Review of thalidomide in the treatment of newly diagnosed multiple myeloma

Figures & data

Table 1 Thalidomide in upfront therapy in SMM/indolent MM and symptomatic MM patients candidates for high dose chemotherapy (HDT)

Trial	Regimen	Thalidomide dose (mg/day)	Duration	Timing	No. of patients	Response (EBMT criteria)	Survival
Phase II (Weber et al 2003)	T	200–600	Until PD	I/M	28	PR 36%	–
	TD (1)	100–400	3 months	I	48	PR + CR 72%	–
Phase II (Rajkumar et al 2003)	T	200–800	Until PD	I/M	29	PR + MR 66%	–
Phase II (Rajkumar et al 2002)	TD (2)	200–800	4 cycles	I	50	PR + CR 64%	–
Phase II (Wang et al 2005)	TD (1)	100–300	2 cycles	I	26	PR + CR 73%	–
Phase II (Abdelkefi et al 2005)	TD (1)*	200	3 months	I	60	PR + CR 74%	–
Phase II (Cavo et al 2005)	TD (2)	100–200	4 months	I	100	PR + CR 76%	–
Phase III (Rajkumar et al 2006)	TD v D (3)	200	4 cycles	I	207	PR + CR 63% v 41%	–
Phase II (Wang et al 2005)	VTD (4)	100–200	2 cycles	I	36	PR + CR 78%	–
Phase II (Zervas et al 2004)	T-VAD doxil (5)	200	4 cycles	I	39	PR + CR 74%	22mos EFS 55% OS 74%
Phase II (Schutt et al 2005)	T-VED (6)	200–400	Until PD	I/M	31	PR + CR 80%	3y EFS 26% 3y OS 62%
Phase II (Hassoun et al 2005)	AD-TD (7)	100–200	2 cycles	I	45	PR + CR 84%	-
Phase III (Goldschmidt et al 2005)	T with HDT v HDT (8)	200–400	Until PD	I/M	604	PR + CR 91% v 88%	-
Phase III (Hussein et al 2005)	T with HDT (9)	100–400	Until PD	I/M	130	PR + CR 80%	-
Phase III (Barlogie et al 2006)	T with HDT v HDT (10)	400, 100, 200, 50	Until PD	I/T/C/M	668	CR 62% v 43%	5y EFS % 56 v 44; similar OS
Phase II (Alexanian et al 2002)	TD (1)	100–300	Until PD	C	21	Further response 57%	Median remission 22 months
Phase II (Sahebi et al 2006)	T	50–400	Until PD	M	29	PR + CR 68%	2y PFS 49% 2y OS 83%
Phase II (Brinker et al 2006)	T	200	Until PD	M	20	–	Median OS 65 months
Phase II (Feyler et al 2005)	T	50, 100,200,250,300	Until PD	M	100	–	Median PFS
							35 months
Phase III (Attal et al 2005)	TP v P v No maintenance	–	Until PD	M	593	–	PFS % 56 v 37 v 34 similar OS

Abbreviations: T, Thalidomide; D, Dexamethasone; P, pamidronate; PD, progressive disease; I, induction; T, transplant; C, consolidation; M, manteinance; EBMT, European Group for Blood and Marrow Transplantation; MR, minimal response; PR, partial response; CR, complete response; EFS, event free survival; PFS, progression free survival; OS, overall survival; TD(1), 20mg/m² d 1–4, 9–12 and 17–20; TD (1)*, D 20mg/m² d 1–4, 9–12 and 17–20(odd cycles) d 1–4 (even cycles); TD(2), D 40 mg d 1–4, 9–12 and 17–20 (odd cycles) d 1–4 (even cycles); TD (3), D 40 mg d 1–4, 9–12 and 17–20; VTD(4), D 20 mg/m² days 1–4, 9–12, and 17–20, v 1.3 mg/m² (15 patients), 1.5 mg/m² (11), and ≥1.6 mg/m² (10); T-VAD doxil (5), Vincristine 2 mg i.v. day 1, Liposomal doxorubicin 40 mg/m² i.v. day 1, D 40 mg days 1–4; T-VED (6), Vincristine 1.5 mg i.v. day 1, Epirubicin 30 mg/m² i.v. days 1–2, D 20 mg/m² days 1–5; AD-TD (7), Doxorubicin 9 mg/m² i.v. d 1–4, D 40 mg d 1–4, 9–12 and 17–20; after 3 AD cycles, T 100–200 mg d 1–28, D40 mg d 1–4, 9–12 and 17–20, (8) HOVON -50/GMMG-HD3. (9) SWOG 0204. (10) Total Therapy 2.

Table 2 Thalidomide in upfront therapy symptomatic MM patients not candidates for high dose chemotherapy (HDT)

Trial	Regimen	Thalidomide dose (mg/day)	Duration	No.of patients	Response (EBMT criteria)	Survival
Phase II (Dingli et al 2005)	TD (1)	200	Until PD	21	PR + MR 48%	Median PFS 18 months
Phase II (Dimopoulos et al 2006)	TDM (2)	300	3 cycles*	50	PR + CR 72%	Median time to progres sion 21.2 months
Phase II (Palumbo et al 2005)	MPT (3)	100	6 cycles^#	41	PR + CR 73%	Median EFS 30 months
Phase III (Palumbo et al 2006)	MPT v MP (3)	100	6 cycles^#	255	PR + CR 76% v 47.6%	2y EFS 54% v 27%
Phase II (Offidani et al 2005)	ThaDD (4)	100	–	41	PR + CR 89%	2y EFS 65% 2y OS 70%
Phase II (Williams et al 2004)	CTD (5)	200	2–6 cycles	15	PR + CR = 100%	–
Phase III (Ludwig et al 2005)	TD v MP for induction (6)	200–400	Until PD	146	PR + CR 57% v 50%	–
	T + IFN v IFN for maintenance
Phase III (Facon et al 2005)	MP v MPT v MEL100	50–400	1 year	436	–	Median PFS 17 v 28 v 19

Abbreviations: T, Thalidomide; D, Dexamethasone; P, prednisone; IFN, interferon α2b; PD, progressive disease; EBMT, European Group for Blood and Marrow Transplantation; MR, minimal response; PR, partial response; CR, complete response; EFS, event free survival; PFS, progression free survival; OS, overall survival; TD (1), D 40 mg d 1–4, 9–12 and 17–20 (odd cycles) d 1–4 (even cycles); TDM (2), D 12 mg/m² d 1–4, 17–20, Thalidomide 300 mg d 1–4, 17–20, oral melphalan 8 mg/m² d 1–4* Patients without evidence of PD received 9 additional cycles of MTD d 1–4; MP (3), Oral melphalan 4 mg/m² d 1–7, Prednisone 40 mg/mq d 1–7; ^#Patients without evidence of PD in the MPT arm continued T until PD; ThaDD (4), Thalidomide 100 mg/day, pegylated liposomal doxorubicin (40 mg/m² on day 1), dexamethasone (40 mg days 1–4, 9–12); 28-day cycle; CTD (5), Oral cyclophosphamide 500 mg, d 1, 8 and 15, thalidomide at a dose of 100 to 200 mg daily, and oral D 40 mg on d 1–4 and 15–18. TD v MP (6), TD: Thalidomide 200 to 400 mg/day, D 40 mg days 1–4 and 15–18 (odd cycles) and days 1–4 (even cycles); MP: M 0.25 mg/kg d 1–4, P 2 mg/kg d 1–4.

Table 3 DVT and pheripheral neuropathy in newly diagnosed patients treated with thalidomide

Trial	DVT (%)	DVT prophilaxis (Y/N)	Peripheral neuropathy (%)
Phase II (Rajkumar et al 2002)	12	N	2 (grade 3–4)
Phase III (Rajkumar et al 2006)	17	N	7 (grade 3–4)
Phase II (Wang et al 2005)	7	Y	4 (grade 3–4)
Phase II (Abdelkefi et al 2005)	3	Y (after the first 13 patients)	5 (grade 3–4)
Phase II (Cavo et al 2005)	15	Y (after the first 19 patients)	4 (grade 3–4)
Phase II (Zervas et al 2004)	10	N	2.5 (grade 3–4)
Phase II (Schutt et al 2005)	26	N	26 (grade not known)
Phase II (Hassoun et al 2005)	11	Y	–
Phase III (Barlogie et al 2006)	30	Y (after the first 162 patients)	27 (≥ grade 2)
Phase III (Goldschmidt et al 2005)	8	Y	–
Phase II (Dimopoulos et al 2006)	9	N	9 (grade 2)
Phase III (Palumbo et al 2006)	12	Y (after the first 65 patients)	8 (grade 3–4)
Phase II (Offidani et al 2005)	12	Y	0
Phase II (Wang et al 2005)	5	Y	8 (grade 3)
Phase III (Ludwig et al 2005)	20	N	19 (grade 2–3)
Phase II (Alexanian et al 2002)	0	N	14
Phase II (Sahebi et al 2006)	0	N	7
Phase II (Brinker et al 2006)	0	N	4
Phase II (Dingli et al 2005)	0	N	5

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