First line vs delayed transplantation in myeloma: Certainties and controversies

Table 1 Phase III clinical trials of chemotherapy vs transplantation

Ref.	Publication year	Random	Patients n	ORR (%)	CR (%)	PFS/EFS	OS
Attal et al[4]	1996	ASCT	100	81	122	28 mo	57 mo
IFM90		CCT	100	57	5	18 mo	44 mo
				P < 0.001	P < 0.001	P = 0.01	P = 0.03
Child et al[5]	2003	ASCT	200	86	44	32 mo	54 mo
MRC VII		CCT	201	48	8	20 mo	42 mo
				P = NR	P < 0.001	P < 0.001	P = 0.04
Fermand et al[25]	1998	ASCT	91	78	57	39 mo	64.6 mo
MAG90		CCT	94	58	20	13 mo	64 mo
Barlogie et al[28]	2006	ASCT	261	93	17	17%	38%
S9321		CCT	255	90	15	14%	38%
						At 7 yr	At 7 yr
Fermand[27]	2005	ASCT	94	62	36	37 mo	79 mo
MAG95		CCT	96	58.5	20	16 mo	43 mo
Bladé et al[26]	2005	ASCT	81	82	30	42 mo	66 mo
PETHEMA		CCT	83	83	11	33 mo	61 mo
					P = 0.002
Palumbo et al[9]	2004	ASCT	95	72	125	28 mo	58 mo
MMSG		CCT	99	66	6	16 mo	42 mo
					P = 0.002	P < 0.001	P < 0.001

¹≥ nCR. Only statistical significant P is reported. CCT: Conventional chemotherapy; ASCT: Autologous stem cell transplantation; ORR: Overall response rate; CR: Complete remission; nCR: Near CR; PFS: Progression free survival; EFS: Event free survival; OS: Overall survival; NR: Not reported; IFM: Intergroupe Francophone du Myèlome; MRC: Medical Research Council; PETHEMA: Programma Para El Estudio y Tratamiento De Las Hemopatìas Malignas; MAG: Myèlome Autogreffe.

Table 2 Improved outcomes with the introduction of novel agents in the upfront treatment of multiple myeloma

Ref.	Publication’s year	Therapy	Patients n	≥VGPR (%) preASCT	≥VGPR (%) postASCT	≥PR %	CR/nCR %	PFS/EFS OS
Thalidomide
Rajkumar et al[32]	2006	TD vs D	200	63 vs 41 (≥ PR)	NR			NR
Cavo et al[10]	2009	TD vs VAD	270	30 vs 15	68 vs 49			PFS 51% vs 31% at 4 yr
								OS 69% vs 53% at 5 yr
Barlogie et al[17]	2006	TT2 + Thal vs TT2	668	NR	62 vs 43			EFS 56% vs 44% at 3 yr
								OS 65% vs 65% at 5 yr
Lokhorst et al[33]	2010	TAD vs VAD	402	32 vs 15	49 vs 32			EFS 34 mo vs 22 mo
								OS 73 mo vs 60 mo
Lenalidomide
Richardson et al[38]	2010	VRD	35			100	57	NR
Palumbo et al[56]	2014		402
		MPR	202			NR	NR	PFS 22.4 mo vs 43 mo
		vs
		HDM	200			NR	NR	OS 65.3% vs 81.6%
		Maintenance R	198			78	23	PFS 41.9 mo vs 21.6 mo
		vs
		No maintenance	204			77	19	OS 79% vs 88%
McCarthy et al[66]	2012	Lenalidomide vs placebo	460					PFS at 3 yr
								66% vs 39%
								OS at 3 yr
								88% vs 80%
Attal et al[67]	2012	Lenalidomide vs placebo	614					PFS at 4 yr
								43% vs 22%
								OS at 4 y
								73% vs 75%
Bortezomib
Harousseau et al[16]	2010	®VD vs VAD	482	38 vs 15	54 vs 37			36 m vs 27 m
Sonneveld et al[34]	2012	®Induction PAD + maint VEL vs induction VAD + maint Thal	626	NR	75 vs 61			46% vs 42% at 3 yr
Cavo et al[13]	2010	®VTD vs TD induction and consolid	480	62 vs 28	82 vs 64			68% vs 56% at 3 yr
Rosiñol et al[37]	2012	®VTD vs TD	202	29 vs 14 (CR)	59 vs 40 (CR)			82% at 2 yr (OS)
Moreau et al[35]	2011	®VD vs vtD	199	49 vs 39	74 vs 58			30 mo vs 26 mo
Leleu et al[36]	2013	VTd-ASCT + consolid VTd vs VTd-ASCT	217	After treatment: 83 vs 64				TTP: 62% vs 29% at 4 yr

VGPR: Very good partial response; TTP: Time to progression; PFS: Progression free survival; NR: Not reported; Thal: Thalidomide; TD: Thalidomide dexamethasone; VAD: Vincristine adriamycin dexamethasone; TAD: Thalidomide adriamycin dexamethasone; MPR: Melphalan prednisone lenalidomide; VTD: Bortezomib thalidomide dexamethasone; VD: Bortezominb dexamethasone; PAD: Adriamycin bortezomib dexamethasone; vtD: Reduced doses bortezomib thalidomide dexamethasone; R: Lenalidomide; VRD: Bortezomib lenalidomide dexamethasone; OS: Overall survival; ASCT: Autologous transplantation; nCR: Near CR; HDM: High dose melphalan; Consolid: Consolidation; Maint: Maintenance.

Table 3 Major studies of delayed autologous stem cell transplantation (for randomised trials only data regarding delayed autologous stem cell transplantation are reported)

Ref.	Publication’s year	Patients n	Type of trial	Median interval between diagnosis or first ASCT and delayed ASCT	Previous ASCT	ORR (%)	PFS (mo)	OS (mo)
Cook et al[49]	2011	106	Retrospective	19 mo (relapse from first transplant)	Yes	63%	NR	37
Jimenez-Zepeda et al[51]	2012	81	Retrospective	39 mo (relapse from first transplant)	Yes	97.4%	16.43	53
Sellner et al[44]	2013	200	Retrospective	NR	Yes	80.4%	15.2	43.2
Cook et al[46]	2014	89	Prospective	2.7 yr	Yes	83%	19	80.3% at 3 yr
Gertz et al[29]	2000	64	Prospective	NR	No	97%	11.4	19.6
Michaelis et al[45]	2013	187	Retrospective	32 mo	Yes	68%	5% at 5 yr	29% at 5 yr
Shah et al[68]	2012	44	Retrospective	30 mo	Yes	90%	12.3	31.7
Kumar et al[48]	2012	112	Prospective	> 12 mo	No	32% (≥ VGPR)	16 (TTP)	73.4% at 4 yr
Dunavin et al[47]	2013	65	Retrospective	17.7 mo	No	NR	23 (TTP)	63% at 5 yr

VGPR: Very good partial response; TTP: Time to progression; PFS: Progression free survival; ASCT: Autologous stem cell transplant; OS: Overall survival; NR: Not reported; ORR: Overall response rate.