1. A Moment to Own It: Multiple Myeloma Treatment in Evolution
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2. Key Concepts in Recent Data in Multiple Myeloma
Amitabha Mazumder, MD
Professor of Medicine
Director, Multiple Myeloma Program
New York University
Clinical Cancer Center
New York, New York
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4. Diagnosis and Risk Classification

5. Diagnosis of MM
Defined as the presence of > 10% clonal plasma cells in the bone marrow
With or without accompanying significant spike in monoclonal protein (M-protein)
Symptomatic disease characterized by CRAB symptoms
Elevated serum calcium levels (C)
Renal insufficiency (R)
Anemia (A)
Bone lesions (B)

6. MM Risk Classification
International Staging System
Incorporates serum β2-microglobulin and albumin levels
Categorizes according to stage I-III
Genetic analysis provides prognostic information
Cytogenetics
FISH
Greipp PR, et al. J Clin Oncol. 2005;23:

7. Induction Therapy

8. General Principles Guiding Induction Therapy in MM
Asymptomatic MM patients typically do not require treatment
Treatment of symptomatic MM
Age (< 65 vs ≥ 65 yrs) and comorbidities determine eligibility for ASCT
Induction therapies shown to have higher efficacy vs previous standard (vincristine/doxorubicin/dexamethasone [VAD])
Bortezomib plus dexamethasone[1]
Bortezomib/doxorubicin/dexamethasone[2]
1. Jagannath S, et al. Br J Haematol. 2005;129:
2. Oakervee HE, et al. Br J Haematol. 2005;129:

9. Bortezomib/Lenalidomide/Dexamethasone as Induction Therapy
EVOLUTION: phase II trial[1]
ORR after primary treatment: 83%
IFM 2008: phase II trial[2]
ORR after primary treatment: 97%
1. Kumar S, et al ASH. Abstract 621.
2. Roussel M, et al ASH. Abstract 624.

10. GIMEMA Randomized phase III trial in previously untreated MM
Bortezomib/thalidomide/dexamethasone (VTD) vs TD as induction and consolidation therapy with double ASCT
Best Response, %
VTD
(n = 236) TD
(n = 238)
P Value
After induction therapy
CR or near CR
≥ VGPR
≥ PR 31 62 93 11 28 79
< .0001
After consolidation therapy 85 92 45 68 84
.0002
.0071
Overall protocol 71 89 96 54 74
.0031
Cavo M, et al. Lancet. 2010;376:

11. Lenalidomide + Dexamethasone Placebo + Dexamethasone
SWOG S0232
Randomized phase III trial in previously untreated MM
Lenalidomide plus high-dose dexamethasone vs placebo plus high-dose dexamethasone
Toxicities greater in lenalidomide arm vs placebo
Grade 3/4 neutropenia: 21% vs 5%; P < .001
Outcome, %
Lenalidomide + Dexamethasone
(n = 97)
Placebo + Dexamethasone
(n = 95)
P Value
1-yr PFS 78 52
.002
1-yr OS 94 88
.25
ORR
≥ VGPR 63 48 16
< .001
Zonder JA, et al. Blood. 2010;116:

12. ECOG E4A03 Randomized phase III trial in previously untreated MM
Lenalidomide plus high-dose dexamethasone vs lenalidomide plus low-dose dexamethasone
Adverse events ≥ grade 3 worse with high- vs low-dose dexamethasone: 52% vs 35%; P = .0001
Trial was discontinued and patients in high-dose arm were switched to low-dose arm
Outcome
Lenalidomide + High-Dose Dexamethasone
(n = 223)
Lenalidomide + Low-Dose Dexamethasone
(n = 222)
P Value
1-yr OS 87 96
.0002
ORR within 4 cycles 79 68
.008
Rajkumar SV, et al. Lancet Oncol. 2010;11:29-37.

13. Transplantation

14. General Principles of Transplantation in MM Patients
ASCT standard of care for transplantation-eligible patients who respond to induction therapy[1]
Ongoing trials evaluating necessity of ASCT
Many treatment centers postpone ASCT procedure until needed or after induction therapy–related toxicity subsides
Lenalidomide may retard egress of stem cells in periphery[2,3]
Mobilization with cyclophosphamide and plerixafor may be preferred
1. NCCN. Clinical practice guidelines in oncology: multiple myeloma. v
2. Kumar S, et al. Blood. 2009;114:
3. De Luisi A, et al. Clin Cancer Res. 2011;17:

15. Tandem ASCT Superior to Single ASCT
399 previously untreated MM patients randomized to receive double (tandem) vs single ASCT
Improved EFS and OS with tandem vs single ASCT
7-yr EFS: 20% vs 10%; P = .03
7-yr OS: 42% vs 21%; P = .01
100 75
Tandem ASCT
OS (%) 50 25
Single ASCT 24 48 72 96
Mos
Attal M, et al. N Engl J Med. 2003;349:

16. ASCT → Allogeneic Stem Cell Transplant
Studies show conflicting results with ASCT followed by allogeneic stem cell transplant
CONSORT: significant survival advantage vs tandem ASCT[1]
Melphalan dosage questioned
BMT CTN 0102: similar 3-yr survival outcomes vs tandem ASCT[2]
Higher rate of treatment-related mortality in ASCT-allogeneic transplant arm
1. Giaccone L, et al. Blood. 2011;117:
2. Krishnan A, et al. Lancet Oncol. 2011;12:

17. Maintenance Therapy

18. General Principles of Maintenance Therapy for MM
Older studies demonstrated increased PFS but not OS with thalidomide maintenance
Unable to show increased PFS in patients with high-risk cytogenetics
Lenalidomide maintenance therapy associated with significant prolonged median TTP
OS data not yet matured
CALGB and IFM

19. 10 mg/day ± 5-15 mg/day as needed for toxicity
CALGB
Randomized, double-blind, placebo-controlled phase III trial
Restage Days
MM patients with Durie-Salmon stage I-III disease, SD following induction, and adequate stem cells
(N = 568)
Lenalidomide
10 mg/day ± 5-15 mg/day as needed for toxicity
Single ASCT
+ Melphalan
200 mg/m2
CR, PR, or SD PD
Placebo
Stratified by baseline b2-microglobulin, thalidomide or lenalidomide therapy during induction
Primary endpoint: TTP following ASCT Secondary endpoints: CR after ASCT, PFS, OS, feasibility of long-term lenalidomide
McCarthy PL, et al ASH. Abstract 37.

20. CALGB : Outcomes
60% reduction in risk of MM disease progression with lenalidomide maintenance vs placebo
Median TTP: 42.3 vs 21.8 mos; P < .0001
TTP benefit maintained across patient subgroups
Increased frequency of grade ≥ 3 adverse events with lenalidomide maintenance vs placebo
Hematologic toxicities: 45% vs 11%; P < .0001
Nonhematologic toxicities: 33% vs 25%; P = .0350
McCarthy PL, et al ASH. Abstract 37.

21. Consolidation Therapy
IFM
Prospective, randomized, placebo-controlled phase III trial
Lenalidomide
10-15 mg/day
MM patients younger than 65 yrs of age with nonprogressive disease ≤ 6 mos after first-line ASCT
(N = 614)
Consolidation Therapy
Lenalidomide 25 mg/day on
Days 1-21 of every 28 days
for 2 mos
Relapse
Placebo
Stratified by baseline b2-microglobulin, del(13) cytogenetics, response following ASCT
Primary endpoint: PFS Secondary endpoints: CR, TTP, OS, feasibility of long-term lenalidomide
Attal M, et al ASH. Abstract 310.

22. IFM : Outcomes
Significantly prolonged PFS with maintenance lenalidomide
Benefit observed across patient subgroups
PFS associated with pre- and postconsolidation response
Long-term maintenance lenalidomide relatively well tolerated
PFS Outcome
Lenalidomide
(n = 307)
Placebo
Median postrandomization PFS, mos 42 24
4-yr postdiagnosis PFS, % 60 33
Overall HR*
0.5
1.0
*P <
Attal M, et al ASH. Abstract 310.

23. Treatment of Older Patients

24. General Treatment Principles in Older Patients
Melphalan administered with prednisone and a novel agent for majority of patients
Typically thalidomide (MPT) or bortezomib (VMP)
MPT prolongs PFS but may not affect OS
VMP efficacy demonstrated in VISTA trial[1,2]
Bortezomib/thalidomide/prednisone (VTP) is equivalent with VMP for older patients with myelosuppression[3]
Toxicity primarily cardiac-related due to thalidomide
1. San Miguel JF, et al. N Engl J Med. 2008;359:
2. Mateos MV, et al. J Clin Oncol. 2010;28:
3. Mateos MV, et al. Lancet Oncol. 2010;11:

25. VISTA Study Design Randomized, open-label, multicenter, phase III
Newly diagnosed, symptomatic MM patients ineligible for ASCT
(N = 682)
VMP
Bortezomib + melphalan + prednisone MP
Melphalan + prednisone
Bortezomib: 1.3 mg/m2 on Days 1, 4, 8, 11, 22, 25, 29, 32 for cycles 1-4, then Days 1, 8, 22, 29 for cycles 5-9; melphalan: 9 mg/m2 on Days 1-4 of every cycle; prednisone: 60 mg/m2 on Days 1-4 of every cycle
Primary endpoint: time to disease progression
Secondary endpoints: CR, duration of response, time to subsequent MM therapy, OS
1. San Miguel JF, et al. N Engl J Med. 2008;359:
2. Mateos MV, et al. J Clin Oncol. 2010;28:

26. Patients Without Progression (%) Surviving Patients (%)
VISTA: Outcomes
VMP superior to MP for TTP and OS
Grade 3 adverse events higher in VMP vs MP arm
No difference in grade 4 events or treatment-related deaths
TTP OS
100
100
VMP 80 80
VMP 60 60
Patients Without Progression (%) MP
Surviving Patients (%) 40 40 MP 20
Median TTP for VMP vs MP: 24.0 vs 16.6 mos; HR: 0.48; P < .001 20
Median OS not reached in either arm; HR: 0.61; P = .008 3 6 9 12 15 18 21 24 27 3 6 9 12 15 18 21 24 27 30
Mos
Mos
Pts at Risk, n
Pts at Risk, n
VMP MP
111 86
65 53
31 22
27 5
VMP MP
72 69
36 29
4 7
1. San Miguel JF, et al. N Engl J Med. 2008;359:
2. Mateos MV, et al. J Clin Oncol. 2010;28:

27. Maintenance and the Older Patient

28. UPFRONT Randomized, open-label, multicenter phase IIIb trial
Induction Therapy
(8 x 21-day cycles)
Maintenance Therapy
(5 x 35-day cycles)
VcD
Bortezomib + Dexamethasone
Transplantation-ineligible newly diagnosed elderly MM patients
(N = 300)
Bortezomib
1.6 mg/m2 on
Days 1, 8, 15, 22
VcTD
Bortezomib + Dexamethasone
+ Thalidomide
VcMP
Bortezomib + Melphalan
+ Prednisone
Bortezomib: 1.3 mg/m2 on Days 1, 4, 8, 11; dexamethasone: 20 mg on Days 1, 2, 4, 5, 8, 9, 11, 12 for cycles 1-4, then Days 1, 2, 4, 5 for cycles 5-8 ; thalidomide: 100 mg on Days 1-21; melphalan: 9 mg/m2 on Days 1-4 of every other cycle; prednisone: 60 mg/m2 on Days 1-4 of every other cycle
Primary endpoint: PFS
Secondary endpoints: ORR, CR/near CR, PR, VGPR, safety and tolerability
Niesvizky R, et al ASH. Abstract 619.

29. UPFRONT: Outcomes
Median PFS not significantly different between treatment arms
High response rates in all arms
Highest frequency of adverse events in VcTD arm
Outcome
VcD
(n = 100)
VcTD
VcMP
Median PFS, mos
13.8
18.4
17.3
OR,* %
CR/nCR
VGPR PR 71 31 8 32 79 38 9 73 34 10 29
*Induction and maintenance.
Niesvizky R, et al ASH. Abstract 619.

30. Neuropathy

31. Management Strategies for MM Patients With Neuropathy
Weekly bortezomib schedule
Subcutaneous bortezomib formulations
Melphalan/prednisone/lenalidomide (MPR) induction followed by single-agent lenalidomide maintenance
MM-015: randomized, double-blind, multicenter phase II trial
Regimen associated with 60% reduced risk of progression vs MPR followed by placebo maintenance
Risk of myelosuppression with lenalidomide plus melphalan
Efficacy mitigated by increased risk of secondary malignancies
Palumbo A, et al ASH. Abstract 622.

32. Relapsed/Refractory Disease

33. Relapsed/Refractory Disease
Nearly all MM patients relapse
Factors affecting choice of treatment for relapsed patients
Patient comorbidities
Presence of significant neuropathy may preclude bortezomib
History of deep vein thrombosis may prevent lenalidomide use
Time from previous therapy
Same regimen may be considered if a sizable amount of time has passed
Response to previous therapy

34. Novel Agents

35. Carfilzomib: A Next-Generation Irreversible Proteasome Inhibitor
PX A1: open-label, single-arm phase II trial[1]
266 refractory MM patients (bortezomib and thalidomide/lenalidomide)
ORR: 24%
Median duration of response: 7.6 mos
Safety: hematologic toxicity; peripheral neuropathy uncommon
PX : ongoing open- label phase II trial[2]
Subset analysis of bortezomib-naive, relapsed MM patients
ORR: 53%
Median duration of response: not reached
Safety: hematologic toxicity, pneumonia; peripheral neuropathy rare
Siegel DS, et al ASCO. Abstract 8027.
Stewart AK, et al ASCO. Abstract 8026.

36. Pomalidomide: A Novel Derivative of Thalidomide
MM002: randomized, open-label, dose-escalation phase I/II trial
Patients with lenalidomide and bortezomib relapsed/refractory MM
Phase I: maximum tolerated dose: 4 mg
Grade 4 neutropenia primary dose-limiting toxicity
Phase II: clinical benefit was 25% and 28% by EBMT and IMWG criteria, respectively
Most frequent grade 3/4 adverse events: neutropenia (42%), infections (31%), thrombocytopenia (22%), anemia (20%)
PD SD MR
PR VGPR CR
100 8 9 80 53 60 63
Patients (%) 40 13 20 22 24 1 5 1
EBMT Criteria
IMWG Criteria
Richardson PG, et al ASH. Abstract 864.

37. Elotuzumab: Humanized Monoclonal Anti-CS1 Antibody
Dose-randomized, open-label, multicenter phase II trial of elotuzumab combined with lenalidomide and dexamethasone
59 patients with relapsed MM; previous lenalidomide excluded
ORR: 84.6% (in 26 patients completing ≥ 2 cycles of therapy)
Treatment-emergent adverse events in 77% of patients
Most common: fatigue (26%) and nausea (21%)
Response, %
Elotuzumab-Treated Patients (N = 26) OR
84.6 CR
3.8
VGPR
26.9 PR
53.8 SD
15.4
Richardson PG, et al ASH. Abstract 986.

38. Supportive Care

39. Bone-Targeted Therapies
Bisphosphonates recommended for all MM patients receiving therapy for symptomatic disease[1]
Potential for anticancer activity in MM
MRC Myeloma IX trial: randomized study of 1970 newly diagnosed MM patients also treated with induction chemotherapy[2]
Improved OS and PFS with zoledronic acid vs clodronate independent of prevention of skeletal-related events
Pamidronate did not produce similar results[3]
Risk Reduction, % (95% CI)
HR (95% CI)
P Value
OS PFS
0.84 ( ) 0.88 ( )
16 (4-26) 12 (2-20)
0.1
1.0 10
Favors zoledronic acid
Favors clodronic acid
1. NCCN. Clinical practice guidelines in oncology: multiple myeloma. v Morgan GJ, et al. Lancet. 2010;376: D’Arena G, et al. Leuk Lymphoma. 2011;52:

40. Other Supportive Care Issues in MM
Risk of deep vein thrombosis with immunomodulatory agents (thalidomide or lenalidomide)
Assess presence of other risk factors
Patients with significant increased risk may benefit from low molecular-weight heparin vs aspirin
Prophylactic agents
Herpes prophylaxis recommended for bortezomib-treated patients
Pneumonia, herpes, and antifungal prophylaxis recommended for patients treated with a high-dose regimen
NCCN. Clinical practice guidelines in oncology: multiple myeloma. v

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