Multiple Myeloma: ASH 2005
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Transcript of Multiple Myeloma: ASH 2005
Multiple Myeloma: ASH 2005
Steven Coutre, M.D.
Associate Professor of Medicine
Division of Hematology
Stanford University School of Medicine
Quality of Remission Impacts Survival
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Alexanian R et al. BMT. 2001;27:1037
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Complete Remission Matters
Alexanian R et al. BMT. 2001;27:1037
Bladé J et al. Br J Haematol. 1998;102:1115
IBMTR (EBMT) Criteria for Complete and Partial Response Complete response requires all of following
– No serum/urine M protein by IFE for ≥6 wk
– <5% plasma cells in bone marrow aspirate
– No increase in size or number of lytic bone lesions
– Disappearance of soft tissue plasmacytomas
Partial response requires all of following
– 50% reduction in serum M protein 6 wk
– 90% reduction in 24-hr urinary light chain excretion
– 50% reduction in soft tissue plasmacytomas
– No increase in size or number of lytic bone lesions
Melphalan 4 mg/m2 Days 1-7 for 6 cycles +Prednisone 40 mg/m2 Days 1-7 for 6 cycles +
Thalidomide 100 mg/day* continuously(n = 129)
Previously untreated patients with multiple myelomaMedian age: 72 years
(N = 255)Melphalan 4 mg/m2 Days 1-7 PO for 6 cycles +
Prednisone 40 mg/m2 Days 1-7 for 6 cycles
(n = 126)
RandomizationSix
4-week cycles
*Thalidomide administration continued until relapse or progressive disease.
Palumbo A, et al. ASH 2005. Abstract 779.
Thalidomide Plus Melphalan/ Prednisone as First-line MM Therapy Italian Myeloma Network study: randomized, multicenter,
phase III trial
Part way through the study, enoxaparin was added to MPT group for 4 months as prophylaxis against clots.
Thalidomide Plus Melphalan/ Prednisone as First-line MM Therapy• Median event-free survival
longer for MPT vs MP
• 29.2 months vs 13.6 months (P < .001)
• 36-month OS: 80% vs 64% for MPT vs MP; P = .20
• Reduced DVT rates in MPT group for patients receiving vs not receiving prophylactic enoxaparin
• 3% vs 18.4% (P = .005)
• More deaths due to adverse events in MPT arm
Palumbo A, et al. ASH 2005. Abstract 779.
CR/nCR
MPT
20
40
60
Per
cen
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f p
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PR
45%
60%
0
28%
7%
P < .001
Response Rates
Grade 3-4 Adverse Event
MPT, %(n =129)
MP, %(n =126) P Value
Thromboembolism 12 2 .001
Infections 10 2 .01
Peripheral neuropathy 10 1 .001
Hematologic 22 25 NS
Standard Melphalan + Prednisone + Thalidomide (up to 400 mg/day*)
(n = 124)12 courses every 6 weeks
Patients with multiple myeloma65-75 years of age
(N = 436)
Standard Melphalan + Prednisone(n = 191)
12 courses every 6 weeks
*Thalidomide administered at maximum tolerated dose.
VAD: Vincristine + Doxorubicin +
Dexamethasone(n = 121)2 courses
Cyclophosphamide(3 g/m2)+ G-CSF
Melphalan (100 mg/m2)+ Autologous SCT
+ G-CSF2 courses
Thalidomide Plus Melphalan/ Prednisone in Older MM Patients
Facon T, et al. ASH 2005. Abstract 780.
Randomized, multicenter trial IFM 99-06: 3rd interim analysis
MPT
MP
MEL100
Thalidomide Plus Melphalan/ Prednisone in Older MM Patients• Longest OS with MPT
• MPT vs MP; P = .0008• Median not reached at Month
56 vs 30.3 months
• MPT vs MEL100; P = .014• Median not reached at• month 56
vs 38.6 months
• Longest PFS with MPT• MPT vs MP; P < .0001
• Median 29.5 vs 17.2 months
• MPT vs MEL100; P = .0001• Median 29.5 vs 19.0 months
Facon T, et al. ASH 2005. Abstract 780.
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Complete Response
≥ 90% Response
≥ 50% Response
MPMPTMEL100
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SevereInfection
Neutropenia DVT
Pat
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ts, %
MPMPTMEL100
Lenalidomide Plus Dexamethasone for Treatment-Naive Multiple Myeloma• Nonrandomized phase II study (N = 34)
• Oral lenalidomide 25 mg/day, Days 1-21• Dexamethasone 40 mg/day, Days 1-4, 9-12, 17-20;• Days 1-4 only after 4 cycles• Daily prophylaxis with aspirin for deep venous thrombosis
• Able to harvest adequate stem cells (> 3 x 106 CD34 cells/kg) in all patients proceeding to ASCT
Rajkumar SV, et al. ASH 2005. Abstract 781.
Response Rates With Lenalidomide Plus Dexamethasone (n=34)Outcome Lenalidomide/Dex, n (%)Objective response 31 (91)Complete response 2 (6)nCR/VGPR 11 (32)Partial response 18 (53)
Lenalidomide Plus Dexamethasone for Treatment-Naive Multiple Myeloma
Rajkumar SV, et al. ASH 2005. Abstract 781.
Grade 3/4 Toxicity in Treatment-Naive Patients Treated With Lenalidomide and Dexamethasone
Grade 3/4 Toxicity Lenalidomide + Dexamethasone, % (n=34)
HEMATOLOGIC• Neutropenia• Anemia• Thrombocytopenia
1560
NONHEMATOLOGIC• Fatigue• Muscle weakness• Anxiety• Agitation• Constipation
186633
Bortezomib in Patients with Previously Untreated Multiple Myeloma
Richardson, P. et al. ASH 2005 abstract # 2548
Best Response: (n=60)
Adverse EventN=29
# of Pts (%)
PN 36 (55)
Fatigue 6 (21)
Rash 5 (17)
Nausea 3 (10)
Constipation 3 (10)
VZV† 3 (10)
URI 2 (7)
All AE were grade 1-2, except two grade 4
(fluid overload and meningitis), one grade 3 PN
Richardson, P. et al. ASH 2005 abstract # 2548
Bortezomib in Patients with Previously Untreated Multiple Myeloma
Treatment-Emergent PN (n = 65)•Reported in 36 pts (55%)
•Grade 1: 23 (2 additional pts had grade 1 PN at study entry but remained stable throughout the study)
•Grade 2: 12•Grade 3: 1
•Dose reduction or discontinuation due to PN•4 pts, grade 1 PN (1.3 to 1.0 mg/m2; 3 had further
reduction to 0.7 mg/m2)•9 pts, grade 2 PN (1.3 to 1.0 mg/m2; 2 had further
reduction to 0.7 mg/m2)•1 pt, grade 3 PN discontinued treatment during cycle 3
Bortezomib + Melphalan and Prednisone in Elderly Untreated MM Patients
Phase II: Expanded up to 60 pts: bortezomib 1.3 mg/m2
Response • Best ORR: 86% (N = 53) following a median of 5 cycles
• CR 30%, nCR 13%, PR 43%
Mateos, M. et al. ASH 2005, abstract #786
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Percent
CR IF+ PR MR SD/PD*Hernandez, Br J H, 2004
42%
6 cycles of MP
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Percent
CR IF- CR IF+ PR SD
Best Response 5 cycles V-MP
86%
Bortezomib ± Dexamethasone as First-line Multiple Myeloma Treatment• Nonrandomized, prospective phase II trial (N = 50)• Overall response rate with bortezomib +
dexamethasone: 90%• Median PFS: 15 months
Jagannath S, et al. ASH 2005. Abstract 783.
8% 2%10% 8%
71%
40%
8%
25%
2%25%
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Bortezomib ± Dexamethasone
Bortezomib Alone at Cycle 2
SD/PD
MR
PR
nCR
CR
Best Response
Per
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Adverse Event Grade 3/4, %
Sensory neuropathy/ neuropathic pain
12
Fatigue 4
Anorexia 2
Abdominal pain/cramps 2
Neutropenia 10
Thrombocytopenia 2
Diarrhea 6
Myalgia 2
clinicaloptions.com/onco
Multiple Myeloma
RESPONSE
– Response Rates: Bortexomib ± Dex (N=48 evaluable)
CR + nCR + PR = 90%; CR + nCR = 19%
– Bortezomib alone: (at cycle 2)
CR + nCR + PR = 50%; CR + nCR = 10%
– Survival:
Median PFS = 15 months
OS = Median OS not reached; estimated survival at 12 months 93%
Newly Diagnosed
Bortezomib +/- Dexamethasone for Previously Untreated Multiple Myeloma
Jagannath S, et al. ASH 2005, abstract #783SLIDE 15
clinicaloptions.com/onco
Multiple MyelomaNewly Diagnosed
Bortezomib +/- Dexamethasone for Previously Untreated Multiple Myeloma
Jagannath S, et al. ASH 2005, abstract #783SLIDE 16
Addition of Dexamethasone (n = 36)
Additional responses observed in 23 of 36 patients (64%)
Response improved by 2 levels in 22% (n = 8)SD to PR: 8
Response improved by 1 level in 42% (n =15)SD to MR: 4MR to PR: 9PR to nCR: 1nCR to CR: 1
clinicaloptions.com/onco
Multiple Myeloma
► CONCLUSIONS
– Bortezomib alone and in combo with Dex is an effective therapy in newly diagnosed MM
– Response rate with bortezomib ± dexamethasone was 90% with a CR + nCR rate of 19%
– Estimated 1-year survival rate is 93%
– Bortezomib is a feasible option for induction therapy
– Stem cell harvest was successful and engraftment was prompt
– Adverse events were predictable and manageable
Bortezomib +/- Dexamethasone for Previously Untreated Multiple Myeloma
Jagannath S, et al. ASH 2005, abstract #783SLIDE 17
Newly Diagnosed
Reduced Dose PAD Combination Therapy Patients: n=20
– Treatment: Induction: four 21 day cycles prior to transplant:
• Bortezomib 1.0 mg/m2 days 1,4, 8, 11
• Adriamycin 9 mg/m2 – by infusion or IV push days 1-4
• Dex 40 mg PO - Cycle 1: d 1-4, 8-11, 15-18; Cycle 2 – 4: d 1-4
• PBSC harvested followed by MEL200 and PBSCT
Popat R, et al. ASH 2005,Abstract #2554 1Oakervee et al., Br J. Haematol 2005; 129 755-762
Response Following PAD (n=19) Following PBSCT (n=13)
CR 2 (11) 6 (46)
nCR 1 (5) 1 (8)
CR + nCR 3 (16%) 7 (54%)
VGPR 5 (26) 1 (8)
PR 9 (47) 5 (38)
CR + PR 89% 100%
–Stem cell mobilization was not affected
Reduced Dose PAD Combination Therapy
Popat R, et al. ASH 2005, Abstract #2554
First-line Bortezomib, Thalidomide + Dexamethasone in Multiple MyelomaNonrandomized, single-center, open-label study (N = 38)
• Treatment-naive patients
• Response compared with previous thalidomide/ dexamethasone study
Wang M et al. ASH 2005. Abstract 784.
Response Outcomes BTD, %(n = 38)
TD, %(n = 137)
P Value
Overall response*• Complete response†
9218
6613
< .01.41
Response following BTD and subsequent intensive therapy‡
• Partial• Complete
1006634
---------
---
*> 50% reduction in serum myeloma protein and/or > 90% reduction in Bence Jones protein excretion.†> 75% reduction in serum myeloma protein and/or > 99% reduction in Bence Jones protein excretion.‡ Intensive therapy supported by autologous blood stem cells for patients without serious complications following BTD.
– Bortezomib continues to demonstrate superior survival despite > 62% of HD dex pts crossing over to bortezomib
– Median OS: 29.8 months (95% CI: 23.2, not estimable) vs 23.7 months (95% CI: 18.7, 29.1); hazard ratio = 0.77; P = 0.0272
• 1-year survival rate: 80% vs 67%; P = 0.0002
Updated Results of APEX Trial
Richardson P, et al. ASH 2005, abstract 2547
SURVIVAL
Overall and 1-Year Survival
P=.0272
RESPONSEOverall response (CR + PR) improved from 38% to 43%
76/135 responders (56%) - improved response after week 6 (cycle 2)
• 20 pts MR or PR to CR• 56 pts MR to PR
Re
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Update
9% CR
34% PR
43%
(7% nCR)
38%
6% CR
32% PR
(7% nCR)
Initial analysis
*CR + PR
Median TTP, months 6.2
Median TTR*, months 1.4
CR 0.8
PR 1.4
nCR 0.8
Median DOR*, months 7.8
CR 9.9
PR 7.6
nCR 11.5
Updated Results of APEX Trial
Richardson P, et al. ASH 2005, Abstract 2547
Conclusions
– Despite rapid initial response, many pts achieve best response after longer duration of therapy
• Responders received median of 10 cycles
• Best M-protein response occurs > cycle 8 for ~20% of pts responding to bortezomib
– Pts receiving bortezomib earlier appear to have longer survival and higher RR
– Pts achieving higher quality of response (100% M-protein reduction) have longer response duration
Updated Results of APEX Trial
Richardson P, et al. ASH 2005, Abstract 2547
Dexamethasone 40 mg on Days 1-4, 9-12, 17-20*
Lenalidomide 25 mg, Days 1-21 and placebo, Days 22-28
(n = 176)
Dexamethasone 40 mg on Days 1-4, 9-12, 17-20*
Placebo on Days 1-28
(n = 175)
*After 4 courses, dexamethasone intensity reduced to 40 mg daily on Days 1-4 only.
Patients with relapsed/refractory multiple myeloma
(N = 351)
Lenalidomide/Dex vs Dex Alone for Relapsed/Refractory MMMM-010: multicenter, phase III trial
Dimopoulos MA, et al. ASH 2005. Abstract 6.
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Time to Progression (Weeks)
P < .001
9010 20 30 40 50 60 70 80
Lenalidomide/Dex vs Dex Alone for Relapsed/Refractory MM
Median time to progression Len/Dex: 11.3 monthsDex: 4.7 months
Lenalidomide/dexamethasone
Dexamethasone alone
Dimopoulos MA, et al. ASH 2005. Abstract 6.
Lenalidomide/Dex vs Dex Alone for Relapsed/Refractory MM• Superior response with addition of
lenalidomide• Improved OS with Len/Dex in North
American study MM-010 (P < .013)• Hematologic side effects more
common for lenalidomide
Grade 3/4 Toxicities Lenalidomide/Dexamethasone, %(n = 176)
Dexamethasone, %(n = 175)
Neutropenia 27 2
Anemia 6 4
Thrombocytopenia 10 6
Deep vein thrombosis 5 5
Pulmonary embolism 4 1
Dimopoulos MA, et al. ASH 2005. Abstract 6.
59
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Overall Partial CR/nCR
Len/DexDexP < .001
Pat
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Response
Bortezomib Plus Lenalidomide for Relapsed/Refractory Multiple Myeloma
• Phase I study of lenalidomide plus bortezomib (n = 24)
• 21-day cycles (maximum of 8) at 8 different dosing schedules• Bortezomib 1.0 or 1.3 mg/m2, Days 1, 4, 8, 11
• Lenalidomide 5-30 mg/day, Days 1-14
• 2 reports of dose-limiting toxicity • No thrombotic events
• Little peripheral neuropathy • Total response rate: 67%
Richardson PG, et al. ASH 2005. Abstract 365.
CRnCRPRMR
SDPD
Response Rates (n = 21)
43%14%
29%5%5%5%
Conclusions
• Combination regimens for front-line therapy are achieving higher response rates including true CR
• No apparent adverse impact on stem cell harvesting
• Challenges
• What patients benefit from transplant?
• Is there a role for maintenance therapy after initial treatment or post-transplant?
• Molecular definitions of response