High Prevalence Of Extramedullary Relapse In Patients With Multiple Myeloma Treated With Novel Biological Agents
Authors: Mangiacavalli Silvia , Pompa Alessandra , Pascutto Cristiana , Ferretti Virginia , Pochintesta Lara , Cocito Federica , Varettoni Marzia , Lazzarino Mario , Cazzola Mario , Corso Alessandro 
Published: October 2019

Abstract
There is widespread concern about a possible higher prevalence of extramedullary relapse (EMR) in patients with multiple myeloma (MM) in the era of novel biological agents.
Aims of this study were: i) to assess the prevalence of treatment-emergent EMR in a cohort of patients extensively exposed to biological drugs; ii) to investigate the association between previous exposure to biological drugs and subsequent EMR.
Following approval by our institutional Ethics Committee, we reviewed clinical and hematologic data of 456 MM patients (pts) who were consecutively observed in our Department between 2000-2010. This time frame allowed us to study the effect of the introduction of the novel biological agents (bortezomib, thalidomide, lenalidomide) in addition to standard chemotherapy and high-dose therapy (HDT) on EMR occurrence. Extramedullary disease was categorized as follows: a) soft tissues masses adjacent to bone; b) localizations in extra-osseous organs. Survival and extramedullary disease prevalence were compared with an historical cohort of 182 patients observed in our Department between 1994-1999, when only HDT was available [Ann Oncol 2010, 21(2):325-30]. Table 1 summarizes the main characteristics of the new cohort at diagnosis. After a median follow-up of 39 months (range 0-150 months), 63 (13%) patients remained asymptomatic. In symptomatic patients (n=393, 87%), first line therapy included HDT in 199 (51%) cases, and novel agents in 137 (35%). In relapsing patients (n=271), the median number of subsequent treatments was 2 (1-8); 40 (14%) patients were treated with chemotherapy alone, the remaining 231 (86%) received various treatments including at least one biological agent
The prevalence of extramedullary disease at clinical onset was 14% in the recent cohort vs 6% in the historical cohort (p=0.004). The prevalence of EMR in patients of the new cohort without extramedullary disease at diagnosis was 24% (92 patients). Sites involved included soft tissue adjacent to bone in 47%, and extraosseous organs in 53% of cases. When compared to the historical cohort, MM patients had a better outcome (median OS 6.4 vs 3.9 years, P<0.001), but higher cumulative incidence of EMR (23.9% vs 5.6% at 5 years; HR 3.1, 95%CI: 1.8-5.4, P<0.001). Median time to first EMR was not statistically different (26 months vs 32 months in the historical cohort, P=0.322). Cox regression for repeated events was performed to investigate the association between previous exposure to novel agents and subsequent EMR occurrence. Patients previously exposed at least twice to the novel biological agents had a higher risk of EMR (HR 2.9, 95% CI 2.0-4.1, p<0.001). In multivariate analysis, no effect of previous HDT was detected (HR=1.13, p=0.541), while the exposure to novel biological agents retained the same effect.
In conclusion, this analysis shows an increased occurrence of EMR in the last decade, which appears to be independent from the better survival. Sequential exposure to novel biological agents emerges as a risk factor for EMR occurrence.Table 1Characteristics at diagnosis of the 456 patients treated from 2000 to 2010CRAB Symptoms:63 (13%)· Absent393 (87%)· PresentMedian Age61 (28-86) yearsMyeloma Type:268 (59%)· IgG100 (22%)· IgA79 (17%)· Light chain5 (1%)· Non-secretory4 (1%)· Other (IgD/IgM)D&S42 (9%)• I132 (30%)• II• III267 (61%)ISS(n=347)· I93 (27%)· II6 (2%)· III248 (71%)Extramedullary disease at diagnosis391 (86%)• No65 (14%)• Yes· Adjacent to bone51 (78%)14 (22%)· Extraosseous organs

Disclosures:
No relevant conflicts of interest to declare.