Phase III

*Attal, 2004 (ASH 535)¹⁰⁸

Thal dose NS
HDT w/VAD then auto SCT w/ melphalan 200 mg/m²

If no progression at 2 mo after second ASCT, randomized to 3 arms:
A=no maintenance
B=pamidronate
C=Thal + pamidronate
[26 mo (6-50)]

580

Inclusion <65 yr
"At diagnosis"
Other pt and MM characteristics NS

580

Arm A=195
Arm B=190
Arm C=195

Probability of PFS @ 40 mo:
   Arm A=53% (95% CI=37-65)
   Arm B=52% (95% CI=36-68)
   Arm C=70% (95% CI=42-80)
   p=0.007

Thal also improves EFS; p<0.01

60% enrolled in Arms A and B received Thal at relapse; OS survival similar in all 3 groups

Barlogie, 2002¹⁰⁹

Quality 2/6

Thalidomide as initial phase of Total Therapy program

400 mg
50% randomized to Thal then Intensive Induction w/ VAD (Thal group) or CAD/DCEP (no Thal group) then MEL & transplant; consolidation with DECP (Thal group) or DCEP/CAD (no Thal group); maintenance IFN
[27 mo]

231
20% >65 yr old

Gender not specified (This is a report on the first 231 randomized of a total 450; patients were randomized to Thal 400 vs. no Thal at the beginning of the Total Therapy II program—these data do not present unblinded outcomes.)

231

Blinded data—do not know which patients received thal

Overall Response (≥25%)=UTD

m protein reduction:
   @ end of induction
   CR + near CR =30% after second HDT cycle
   CR + near CR=66%
   100% CR=46%
   Near CR=20%
   ≥90%=NS
   ≥50%=%

Blinded data—do not know which patients received thal

Overall 3 year estimated

Followup:
   EFS=71%
   OS=77%

*Barlogie, 2004 (ASH 1483)¹¹⁰

Quality*

Thalidomide as initial phase of Total Therapy program

Updated report from Barlogie, 2004 (ASH 1483)
[Evaluated at time of treatment failure=med 23 mo from enrollment]

As of 8/4/04, 104 of 668 pts enrolled have been randomized
Thal=61
No Thal=43

Thal salvage response rate =26%

No Thal salvage response rate=51%;  p=0.028

Survival from time of relapse on Total Therapy II was better for those who did not receive Thal maintenance (med 29 vs. 8 mo, p=0.0001)

Hazard ratio for OS post-relapse when Thal maintenance used=2.6; p=0.0006

Lee, 2003²¹

Quality 4/5

50-400 mg within DTPACE regimen
DTPACE x 2 cycles then if >50% response randomized to tandem SCT with high-dose melphalan or 4 more cycles of DTPACE or if <50% SCT; maintenance with Thal 50-200mg and Dex 20mg/dx4d q 4 wks—10% required a 50% dose reduction of Thalidomide by 2nd cycle of DTPACE
Dex 40qd x 4d
Thal 400 qhs
Cisplatin 10mg/m2/d x 4d
Doxorubicin 10mg/m2/d x 4d
Cyclophosphamide 400 mg/m²/d x 4d
Etoposide 40mg/m²/d x 4d

236
60 yr (31-84)
64% M
Previously treated
63% progressive disease after chemo
IgG=56%
IgA=19%
Light chain=2%

DTPACE cycle #1:
229
DTPACE cycle #2: 229

Overall Response (≥25%)=73%

m protein reduction:
   100%=3%
   Near CR=5%
   ≥90%=NS
   ≥75%=9%
   ≥50%=53

Overall Response (≥25%)=86%

m protein reduction:
   100%=7%
   Near Cr=9%
   ≥90%=NS
   ≥75%=16%
   ≥50%=54%

Extensive toxicity data—cannot determine what is due to thalidomide

Phase II

Alexanian, 2002¹¹¹

Quality 2/5

Alexanian, 2003⁶⁴

Quality=1/6

Two papers with the same data

100-300 mg
+ Dex20 mg/m² x 4d on d1, 9 and 17 q28 days—started 7 mo (4-20) after intensive therapy
Responders maintain Thal 100-150 mg
[treatment > 3 mo; Median f/u not stated]

21
54 yr (37-61)
71% M

Stable, partial responders after intensive CT and SCT (consolidation therapy after SCT)

21

Overall Response (≥25%)=81%

m protein reduction:
   100%=19%
   ≥90%=38%
   ≥75%=19%
   ≥50%=5%

*Sengar, 2005 (ASCO 6731)¹¹²

Quality*

50 mg
After high dose melphalan+ SCT:
Randomized to maintenance Thal vs. IFN randomized (unclear if phase II or phase III)

70—Unclear if enrollment continuing or goal n
52 yr (26-65)
74% M

Stage III=70%
Other MM characteristics NS

17 randomized

Unblinded data not presented

PFS=55%

OS=60%

Median duration of maintenance=14 mo

*Stewart, 2004 (ASH 335)¹¹³

200-400 mg
Thalidomide/Prednisone maintenance after ASCT with Melphalan 200 mg/m²:
Prednisone 50 mg qod + Thal 200 vs.400 mg
Randomized Phase II
[36.8 mo]

67

Pt and MM characteristics NS
Numbers randomized to each arm NS

67

Overall Response (≥25%)=UTD

m protein reduction:
   post-tx CR or near CR=15%
   @ 1 yr CR + near CR=38%
   ≥90%=NS
   ≥50%=NS

PFS post-ASCT=32.3 mo

OS @ 1 yr=91%

Primary endpoint=incidence of dose reduction or dropout:
   Thal 200 arm=31%
   Thal 400 arm=64%

Allowing for dose reductions, # on each arm at 18 mo after registration:
   Thal 200 arm=76%
   Thal 400 arm=41%

Because of excessive treatment toxicity enrollment in the 400mg dose arm was closed after completing the first phase of the planned enrollment.