Comparative Outcomes of Functional High-Risk Multiple Myeloma Patients with and without High-Risk Features at Diagnosis: A Commpass Study Analysis
Authors: Shan Xinhe , Susanibar-Adaniya Sandra 
Published: December 2024

Background
Risk stratification in Multiple Myeloma (MM) traditionally relies on cytogenetics and ISS staging at the time of diagnosis. The concept of ‘functional high-risk’ (FHR), defined by disease progression within one year of initial treatment or stem cell transplantation (SCT) can potentially identify an additional subset of patients with poor prognosis but without high-risk features. By using data from the MMRF CoMMpass study, we aimed to analyze the clinical outcomes of FHR patients and compare the treatments and responses of those with and without high-risk features at diagnosis.
Method
The MMRF CoMMpass study is an international, prospective, observational study involving 1169 patients with newly diagnosed MM. The IA19 dataset was used for all analyses. FHR patients are defined as those who relapse or die within 12 months of initial treatment. We define high risk features as the presence of any HR cytogenetics-t(4;14), t(14;16), t(14;20), 1q amplification (amp1q), 17p deletion(del17p), TP53 mutations or having ISS-stage III disease. Patients are categorized into high-risk (HRG) and standard-risk groups (SRG) based on the presence or absence of these features.
Results
Out of 228 patients classified as FHR, 63 were in the SRG and 165 in the HRG. Median OS estimated by Kaplan-Meier was 13.2 months for SRG and 11.6 months for HRG (p = 0.29). Both groups had a median age of 67. In HRG, 61.2% had ISS-Stage III disease, 54.5% had amp1q, 16.4% had del17p, 7.9% had TP53 mutations, 10.3% had t(4;14), 3.6% had t(14;16), and 2.4% had t(14;20). Additionally, 26.1% had two high-risk features, while 14.5% had three or more. No significant differences were observed in gender, racial composition, or ECOG Performance Status between groups (p-values: 0.9, 0.8, and 0.4, respectively).
First-line therapeutic approaches were similar between groups. Bortezomib-based regimens were most common (37.5% SRG vs. 39.1% HRG), followed by combined bortezomib/IMiD-based regimens (34.0% SRG vs. 35.7% HRG). First-line stem cell transplant (SCT) rates were comparable (12.7% SRG vs. 8.5% HRG; p = 0.5). The proportion achieving partial response (PR) or better was similar (36.5% SRG vs. 33.3% HRG; p = 0.767). 57.0% FHR patients had primary refractory disease (PRD), which comprised 61.9% of the SRG and 55.2% of the HRG (p = 0.44). Among PRD patients, the SRG has better OS compared to the HRG (median OS: 7.8 vs. 5.0 months, p = 0.048).
For patients who relapsed after initial response, treatment patterns differed. The SRG predominantly received combined bortezomib/IMiDs-based regimens (41.2%), while the HRG received IMiDs-based (29.3%), bortezomib-based (12.1%), and carfilzomib-based (12.1%) regimens. The use of salvage SCT for relapsed patients was similar (17.6% SRG vs. 24.1% HRG; p = 0.816). Despite slight differences in treatment regimens (p = 0.048), response rates were comparable, with 41% of SRG and 40% of HRG patients achieving PR or better. Median OS for this subgroup was 27.1 months for SRG and 20.2 months for HRG (p = 0.22).
Conclusion
FHRMM patients have poor prognosis regardless of their risk profiles at diagnosis. Among primary refractory patients, high-risk features correlate with worse OS. Second-line treatment approaches differ, with SRG receiving more triplet regimens and HRG more doublet regimens, yet response rates remain similar. Importantly, MM patients who relapse within 12 months of initial therapy have an OS less than 24 months, regardless of the presence of high-risk features at diagnosis. Our findings suggest that functional high-risk status could be a useful tool for identifying patients with poor prognosis. Prospective studies are needed to validate the prognostic impact of FHRMM and to optimize management for this challenging patient population.