EXTRAMEDULLARY DISEASE
Authors: Meral Beksac
Journal: HemaSphere (2022)

High risk or ultra-high risk Multiple Myeloma are observed among 15 to 10% of newly diagnosed Multiple Myeloma(NDMM). These consititute the group of patients which are the most difficult to treat. Cytogenetic, molecular and clinical parameters define such high risk patients at diagnosis. Among clinical findings extra-medullary plasmacytoma(EMP), plasma cell leukemia (PCL) can be recognized immediately. The incidence of EMP at diagnosis ranges between 7-18% (1) However incidence increases at later phases of disease to reach 70%. Central nervous system or liver plasma cell infiltration has been reported at autopsy highly frequently (1) Classification of EMP is not standardized yet. It is of great importance to exclude solitary plasmacytoma and para-osseous (PO) expansion of bone plasmacytomas from soft-tissue plasmacytoma(1,2). Table 1 is adapted from a recent review from the Mayo Group(3). Table 1. - Classification of EMD adapted from Bansal et al (Blood Cancer Journal 2021) Solitary plasmacytoma with no marrow involvement Biopsy proven single plasmacytoma with no marrow plasma cell infiltration Solitary plasmacytoma with minimal marrow involvement Solitary plasmacytoma with < 10% clonal plasma cells in bone marrow Bone associated EMD with MM (EMM) Extra-medullary para-osseous (PO) myeloma extending from bone and growing contiguously Bone independent EMD with MM (EMM) İsolated extra-osseous plasmacytoma (EMP) not contigous with any bone lesion Organ infiltrating EMD Diffuse or nodular infiltration in liver, central nervous system, skin, lymph node etc Plasma cell leukemia Presence of clonal plasma cells in circulation (>5% or >2 x 109/L) Treatment: Apart from radiotherapy there is no standard treatment of EMD(4). Until recently there are no prospective trials aiming to analyze efficacy in particular among patients presenting with EMD at diagnosis. Montefusco et al performed a meta analysis comparing outcome of EMD patients versus those without EMD among eight prospective NDMM GIMEMA trials(5). IMiD- or PI-based therapy in patients (n = 2332) with NDMM included 267 patients with soft-tissue plasmacytomas (PO, n = 243; EMD, n = 12; not classified, n = 12). Median PFS and OS were similar (PFS: 26.1 months and 25.2 months; OS: 70.1 months and 79.9 months) In patients with EMD and without plasmacytomas, respectively. Another retrospective analysis by the Balkan Myeloma Study Group among 226 patients showed higher complete response among those presenting with PO involvement vs. EMP at diagnosis (34.2 % vs. 19.3 %; p=NS) and relapse (54.5 % vs. 9 %; p=0.001)following a median of two lines of treatment(6). Also PO disease had a better PFS when recognized at initial diagnosis of myeloma than at relapse (51.7 vs. 38.9 months). In addition, OS was also better for PO involvement compared to EMP at diagnosis (not reached vs. 46.5 months). EMP at relapse had the worst prognosis with a PFS of (9.1 months) and overall survival (11.4 months). Since anti-CD38 monoclonal antibodies in particular combined with Carfilzomib or Pomalidomide are highly effective against advanced myeloma cells we have attempted to treat a patient presenting with pleural EMD. Our results in view of the published similar reports favour this combination as a bridging therapy to stem cell transplantation(10). Among recent randomized clinical trials EMD is gradually being recognized as a risk factor but response rate and durations are rarely reported. The ICARIA study comparing the efficacy of Isatuximab in the Pomalidomide-dexamethasone backbone is an exception and EMD results have been reported at two Congresses(9). Among 307 RRMM patients randomized to two study arms: Isa-Pd (n=154) or Pd (n=153). At study entry, soft-tissue plasmacytomas were present in 24 (7.8%) patients. Of those, 14 (9.1%) patients were in the Isa-Pd and 10 (6.5%) patients in the Pd arm. Limited to only EMD patients PFS was improved by adding Isa to Pd: HR: 0.22, 95% CI: 0.07–0.69. Median PFS was 4.57 (95% CI: 2.40–not calculable [NC]) months in the Isa-Pd arm versus 1.56 (95% CI: 0.95–4.47) months in the Pd arm. A multivariate analysis of PFS adjusted for ISS stage, cytogenetics risk, and number of prior lines was performed. The difference in the HR after adjustment (adjusted hazard of 0.555, 95%CI: 0.119–2.582, versus 0.22, 95% CI: 0.07–0.69) indicates that the prognostic factors may have influenced the treatment effect in favor of Isa-Pd arm, but the adjusted HR was still in favor of the Isa-Pd arm. The overall response rate also improved with 50% (7/14) and 10% (1/10) responders in the Isa-Pd and Pd arms, respectively. Very good partial response occurred in 21.4% (3/14) of patients in the Isa-Pd arm and 10% (1/10) of patients in the Pd arm. The prospective phase 2 EMN19 study (acronym ANTARES) is currently ongoing to evaluate the efficacy of Daratumumab combined with Cyclophosphamide Bortezomibe and Dexamethasone among both NDMM and first relapse MM presenting with EMD exclusing PCL. Results are expected to be presented in 2022. Autologous Stem Cell Transplantation: The multi-center, multi-national retrospective study of the Balkan Myeloma Group included patients who received autologous SCT (44%) following their EMD diagnosis. In the multivariate analysis, PO, EMD at diagnosis, ISS-I and undergoing ASCT improved OS independently(6). Within the EBMT Registry data on clinical and cytogenetic data from 488 patients with NDMM and EMD (PO, n=374; EMP, n=87; both, n=27) high-risk cytogenetics were over-expressed (41%)(7). Outcomes following single autologous SCT were significantly worsened in the presence of high-risk cytogenetic abnormalities, whereas a tandem autologous transplant strategy was shown to offset the poor prognosis. A analysis on EMD effect among 3744 NDMM patients reported no difference in 3-year PFS following first-line autologous SCT between those with single sites of EMD (any location) and patients without EMD. However, single EMP involvement was associated with worse 3-year OS compared with no EMD, which worsened still further when multiple sites of organs were involved. (8) Depth of response measurement must include functional imaging among patients presenting with EMD. PET-CT has contributed to an increase in the incidence of EMD both at diagnosis and at relapse. Patients responding in the marrow and a reduction in M protein secretion may continue to harbour clonal plasma cells outside of the marrow. PET-CT metabolic response has been developed to quantify and standardize such cases(11). Novel Treatments: Recently CAR-T treatments have provided unprecented high and durable responses among advanced and highly refractory myeloma patients. The incidence of EMD among such patients is higher that at diagnosis. In the KARMA study as presented at ASH 2020 EMD incidence was 40 % with a rate (24 % vs 39%) and median duration (9.2 vs 11.1 months) of complete response inferior to those without EMD. Thus CAR-T is a potential treatment approach which is currently far from being curative. BITEs are also moving forward and there are anecdotal cases achieving good quality responses with Teclistamab or Talquetamab. Currently the unmet need for treatment of high risk myeloma including patients presenting with EMD is still unanswered. 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