Background
Phase 2, multicenter, open-label, single-arm trial. 202 patients with relapsed multiple myeloma refractory to their most recent therapy (median 6 prior lines, ≥75% with prior ASCT). All had progressive disease at enrollment. Bortezomib (PS-341, Velcade) is a first-in-class reversible proteasome inhibitor that blocks the 26S proteasome, leading to accumulation of pro-apoptotic regulators (p53, p27, Bax, IκB) and induction of myeloma cell apoptosis.
Interventions and follow up
Regimen: Bortezomib 1.3 mg/m² IV bolus twice weekly (days 1, 4, 8, 11) for 2 weeks, then 10 days off, repeated every 21 days for up to 8 cycles
Dexamethasone add-back: 20 mg PO on the day of and the day after each bortezomib dose, added for stable disease after 2 cycles or progressive disease after 4 cycles
Primary endpoint: Response rate by EBMT criteria (CR + PR + MR)
mFollow up: ~6 months (24-week treatment period); extended follow-up reported separately (Richardson Br J Haematol 2006; PMID 16470606)
Dexamethasone add-back: 20 mg PO on the day of and the day after each bortezomib dose, added for stable disease after 2 cycles or progressive disease after 4 cycles
Primary endpoint: Response rate by EBMT criteria (CR + PR + MR)
mFollow up: ~6 months (24-week treatment period); extended follow-up reported separately (Richardson Br J Haematol 2006; PMID 16470606)
Results
ORR (bortezomib alone): 35% (CR 4%, near-CR 6%, PR 18%, MR 7%)
ORR (with dexamethasone add-back): ~50%
Median time to progression: 7 months
Median duration of response: 12 months
Median overall survival: 16 months (extended follow-up confirmed ~17 mo)
ORR (with dexamethasone add-back): ~50%
Median time to progression: 7 months
Median duration of response: 12 months
Median overall survival: 16 months (extended follow-up confirmed ~17 mo)
Adverse events
Neurologic: Peripheral neuropathy ~35% (grade ≥3 in ~12%); herpes zoster reactivation common (acyclovir prophylaxis now standard)
Hematologic/GI/constitutional: Cyclic thrombocytopenia (recovers between cycles), neutropenia, fatigue, GI toxicity (nausea, diarrhea, constipation); grade 4 AEs ~14%, discontinuation for AEs ~18%; no cumulative myelosuppression
Hematologic/GI/constitutional: Cyclic thrombocytopenia (recovers between cycles), neutropenia, fatigue, GI toxicity (nausea, diarrhea, constipation); grade 4 AEs ~14%, discontinuation for AEs ~18%; no cumulative myelosuppression
Conclusions
Single-agent bortezomib produced clinically meaningful and durable responses in heavily pretreated relapsed/refractory multiple myeloma. Addition of dexamethasone increased response rate further. SUMMIT established proteasome inhibition as a new therapeutic modality in MM and led to FDA accelerated approval of bortezomib (Velcade) on May 13, 2003 for R/R MM after ≥2 prior therapies — the first proteasome inhibitor approved for cancer.
Key Limitations
Single-arm, non-randomized — no direct comparator. Heavily pretreated population (median 6 prior lines) limits generalizability to earlier-line use. Short primary follow-up at publication. Peripheral neuropathy was substantial and dose-limiting in many patients; the later switch to subcutaneous and weekly dosing reduced this. EBMT response criteria differ from modern IMWG criteria, complicating cross-trial comparison.
Clinical Context
SUMMIT was the foundational trial for proteasome inhibition in myeloma and the basis for bortezomib's accelerated FDA approval (May 2003). The subsequent APEX trial (Richardson NEJM 2005, PMID 15958804) confirmed superiority over high-dose dexamethasone and converted the approval to full. Bortezomib became a backbone of modern MM therapy (VRd, VCD, Dara-VRd in PERSEUS and GRIFFIN) and substantially extended median OS from ~3 years pre-bortezomib to 6+ years today. Subcutaneous weekly dosing has largely replaced twice-weekly IV due to reduced neuropathy with equivalent efficacy.