Bortezomib (Velcade™) in the Treatment of Multiple Myeloma

Figures & data

Table 1 Recommended dose modification for bortezomib-related neuropathy and/or neuropathic pain (NCI 2003)

Severity	Signs and symptoms of peripheral neuropathy	Dose modification
Grade 1	Asymptomatic; loss of deep tendon reflexes or parathesia (including tingling) but not interfering with function	No action
Grade 2 or Grade 1 with pain	Sensory alteration or parathesia (including tingling) interfering with function but not with ADL	Reduce bortezomib to 1.0 mg/m2 (25% dose reduction)
Grade 3 or Grade 2 with pain	Sensory alteration or parathesia interfering with ADL	Withhold bortezomib until toxicity resolves then restart at 0.7 mg/m2 (50% dose reduction)
Grade 4	Permanent sensory loss interfering with function (disabling)	Discontinue bortezomib

Abbreviations: ADL, activities of daily living.

Table 2 Combinations of bortezomib with other chemotherapeutic agents in relapsed and refractory disease

Study drugs		Reference	No of assessable patients	Median no of prior regimes	Median no of cycles	Major response rate (CR+PR)	Response rates	Follow up	Toxicities
Bortezomib Cyclophosphamide Dexamethasone	Phase II	Kropff et al 2005	50	2	6	76%	CR 10% PR 66% MR 12%	Median EFS 10 months	Neuropathy Infections, herpes zoster Thrombocytopenia Cardiovascular events
Bortezomib Cyclophosphamide Prednisolone	Phase I/II	Reece et al 2005	15	All had at least 1 prior autograft	2 patients completed	31%	CR 6% PR 25% MR 25%	Not yet complete	Infections Hypophosphatemia Cytopenia
Bortezomib Thalidomide +/− Dexamethasone	Phase I/II	Zangari et al 2005	85	66% received 2 prior autografts	2–12 cycles given	71%	≥n-CR 16% PR 55% MR 15%	Median OS/EFS9/22 months	Myelosuppression Neuropathy
Bortezomib +/− Methylprednisolone (weekly dosing)	Phase II	Suvannasankha and Smith 2005	28	70% prior autograft	5	59%	CR 3% n-CR 3% PR 53%	Not yet complete	Neuropathy Gastrointestinal Congestive heart failure
Bortezomib Low dose Melphalan +/− Dexamethasone	Phase I/II	Popat et al 2005	16	3	4	50% ORR (75% with dex)	Median time to any response 1 cycle	Not yet complete	Neuropathy Myocardial infraction Thrombocytopenia Neutropenia
Bortezomib Melphalan	Phase I/II	Berenson et al 2006	34	3	15 patients completed 8 cycles	47%	CR 6% n-CR 9% PR 32% MR 21%	Median free PFS 8 months	Myelosuppression Neuropathy Gastrointestinal
Bortezomib Melphalan Prednisolone Thalidomide	Phase II	Palumbo et al 2005	20	55% received 2 prior therapies	3	50%	CR 10% n-CR 5% PR 35% MR 13%	Not yet complete	Thrombocytopenia Febrile neutropenia Herpes Zoster Neuropathy
Bortezomib Lenalidomide +/− Dexamethasone	Phase I	Richardson, Schlossman, et al 2005	17	7	4	59%	CR 6% n-CR 6% PR 47% MR 17%	Not yet complete	Thrombocytopenia Hyponatraemia Hypotension Fatigue
Bortezomib Pegylated liposomal doxorubicin (advanced hematological malignancies)	Phase I	Orlowski et al 2005	22 patients with myeloma	5 (all patients)	4	73%	CR 23% n-CR 14% PR 36% MR or stable disease 23%	Not yet complete	Myelosuppression Fatigu Pneumonia Neuropathy Diarrhea

Abbreviations: CR, complete response; EFS, event free survival; MR, minor response; n-CR, near complete response; ORR, overall response rate (CR+PR+MR); OS, overall survival; PR, partial response; TTP, time to progression.

Table 3 Combinations of bortezomib with other chemotherapeutic agents as first line therapy

Study drugs		Reference	No of patients	Median assessable cycles	Major no of rate (CP+PR)	Response rates response	Follow up	Toxicities
Bortezomib +/− Dexamethasone	Phase II	Jagannath, Durie, et al 2005	40	Up to 6 cycles given	85%	28 patients had dex added and 64% showed improved response	12 patients underwent SCT	Neuropathy Fatigue Constipation Neutropenia
Bortezomib Dexamethasone	Phase II	Harousseau et al 2004	18	16 patients received 4 cycles	83%	CR 17% VGPR 11% PR 55%	Stem cells collected in all cases	Neuropathy
Bortezomib Doxorubicin Dexamethasone	Phase I/II	Oakervee et al 2005	21	19 patients received 4 cycles	95%	CR 24% n-CR 5% VGPR 33% PR 33%	18 patients underwent SCT with 44% CR and 95% ORR at 3 months	Neuropathy Postural hypotension Shingles Gastrointestinal
Bortezomib Melphalan Prednisolone	Phase I/II	Mateos et al 2005	53	3	84%	CR 28% n-CR 11% PR 45% MR 2%	90% alive at 7 months	Gastrointestinal Myelosuppression Infection Neuropathy
Bortezomib Thalidomide Dexamethasone	Phase I/II	Alexanian et al 2004	25	Up to 2 cycles given	84%	76% had >75% reduction in paraprotein +/− >l95% reduction in BJP	Median time to remission 0.6 months (compared with 1.1 months with Thal/Dex)12 patients underwent SCT	Infection Postural DVT Cytopenia
Bortezomib Thalidomide Dexamethasone	Phase I/II	Wang et al 2005	36	No more than 2 cycles needed for response	92%	CR 19% PR 73%	22 patients underwent SCT 89% in remission (31% CR) at 4 months	Neuropathy DVT Infections

Abbreviations: CR, complete response; DVT, deep vein thrombosis; MR, minor response; n-CR, near complete response; ORR, overall response rate (CR+PR+MR); PR, partial response; SCT, stem cell transplant; VGPR, very good partial remission.

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