multiple myeloma: ash 2005 steven coutre, m.d. associate professor of medicine division of...

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

tag

e o

f p

atie

nts MP

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.

2 7

40

15

49

81

17

41

72

0

20

40

60

80

100

Complete Response

≥ 90% Response

≥ 50% Response

MPMPTMEL100

Per

cen

tag

e o

f P

atie

nts

17

41

1211

32

5

39

100

6.50

20

40

60

80

100

SevereInfection

Neutropenia DVT

Pat

ien

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

0

10

20

30

40

50

60

70

Percent

CR IF+ PR MR SD/PD*Hernandez, Br J H, 2004

42%

6 cycles of MP

0

10

20

30

40

50

60

70

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%

0

20

40

60

80

100

Bortezomib ± Dexamethasone

Bortezomib Alone at Cycle 2

SD/PD

MR

PR

nCR

CR

Best Response

Per

cen

tag

e o

f P

atie

nts

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

sp

on

se,

%

0

10

20

30

40

50

60

70

80

90

100

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.

0.00

0.25

0.50

0.75

1.00

%

Wit

ho

ut

Pro

gre

ssio

n

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

42

1724 20

40

20

40

60

80

100

Overall Partial CR/nCR

Len/DexDexP < .001

Pat

ien

ts, %

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