Ninkovic, Slavisa

Abstract Solitary bone plasmacytoma (SBP) and SBP with minimal marrow involvement (SBPmm) are treated similarly with definitive radiation therapy (RT) followed by observation. However, differences in the natural disease course after RT between the two, are not well described. We performed a multicenter study assessing outcomes after RT in 141 patients with SBP and 102 with SBPmm diagnosed between January 2010 and December 2024. About 92% of patients with SBPmm progressed to multiple myeloma (MM) vs 76% of those with SBP (P = .01). Among patients with SBP, 21% progressed with a second solitary bone lesion vs 4% with SBPmm (P< .01). Patients with longer time to progression (TTP) after initial RT could achieve durable responses with RT to a second solitary plasmacytoma in the absence of other myeloma-defining events (MDE). Multifocal lytic bone lesions were the most common MDE, occurring in 89% and 81% of patients with SBPmm and SBP, respectively. Patients with SBPmm had a median TTP of 15 months (95% confidence interval [CI], 14-21) compared to 43 months (95% CI, 34-55) for those with SBP (P< .0001); 67% with SBPmm progressed within 2 years of diagnosis. Del(17p) and 1q+ (gain or amplification) were associated with shorter TTP to MM in SBPmm, with 2-year progression rates of 100% and 82%, respectively. We report significant differences in risk and modes of progression between SBP and SBPmm. Patients with SBPmm are at particularly high risk for early progression to MM, with most developing bone disease as the MDE. These findings support prospective studies incorporating frontline systemic therapy for SBPmm.

Aim: The definition of high-risk (HR) in Multiple Myeloma (MM) is ever evolving with the discovery of new genomic abnormalities and increasing therapeutic options. There are various stratification models incorporating laboratory and genetic features with different definitions of high-risk and varied emphasis on individual risk factors. Recognized high-risk cytogenetic abnormalities (HRCA) include t(4;14), t(14;16), t(14;20), del(17p) with recent inclusion of del(1p) and gain/amplification (amp) of 1q (+1q) . In addition to del(17p), the presence of biallelic del(1p) and ≥2 HRCAs (“double-” or “triple-hit”) appear to confer poorer outcomes. A new definition proposed by the International Myeloma society (IMS) defines HR as the presence of del(17p) and/or TP53 mutation; an IgH translocation - t(4;14), t(4;16) or t(14;20) along with +1q and/or del(1p); monoallelic del(1p32) along with +1q; bi-allelic del(1p32); or β2 microglobulin ≥5.5 with normal creatinine (<1.2mg/dL). Herein, we report real-world outcomes on these HRCAs and the new IMS consensus definition of HR MM. Method: We retrospectively reviewed newly diagnosed MM patients from the Australian and New Zealand Myeloma and Related Diseases Registry across 4 Australian states. Patients with FISH and/or SNP microarray testing for IgH translocations, 1q21 (CKS1B), del(1p32) (CDKN2C) and del(17p) (TP53) were identified. Positive threshold was 30%. We used Kaplan-Meier methods to compare progression free survival (PFS) and overall survival (OS) between groups and first performed univariate analysis (UA) for each HRCA. We next analyzed patients with gain1q vs amp1q and monoallelic vs biallelic del(1p). In the final analysis, two risk groups were formed: cases meeting the new IMS-defined HR criteria were considered IMS-HR and the rest were considered standard risk (IMS-SR). Indeterminate cases with missing variables that could influence risk classification were excluded. Results: Of 839 newly diagnosed patients (pts) included, 31% had ISS (International staging system) stage 3 disease. High-risk IgH translocations t(4;14) and t(14;16) were present in 8% and 4%. Secondary HRCAs del(17p), del(1p), gain1q and amp1q were present in 9%, 14%, 30% and 11% respectively. In this cohort, 41% received ASCT. Of the transplant eligible pts, 41% received triplet therapy (PI, IMiD and corticosteroid) and 57% received PI-based induction. Of the transplant ineligible pts, 31% received triplet therapy, 47% PI-based and 19% IMiD-based therapy. Frontline Anti-CD38 antibody use was <1%. Median follow up was 35 months[m] (IQR 18-60). On UA, the risk of progression and/or death was increased with ISS III vs I, amp1q, del(17p), t(14;16), del(1p) and gain1q in descending order by hazard ratio. The risk remained significant in ISS III, del(17p), amp1q and gain1q after multi-variate analysis (MVA). The risk of death was increased with ISS III vs I, del(17p), amp1q, del(1p) and t(14;16), ISS II vs I in descending order by hazard ratio. After MVA, the risk remained significant for ISS stage III, del(17p), amp1q and t(14;16). Of the 117 pts with del(1p32), 108 had monoallelic and 9 had biallelic loss. Pts with biallelic del(1p32) had an inferior PFS (median 16.3 vs 23.2m, p<0.001) and OS (median 24.8m vs NR, p<0.001) compared to those with monoallelic del(1p32). In pts with 1q+, pts with amp1q had an inferior PFS (median 16.3 vs 27.5m, p<0.001) and OS (median 37.0m vs NR, p<0.001) vs pts with gain1q. Based on the new definition of HR myeloma - 385 pts met the criteria for IMS-HR and 216 for IMS-SR. There were 238 indeterminate cases due to missing data. The IMS-HR group had an inferior PFS (median 20.2 vs 39.7m, p<0.001) and OS (median 44.2m vs NR, p<0.001) when compared to IMS-SR. Noting that the IMS-HR group had a higher median age, poorer performance status and lower rates of ASCT use, adjusted analysis for these variables still showed an inferior PFS (aHR 1.68; 95% CI 1.30-2.16, p<0.001) and OS [aHR 1.72; 95% CI 1.21-2.44, p=0.002). Conclusion: ISS III, del(17p), amp1q are the strongest predictor of OS and PFS. Differentiating between monoallelic vs biallelic del(132p) and gain vs amp1q21 has important prognostic value. The IMS- HR definition which takes into account del(1p), “double-” and “triple-hit” disease predicts for a group of patients with a PFS of ~20 months and inferior OS, and provides a standardized approach to risk stratification in MM.