Background: Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) are asymptomatic clonal precursors to multiple myeloma, a hematological malignancy. Because observation is currently the standard of care, a diagnosis of MGUS or SMM can be associated with stress and worry about progression. We evaluated the efficacy of the evidence-based mind-body intervention, the Stress Management and Resiliency Training: Relaxation Response Resiliency Program (SMART-3RP) in reducing distress and stress reactivity in patients with MGUS and SMM. Methods: In participants diagnosed with intermediate or high risk MGUS or SMM, this randomized, waitlist controlled trial (Oct 2013 – Sep 2016) assessed distress (10-point scale) as the primary outcome and perceived stress (PSS-10), stress reactivity (MOCS-A), and mindfulness (FFMQ) as secondary outcomes and hypothesized mediators of distress reduction. We collected self-report measures at enrollment (T1), 3 months (T2), and 6 months (T3). The immediate treatment arm received the 8-session, 1.5 hour/week SMART-3RP group intervention from T1 to T2 and continued practicing skills from T2 to T3; the waitlist arm received the intervention from T2 to T3. Results: 93 participants (59% women) diagnosed with MGUS (n = 49) or SMM (n = 44) were randomized to immediate treatment (n = 45) or waitlist (n = 48). In an ITT analysis of immediate SMART-3RP vs. waitlist (T1-T2), we found significantly greater improvement in distress (-1.4 vs. -0.3, p = .04) and stress reactivity (0.39 vs. 0.02, p < .001), but not perceived stress (-3.9 vs. -2.2, p = .12) or mindfulness (2.4 vs. -0.1, p = .17). Improvements in stress reactivity were maintained for the immediate treatment group (T2-T3), but only partially for distress. Conclusions: The SMART-3RP, compared to waitlist, reduced distress in participants with intermediate or high-risk MGUS and SMM, with improvements in stress reactivity as a primary mediator of distress reduction. Participants strongly endorsed the intervention’s ability to enhance coping and reduce distress. Clinical trial information: NCT01955395