Background: CFZ, a next-generation selective, irreversible epoxyketone proteasome inhibitor, has promising single-agent activity in relapsed/refractory (R/R) MM and a favorable side effect profile. CFZ is tolerable in a broad range of pts including those with baseline peripheral neuropathy (PN) or renal insufficiency. LEN/low-dose Dex (Rd) is a current standard of care for relapsed MM. While the combination of bortezomib + LEN + moderate- to high-dose Dex is active in R/R MM, it is associated with development of PN in the majority of cases, limiting extended treatment at optimal doses. Alternatively, the addition of CFZ to Rd (CRd) may provide superior activity compared to Rd alone, without additional significant toxicity. The ph 1b/2 PX-171-006 study has shown both activity and tolerability of full-dose CRd, and that prolonged treatment is possible. CRd has also shown impressive activity in the front-line setting in an ongoing, open-label independent ph 1/2b trial (NCT01029054). ASPIRE (NCT01080391) is a ph 3, randomized, open-label, multicenter study comparing CRd to Rd treatment in pts with relapsed MM. Methods: Eligible pts have an Eastern Cooperative Oncology Group performance score of 0–2 and relapsed or progressive MM following 1–3 prior treatment regimens and may be refractory to their most recent therapy. Enrollment was initiated in July 2010 with a final accrual goal of 700 patients. Pts are randomized 1:1 to receive either Rd or CRd. Treatment schedules are below. Pts will continue treatment until disease progression or unacceptable toxicity and will be followed for 30 days for safety. The primary endpoint is progression-free survival. Secondary endpoints include overall survival, overall response rate, disease control rate, duration of response, and safety. Disease outcome will be graded by study investigators using International Myeloma Working Group criteria and also be reviewed by Independent Review Committee.