Relative efficacy of treatment options in transplant-ineligible newly diagnosed multiple myeloma: results from a systematic literature review and network meta-analysis

Figures & data

Figure 1. PRISMA flow diagram for SLR and NMA study selection. NMA: network meta-analysis; PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses; SLR: systematic literature review.

Table 1. Extracted efficacy data from RCTs in the primary and extended analysis networks.

Study	Comparison (N patients)	PFS HR (95% CI)	OS HR (95% CI)
Primary analysis network
FIRST [11]	Rd (535) vs MPT (547)	0.69 (0.59‒0.80)	0.78 (0.67‒0.92)
IFM 01/01 [19]	MPT (113) vs MP (116)	0.62 (0.47‒0.82)^a	0.68 (0.48‒0.96)^a
IFM 99-06 [16]	MPT (125) vs MP (196)	0.51 (0.39‒0.67)	0.59 (0.46‒0.81)
MM03 [21]	MPT (64) vs MP (54)	0.67 (0.38‒1.18)^b	0.42 (0.18‒0.98)^a
VISTA [22]	VMP (344) vs MP (388)	0.56 (0.43‒0.72)	0.69 (0.57‒0.85)
SWOG S0777 [15]	RVd (264) vs Rd (261)	0.71 (0.56‒0.91)	0.71 (0.52‒0.96)
ALCYONE [24]	VMP + D (350) vs VMP (356)	0.50 (0.38‒0.65)	NR
MAIA [25]	D + Rd (368) vs Rd (369)	0.56 (0.43‒0.73)	NR
Additional studies in extended analysis network
AFAC [26]	TD (145) vs MP (143)	1.30 (0.95‒1.78)	1.55 (1.06‒2.27)
CLARION [27]	KMP (478) vs VMP (477)	0.91 (0.75‒1.10)	1.21 (0.90‒1.64)
E1A06 [28]	MPT + T (154) vs MPR + R (152)	0.84 (0.64‒1.09)	0.88 (0.63‒1.24)^c
FIRST [11]	Rd18 (541) vs MPT (547)	0.99 (0.86‒1.14)	0.77 (0.66‒0.90)
GEM05 [29,30]	VMP (130) vs VTP (130)	1.20 (0.90‒1.70)	0.67 (0.49‒0.91)
GIMEMA [31]	MPT + T (167) vs MP (164)	0.63 (0.48‒0.81)	1.04 (0.76‒1.44)
GIMEMA-MM-03-05 [32]	VMPT + VT (254) vs VMP (257)	0.58 (0.47‒0.71)	0.70 (0.52‒0.92)
HOVON-49 [33]	MPT + T (165) vs MP (168)	0.54 (0.38‒0.76)^b	0.84 (0.61‒1.16)^b
HOVON-87/NMSG18 [34,35]	MPR + R (280) vs MPT + T (280)	0.84 (0.70‒1.05)	0.79 (0.60‒1.05)
Hungria [36]	CTD (32) vs MPT (32)	0.89 (0.48‒1.64)	1.08 (0.54‒2.19)
IFM-95/01 [37]	MD (118) vs MP (122)	0.86 (0.65‒1.13)	0.85 (0.62‒1.17)^b
	D (127) vs MP (122)	1.70 (1.30‒2.22)^b	1.14 (0.84‒1.55)^b
	D-IFN (121) vs MP (122)	1.46 (1.12‒1.92)^b	1.10 (0.80‒1.50)^b
Magarotto [38]	Rd (217) vs CPR + MPR (437)	1.10 (0.90‒1.35)	1.06 (0.78‒1.43)
MM-015 [10]	MPR (153) vs MPR + R (152)	2.04 (1.43‒2.94)^a	1.27 (0.85‒1.89)^a
	MP (154) vs MPR + R (152)	2.50 (1.75‒3.57)^a	1.05 (0.69‒1.60)
MRC Myeloma IX [39]	CTDa (426) vs MP (423)	0.82 (0.70‒0.96)	0.89 (0.74‒1.08)
Myeloma XI [40]	CTD (924) vs CRD (928)	0.96 (0.86‒1.07)	0.92 (0.79‒1.07)
NMSG [41]	MPT + T (182) vs MP (175)	0.89 (0.70‒1.13)	1.12 (0.85‒1.47)
San-Miguel [42]	VMP + S (52) vs VMP (54)	1.00 (0.58‒1.75)^b	1.00 (0.33‒3.00)^c
TMSG [43]	MPT + T (58) vs MP (57)	0.70 (0.42‒1.17)	0.86 (0.46‒1.60)^a
UPFRONT [44]	VMP (167) vs VD (168)	1.00 (0.78‒1.29)^b	0.96 (0.65‒1.41)^b

CI: confidence interval; CPR + MPR: cyclophosphamide, prednisone, and lenalidomide plus melphalan, prednisone, and lenalidomide; CRD: cyclophosphamide, lenalidomide, and dexamethasone; CTD: cyclophosphamide, thalidomide, and dexamethasone; CTDa: cyclophosphamide, thalidomide, and dexamethasone (attenuated); D: dexamethasone; D-IFN: dexamethasone and interferon alpha; D + Rd: daratumumab, lenalidomide, and dexamethasone; HR: hazard ratio; KMP: carfilzomib, melphalan, and prednisone; MD: melphalan and dexamethasone; MP: melphalan and prednisone; MPR: melphalan, prednisone, and lenalidomide; MPR + R: melphalan, prednisone, and lenalidomide plus lenalidomide maintenance; MPT: melphalan, prednisone, and thalidomide; MPT + T: melphalan, prednisone, and thalidomide plus thalidomide maintenance; NR: not reached; PFS: progression-free survival; OS: overall survival; Rd: lenalidomide and dexamethasone; Rd18: lenalidomide in 3 of 4-week cycles; RCT: randomized controlled trial; RVd: lenalidomide, bortezomib, and dexamethasone; TD: thalidomide and dexamethasone; VD: bortezomib and dexamethasone; VMP: bortezomib, melphalan, and prednisone; VMP + D: bortezomib, melphalan, prednisone, and daratumumab; VMP + S: bortezomib, melphalan, and prednisone plus siltuximab maintenance; VMPT + VT: bortezomib, melphalan, prednisone, and thalidomide plus thalidomide maintenance; VTP, bortezomib, thalidomide, and prednisone.

a CI estimated from p-value.

b HR and CI estimated from the Kaplan–Meier curve.

c HR and CI estimated from number of deaths and survival rate.

Figure 2. Evidence networks. (A) Overall survival (OS). (B) Progression-free survival (PFS). CPR + MPR: cyclophosphamide, prednisone, and lenalidomide plus melphalan, prednisone, and lenalidomide; CRD: cyclophosphamide, lenalidomide, and dexamethasone; CTD: cyclophosphamide, thalidomide, and dexamethasone; CTDa: cyclophosphamide, thalidomide, and dexamethasone (attenuated); D: dexamethasone; D + IFN: dexamethasone and interferon alpha; D + Rd: daratumumab, lenalidomide, and dexamethasone; KMP: carfilzomib, melphalan, and prednisone; MD: melphalan and dexamethasone; MP: melphalan and prednisone; MPR: melphalan, prednisone, and lenalidomide; MPR + R: melphalan, prednisone, and lenalidomide plus lenalidomide maintenance; MPT: melphalan, prednisone, and thalidomide; MPT + T: melphalan, prednisone, and thalidomide plus thalidomide maintenance; NR: not reported; PFS: progression-free survival; OS: overall survival; Rd: lenalidomide and dexamethasone; Rd18: lenalidomide in 3 of 4-week cycles; RVd: lenalidomide, bortezomib, and dexamethasone; TD: thalidomide and dexamethasone; VD: bortezomib and dexamethasone; VMP: bortezomib, melphalan, and prednisone; VMP + D: bortezomib, melphalan, prednisone, and daratumumab; VMP + S: bortezomib, melphalan, and prednisone plus siltuximab maintenance; VMPT + VT: bortezomib, melphalan, prednisone, and thalidomide plus thalidomide maintenance; VTP: bortezomib, thalidomide, and prednisone.

Table 2. Baseline age and ISS stage from RCTs in the primary analysis network.

Study	Treatment	N	Age, median (range), y	ISS stage 3, n (%)	High-risk cytogenetic profile^a, n (%)
VISTA [22]	VMP	344	71 (57‒90)	115 (34.0)	26 (7.5)
	MP	338	71 (48–91)	119 (34.9)	20 (5.9)
IFM 01/01 [19,20]	MPT	113	78.5 (75–89)	34 (30.1)	NR
	MP	116	78.5 (75–89)	31 (26.7)	NR
IFM 99-06 [16]	MPT	125	NR (65–75)	32 (25.6)	NR
	MP	196	NR (65–75)	54 (27.6)	NR
MM03 [21]	MPT	64	76 (66–89)	14 (21.9)	NR
	MP	54	79 (68–88)	16 (29.6)	NR
FIRST [11,17,18,23]	Rd	535	73 (44–91)	216 (40.4)	43 (8.0)
	MPT	547	73 (51–92)	224 (41.0)	47 (8.6)
SWOG S0777 [15]	Rd	261	63 (56‒71)^b	79 (34.5)^c	NR
	RVd	264	63 (56‒70)^b	78 (32.2)^c	NR
ALCYONE [24]	VMP + D	350	71 (40–93)	142 (40.6)	53 (15.1)
	VMP	356	71 (50–91)	129 (36.2)	45 (12.6)
MAIA [25]	D + Rd	368	73 (50–90)	107 (29.1)	48/319 (15.0)
	Rd	369	74 (45–89)	110 (29.8)	44/323 (13.6)

D + Rd: daratumumab, lenalidomide, and dexamethasone; ISS: International Staging Score; MP: melphalan and prednisone; MPT: melphalan, prednisone, and thalidomide; NR: not reported; RCT: randomized controlled trial; Rd: lenalidomide and dexamethasone; RVd: lenalidomide, bortezomib, and dexamethasone; VMP: bortezomib, melphalan, and prednisone; VMP + D: bortezomib, melphalan, prednisone and daratumumab.

a Presence of at least one of the following chromosomal aberrations: translocation (4;14), translocation (14;16), or deletion 17p.

b Interquartile range.

c Calculated on the population eligible for efficacy analysis.

Figure 3. Results of the primary analysis. (A) Overall survival (OS). (B) Progression-free survival (PFS). Data are HR (95% CrI). CrI: credible interval; D + Rd: daratumumab, lenalidomide, and dexamethasone; HR: hazard ratio; MP: melphalan and prednisone; MPT: melphalan, prednisone, and thalidomide; PFS: progression-free survival; OS: overall survival; Rd: lenalidomide and dexamethasone; RVd: lenalidomide, bortezomib, and dexamethasone; VMP: bortezomib, melphalan, and prednisone; VMP + D: bortezomib, melphalan, prednisone, and daratumumab.

Figure 4. Surface under the cumulative ranking plot for the primary analysis. (A) Overall survival (OS). (B) Progression-free survival (PFS). Higher SUCRA scores indicate a higher probability that the treatment was in the top rank or one of the top ranks. D + Rd: daratumumab, lenalidomide, and dexamethasone; ITT: intentionto-treat; MP: melphalan and prednisone; MPT: melphalan, prednisone, and thalidomide; PFS: progression-free survival; OS: overall survival; Rd: lenalidomide and dexamethasone; RVd: lenalidomide, bortezomib, and dexamethasone; SUCRA: surface under the cumulative ranking curve; VMP: bortezomib, melphalan, and prednisone; VMP + D: bortezomib, melphalan, prednisone, and daratumumab.

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