Phase II

*Badros, 2004 (ASH 2400)⁸⁹

Quality*

100-400 mg
Oblimerson 5-7 mg/kg/d x 7d q21d.
D=Dex 40 mg x 4d
Thal 100-400 mg
[12 mo (1.5-16.6)]

33
60 yr (28-76)
67% M

Relapsed MM
Median 3 prior regimens (2-4)
Other MM characteristics=NS

30 evaluable

Overall Response (≥25%)=80%

m protein reduction:
   100%=7%
   Near CR=13%
   ≥75%=NS
   ≥50%=40%
   ≥25-49%=20%

Estimated PFS=12 mo

Estimated OS=17.4 mo

Median response duration=13 mo

Biagi, 2001⁹²

Quality 1/6

(While called "phase II" by authors, reported more as a case series of 4 patients selected on response to Thal)

200-800 mg
IFNα added @ 12 wk

4
44.8 yr (40-50)
75%M

75% extramedullary (EM) relapse after alloBMT

4

All 3 with EM MM had complete resolution of EM disease (but not necessarily other systemic response)

"Extramedullary myeloma is particularly sensitive to Thalidomide"

*Bibas, 2004 (ASH 4927)⁹⁰

Quality*

100+ mg
Low dose Thal 100mg up to max tol dose + Dex 40 mg+ zoledronate 4 mg
[2-21 mo]

30
(53-81 yr)
73% F

Refractory, relapsed
IgG=80%
IgA=17%
B-J protein=3%

30

Overall Response (≥25%)=63%

m protein reduction:
   100%=13%
   ≥75%=NS
   ≥50%=50%
   ≥25-49%=NS

Responders with neuropathy were decreased to Thal for only 10 days/mo

*Chanan-Khan, Miller, McCarthy, DiMiceli, et al., 2004 (ASH 2421)⁹¹

Quality*

200 mg
VDT:
Bortezomib (V), liposomal doxorubicin(D), & low-dose Thal
V=1.3 mg/m² (d1,4, 15, 18);
D=20 mg/m² (d1, 15);
Thal 200 mg.
Repeated q 4 wks for 4-6 cycles

18
56 yr (44-80)
61% F

Refractory/relapsed
Prior SCT=46%
16 MM & 2 Waldenström’s Macroglobulinemia; all stage III, pretreated median 2 (1-7) other prior regimens
46% SCT

13 evaluable

Overall Response (≥25%)=100%

m protein reduction:
   100%=NS
   ≥75%=38%
   ≥50%=62%
   ≥25-49%=NS

Ciepluch, 2002⁹³

Quality 1/5

200-400 mg
+ Pamidronate 90 mg q28d

Mean treatment duration 12.4 wk (3-36 wk)
[Median f/u=NS]

13
61.5 yr (35-87)
62% M

Resistant w/ osteolytic lesions

13

Overall Response (≥25%)=76%

m protein reduction:
   100%=23% "good clinical response" inclusive ≥25-99%=53%
   ≥75%=NS
   ≥50%=NS
   ≥25-49%=NS

85% of responders responded in first 4-8 wk of treatment

Osteodynia:
   Partial improvement=31%
   Marked improvement=23%

(measurement of osteodynia and definitions of improvement not stated)

Dimopoulos, 2004⁹⁴

Quality 3/5

400 mg
CTD: Cyclophosphamide 150mg/m² q12h d1-5 + Thal 400 mg/d d1-5 & 14-18 + Dex 20mg/m² d1-5 & 14-18
Repeated q 4 wks x 3
[Median f/u=NS]

53
64 yr (36-86)
49% M

Treatment resistant=87%
3 prior chemo regimens=55%
Prior tx with Thal=19%

Med time from initial dx to enrollment=26 mo (3-141)
IgG=55%
IgA=25%
B-J protein=18%
Non-secretory=2%

53

Overall Response (≥25%)=94%

m protein reduction:
   100%=5%
   ≥75%=34
   ≥50%=55%
   ≥25-49%=NS

Med time to response=1.5 mo (0.46-4.82)

Pts with prior treatment with Thal less likely to respond (PPR 50%, prior Thal vs. no prior Thal=30% vs. 67%, p=0.03)

Med TTP=8.9 mo

Med TTP if achieved a PPR50%= 12 mo

Med OS=17.5 mo

Garcia-Sanz, 2004⁹⁵

Quality 4/5

200-800 mg
ThaCyDex:
Thal 200-800 mg + cyclophosphamide 50 mg qd + pulsed Dex 40mg/d x 4 days q3 weeks
Med dose thal=600mg
[Median f/u=1.5 yr]

71
65% >65 yr
52% M

Refractory/relapsed
Stage III=42%
IgG=60%
IgA=20%
B-J protein=20%

66
evaluable

Overall Response (≥25%)=89%

m protein reduction:
   100%=2%, CR increased to 10% @ 6 mo
   ≥75%=
   ≥50%=55%
   ≥25-49%=26%

@ 2 years, EFS=57% & OS=66%

*Hollmig, 2004 (ASH 2399)⁹⁶

Quality*

50-100 mg
VATD: Bortezomib 1.0 or 1.3mg/m² d1,4, 9,11);
Doxorubicin 2.5-10 mg/m² d1-4 & d9-12 cont infusion;
Thal 50-100 mg d 1-12;
Dex 20-40 mg. d1-4, & 9-12
[Median f/u=NS]

20

Pt and MM characteristics NS

14 evaluable

Overall Response (≥25%)=50%

m protein reduction:
   100%=0%
   ≥75%=50%
   ≥50%=NS
   ≥25-49%=NS

Kasper, 2004⁹⁷

Quality 2/5

Thal 100-400 mg + PegIFNα 20-50 μg

15
60 yr (56-79)
53% F

Heavily pretreated
73% with 1 cycle of HDCT (SCT not stated)
80% Stage III
Myeloma sub-types not stated

15

Overall Response (≥25%)=40%

m protein reduction:
   100%=NS
   ≥75%=NS
   ≥50%=7%
   ≥25-49%=33%

PFS 14 mo (3-14)

PegIFNα had to be stopped in 46% due to adverse effects

Kropff, 2003⁹⁸

Quality 5/5

100-400 mg + Dex 20mg/m² x4d on d1, 9, 17 during cycle 1 then option to reduce to q28d + hyperfractionated cyclophosphamide 300 mg/m² iv q12 hrs x6 doses (median 4 cycles)
[Median f/u=NS]

60
43% >60 yr
67% M

Refractory or relapsed
IgG=69%
IgA=16%
Light chain only=9%

57 evaluable

Overall Response (≥25%)=84%

m protein reduction:
   100%=4%
   ≥75%=NS
   ≥50%=68%
   ≥25-49%=12%

Median EFS=11 mo

Median OS=19 mo

67% grade IV neut w/ ≥1 cycle (median duration 3 d)

Infections:
   Grade 3=17%
   Grade 4=9%

Neutropenic infection=2 deaths

Thal d/c ‘d for thromboembolic event=1:
   Cerebrovascular event=3
   Pt choice=1
   Not documented=3

Mileshkin, Biagi, et al., 2003⁹⁹

Quality 5/6

200-1000 mg
± IFNα @ week 12
[18 mo (6-26)]
Not randomized

75
56 Thal alone
19 Thal + IFN
64 yr (36-83, 48% >65)
61% M

Relapsed or resistant (must have had systemic combination chemotherapy, Dex alone was not acceptable)
Prior chemo regimens median=3 cycles (1-7)
27% prior HD chemo

All: 75

Overall Response (≥25%)=29%

m protein reduction:
   100%=1%
   ≥75%=NS
   ≥50%=28%
   ≥25-49%=NS

38% for those ≤ 65 yr responded

17% for those > 65 yr responded (p=0.043)

Median time to response=12.4 wk (4-114)

Median PFS by KM=5.5 mo (CI, 3.6-6.8 mo)

Median OS by KM=14.6 mo (CI, 9.7 to >26.3 mo)

KM Estimated for 1-year:
   PFS 23 % (CI, 14-34%)
   OS 56% (CI, 44-67%)

Median survival:
   ≤ 65 yr=6.7 mo
   > 65 yr=4.1 mo
   p=0.045

*Mileshkin, 2005 (ASCO 8233)¹⁰⁰

Quality*

Up to 800 mg
Thal + celecoxib 400mg bid
EORTC QLQ-C30 QOL questionnaires administered at baseline, monthly and after therapy
[20 mo]

66

No pt or MM characteristics reported

66

Overall Response (≥25%)=42%

m protein reduction:
   100%=NS
   ≥75%=NS
   ≥50%=NS
   ≥25-49%=NS

PFS @ 20 mo=6.8 mo

OS @ 20 mo=21.4 mo

Med baseline global health score GHS=58 (range 8-100; higher is better)

GHS decreased in 80% between baseline and 1st score. For CR+PR pts (n=28):
   GHS declined=54%
   GHS improved=29%
   GHS same=14%

PR+CR pts vs. non-responders more likely to show improvement in best on-treatment GHS: 61% vs. 27%, p=0.024

Offidani, Corvatta, Marconi, Malerba, et al, 2004¹⁰¹

Quality 0/6

May include pts presented below

100-400 mg
± melphalan 0.20mg/kg/d x 4d q 28d
Thal mean daily dose=158mg (SEM ± 12.6)
[Median f/u not stated]
Not randomized

59
69 yr

Advanced MM
4=stable
55=active progressive
4=new diagnosis

59

32 Thal alone
27 Thal + Melphalan

Overall Response (≥25%)=64%

m protein reduction:
   100%=NS
   ≥75%=10%
   ≥50%=34%
   ≥25-49%=20%

PPR ≥50% (inclusive)=44%
   TM=63%
   T alone=37%
   p=0.015

Mean duration/pt=320 days

Mean Thal dosage /pt=52g:
   100 mg=15%
   200 mg=46%
   300 mg=10%
   400 mg=29%

Thal d/c’d for AE=27% but not dose dependent

2 yr OS=58%

Peripheral neuropathy 39%:
   median time to PN=16 mo

PN risk factors=
   median dose>150 mg (p=0.038)
   disease history > 3yr (p=0.099)
   and prior tx w/ VCR (p=0.104)

Offidani, Corvatta, Marconi, Olivieri, et al., 2004¹⁰²

Quality 6/6

May include pts presented above

100-600 mg
± melphalan 0.20mg/kg/d x4d q 28d (Thal-M)
[13 mo]

50
74 yr (46-84)
40% M
27 pts recruited on study and 23 pts met same eligibility criteria and included in analysis but not consented into the study
>2 previous chemo tx=54%
IgG=82%
Disease hx > 60 mo=34%
Other MM characteristics NS

50
Thal-M=23
Thal=23

Thal-Melphalan:
Overall Response (≥25%)=81 %

m protein reduction:
   100%=13%
   ≥75%=2%
   ≥50%=44%
   ≥25-49%=22%

Thal:
Overall Response (≥25%)=%

m protein reduction:
   100%=NS
   ≥75%=4%
   ≥50%=22%
   ≥25-49%=17%

TM response superior to T
p=0.009

2 yr PFS=57%

2-yr OS=59%

PFS:
   Thal-Melphalan=med not reached
   2yr PFS=61%
   Thal=13.1 mo
   2yr PFS=45%
   p=0.0356

No difference between Thal-M and Thal for OS

*Suvannasankha, 2005 (ASCO 6591)¹⁰³

Quality*

200 mg
CTP: Thal 200 mg+ Cyclophosphamide 50 mg bid x21d q 28d + Prednisone 50 mg qod
[18.37 mo, 95% CI 15.18-21.52]

37
65 yr (49-87)

Gender NS
Prior HDSCT=43%
Other MM characteristics NS

35

Overall Response (≥25%)=69%

m protein reduction:
   100%=22%
   Near CR=6%
   ≥75%=NS
   ≥50%=41%
   ≥25-49%=NS

Median TTP=13.24 mo (95% CI 9.40-20.99)

Median OS=20.4+ mo

Median # treatment cycles=7 (1-12)

*Teoh, 2004 (ASH 4915)¹⁰⁴

Quality*

50mg
DTZ: Thal 50 mg daily + Dex 20 mg d1-4qmo +zoledronate 4mg qmo
Pts treated for 3 mo
[Median f/u=NS]

18

Previously treated with symptomatic MM and unable to tolerate "conventional doses of Dex and/or Thal and/or chemo"

Overall Response (≥25%)=UTD

m protein reduction:
   100%=22%
   "Good responses" (undefined)=61%
   ≥75%=NS
   ≥50%=NS
   ≥25-49%=NS

Median time to remission=8.2 mo

*Williams, 2004 (ASH 1499)¹⁰⁵

Quality*

100-200 mg
CTD: Cyclophosphamide 500 mg. orally d1,8 &15
Thal 100-200
Dex 40 mg d1-4, 15-18
Repeated q4 wks for 2-6 cycles
[19 mo]

62
55 yr (31-73)

Gender not specified
Newly diagnosed=24%
Refractory to VAD=47%
Relapsed MM=27%
IgG=61%
IgA=27%
B-J protein=10%
Non-secretory=2%

62

New dx=15
VAD refractory=29
Relapsed=17

Newly diagnosed:
Overall Response (≥25%)=100%

m protein reduction:
   100%=20%
   ≥75%=NS
   ≥50%=80%
   ≥25-49%=NS

VAD refractory:
Overall Response (≥25%)=83%

m protein reduction:
   100%=NS
   ≥75%=NS
   ≥50%=NS
   ≥25-49%=83%

Relapsed:
Overall Response (≥25%)=71%

m protein reduction:
   100%=NS
   ≥75%=NS
   ≥50%=71%
   ≥25-49%=NS

*Zangari, Barlogie, Hollmig, et al, 2004 (ASH 1480)¹⁰⁷

Quality*

50-200 mg
V+Thal: Bortezomib (V) 1.0-1.3 mg/m² d1,4, 8, 11) + Thal (T) 50-200 mg at increasing doses per cohort
Repeated q 21 days
[Median f/u=NS]

79
Age >65=28%
Gender NS

Advanced refractory MM
IgA=18%
Other MM characteristics NS

79

V alone:
Overall Response (≥25%)=25%

m protein reduction:
   100%=NS
   Near CR=10%
   ≥75%=NS
   ≥50%=15%
   ≥25-49%=NS

V+Thal:
Overall Response (≥25%)=70%

m protein reduction:
   100%=NS
   Near CR=10%
   ≥75%=NS
   ≥50%=20%
   ≥25-49%=40%

EFS=7 mo

Median OS=21 mo