One of the ‘Meet the Professor’ sessions at the 19th International Myeloma Society Annual Meeting was focused on Smoldering Multiple Myeloma (SMM) charied by Prof Claudio Cerchione and Prof Natalie Callander.
The session opened with an disucssion about the term ‘Smoldering’ and the first evidence of it, described by Kyle and collaborators in 1970s and adopted by IMWG for the first time in 2003. The epidemiology of SMM is currently uncertain, and is considered rare. A 2016 study by Ravindran, demonstrated a potential incidence of 14% in MM and a median age of 67 years, with a higher proportion in women, African Americans, and older patients.
The first study that focused on risk of progression was published in 2007 by Dr. Robert Kyle, and a recent study by the iStop MM Project, demonstrates the incidence of SMM is 0.5% in people over 40 years of age, among 75.000 screened: of them about 1/3 met definition of intermediate/high-risk SMM, confirming the need for further study about this heterogeneous condition, considering important implications for future treatment policies.
According to the criteria set by the IMWG, SMM is an asymptomatic stage characterized by M-spike < 3 g/dl serum and/or bone marrow plasma cells infiltration between 10-59% in the absence of myeloma-defining events and organ damage. Recent studies show the need to alter diagnostic criteria. Free light chains ratio and “advanced” imaging are mandatory to discriminate SMM from MM, and also better clarify the risk of progression integrating also cytogenetic and FISH.
The “20/20/20 model” analyzed 421 patients with SMM between 2003-2015, in which the risk of pregression was correlated with > 20% PCs, > 2 g/dl M-spike, > 20 FLC ratio (0 factors: 110 months, 1 factor: 68 months, >= 2 factors: 29 months). This model was validated in a larger data set by San Miguel and collaborators in 2004. SMM, confirming similar evidences, and the importance to deeply indentify individual risk for each SMM patient in order to inform them about the potential short and long term potential rate of progression.
Further studies demonstrated the risk of progression can be more accurately determined by a fourth parameter, cytogenetic alterations (t(4;14), t(14;16), +1q and del 13q/monosomy), with High risk patients (>= 3 factors) showing 59% 2-years risk of progression. Immunoparesis is another important aspect to be considered, and potentially integrated in future pronostic scores.
Genomic studies are helping to find a better understanding of risk, and new risk factors: the need of detecting biomarkers is particularly needed in this setting of patients, considering the concrete opportunity to select the higher risks in which treatment could prevent the evolution in MM. The availability of clinical trials confirms the importance of differential diagnosis between MGUS (Monoclonal Gammopathy of Undetermined Significance) and Smoldering Myeloma, and, between them, low-intermediate-high risk.
Low-risk and intermediate-risk should be monitored according to recommandations, but are, according to present data, not needed to be evaluated for invasive diagnostic procedures and/or active treatment. Conversly, if there is suspicion of high-risk SMM, the patient should undergo to complete a serum and urinary evaluation, bone marrow aspirate + biopsy and advanced imaging with PET/CT combined with WB-MRI. Novel manageable drugs, like lenalidomide and monoclonal antibodies, with high efficacy and limited toxicity, improvement in imaging and prognostication, challenge physicians to offer early treatment to high-risk SMM.
The ongoing debate centers on the best approach between:
- modest treatment to slow Progression to Active Myeloma,
- aggressive “MM” treatment to completely stop MM from developing
- limited, well tolerated myeloma therapy for longer disease control but reasonable toxicity.
In high risk patients, QUIRIDEX was the first randomized trial to show the advantage of PFS and OS for early intervention. Median follow-up is about 10.8 years, and, even if confirming the strong need of intervention in high risk settings, some caveats emerge: advanced imaging was not required, the contribution of dexamethasone unclear and 10% SPM in treated were detected.
The ECOG trial confirms this data and also adds the FLC ratio in the elegibility criteria as well as focusing on toxicities and quality of life, which are important aspects in this setting.
The use of novel agents, particularly monoclonal antibodies, is being explored in international randomized clinical trials. Single agent opportunities seem not to provide the best results, even in the low rate of deep responses and lower PFS than lenalidomide-based regimens, the Centaurus trial has shown the effectiveness of anti-CD38 with a impressive tolerability. The currently ongoing Aquila phase-3 trial compares different schedules of daratumumab versus monitoring.
This data was the basis for ongoing clinical trials in which monoclonal antibodies anti-CD38 are added to lenalidomide versus lenalidomide-dexa with OS/PFS as endpoints (i.e. EAA173 and ITHACA/EFC15992). Carfilzomib in different combinations has also shown promising results in this setting, and is being explored in GEM-CESAR trial.
Considering the evidence of effectiveness of anti-CD38 antibodies and Carfilzomib, the IMF/Black Swan Research group designed the Aggressive Smoldering Curative Approach Evaluating Novel Therapies and Transplant (ASCENT) trial, in which patients are treated with quadriplet Carfilzomib-Lenalidomide-Daratumumab-Dexamethasone with following consolidations randomizing 4 cycles of the same regimen versus ASCT, following intensification and maintenanc. The preliminary data was presented by Professor Shaji Kumar at ASH 2022 and appeared interesting in terms of efficacy, particularly in deepness of response, with adequate tolerability.
Gene-expression-profiling plus Integrated Multidisciplinary approach to detect new-generation risk-adapted Prognostic Index in Smoldering Myeloma and Multiple Myeloma (GIMPI) (PI: Claudio Cerchione) is an ongoing traslational trial at Istituto Romagnolo per lo Studio dei Tumori “Dino Amadori” – IRST IRCCS – Meldola – Italy. It aims to better focus on patients risk, combining deep molecular and advanced imaging analysis focusing on the importance of these data in the pathogenesis, prognostication and, in high risk patients, in response evaluation and monitoring, with the final endpoint to detect new biomarkers in order to improve risk stratification and monitoring with a future, hopefully, biomarkers-driven therapy.
