Screening for AL Amyloidosis in Smoldering Multiple Myeloma

• Published in: Blood 2024-11, Vol.144, p.6874-6874
• Main Authors: Toskic, Denis, Mansukhani, Mahesh, Zhou, Ping, Scalia, Stephanie, Ma, Xun, Fogaren, Teresa, Lee, Lisa X., Chung, Alfred, Tuchman, Sascha Alexander, Bianchi, Giada, Godara, Amandeep, Landau, Heather J., Bal, Susan, Kaur, Gurbakhash, Sanchorawala, Vaishali, Morgan, Gareth, Mann, Hashim, Vescio, Robert Allen, Chaulagain, Chakra, Varga, Cindy, Lentzsch, Suzanne, Doros, Gheorghe, Comenzo, Raymond
• Format: Article
• Language: English
• ISSN: 0006-4971
• DOI: 10.1182/blood-2024-201755

Background and Significance: Over half of new AL patients present with heart involvement. The failure to diagnose them early underlies their 20% mortality within 6 months. Eighty percent of AL patients harbor clonal free light chain (FLC) abnormalities for 10 years prior to presenting with symptoms of heart and kidney failure due to toxic FLC and amyloid deposits.(J Clin Oncol 2014;2699-704) Only efforts to diagnose AL in the precursor phase of the disease will reduce the early mortality rate. Smoldering multiple myeloma (SMM) is a disease in which patients can make FLC but be relatively asymptomatic; yet a fraction of them develop AL.(N Engl J Med 2007;2582-90; Blood 2018 S1;1903) Study and Methods: In this study (NCT06365060; 1R01CA279808) we are screening patients with SMM for undiagnosed AL and risk of AL. Patients > 40 years of age with SMM and FLC differential > 23mg/L and no history of amyloidosis are eligible. Patients with prior biopsies positive for amyloid are ineligible. In order to develop a likelihood algorithm for AL in SMM patients we have created a multicenter network spanning the USA that will enroll 340 SMM patients and collect marrow and blood specimens and data for a training set of likelihood statistics. The likelihood algorithm employs 5 parameters: (1) the presence of SMM; (2) a difference between involved (pathologic) and uninvolved FLC > 23mg/L; (3) clonal plasma cell studies showing t(11;14), cyclin D1 over-expression or gain 1q (covering 75% of AL cases), (4) AL-related κ or λ IGVL genes by NGS (the clonal κ and λ IGVL genes in AL cases are restricted), and (5) NT-proBNP > 332pg/mL (the threshold for cardiac involvement with AL). All subjects will be evaluated for the presence of AL after enrollment and have their clonal IGVL genes identified by NGS enabling the creation and validation of a laboratory developed test in a precision medicine laboratory. Patients will be followed for progression to AL and to MM requiring therapy at their centers. Investigators will participate in regular conferences to track the patient status. We have powered our study based on the hypothesis that presence of t(11;14) or gain 1q and of AL-related IGVL clonal genes discriminates between patients who have or are at risk for AL. Based on prior studies we estimate that at least 10% of SMM patients with dFLC > 23mg/L, t(11;14) or gain 1q and AL-related IGVL genes may have or be at risk for AL. At a two-sided alpha of 0.05 and power of 0.8, assuming a 1