348:1875.

§ Significant P value

Does Transplant Timing Matter?

Fermand J et al. Blood 1998;92:3131-3136

Does Consolidation With ASCT Improve Outcomes?

Impact of Response To Induction Therapy

Lahuerta, J. J. et al. J Clin Oncol 26:5775-5782 2008

Significance of Depth of Response

Lahuerta, J. J. et al. J Clin Oncol 26:5775-5782 2008

Significance of Continued Response to HDT

“Upgraders” do better

Lahuerta, J. J. et al. J Clin Oncol 26:5775-5782 2008

Improvement for PR to nCR or CR post transplant

increases OS

Initial Response to Induction Conventional Chemotherapy does not Impact Transplant Benefit

• Singhal et al, 2002. Survival post C-VAMP induction ASCT had no correlation with C-VAMP response.

• Kumar et al, 2004. 50 patients with primary refractory MM (mostly VAD) compared to 100 with chemosensitive disease pre-ASCT. 20% vs. 35% CR post transplant (P = 0.06). 1-year PFS 70% vs. 83% (P=0.65).

• Alexanian et al, 1995. MM resistant to VAD or high-dose dex quadrupled OS compared to matched controls.

Initial Response to Induction Chemotherapy does not Impact Transplant Benefit

Important factors on MV analysis: PCLI >1, CR, abnormal cytogenetics, serum M-protein, circulating PC at harvest.

Kumar et al. Bone Marrow Transplantation. 2004. 34: 161-167.

Initial Response to Induction Chemotherapy does not Impact

Transplant Benefit

Is this still true in the era of novel agents?

Impact of Response Failure To Induction with Immunomodulators

• N = 286• PFS from Day 0 of

transplantation• Plateau (232), Refractory

(29), Relapse (25)• Thal/Dex (189), Len/Dex

(97)• Medians: 22.1 m (plateau),

15.1 (refractory), 12.0 (relapse) on induction therapy

Gertz, M. A. et al. Blood 2010;115:2348-2353

Impact of Response Failure To Induction with Immunomodulators

• Overall survival from Day 0 of transplant

• Med OS 73.5 (plateau), 32.7 (refractory), 23.8m (relapse on tx)

Gertz, M. A. et al. Blood 2010;115:2348-2353

Factors That Impact Transplant Success with Immunomodulator Induction

Variable Univariable P Multivariable P Plateau vs. relapse-refractory

< 0.001 0.04

Albumin 0.58

Sex 0.78

B2 Microglobulin 0.016 0.30

Bone marrow plasma cells <0.001 0.33

Age 0.92

Abnormal Cytogenetics <0.001 0.02

CTX mobilization 0.036 0.30

Labeling Index <0.001 <0.001

Gertz, M. A. et al. Blood 2010;115:2348-2353

Multiple Studies Comparing Novel Agents to CC followed by ASCT

Study (N) Post Induction (%) Post-Transplant(%) PFS/OS (months)

ORR CR/VGPR ORR CR/VGPR

Macro et al TD VAD

100104

NRNR

25 > VGPR7 > VGPR

NRNR

44 > VGPR42 > VGPR

NRNR

HOVON-50 TAD VAD

268268

7157

37 > VGPR18 > VGPR

8879

66>VGPR54 > VGPR

PFS 34; OS 73PFS 25; OS 60

IFM 2005-01* Bort/Dex VAD

240242

7963

38 > VGPR15 > VGPR

8479

54 > VGPR37 > VGPR

PFS 36; 3-yr OS: 81PFS 30; 3-yr OS: 77

GIMEMA - 3006 VTD** TD

236238

9479

62 > VGPR31 > VGPR

NRNR

87 > VGPR69 > VGPR

2yr: PFS 85, OS 962yr: PFS 75, OS 91

IFM 2007-02 Bort/Dex VTD

99100

8190

35 > VGPR51 > VGPR

8490

60 > VGPR73 > VGPR

NRNR

Do You Need a Transplant if You Achieve CR With Induction Therapy?

Chemo-alone ASCT within 1 yr

Wang et al., 2010, Bone Marrow Transplant, 45, 498-504

• No transplant: 42 patients, 15 events. Median EFS not reached. • 3-year EFS = 65% (95% CI = 47.6%, 77.9%)• Transplant: 29 patients, 14 events. Median EFS = 37.3 months. • 3-year EFS 50.3% (95% CI = 27.2%, 69.5%

P=0.64

Do You Need ASCT if You Continue Induction Instead?

Conclusions• Combinations of novel agents lead to deeper responses

pre-transplant• Deeper responses pre-transplant translate to better

responses post transplant– ASCT is supplementary to induction, not a

substitute.– ASCT is a tool to achieve high CR and prolonged

PFS• Lack of difference in OS is a reflection on efficacy of

salvage tx.• Achievement of CR prior to transplant gives an equal

outcome to CR post-transplant– MRD detection may change this conclusion

What Induction Therapy Should be Used?

• What is More Important? a) Choice of Agent for Induction b) Response attained in Induction

Can’t See The Forest for The Trees

CyBORD3

N=35BCD + BDT4

N=65BiRD1

N=72VRD2

N=65

CR 39 28 38.9 26

nCR NA 18 13.9 18

VGPR 22 30 20.8 30PR 27 NA 16.7 25MR 1 NA 5.6 NARefractory 1 NA 0 0

Overall 88 100 90.3 1001. Niesvizky et al Blood, 111, 1101-1109; 2008.2. Richardson et al. ASH 2008, Abstract 92

61 76 73 74

3. Reeder et al, Leukemia 2009, 23:1337-414. Bensinger et al. ASH 2008, Abstract 94

Thank You