Update on the optimal use of bortezomib in the treatment of multiple myeloma

Figures & data

Figure 1 Mechanisms of action of bortezomib

Table 1 Combination of bortezomib with other chemotherapeutic agents in relapsed and refractory myeloma

Study drugs	Phase	Reference	OR%	CR%	PFS (months)	TTP (months)	Median OS
VD	II	Richardson et al^Citation5,Citation6	PR ≥ 27	10	–	7	17 months
Bortezomib or VD	II	Jagannath et al^Citation8	PR ≥ 20; PR ≥ 38	11; 4	–	7	26.8 months
Bortezomib vs dexamethasone	III	Richardson et al^Citation9	38 vs 18	6 vs 1	–	6.2 vs 3.5	80% vs 66% (at 1 year)
Bortezomib vs bortezomib plus PEG-doxorubicin	III	Orlowski et al^Citation11	41 vs 44	2 vs 4	6.5 vs 9.0	6.5 vs 9.3	65% vs 76% (at 15 months)
VTD vs TD	III	Garderet et al^Citation12	45 vs 25	45 vs 21	18.3 vs 13.6	19.5 vs 13.8	71% vs 65% (at 2 years)
Lenalidomide, bortezomib, and dexamethasone	II	Richardson et al^Citation13	64	11	9.5	–	30
Bortezomib, dexamethasone, and panobinostat vs VD	III	San-Miguel et al^Citation38	60.7 vs 54.6	27.6* vs 16.7	11.9 vs 8.08	–	33.6 vs 30.4
Panobinostat, bortezomib, and dexamethasone	II	Richardson et al^Citation39	34.5	0	5.4	–	Not reached
Vorinostat and bortezomib vs bortezomib	III	Dimopoulus et al^Citation37	56.2 vs 40.6	7.9 vs 5.3	7.63 vs 6.83	7.73 vs 7.03	Not reached

Note:

* Includes CR and nCR.

Abbreviations: CR, complete response; nCR, near CR; OR, overall response; OS, overall survival; PFS, progression-free survival; PR, partial response; TD, thalidomide and dexamethasone; TTP, time to progression; VD, bortezomib and dexamethasone; VTD, bortezomib, thalidomide, and dexamethasone.

Table 2 Combination of bortezomib with other chemotherapeutic agents in newly diagnosed myeloma

Study drugs	Reference	OR%	CR%	PFS (months)	TTP (months)	Median OS (months)	Median follow-up (months)
VDT-PACE: induction + consolidation, 2 × melphalan ASCT	Barlogie et al^Citation1	–	83	84% at 2 years	–	88% at 2 years	20
VAD induction/high-dose melphalan ASCT/maintenance thalidomide; PAD induction/high-dose melphalan ASCT/maintenance bortezomib	Sonneveld et al^Citation19	83; 91	34; 49	28; 35	–	78 (3 years); 70 (3 years)	41
Intl: VD and no consolidation Intl2: VD plus DCEP as consolidation → ASCT	Harousseau et al^Citation18	Post induction: 78.5; post induction:	Post induction: 14.8; post first transplant: 40.8; post induction:	36; 29.7	–	Not reached	32.2
Control 1: VAD and no consolidation		62.8	6.4; post first transplant: 28.8
Control 2: VAD plus DCEP as consolidation → ASCT
VTD vs TD	Cavo et al^Citation20	92 vs 78.5	Induction: 33 vs 12; after transplant: 41 vs 20	93% vs 86%		Not statistically significant (at 20 months)	15
VTD vs VCD	Moreau et al^Citation22	92.3 vs 83.4	13.0 vs 8.9	–	–	–	–
Bortezomib, melphalan, and prednisolone vs melphalan and prednisolone	San Miguel et al^Citation24	71 vs 35	30 vs 4	–	24 vs 16.6	NE	36.7
Induction: bortezomib, melphalan, and prednisolone vs bortezomib, thalidomide, and prednisolone. Maintenance: bortezomib and thalidomide vs bortezomib and prednisolone	Mateos et al^Citation25	Induction: 81 vs 80	Induction: 28 vs 20; after maintenance: 44 vs 39	Median 31. No statistical difference	Median 35. No statistical difference	3-year OS, 70%. No statistical difference	32
Bortezomib, lenalidomide, and dexamethasone vs lenalidomide and dexamethasone	Durie et al^Citation26	–	–	43 vs 31	–	Not reached vs 63	–
VD vs bortezomib, lenalidomide, and dexamethasone vs bortezomib, melphalan, and prednisolone	Niesvizky et al^Citation31	73 vs 80 vs 70	3 vs 4 vs 4	14.7 vs 15.4 vs 17.3	–	49.8 vs 51.5 vs 53.1	42.7

Note: VDT-PACE, bortezomib, dexamethasone, thalidomide, with 4-day continuous infusion of cisplatin, doxorubicin, cyclophosphamide, and etoposide.

Abbreviations: ASCT, autologous stem cell transplant; CR, complete response; DCEP, dexamethasone, cyclophosphamide, etoposide, and platinum; Intl, interventional; NE, not estimable; OR, overall response; OS, overall survival; PAD, bortezomib, adriamycin, and dexamethasone; PFS, progression-free survival; TD, thalidomide and dexamethasone; TTP, time to progression; VAD, vincristine, adriamycin, and dexamethasone; VCD, bortezomib, cyclophosphamide, and dexamethasone; VD, bortezomib and dexamethasone; VTD, bortezomib, thalidomide, and dexamethasone.

Table 3 Recommended dose modification for bortezomib-related neuropathy and/or neuropathy pain

Severity	Symptoms and signs of peripheral neuropathy	Dose modification
Grade 1	Asymptomatic: loss of deep tendon reflexes or paresthesia (including tingling) but not interfering with function	Monitor closely and consider dose reduction to either 1.3 mg/m^2 weekly or 1.0 mg/m^2
Grade 2 or grade 1 with pain	Sensory alteration or paresthesia (including tingling or calf cramps at night) interfering with function but not with activities of daily living	Consider withholding bortezomib for 1–2 weeks until toxicity resolves, then reduce bortezomib to 1.0 mg/m^2 (25% dose reduction) and change to weekly dosing
Grade 3 or grade 2 with pain	Sensory alteration or paresthesia interfering with activities of daily living	Withhold bortezomib until toxicity resolves, then restart at 0.7 mg/m^2 (50% dose reduction) on a weekly schedule
Grade 4	Permanent sensory loss interfering with function (disabling)	Discontinue bortezomib

Note: National Cancer Institute. Common terminology criteria for adverse events v3.0 (online) 2003.⁵¹

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