Spotlight: Smoldering Myeloma High-Risk Patient Observation and Longitudinal Insight Trial
Authors: Nuli Sharmilee , Chakraborty Rajshekhar , Abdallah Al-Ola , Lentzsch Suzanne , Ouchveridze Evguenia , Sborov Douglas W , Godara Amandeep , McClune Brian , Jeong Ah-Reum , Rubinstein Samuel M. , Goodman Aaron , Mohyuddin Ghulam Rehman 
Published: December 2024

Background:
Smoldering Multiple Myeloma (SMM) is a precursor stage to Multiple Myeloma (MM), impacting 1 in 200 individuals aged 40 and above. For those patients with SMM considered to have a 50% or higher risk of progression to MM at two years (i.e. high-risk SMM), the current National Comprehensive Cancer Network guidelines recommend early intervention with lenalidomide as a therapeutic option to delay progression to MM. However, lenalidomide has significant short-term and late toxicities, including risk of secondary malignancies. Furthermore, the natural history of contemporary patients with SMM is unknown due to two reasons. First, diagnostic reclassifications in 2014 by the International Myeloma Working Group have reclassified some patients previously considered as SMM to MM. Second, advancements in imaging such as whole-body diffusion-weighted MRI (WB DW-MRI) have led to more sensitive detection of bone marrow focal lesions, which are a precursor to lytic bone lesions (a common diagnostic marker of MM). Furthermore, patients with two or more focal marrow lesions on WB DW-MRI are now categorized as MM, which enables earlier diagnosis of MM before morbid progression events, such as lytic lesions or fractures. Despite these important caveats, there are no trials with control arms of active surveillance currently enrolling for SMM, as all other trials offer pharmacological therapies with resultant physical and financial toxicity. Hence, there is a critical unmet need for prospective studies on contemporary patients to investigate the natural history of SMM in the context of longitudinal imaging with WB DW-MRI.
Study Design and Methods:
This is a prospective study of 100 patients with high-risk SMM (NCT06212323), as defined by 2 or more of the 2/20/20+ cytogenetics scoring system, or an International Myeloma Working Group (IMWG) SMM score of 9 or greater. We hypothesize that morbid progression events (fracture, death due to MM, AL Amyloidosis, plasma cell leukemia, lytic bone lesions, or irreversible renal failure) will occur in ≤8% in this cohort of high-risk SMM patients at two years of follow-up. With 100 patients, the margin of error corresponding to the upper 95% confidence bound (one-sided) will be approximately 0.05. Each participant will be under surveillance utilizing regular blood tests, WB DW-MRIs every 6 months, and bone marrow biopsies done annually. A PROMIS-29 questionnaire will also be administered to measure quality of life every 6 months.
Trial enrollment began in January 2024 and is being completed in a decentralized fashion, with study procedures done remotely. Enrollment is currently focusing at five sites in the United States (University of Utah, Columbia University Medical Center, University of California San Diego, University of North Carolina and University of Kansas). There are plans to open this study at community sites, and enroll more patients remotely, given the decentralized nature of enrollment.
Conclusion:
In contrast to all other pharmacological trials, the SPOTLIGHT trial aims to describe the natural history of high-risk SMM in the context of close surveillance with advanced imaging while off therapy. Our hypothesis is that with close surveillance and advanced imaging, we can prevent morbidity while keeping patients off therapy with an excellent quality of life. If our hypothesis on rate of morbid progression events with active surveillance in SMM is true, it would lead to a new paradigm for patients with high-risk SMM and spare patients the toxicity of pharmacological therapy. Furthermore, it would set a benchmark for active surveillance as an ideal control arm in future randomized controlled trials testing new drugs in this space. If our hypothesis is incorrect, it would still define the natural history and characterize progression events in contemporary patients with high-risk SMM. Hence, either a positive or negative result for this study will advance the field of SMM and will immediately impact clinical practice and future research. Notably, this study stands apart from all existing research as it focuses on evaluating SMM without any pharmaceutical intervention.