A systematic literature review and network meta-analysis of treatments for patients with untreated multiple myeloma not eligible for stem cell transplantation

Figures & data

Figure 1. Methodology figures. (A) Study selection for meta-analysis. CENTRAL, Cochrane Central Register of Controlled Trials. (B) Network diagram including studies with similar MPT doses and schedules in the primary analysis network. (C) Network diagram for sensitivity analysis of MPT and MPT-T studies and studies with 1- to 2-degree linkages. MP: melphalan and prednisone; MPR: melphalan and prednisone with lenalidomide; MPR-R: melphalan and prednisone with lenalidomide followed by lenalidomide maintenance; MPT: melphalan and prednisone with thalidomide; MPT-T: melphalan and prednisone with thalidomide followed by thalidomide maintenance; Rd: lenalidomide and low-dose dexamethasone; VMP: melphalan and prednisone with bortezomib.

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

Study Group [Reference]	Comparison (N patients)	OS HR (95% CI)	PFS HR (95% CI)
Primary analysis
MM-020 (FIRST) [5,21]	Rd (535) versus MPT (547)	0.75 (0.62–0.90)	0.69 (0.59–0.80)
IFM 99/06 [16]	MPT (125) versus MP (196)	0.59 (0.46–0.81)	0.51 (0.39–0.66)
IFM 01/01 [17,37]	MPT (113) versus MP (116)	0.68 (0.48–0.96)^a	0.62 (0.47–0.82) ^a
VISTA [30]	VMP (344) versus MP (338)	0.70 (0.57–0.85)	0.56 (0.43–0.72)
Sacchi et al., 2011 [18]	MPT (64) versus MP (54)	0.42 (0.18–0.98)^a	0.67 (0.38–1.18)^b
Additional studies in sensitivity analysis
TMSG [22,37]	MPT-T (58) versus MP (57)	0.86 (0.46–1.60)^d	0.70 (0.42–1.17)^d
GIMEMA [26,37]	MPT-T (167) versus MP (164)	1.04 (0.76–1.44)	0.63 (0.48–0.81)
MM-015 [28]	MPR (153) versus MPR-R (152)	1.27 (0.85–1.89)^a	2.04 (1.43–2.94)^a
	MP (154) versus MPR-R (152)	1.05 (0.69–1.60)^a	2.50 (1.75–3.57)^a
EIA06 [34]	MPT-T (154) versus MPR-R (152)	1.00 (0.67–1.50)^c	0.84 (0.64–1.09)
NMSG [32,37]	MPT-T (182) versus MP (175)	1.12 (0.85–1.47)^d	0.89 (0.70–1.13)^d
HOVON 49 [33,37]	MPT-T (165) versus MP (168)	0.84 (0.61–1.16)^b	0.54 (0.38–0.76)^b
Additional studies in full sensitivity analysis
IFM 95/01 [23]	MD (118) versus MP (122) D (127) versus MP (122) D-IFN (121) versus MP (122)	0.85 (0.62–1.17)^b 1.14 (0.84–1.55)^b 1.10 (0.80–1.50)^b	0.86 (0.65–1.13)^b 1.70 (1.30–2.22)^b 1.46 (1.12–1.92)^b
GEM05 [24]	VMP (130) versus VTP (130)	1.20 (0.60–2.40)	1.20 (0.90–1.70)
MRC Myeloma IX [25]	MP (423) versus CTD (426)	0.89 (0.74–1.08)	0.82 (0.70–0.96)
Palumbo et al. [27]	VMPT + VT (254) versus VMP (257)	0.70 (0.52–0.92)	0.58 (0.47–0.71)
Palumbo et al. [29]	MPR/CPR (430) versus Rd (211)	0.93 (0.60–1.41)	0.86 (0.66–1.12)
San Miguel et al. [31]	VMP + S (52) versus VMP (54)	1.00 (0.33–3.00)^c	1.00 (0.58–1.75)^b

CTD: cyclophosphamide, thalidomide, and dexamethasone; D: dexamethasone; D-IFN: dexamethasone and interferon; MP: melphalan and prednisone; MPR/CPR; melphalan, prednisone, and lenalidomide or cyclophosphamide, prednisone, and lenalidomide; MPT: melphalan, prednisone, and thalidomide; MPT + T; melphalan, prednisone, and continuous thalidomide; MPR; melphalan, prednisone, and lenalidomide; MPR + R; melphalan, prednisone, and continuous lenalidomide; Rd; lenalidomide and dexamethasone; VMP: bortezomib, melphalan, and prednisone; VMP + S; bortezomib, melphalan, prednisone, and siltuximab; VMPT + VT: melphalan, prednisone, and continuous bortezomib and thalidomide; VTP: bortezomib, thalidomide, prednisone.

^a Confidence interval estimated from p value.

^b Hazard ratio and confidence interval estimated from the Kaplan–Meier curve.

^c Hazard ratio and confidence interval estimated from number of deaths and survival rate.

^d Data obtained from meta-analysis [37].

Table 2. Summary of baseline patient characteristics from the primary analysis network.

Study	Treatment	N	Age, median (range)	ISS Stage III, n (%)
MM-020 (FIRST) [5,21]	Rd	535	73 (44–91)	216 (40.4)
	MPT	547	73 (51–92)	224 (41)
IFM 99/06 [16]	MP	196	(65–75)	54 (27.6)
	MPT	125	(65–75)	32 (25.6)
IFM 01/01 [17,37]	MP	116	(75–89)	NR
	MPT	113	(75–89)	NR
VISTA [30]	MP	338	71 (48–91)	115 (34)
	VMP	344	71 (57–90)	119 (34.9)
Sacchi et al. [18]	MP	54	79 (68–88)	16 (29.6)
	MPT	64	76 (66–89)	14 (21.9)

ISS: international staging system; NR: not reported; MP: melphalan and prednisone; MPT: melphalan, prednisone, and thalidomide; VMP: bortezomib, melphalan and prednisone.

Figure 2. Mixed treatment comparison survival data: fixed effects analyses with Rd as reference. (A) overall survival (OS); (B) progression free survival (PFS). CrI: credible interval; HR: hazard ratio; MP: melphalan and prednisone; MPT: melphalan and prednisone with thalidomide; Rd: lenalidomide and low-dose dexamethasone; VMP: melphalan and prednisone with bortezomib.

Figure 3. Mixed treatment comparison survival data: fixed-effects analyses with Rd as reference. (A) overall survival (OS); (B) progression free survival (PFS). CrI: credible interval; HR: hazard ratio; MP: melphalan and prednisone; MPR: melphalan and prednisone with lenalidomide; MPR-R: melphalan and prednisone with lenalidomide followed by lenalidomide maintenance; MPT: melphalan and prednisone with thalidomide; MPT-T: melphalan and prednisone with thalidomide followed by thalidomide maintenance; Rd: lenalidomide and low-dose dexamethasone; VMP: melphalan and prednisone with bortezomib.

Benboubker L, Dimopoulos MA, Dispenzieri A, et al. Lenalidomide and dexamethasone in transplant-ineligible patients with myeloma. N Engl J Med. 2014;371:906–917.

 PubMed Web of Science ®Google Scholar

Facon T, Dimopoulos MA, Hulin C, et al. Updated overall survival analysis of the FIRST study: continuous lenalidomide plus low-dose dexamethasone vs melphalan, prednisone, and thalidomide in patients with newly diagnosed multiple myeloma. Haematologica. 2015;100:3 (Abstract S105).

 Google Scholar

Facon T, Mary JY, Hulin C, et al. Melphalan and prednisone plus thalidomide versus melphalan and prednisone alone or reduced-intensity autologous stem cell transplantation in elderly patients with multiple myeloma (IFM 99-06): a randomised trial. Lancet. 2007;370:1209–1218.

 PubMed Web of Science ®Google Scholar

Hulin C, Facon T, Rodon P, et al. Efficacy of melphalan and prednisone plus thalidomide in patients older than 75 years with newly diagnosed multiple myeloma: IFM 01/01 trial. J Clin Oncol. 2009;27:3664–3670.

 PubMed Web of Science ®Google Scholar

Fayers PM, Palumbo A, Hulin C, et al. Thalidomide for previously untreated elderly patients with multiple myeloma: meta-analysis of 1685 individual patient data from 6 randomized clinical trials. Blood. 2011;118:1239–1247.

 PubMed Web of Science ®Google Scholar

San Miguel JF, Schlag R, Khuageva NK, et al. Persistent overall survival benefit and no increased risk of second malignancies with bortezomib-melphalan-prednisone versus melphalan-prednisone in patients with previously untreated multiple myeloma. J Clin Oncol. 2013;31:448–455.

 PubMed Web of Science ®Google Scholar

Sacchi S, Marcheselli R, Lazzaro A, et al. A randomized trial with melphalan and prednisone versus melphalan and prednisone plus thalidomide in newly diagnosed multiple myeloma patients not eligible for autologous stem cell transplant. Leuk Lymphoma. 2011;52:1942–1948.

 PubMed Web of Science ®Google Scholar

Beksac M, Haznedar R, Firatli-Tuglular T, et al. Addition of thalidomide to oral melphalan/prednisone in patients with multiple myeloma not eligible for transplantation: results of a randomized trial from the Turkish Myeloma Study Group. Eur J Haematol. 2011;86:16–22.

 PubMed Web of Science ®Google Scholar

Palumbo A, Bringhen S, Liberati AM, et al. Oral melphalan, prednisone, and thalidomide in elderly patients with multiple myeloma: updated results of a randomized controlled trial. Blood. 2008;112:3107–3114.

 PubMed Web of Science ®Google Scholar

Palumbo A, Hajek R, Delforge M, et al. Continuous lenalidomide treatment for newly diagnosed multiple myeloma. N Engl J Med. 2012;366:1759–1769.

 PubMed Web of Science ®Google Scholar

Stewart AK, Jacobus S, Fonseca R, et al. E1A06: A phase III trial comparing melphalan, prednisone, and thalidomide (MPT) versus melphalan, prednisone, and lenalidomide (MPR) in newly diagnosed multiple myeloma (MM). Haematologica. 2014;99:220 (Abstract S642).

 Google Scholar

Waage A, Gimsing P, Fayers P, et al. Melphalan and prednisone plus thalidomide or placebo in elderly patients with multiple myeloma. Blood. 2010;116:1405–1412.

 PubMed Web of Science ®Google Scholar

Wijermans P, Schaafsma M, Termorshuizen F, et al. Phase III study of the value of thalidomide added to melphalan plus prednisone in elderly patients with newly diagnosed multiple myeloma: the HOVON 49 Study. J Clin Oncol. 2010;28:3160–3166.

 PubMed Web of Science ®Google Scholar

Facon T, Mary JY, Pegourie B, et al. Dexamethasone-based regimens versus melphalan-prednisone for elderly multiple myeloma patients ineligible for high-dose therapy. Blood. 2006;107:1292–1298.

 PubMed Web of Science ®Google Scholar

Mateos MV, Oriol A, Martinez-Lopez J, et al. Bortezomib, melphalan, and prednisone versus bortezomib, thalidomide, and prednisone as induction therapy followed by maintenance treatment with bortezomib and thalidomide versus bortezomib and prednisone in elderly patients with untreated multiple myeloma: a randomised trial. Lancet Oncol. 2010;11:934–941.

 PubMed Web of Science ®Google Scholar

Morgan GJ, Davies FE, Gregory WM, et al. Cyclophosphamide, thalidomide, and dexamethasone (CTD) as initial therapy for patients with multiple myeloma unsuitable for autologous transplantation. Blood. 2011;118:1231–1238.

 PubMed Web of Science ®Google Scholar

Palumbo A, Bringhen S, Rossi D, et al. Bortezomib-melphalan-prednisone-thalidomide followed by maintenance with bortezomib-thalidomide compared with bortezomib-melphalan-prednisone for initial treatment of multiple myeloma: a randomized controlled trial. J Clin Oncol. 2010;28:5101–5109.

 PubMed Web of Science ®Google Scholar

Magarotto V, Bringhen S, Offidani M, et al. Triplet vs doublet lenalidomide-containing regimens for the treatment of elderly patients with newly diagnosed multiple myeloma. Blood. 2016;127:1102–1108.

 PubMed Web of Science ®Google Scholar

San-Miguel J, Blade J, Shpilberg O, et al. Phase 2 randomized study of bortezomib-melphalan-prednisone with or without siltuximab (anti-IL-6) in multiple myeloma. Blood. 2014;123:4136–4142.

 PubMed Web of Science ®Google Scholar