Background: Current treatments for Waldenstrom’s macroglobulinemia (WM) are not curative, and a standard of care does not exist. A highly recurrent somatic mutation in WM, MYD88 L265P, signals through interleukin-1 receptor-associated kinase 1 and Bruton’s tyrosine kinase (BTK) to mediate the constitutive activation of the NF-κB pathway (Yang, 2013). Ibrutinib (ibr), an oral inhibitor of BTK, impairs crosstalk between MYD88 and BTK, and blocks BTK dependent downstream signaling within the B-cell receptor pathway inducing apoptosis of WM cells (Treon, 2012).Thus, ibr offers a novel therapeutic approach for pts with WM. Pts with previously treated WM receiving different ibr doses achieved durable responses in a phase (Ph) 1 study (Advani, 2013). This was confirmed in a Ph 2 trial of ibr 420 mg daily (overall response rate [ORR] of 87%; Treon, 2014) leading to the first FDA approval in WM. Ibr + rituximab (rtx) showed activity and tolerability in high-risk CLL and MCL. This Ph 3 study evaluates the safety and efficacy of ibr + rtx vs. placebo + rtx in pts with WM. Methods: Approximately 150 pts will be randomized in a 1:1 ratio to receive rtx 375 mg/m² IV weekly for 4 weeks, followed by a second 4-weekly rtx course 3-months later, and either ibr 420 mg daily or matching placebo until progressive disease (PD) or unacceptable toxicity. Key inclusion criteria include WM with documented PD or no response (stable disease) to last treatment if previously treated; symptomatic disease requiring treatment per the 2^nd International Workshop on WM; and adequate hematologic, hepatic, and renal function. Exclusion criteria include CNS involvement and clinically significant cardiovascular disease. Pts refractory to the last rtx-containing therapy excluded from the randomized study are eligible for the open-label single-agent ibr substudy (n = 30). The primary endpoint is progression-free survival assessed by an independent review committee. Secondary endpoints are ORR, overall survival, hematologic improvement, time to next treatment, and safety. Pts in the control arm may receive single-agent ibr after confirmation of PD. Enrollment began in July 2014 (NCT02165397). Clinical trial information: NCT02165397