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V. Montefusco et al.
Introduction
Extramedullary disease definition and assessment
Extramedullary disease was classified as PO disease, consisting of tumor masses arising directly from bones, or EMP, consisting of masses not contiguous to the bones and derived from hematogenous spread. EMD was identi- fied at study enrollment with the diagnostic procedure required by the patient’s study protocol, such as X-ray skeletal survey, magnetic resonance imaging (MRI), com- puted tomography (CT), and physical examination.
Statistical analysis
Differences in patients' and disease characteristics for EMD patients versus non-EMD patients were investigated using Kruskal Wallis test for continuous variables and Fisher’s exact test for categorical variables. Data of trials were pooled together and analyzed. Time-to-event data were analyzed using the Kaplan-Meier method; EMD and non-EMD patients were compared with the log-rank test. The Cox proportional hazards models were used to esti- mate adjusted hazard ratios (HRs) and the 95% confi- dence intervals (CI) for the main comparisons, EMD patients versus non-EMD patients. To account for potential confounders, the Cox models were adjusted for the age, sex, International Staging System (ISS) stage (I vs. II; I vs. III), cytogenetic risk defined by fluorescence in situ hybridization (FISH) analysis [high, i.e. presence of del(17p), t(4;14), t(14;16), vs. standard risk; missing vs. standard risk], and autologous stem cell transplantation (ASCT) (ASCT vs. non-ASCT; not applicable, i.e. patients not candidate to ASCT, vs. non-ASCT). Subgroup analyses were performed to determine the consistency of the over- all effect in different subgroups using interaction terms for the comparison between EMD versus non-EMD and each of the co-variates included in the Cox model plus Revised ISS stage (RISS) and type of therapies (IMID and PI). All Hazard Ratios (HR) were estimated with their 95%CI and two sided P-values. In order to evaluate the impact of dif- ferent size and types of EMD, further subgroup analyses were performed: EMD size ≤ 3 > 3 cm; EMD size ≤ 5 vs. > 5 cm; PO or EMP. Data were analyzed as of December 2018 using and R (Version 3.1.1).
Results
Patients
A total of 2,332 patients were included in this analysis: 267 (11%) had EMD, while 2,065 (89%) had no EMD. Median age of EMD patients was 68 years (IQ range 60-74), and 69 years (IQ range 61-74) in patients without EMD. International Staging System was I in 119 (45%) and 682 (33%), II in 85 (32%) and 782 (38%), and III in 38 (14%) and 509 (25%) patients with or without EMD, respectively. Clinical trials were based on IMiD in 166 (62%) and 1,279 (62%) patients, on a PI in 66 (25%) and 464 (22%) patients, or both in 35 (13%) and 322 (16%) patients with or without EMD, respectively. Patients' characteristics are summa- rized in Table 2. Patients with EMD had PO in 243 (91%), and an EMP in 12 (4%) cases, while the information was not available for the other 12 (4%) patients. EMD localizations were single in 195 (73%), and multiple in 60 (22%) patients. Median EMD size was 4.2 cm (IQ range 3-7). EMD characteristics are summarized in Table 3. No differences were observed in patients with EMD ≤ or > 3 cm. EMD patients had a lower systemic tumor burden with respect to patients without EMD, as shown by: plasma cell bone marrow infiltration 30% (IQ range 15-50%) versus 50% (IQ range
Multiple myeloma (MM) is a plasma cell neoplasia char- acterized by a diffuse tumor infiltration of the bone mar- row, resulting, among others, in anemia, bone damage with hypercalcemia, and bone lesions. Occasionally, neo- plastic plasma cells acquire a different growth pattern gen- erating tumor masses, that are referred to as extra- medullary disease (EMD).1 EMD can arise from skeletal focal lesions, which disrupt the cortical bone and grow as extra-bone masses, and is referred to as paraosseous plas- mocytoma (PO), or derive from hematogenous spread as manifestation in soft tissues, and is called extramedullary plasmocytomas (EMP). Incidence of EMD at diagnosis ranges between 6% and 10%,2-4 while later in the course of the disease this increases to 13%-26%,2,4 with a 32-35% peak in case of relapse after allogeneic stem cell transplan- tation.5,6 In the final stage of the disease, an extraskeletal involvement is observed in approximately 70% of cases studied with autopsy,7 with a peculiar involvement of vis- ceral sites.8 As expected, patients with EMD at diagnosis tend to maintain the same pattern at relapse.2
The biological mechanisms behind the acquisition of the EMD-forming phenotype have not yet been fully elu- cidated. Increased expression of CXCR4 and CXCL12 plays a major role in promoting a bone marrow-indepen- dent behavior, favoring dissemination, and homing to dis- tant and unusual sites.9,10 Other mechanisms are represent- ed by reduced expression of several adhesion molecules, in particular VLA-4, CD44, and CD56, and chemokine receptors, such as CCR1, and CCR2. Diversely, the cyclin D1 pathway seems to favor the bone marrow homing, protecting from extramedullary localizations, as t(11;14) is not observed in MM patients with EMD.11
Despite its frequency and clinical relevance, EMD has often been neglected by the medical literature. In fact, almost all the available data derive from retrospective series and single center experiences, mainly reported in the pre-new drug era, with the limitations of this type of studies. In order to fill this gap and clarify the role of new drugs in MM with EMD, we conducted the largest meta- analysis so far reported, based on eight prospective trials by the same sponsors (Fonesa Onlus and Hovon Foundation).
Methods
Study design
Patients with newly diagnosed MM enrolled in eight clinical trials were retrospectively analyzed. Details on tri- als and treatment regimens are summarized in Table 1. Briefly, three trials enrolled transplant eligible and five tri- als transplant ineligible patients. Three trials included an immunomodulatory (IMiD) drug in the treatment, lenalidomide in almost all cases, three trials a proteasome inhibitor (PI), and four trials both. Six out of eight trials included maintenance. Trials were approved by the Independent Ethics Committees/Institutional Review Boards at all participating centers. Patients provided writ- ten informed consent before entering the study, prepared in accordance with the Declaration of Helsinki. For the purpose of this meta-analysis, we considered the sub- group of patients with EMD, and compared them with patients without EMD.
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haematologica | 2020; 105(1)