Table 1.

Select trials of doublet and triplet regimens in patients with transplant-ineligible NDMM and high-risk cytogenetic abnormalities

Trial	Patient population	Regimens	N	Median age (range), y	High-risk cytogenetics	Response by cytogenetics	PFS and OS by cytogenetics
Retrospective study [10]	NDMM	Rd vs RD	100	HR: 67 (48–78) SR: 63 (32–78)	HR (n = 16): hypodiploidy, del(13q), del(17p), t(4;14), t(14;16), or plasma cell labeling index ≥3%	ORR: HR vs SR, 81 vs 89%; P = 0.56  ≥ VGPR: HR vs SR, 38 vs 45%; P = 0.36	Median PFS: HR vs SR, 18.5 vs 36.5 mo; P < 0.001
Ph III E4A03 [16, 17]	NDMM	Rd vs RD	445	HR: 62 SR: 66	126 pts with FISH; HR (n = 21): t(4;14), t(14;16), or del(17p) deletions	ORR: HR vs SR, 75% vs 77%  ≥ VGPR: HR vs SR, 30 vs 46%	Median PFS: HR vs SR, 11 vs 29 mo; P = 0.047 OS: HR vs SR hazard ratio, 3.48 [95% CI, 1.42–8.53]; P = 0.004
Ph III FIRST [18, 19]	NDMM TI	Rd continuous vs Rd18 vs MPT	1623	73 [94% ≥ 65 y]	762 pts with FISH; 19% HR [t(4;14), t(14;16), or del(17p)]	ORR: HR patients: 77% (Rd continuous) vs 67% (Rd18) vs 68% (MPT) SR patients: 81% (Rd continuous) vs 80% (Rd18) vs 71% (MPT)  ≥ VGPR: HR patients: 30% (Rd continuous) vs 35% (Rd18) vs 11% (MPT) SR patients: 49% (Rd continuous) vs 47% (Rd18) vs 39% (MPT)	Median PFS: HR: Rd continuous, 8.4 mo Rd18, 17.5 mo MPT, 14.6 mo SR: Rd continuous, 31.1 mo Rd18, 21.2 mo MPT, 24.9 mo Median OS: HR: Rd continuous, 29.3 mo Rd18, 24.3 mo MPT, 35.5 mo SR: Rd continuous, 69.9 mo Rd18, 68.7 mo MPT, 53.6 mo
Ph III, SWOG S0777 [28]	NDMM without intent for immediate ASCT	RVd vs Rd	471	63 [43% ≥ 65 y]	316 pts with FISH; 33% HR [t(4;14), t(14;16), or del(17p)]a	NR	Median PFS: HR: RVd, 38 mo Rd, 16 mo P = 0.19 t(4;14): RVd, 34 mo Rd, 15 mo P = 0.96
Ph III VISTA [11, 12]	NDMM TI	VMP vs MP	682	71 [97% ≥ 65 y]	168 pts in VMP with cytogenetics data; 15% HR [t(4;14), t (14;16), or del(17p)]	NR	Median OS in VMP arm only: HR vs SR cytogenetics: 40.0 mo vs not reached; P = 0.399
Ph III Spanish GEM05MAS65 [29, 30]	Elderly NDMM	VMP vs VTP	260	HR: 72 SR: 72 [100% ≥ 65 y]	232 pts with cytogenetics data; HR (n = 44): t(4;14), t (14;16), and/or del(17p) SR (n = 188)	ORR after induction: HR, 79% SR, 82%	Median PFS: HR vs SR, 24 vs 33 mo; P = 0.04 Median OS: HR vs SR, 38 mo vs not reached; P = 0.001
Ph III GIMEMA [31]	NDMM TI	VMPT → VT vs VMP	511	71 [96% ≥ 65 y]	376 pts with cytogenetics data; 16% t(4;14), 4% t(14;16), 15% del(17p)	NR	PFS: VMP → VT vs VMP in pts with HR CAs hazard ratio, 0.98 [95% CI, 0.58–2.10]; P = 0.215
Ph II Spanish GEM2010 [32, 33]	Elderly NDMM	Sequential or alternating VMP and Rd	242	NR [100% ≥ 65 y]	174 pts with FISH; HR (n = 32): t(4;14), t (14;16), and/or del(17p) SR (n = 142)	ORR: Sequential (HR vs SR) 74 vs 79% Alternating (HR vs SR) 69 vs 86%	Median PFS: sequential (HR vs SR) 29.5 vs 31.5 mo; P = 0.9 Alternating (HR vs SR) 24 vs 33 mo; P = 0.03 Median OS: sequential (HR vs SR) 46 vs 63 mo; P = 0.1 Alternating (HR vs SR) 38.4 mo vs not reached; P = 0.002
Ph III [34]	NDMM TI	MPT-T vs MPR-R	668	MPT-T: 72 (33% ≥ 76 y) MPR-R: 73 (34% ≥ 76 y)	367 pts with FISH; HR (n = 174): del(17p), t(4;14), gain(1q21)	NR	PFS and OS: no significant difference in treatment with MPT-T vs MPR-R for all analyzed subgroups (HR CAs) Median PFS: gain(1q21) (MPT-T vs MPR-R) 17 vs 19 mo del(17p) (MPT-T vs MPR-R) 15 vs 15 mo t(4;14) (MPT-T vs MPR-R) 12 vs 14 mo Median OS: gain(1q21) (MPT-T vs MPR-R) 39 vs 50 mo del(17p) (MPT-T vs MPR-R) 41 vs 35 mo t(4;14) (MPT-T vs MPR-R) 23 mo vs not reached
Retrospective institutional study [20]	NDMM TI	CyBorD vs VMP vs Vd	122	CyBorD: 76 VMP: 73 Vd: 77	t(4;14), t(14;16), and p53 del, 21 pts (17%)	NR	Median PFS: HR vs SR, 11.8 vs 15.9 mo; P = 0.002 Median OS: HR vs SR, 22.4 vs 39.7 mo; P = 0.029

ASCT autologous stem cell transplant, CA cytogenetic abnormality, CyBorD cyclophosphamide, bortezomib, dexamethasone, FISH fluorescent in situ hybridization, HR high risk, MP melphalan, prednisone, MPR-R melphalan, prednisone, lenalidomide, followed by lenalidomide maintenance, MPT melphalan, prednisone, thalidomide, MPT-T melphalan, prednisone, thalidomide, followed by thalidomide maintenance, NDMM newly diagnosed multiple myeloma, NR not reported, ORR overall response rate, OS overall survival, PFS progression-free survival, ph phase, pt patient, Rd lenalidomide plus low-dose dexamethasone, RD lenalidomide plus high-dose dexamethasone, Rd18 lenalidomide plus low-dose dexamethasone for 18 cycles, RVd lenalidomide, bortezomib, dexamethasone, SR standard risk, TI transplant ineligible, TTP time to progression, Vd bortezomib, dexamethasone, VGPR very good partial response, VMP bortezomib, melphalan, prednisone, VMPT bortezomib, melphalan, prednisone, thalidomide, VT bortezomib, thalidomide

^a Per preliminary analyses from available data at trial entry