Table 5.

Summary of select data from randomized trials for induction therapy for transplant-ineligible NDMM

ReferencePatients: total/arms, No.Median follow-up, moMedian age (range), yRegimenPFSOSPrimary end point/comments
PETHEMA53  260 patients; 130/130 32 73 (68-77)
73 (69-76) 		VMP vs VTP
Maint VT or VP 		31 mo, all patients 3-y OS: 70% (64%-76%), all patients ORR
VTP 81%, VMP 80%, VTP more serious AEs (40 [31% vs 20 [15%], P  =  .01) and drug discontinuations 
GIMEMA 030535,54 511 patients;
254/257 		23.2 71 VMPT-VT
vs
VMP 		3-y PFS:
VMPT-VT 56%; VMP 41%;
HR 0.67
(95% CI, 0.50-0.90; P  =  .008) 		5-y OS:
VMPT-VT 61%
VMP 51%
HR 0.70
(P  =  .01) 		PFS
VMPT-VT arm: more frequent grade 3/4 AEs: neutropenia (38%), thrombocytopenia (22%), peripheral neuropathy (11%), cardiac events (11%) 
MRC-IX (59)55 
 		859 patients; 423/426 44 73 MP vs CTd MP 12.4 mo; CTd 13 mo
HR 0.82 (95% CI, 0.70-0.96; P  =  .01) 		MP 30.6 mo; CTd 33.2 mo; HR 0.89 (95% CI, 0.74-1.08; P  =  .24) ORR/PFS/OS
ORR: MP 32.6%; CTd 63.8% (P  < . 0001)
CTDa arm: higher rates of thromboembolic events, constipation, infection, and neuropathy 
FIRST56  1623 patients; 535/541/547 67 73 (40-92) Rd vs Rd18 vs MPT Rd 25.5 mo; Rd18 20.7 mo; MPT 21.2 mo; HR 0.72, Rd vs MPT
HR 0.70, Rd vs Rd18; P  <  .001 for both. Rd was superior to MPT for all secondary efficacy end points, including OS. 		4-y OS: Rd 59%; Rd18 56%; MPT 51% PFS
Grade 3/4 AEs more frequent with Rd than MPT (70% vs 78%) 
UPFRONT57 
 		502 patients;
168/167/167 		42.7 74.5 (67-69) Vd + V
73 (66-77) VTd + V
72 (68-77) VMP + V
 		Vd 14.7 mo; VTd 15.4 mo; VMP 17.3 mo (P  =  NS) Vd 49.8 mo
VTd 51.5 mo
VMP 53.1 mo (P  =  NS) 		PFS
Peripheral neuropathy near 50% in all arms. Early drug discontinuation (29%-38%).
QoL scores decreased during induction and improved or stabilized thereafter. 
HOVON-8758  668 patients
318/319 		36 72 (60-91) MPT-T vs MPR-R MPT-T 20 mo; MPR-R 23 mo; HR 0.87 (95% CI, 0.72-1.04; P  =  .12) 4-y OS:
MPT-T 52% MPR-R 56% 		PFS
Grade 3/4 hematologic toxicity with MPR-R vs clinically significant neuropathy with MPT-T 
SWOG S07775,59
 		525 patients; 264/261 84 43% ≥ 65 VRd vs Rd VRd 41 mo
Rd 29 mo
HR 0.742 (95% CI 0.594-0.9028; 1-sided P  =  .003) 		VRd NR; Rd 69 mo; HR 0.709 (95% CI, 0.543-0.926; 2-sided P  =  .0114) PFS
VRd (23%) and Rd (10%) discontinued induction treatment due to AE 
MAIA38 
 		737 patients: 368/369 56.2 73 (50-90) D-Rd continuous
74 (45-89) Rd continuous
43%-44% ≥ 75 		D-Rd NR
Rd 34.4 mo
HR 0.53 (95% CI, 0.43-0.66; P  <  .0001) 		NR in either arm. HR 0.68 (95% CI, 0.53-0.86; P  =  .0013) PFS
Median duration on continuous treatment 47.5 mo (D-Rd) and 22.6 mo (Rd) 
HOVON-126/NMSG60 
 		143 patients
 		23.4
 		73 (64-90) ITd → maintenance ixazomib vs placebo
 		PFS-R:
ITd-I 9.5 mo; ITd- P 8.4 mo 		OS-R at 18 mo, all patients 96% (88%-99%) PFS
Early mortality 8% age >75, only 55% randomly assigned to maintenance therapy 
ALCYONE10 
 		706 patients; 350/356 40.1 71 (40-93)
71 (50-91) 		D-VMP-D
VMP 		D-VMP-D 36.4 mo; VMP 19.3 mo; HR 0.42 (95% CI, 0.34-0.51; P  <  .0001) 3-y OS: D-VMP-D 78%; VMP 67.9%; HR 0.60 (95% CI, 0.46-0.80; P  =  .0003) PFS
Common 
ECOG E1A1120 
 		1087 patients;
542/545 		9 65 (57-71)
64 (59-71) 		VRd-R
KRd-R 		VRd 34.4 mo
KRd 34.6 mo 		Median OS NR either arm PFS, OS; excluded high-risk disease; 17.3% discontinued VRd early due to AEs 
TOURMALINE-MM261  705 patients;
351;354 		IRd 53.3
Rd 55.8 		73 (48-90)
74 (48-88) 		IRd-IR
Rd-R 		IRd 35.3 mo
Rd 21.8 mo
(HR, 0.830; 95% CI, 0.676-1.018; P  =  .073) 		Median OS NR either arm at 58 mo. HR 0.998 (95% CI, 0.790-1.261; P  =  .988) PFS
PFS not improved in age ≥75 in IRd 
ReferencePatients: total/arms, No.Median follow-up, moMedian age (range), yRegimenPFSOSPrimary end point/comments
PETHEMA53  260 patients; 130/130 32 73 (68-77)
73 (69-76) 		VMP vs VTP
Maint VT or VP 		31 mo, all patients 3-y OS: 70% (64%-76%), all patients ORR
VTP 81%, VMP 80%, VTP more serious AEs (40 [31% vs 20 [15%], P  =  .01) and drug discontinuations 
GIMEMA 030535,54 511 patients;
254/257 		23.2 71 VMPT-VT
vs
VMP 		3-y PFS:
VMPT-VT 56%; VMP 41%;
HR 0.67
(95% CI, 0.50-0.90; P  =  .008) 		5-y OS:
VMPT-VT 61%
VMP 51%
HR 0.70
(P  =  .01) 		PFS
VMPT-VT arm: more frequent grade 3/4 AEs: neutropenia (38%), thrombocytopenia (22%), peripheral neuropathy (11%), cardiac events (11%) 
MRC-IX (59)55 
 		859 patients; 423/426 44 73 MP vs CTd MP 12.4 mo; CTd 13 mo
HR 0.82 (95% CI, 0.70-0.96; P  =  .01) 		MP 30.6 mo; CTd 33.2 mo; HR 0.89 (95% CI, 0.74-1.08; P  =  .24) ORR/PFS/OS
ORR: MP 32.6%; CTd 63.8% (P  < . 0001)
CTDa arm: higher rates of thromboembolic events, constipation, infection, and neuropathy 
FIRST56  1623 patients; 535/541/547 67 73 (40-92) Rd vs Rd18 vs MPT Rd 25.5 mo; Rd18 20.7 mo; MPT 21.2 mo; HR 0.72, Rd vs MPT
HR 0.70, Rd vs Rd18; P  <  .001 for both. Rd was superior to MPT for all secondary efficacy end points, including OS. 		4-y OS: Rd 59%; Rd18 56%; MPT 51% PFS
Grade 3/4 AEs more frequent with Rd than MPT (70% vs 78%) 
UPFRONT57 
 		502 patients;
168/167/167 		42.7 74.5 (67-69) Vd + V
73 (66-77) VTd + V
72 (68-77) VMP + V
 		Vd 14.7 mo; VTd 15.4 mo; VMP 17.3 mo (P  =  NS) Vd 49.8 mo
VTd 51.5 mo
VMP 53.1 mo (P  =  NS) 		PFS
Peripheral neuropathy near 50% in all arms. Early drug discontinuation (29%-38%).
QoL scores decreased during induction and improved or stabilized thereafter. 
HOVON-8758  668 patients
318/319 		36 72 (60-91) MPT-T vs MPR-R MPT-T 20 mo; MPR-R 23 mo; HR 0.87 (95% CI, 0.72-1.04; P  =  .12) 4-y OS:
MPT-T 52% MPR-R 56% 		PFS
Grade 3/4 hematologic toxicity with MPR-R vs clinically significant neuropathy with MPT-T 
SWOG S07775,59
 		525 patients; 264/261 84 43% ≥ 65 VRd vs Rd VRd 41 mo
Rd 29 mo
HR 0.742 (95% CI 0.594-0.9028; 1-sided P  =  .003) 		VRd NR; Rd 69 mo; HR 0.709 (95% CI, 0.543-0.926; 2-sided P  =  .0114) PFS
VRd (23%) and Rd (10%) discontinued induction treatment due to AE 
MAIA38 
 		737 patients: 368/369 56.2 73 (50-90) D-Rd continuous
74 (45-89) Rd continuous
43%-44% ≥ 75 		D-Rd NR
Rd 34.4 mo
HR 0.53 (95% CI, 0.43-0.66; P  <  .0001) 		NR in either arm. HR 0.68 (95% CI, 0.53-0.86; P  =  .0013) PFS
Median duration on continuous treatment 47.5 mo (D-Rd) and 22.6 mo (Rd) 
HOVON-126/NMSG60 
 		143 patients
 		23.4
 		73 (64-90) ITd → maintenance ixazomib vs placebo
 		PFS-R:
ITd-I 9.5 mo; ITd- P 8.4 mo 		OS-R at 18 mo, all patients 96% (88%-99%) PFS
Early mortality 8% age >75, only 55% randomly assigned to maintenance therapy 
ALCYONE10 
 		706 patients; 350/356 40.1 71 (40-93)
71 (50-91) 		D-VMP-D
VMP 		D-VMP-D 36.4 mo; VMP 19.3 mo; HR 0.42 (95% CI, 0.34-0.51; P  <  .0001) 3-y OS: D-VMP-D 78%; VMP 67.9%; HR 0.60 (95% CI, 0.46-0.80; P  =  .0003) PFS
Common 
ECOG E1A1120 
 		1087 patients;
542/545 		9 65 (57-71)
64 (59-71) 		VRd-R
KRd-R 		VRd 34.4 mo
KRd 34.6 mo 		Median OS NR either arm PFS, OS; excluded high-risk disease; 17.3% discontinued VRd early due to AEs 
TOURMALINE-MM261  705 patients;
351;354 		IRd 53.3
Rd 55.8 		73 (48-90)
74 (48-88) 		IRd-IR
Rd-R 		IRd 35.3 mo
Rd 21.8 mo
(HR, 0.830; 95% CI, 0.676-1.018; P  =  .073) 		Median OS NR either arm at 58 mo. HR 0.998 (95% CI, 0.790-1.261; P  =  .988) PFS
PFS not improved in age ≥75 in IRd 

CTd, cyclophosphamide, thalidomide, dexamethasone; IRd, ixazomib, lenalidomide, dexamethasone; IRd-IR, ixazomib, lenalidomide, dexamethasone followed by ixazomib, lenalidomide continuous therapy; ITd, ixazomib, thalidomide, dexamethasone; ITd-I, ixazomib, thalidomide, dexamethasone induction and ixazomib continuous therapy; ITd-P, ixazomib, thalidomide, dexamethasone and placebo continuous therapy; MP, melphalan, prednisone; MPR, melphalan, prednisone, lenalidomide; MPT, melphalan, prednisone, thalidomide; ORR, overall response rate; QoL, quality of life; Rd, lenalidomide, dexamethasone; Rd18, lenalidomide, dexamethasone for 18 months; Vd, bortezomib, dexamethasone; VMPT, bortezomib, melphalan, prednisone, thalidomide; VTd, bortezomib, thalidomide, dexamethasone.

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