Phase II

Barlogie, 2001⁴³

Quality 4/6

200-800 mg
[22 mo]

169
40% >60 yr

Gender not specified
advanced refractory

169

Overall response (≥25%)=83%

m protein reduction:
   100%=2%
   ≥90%=14%
   ≥50%=30%
   ≥25-49%=37%

Est. OS from KM at 12 mo=70%

Est. EFS from KM at 12 mo=25%

2-year EFS: 20% ± 6%

2-year OS: 48% ± 6%

Of patients achieving PPR 25%, 70% achieved that response within 2 months and 90% within 4.5 months.

Relationship to total dose >42 g in 3 mo had a higher response rate 25% PPR (54% v 21%): p<0.001 and superior OS (63% v 45%) p<0.001.

Corso, 2002⁴⁴

Quality 0/5

Not randomized

Group 1=11 pts treated w/Thal 200 mg
duration 210 d (90-460); 4/21 also received Dex 20mg x2d q 2wks x 4

Group 2=10 pts treated with CAVD (≥ 4 cycles)
CAVD (q4-6 wks):
Lomustine 80mg/m2 d1
Melphalan 5mg/m2/d d1-5
Etoposide 60mg/m2/q12 D1-5
Dex 8mg/d D1-5
[Median f/u=NS]

21

Gender not specified
Thal: 59 yr (52-67)
Chemo: 61 yr (46-76)

21

Thal 11
Chemo 10

Response (≥25%)=100%

m protein reduction:
   100%=9%
   ≥90%=NS
   ≥50%=36%
   ≥25-49%=55%

Overall response (≥25%)=66%

m protein reduction:
   100%=NS
   ≥90%=NS
   ≥50%=66%
   ≥25-49%=NS

Group 1: Median time to response=60 d (30-190)

Group 2: Median duration of response=9 mo (3-18)

Hattori, 2004⁴⁵

Quality 4/5

200-400 mg
[Median f/u NS]

44
55.9 yr (30-70)
58% M

relapsed autoSCT=39%;
stage 3=91%
IgG=55%,
BJ protein=23%
IgA=16%
IgD=>1%

44

Overall response (≥25%)=68%

m protein reduction:
   100%=0%
   ≥90%=NS
   ≥50%=27%
   ≥25-49%=41%

Hus, 2001⁴⁶

Quality 3/6

200-400 mg
[Median f/u=NS]

53
63 yr (32-79)
51% M

Relapsed, refractory w/ hypocellular BM w/ severe pancytopenia

Median time since dx=38 mo (6-144)

Historical control=35 relapsed or resistant MM pts treated in 3 participating centers during 1990-4

53

Stage II=25%

Stage III=75%

Refractory=17%

Relapsed=83%

Overall response(≥25%)=58.5%

m protein reduction:
   100%=7.5%
   ≥90%=NS
   ≥75%=13%
   ≥50%=23%
   ≥25-49%=15%

Est. OS by KM w/Thal=250 wk (vs. 210 wk in historical controls, p<0.001)

PFS=240 wk

Johnston, 2002⁴⁷

Quality 3/5

50-500 mg
Median duration of Thal=11 mo (7-15)
[Median f/u=NS]

12
67.5 yr (34-85; 42% >70 yr)
42% M

Refractory or intolerant to at least 2 prior tx not including HDT
IgG=64%
Plasma cell leukemia=4

Median time since diag=10.5 mo ( 3-48)

12
MM=8
PCL=4

Overall response (≥25%)=59%

m protein reduction:
   100%=0%
   ≥90%=13
   ≥75%=13
   ≥50%=25
   ≥25-49%=0%
   <25%=25%

Median dose for PR=175 mg (100-300)

Juliusson, 2000⁴⁸

Quality 1/5

200-800 mg
[Median f/u=NS]

23
61.1 yr (44-78)
70% M

Median 44 mo (7-137) since initial diagnosis
Advanced, heavily pretreated
Previous SCT=43%
IgG=61%
IgA=22%
B-J protein only=17%
Non-secretory=NS

23

Overall response (≥25%)=65%

m protein reduction:
   100%=NS
   ≥90%=NS
   ≥75%=NS
   ≥50%=43% partial
   ≥25-49%=22% minor

(% PPR not specified)

Median time to PR=31d (28-81 d) 8/16 (50%) PRs on twice daily divided dosing and 2/7 (29%) on single daily dosing (actual doses in categories=NS)

Kees, 2003⁴⁹

Quality 2/6

50-400 mg
Not randomized
Thal only=50% (n=12)
Thal/Dex=33% (n=8; Dex started if no response to thal alone at 6 months)
Thal+ VAD=17% (n=4)
Med Thal dose=100 mg/d
[Median f/u=NS]

24
62 yr (45-83)
50% M

Relapsed (19), resistant (5)
IgG=79%
IgA=8%
Light chain only=12%
Stage III=62%

Overall response (≥25%)=50%

m protein reduction:
   100%=NS
   ≥90%=NS
   ≥75%=12%
   ≥50%=25%
   ≥25-49%=13% inclusive
   ≥50%=50%
   Thal only=42%
   Thal/Dex=63%
   VAD + Thal=50%

3/24 pts d/c’d Thal due to side effects

1 pt died

*Kroeger, 2004 (ASH 1646)⁵⁰

Quality*

100-300 mg
Pre donor lymphocyte infusion (DLI)
[Median f/u=NS]

18
53 yr ( 31-64)

Gender not specified
Progressive or residual disease not responding to prior DLI
Prior allogeneic SCT=100%

18

Overall response (≥25%)=67%

m protein reduction:
   100%=22%
   ≥90%=NS
   ≥75%=NS
   ≥50%=NS
   ≥25-49%=45%

2 yr estimated OS=100%

2 yr estimated DFS=84%

Med time to response=108 d (36-266)

Kumar, 2003⁵¹

Quality 4/5

200-800 mg
[18.7 mo; Survivors 28.5 mo (19.3-34)]

32
67 yr (36-78)
66% M

Relapsed
IgG=72%
Previous SCT=16%
Median time since dx=35.1 mo (3.1-114.9)

32

Overall Response (≥25%)=51%

m protein reduction:
   100%=0%
   ≥90%=NS
   ≥75%=NS
   ≥50%=31%
   ≥25-49%=22%

Median PFS-KM=15.7 mo (95% CI, 8.6-25.6 mo)

Median OS-KM=22 mo (95% CI, 10.6-35.9 mo)

Median duration of response for those achieving a PR=11.9 mo (3.7-20.3)

Neben, Moehler, Egerer, et al., 2001⁵²

Quality 3/6

100-400 mg
[15 mo, 0.3-20]

54
57 yr (34-79)
69% M

Progressive MM
Stage III=87%
Median prior chemo cycles=6 (0-30) &
72% ≥ 1 HDT/PBSCT
IgG 44%
IgA 35%

54

Overall Response (≥25%)=57%

m protein reduction:
   100%=2%
   ≥90%=9%
   ≥75%=NS
   ≥50%=26%
   ≥25-49%=57%

Estimated 6 mo PFS=73% (95% CI, 62-86%)

Rajkumar, 2000⁵³

Quality 3/5

200-800 mg
[Median f/u=NS]

16
64 yr (48-85)
69% M

Median time since dx=32 mo
Relapsed, advanced
100% Stage III
88% with 2 prior chemotherapy regimens including 25% with prior HDT/SCT

16

Overall Response (≥25%)=57%

m protein reduction:
   100%=0%
   ≥90%=NS
   ≥75%=NS
   ≥50%=25%
   ≥25-49%=<1%

Median duration of stability=5 mo (2-9)

After Thal:
   Median OS=5 mo
   Median PFS=3 mo

Median Survival since diagnosis=56 mo

Richardson, 2004⁵⁴

Quality 3/5

200-600 mg, 200 mg maintenance for those with response or stable disease after week 12
[7 mo]

30
58 yr (39-70)
63% M

Relapsed after HDC & SCT
Stage III=57%
IgG=46%
IgA=27%
Light chain disease=27%

Median time since dx=
4.3 yr (10 mo- 10 yr)
Median number of prior tx=5 (2-7)

26 evaluable

Overall Response (≥25%)=57%

m protein reduction:
   100%=0%
   ≥90%=NS
   ≥75%=NS
   ≥50%=33%
   ≥25-49%=10%

PFS=67% in 26 evaluable (95% CI, 48-86%)

Median PFS=6 mo

Median OS not reached; 6-month OS estimate from KM=83%

Median duration of response=6 mo

Schey, 2003⁵⁵

Quality 4/5

100-600 mg, 200 mg maintenance

Median therapy duration=6 mo (3-18)

Med MTD thal=300mg
[13 mo, 1-38]

69
62 yr ( 39-84)

Gender not specified

Relapsed or refractory, including light chain & relapsed after >3 mo SCT 36% had prior autoSCT

Median time since dx=31 mo (3-132)

69

Overall Response (≥25%)=49%

m protein reduction:
   100% CR=2%
   ≥90%=9%
   ≥75%=9%
   ≥50%=17%
   ≥25-49%=22%

Discontinued Thal:
   12% neuropathy
   4% constipation

Median OS=19 mo

Median PFS=14 mo

Singhal, 1999³⁵

Quality 5/5

200-800 mg
86% to 400 mg
68% to 600 mg
55% to 800 mg
[14.5 mo (12-16)]

84
38% > 62 yr;
73% M

Previously treated & progressive
IgG 61%
Duration of prior therapy > 5yrs=21%
Prior HDT=90%
Interval between last cycle of chemo and thal > 1 yr=37% (med 14 mo)

84

Overall Response (≥25%)=32%

m protein reduction:
   100%=2%
   ≥90%=7%
   ≥75%=7%
   ≥50%=8%
   ≥25-49%=7%

12 mo OS=58 ± 5%

Median EFS=3 mo

At 12 mo, 22± 5% event free.

Median TTP had not been reached 12 mo rate of progression=44 ± 10%.

Median interval between start of thal and PPR by 25%=29d (4d-6 mo).

78% of 25% responses were evident by 2 mo.

Median interval between start of thal and decrease in paraprotein by 50%=2 mo and 75%=3 mo.

23% still receiving thal 4-15 mo after starting thal (median 13 mo).

Thal discontinued after med 52d (2-286) due to lack of response in 63% of pts and due to relapse in 14%.

Tosi, 2001⁵⁶

Quality 3/5

100-800 mg
[5 mo]

11
54.5 yr (42-60)
64% M

Stage III, Relapsing after autoSCT (7/11 with >1 autoSCT)

Median time to Thal since dx=51 mo
Median time between SCT & start of Thal=16 mo

11

Overall Response (≥25%)=72%

m protein reduction:
   100%=NS
   ≥90%=NS
   ≥75%=NS
   ≥50%=36%
   ≥25-49%=36%

Median response duration=5 mo

Maximal PPR at median 2 mo after initiation of thal

Tosi, 2002⁵⁷

Quality 2/5

100-800 mg  [9 mo]

65
63 yr (35-78)
71%M

Relapsed/refractory (1 pt with newly diagnosed MM)
Stage III=94%

Median time since dx=44 mo (0-192)
Prior autoSCT=37%
IgG=75%
IgA=15%
Bence Jones=8%

60 evaluable

Overall Response (≥25%)=46.6%

m protein reduction:
   100%=NS
   ≥90%=NS
   ≥75%=8.3%
   ≥50%=20%
   ≥25-49%=18.3%

Median response duration=8 mo (2-16+)

At Median f/u 9 mo PFS=25% and OS=92% (calculated from numbers in text)

Waage, 2004⁵⁸

Quality 4/5

200-800 mg
[2.4 yr]

65
63 yr (31-78)
59% M

Refractory, relapsed
Median time since dx=
4.2 yr (1-16)
autoSCT=83%
Stage III=88%
IgG=66%
IgA=15%
Light chain =14%

65

Overall Response (≥25%)=34%

m protein reduction:
   100%=6%
   ≥90%=NS
   ≥75%=NS
   ≥50%=14%
   ≥25-49%=14%

Median OS=12 mo

Survival landmarks:
   3 mo=74%
   6 mo=66%
   12 mo=49%
   24 mo=32%

16/22 responders with some reduction in paraprotein levels by 1 week of thal; by 3 weeks all responders with paraprotein reduction (70% had reached 25% reduction).

15% received full dose thal at 800 mg; 25% reduced dose due to side effects; 26% discontinued thal.

Side effects leading to Thal d/c:
   ileus (n=3)
   exanthema (n=2)
   neuropathy (n=2)
   somnolence (n=2)

HRQOL (measured on QLQ C-30 at baseline (n=62), 12 wks (n=38), and 24 wks (n=20)): "HRQOL scores relatively stable throughout study," except:
   Pain decrease by 15 (0-100 scale)
   Constipation increase by 32 (0-100 scale)

*20 pts completing 24 wk questionnaire were responders and had higher HRQOL at baseline

Yakoub-Agha, 2000⁵⁹

Quality 4/5

100-800 mg
[105 d, 44-272]

27
62 yr (35-71)
55% M

Advanced, progressed after ≥2 lines of therapy
Prior autoSCT=82%
IgG=62%
IgA=26%
Light chains=8%

27

Overall Response (≥25%)=45%

m protein reduction:
   100%=NS
   ≥90%=NS
   ≥75%=15%
   ≥50%=18%
   ≥25-49%=12%

Median interval between initiation of thal and 25% PPR=30d (10-97)

Yakoub-Agha, 2002⁶⁰

Quality 6/6

50-800 mg
[338 d, 247-611]
Median total dose of thal received in first 3 mo of therapy=34.4g (1.6-72)
Mean daily dose=400 mg/d (27-800)

83
64 yr (40-81)
55% M

Advanced, progressed after ≥2 lines of therapy
IgG=73%
IgA=18%
Light chain=6%
Prior autoSCT=70%
Median time since dx=4.2 yr (1.7-11.4)

83

Overall Response (≥25%)=66%

m protein reduction:
   100%=NS
   ≥90%=NS
   ≥75%=13%NS
   ≥50%=35%
   ≥25-49%=18%

Estimated OS=391 d (95% CI, 363-577d)

Median interval from initiation of thal to 25% PPR=39d (4-123)