Clinical Characteristics Of Testicular Extramedullary Involvement In Multiple Myeloma

To the Editor: Extramedullary multiple myeloma (EMM) is an aggressive sub entity of multiple myeloma (MM) characterized by the ability of MM cells to proliferate outside the bone marrow (BM) and is associated with overall poor prognosis. There appears to be heterogeneity in outcome between locations of EM disease (EMD), with central nervous system (CNS) involvement and transformation into the leukemic phase, termed plasma cell leukemia (PCL) being aggressive forms of EMD with an overall survival of <6 months.1-4 Testicular EMD is extremely rare and the disease course remains largely unexplored.5 Herein, we report a case series of 14 patients with testicular EMD treated at our institution. The institutional myeloma database was interrogated to identify patients with documented testicular involvement by either biopsy or/and imaging studies and clinical parameters were obtained. Clinical characteristics are as shown in Table 1. Between 1980 to 2019, 9069 MM patients were treated at our institution. The EMD analysis was limited to the period of 2000 to 2019 since our institution started to perform routine 18fluoro-deoxyglucose positron emission tomography computed tomography (18F-FDG PET) scanning only in January 2000. In addition, whole body magnetic resonance imaging (MRI) and MRI with diffusion-weighted MRI with background suppression (DWIBS) were also integrated due to the complementary nature of these novel imaging techniques. A total of 631 patients had EMD either at diagnosis or during the disease course and among these, testicular involvement accounted for 2.2% (n = 14) of EMD. The median age at diagnosis was 60.5 years (range 42–68 years) with 75% of patients being Caucasian (Table 1). Of note, two patients in our series had a diagnosis of HIV/AIDS. The predominant immunoglobulin isotype was IgA accounting for 50% (7/14) of all the cases. There was a predominance of ISS stage III disease at diagnosis of 45% (5/11). Among these, 12 patients presented with testicular EMD in the setting of relapsed disease, whilst two patients presented with a primary testicular involvement at diagnosis. At the time of testicular involvement, bone marrow (BM) infiltration was absent in 58% of patients with a fifth of these fulfilling the criteria for non-secretory MM.6 The median time to testicular EMD from initial diagnosis was 1.8 years (range 0.03–8.4 years). A 18F-FDG PET scan led to a diagnosis in 71.4% (10/14) of cases, while a testicular biopsy led to diagnosis in four patients (Table 1 and Figure 1). Abnormal FISH studies (available in only five patients) with del(17p) and 1q21 abnormalities and abnormal metaphase karyotype (including complex karyotype, chromosome 1 and 17 abnormalities) were seen in 60% (3/5) and 57.1% (8/14) respectively. Gene-expression profiling (GEP) on CD138 enriched plasma cells from bone marrow aspirate samples were obtainable in three patients and showed a GEP70 score of ≥0.66 (high risk MM) in all.7 Interestingly, GEP analysis of CD138 sorted plasma cells from the testicular site in patient # 4 showed PR subtype with a high risk GEP70 signature. Imaging studies at the time of diagnosis of testicular EMD was available in 10 out of the 14 patients and showed focal bone lesions (FL) and additional EMD at more than one site in 70% (7/10) and 60% (6/10) of patients, respectively. Interestingly, majority of patients with additional multiple PET defined FL had no concomitant BM involvement.8 DTPACE VDTPACEx2a In the current series, 42.8% (6/14) had local treatment of the testicular EMD (five undergoing a surgical resection and one local radiation therapy) in addition to systemic therapy. Eleven patients were treated with multi-agent chemotherapy regimen (Table 1). Six patients underwent a second salvage ASCT at relapse. Disease response assessments in seven evaluable patients showed a IMWG CR in the majority of the patients 71.4% (5/7)6 with median duration of response of 6.5 (range 3–16) months. The median overall survival (OS) from EMD diagnosis was 1.28 years (95% CI 0.65–NA) (Figure 1) with 57.1% (8/14) surviving more than 12 months following testicular EMD diagnosis. An impediment to curing MM is the intra and inter tumor heterogeneity leading to the coexistence of tumor subclones with different drug sensitivities especially in the RRMM.9 The EMD in MM exemplifies clonally evolved population of myeloma cell that can survive independent of the bone marrow microenvironment thus conferring treatment resistance and adverse clinical outcome.10, 11 Based on a recent registry study between 2005 and 2014, the incidence of EMD per year increased from 6.5% to 23.7% and this is ascribed to enhanced detection to routine integration of novel imaging techniques in addition to the expanded therapeutics improving survival of patients. The reported incidence of testicular myeloma involvement is 4% of NDMM and 3.5% in relapsed setting, while this accounts for 2.2% of all EMDs in our own experience.4 It is conceivable that the true incidence in a real-world setting is mostly unknown as majority of these were detected on 18F-FDG PET scans in our experience. While detailed genomic characterization of EMD is lacking, the whole-exome sequencing and gene expression profiling analysis in primary PCL, the most aggressive form of MM showed enrichment for high-risk mutation like TP53 and RAS, in addition to downregulation of adhesion molecules supporting plausible “bone marrow escape phenomenon” akin to those expected in EMD.12, 13 There is lack of a feasible and accurate prediction model that can predict occurrence of EMD, although we have shown that GEP707 high risk molecular subtype MF, PR, centromere index of ≥3 and abnormal cytogenetics at diagnosis were associated with increased risk of EMD (odd ratio of 6.39, 3.79 and 2.77 respectively).4 Thus far, this series of 14 patients is the largest single institution series of testicular EMD to be reported. Compared to our cohort of newly diagnosed MM (NDMM) treated on total therapy protocols,14 adverse clinical predictive factors like an ISS stage III disease (41.6% vs. 25.5%) and abnormal metaphase karyotype (46.6% vs. 20.6%) were enriched in this series of patients with testicular EMD. The IgA subtype was noted in 45% of the patients, in contrast to 20.6% observed in NDMM. Intuitively, del(17p) was present in 60% and 40% of patients on FISH studies at diagnosis and relapse respectively.2-4 Also, majority of patients had additional FL and/or other site EMD at the time of relapse. About 58% of the patients presented without BM involvement, thus emphasizing the value of novel imaging techniques especially in the relapsed setting.8 Existing literature reports concomitant central nervous system (CNS) manifestations in a fifth of patients in the setting of EMD,5 however this data was missing in our series, possibly due to lack of neurological symptoms warranting further investigation and future studies are needed to elucidate if routine CNS studies and chemotherapy prophylaxis is merited, as in high grade lymphomas. Role of local treatment like surgical orchiectomy and local radiation therapy outside of palliation of symptoms is largely unknown. Overall, the prognosis of MM patients with testicular involvement is poor with a median OS of 19.6 months in our series, yet this is better than the previously described other forms of EMD, such as CNS involvement and PCL.1, 3 While an ASCT based treatment approach was associated with >12 months OS in half of the patients in our series, there is no consensus in the optimal management of this subset of patients. Immunotherapeutics like monoclonal antibodies, antibody drug conjugates and T cell directing therapies like CAR-T and bispecific antibodies are revolutionizing the existing treatment paradigm and have hinted at efficacy even in the setting of high risk MM.15, 16 Taken together, our series demonstrates an enrichment of IgA subtype, abnormal baseline metaphase cytogenetics with a clinical presentation with no/minimal BM involvement and co-existence of other FL and/or EMD in this cohort of patients with testicular EMD. None. The data that support the findings of this study are available from the corresponding author upon reasonable request.