Hematogenous Extramedullary Relapse in Multiple Myeloma - A Multicenter Retrospective Study in 127 Patients

Abstract

Background: Hematogenous extramedullary multiple myeloma (HEMM), though rare, is mainly observed in MM patients at relapse. The current study assesses the characteristics and outcomes of patients with MM who develop HEMM in the novel agent era. Methods: Consecutive patients, treated in 16 participating centers and diagnosed with HEMM, were included. Patient characteristics at diagnosis and at HEMM presentation, treatment regimens, response to therapy, response duration and survival were recorded. Factors predicting time to HEMM and survival from HEMM diagnosis were analyzed. Results: 127 patients were included. Median age at MM diagnosis was 63 years (31-94). 50% of patients had IgG MM, 26% had IgA, 23% had light chain, and 1% had other MM types. 44% had ISS 3 and 57% presented with plasmacytomas. 30% presented with high-risk cytogenetics: 19% with t(4;14),11% had 17p deletion. CD56 was expressed in 72% of cases and CD20 in 16%. 55% of the patients were treated for MM with PI, 55% with IMIDs, 62% with chemotherapy and 59% underwent autologous stem cell transplantation (ASCT) prior to HEMM. The median time to the development of HEMM was 2.8 years (95% CI 2.2-3.6). B2M levels (HR 1.04, 95% CI 1.00-1.07, p=0.03), del17p (HR 3.3, 95% CI 1.6-7.1, p=0.002) and plasmacytomas at MM diagnosis (HR 1.6, 95% CI 1.1-2.4, p=0.01) were associated with a shorter duration from diagnosis to HEMM, while upfront ASCT was associated with a longer period to the development of HEMM disease (HR 0.6, 95% CI 0.4-0.9, p=0.01). 47 patients (38%) patients had no concomitant plasmacytomas at HEMM diagnosis. 33% of patients had ≥2 HEMM sites, in 53% HEMM lesion was ≥5 cm, 20% had non-secretory disease at HEMM, and 59% had an increased LDH. 61% received at least 2 lines for MM prior to HEMM. First treatment for HEMM included PIs in 50%, IMIDs in 39%, MoAbs in 10% and chemotherapy in 53%. Overall response rate (ORR) was 49% and 51% failed to respond to first treatment for HEMM. IMIDs were associated with higher odds for ORR (OR 2.2, 95% CI 1.02-4.7, p=0.04). Median survival from MM diagnosis and from HEMM diagnosis were 4.3 (CI 95% 3-5.5) and 0.5 (CI 95% 0.4-0.6) years, respectively. 5-year OS from HEMM diagnosis was 6% (1-15%)(Figure 1A). Increased LDH level at the time HEMM (HR=2.2, 95% CI 1.3-3.8, p=0.002, Figure 1B), FISH positive for t(4;14) (HR=2.3, 95% CI 1.2-4.2, p=0.01)(Figure 1C), t(14;16) (HR=5.6, 95% CI 1.3-25, p=0.02)(Figure 1D), as well as ≤3 years between MM diagnosis and HEMM (HR=1.6, 95% CI 1.04-2.4, p=0.03(Figure 1E)), were found to be associated with a significantly shorter survival from HEMM diagnosis. The achievement of CR or VGPR to treatment administered for HEMM therapy were both associated with improved OS (HR=0.2, 95% CI 0.1-0.3, p<0.001 and HR=0.5, 95% CI 0.3-0.9, p=0.02, respectively) (Figure 1F). No specific treatment was found to be associated with improved survival in patients that develop HEMM. Conclusion: In MM patients who develop HEMM, the median time from MM to HEMM diagnosis is 2.8 years. Despite the improvement in MM therapy over the last decades, patients with HEMM diagnosis have a dismal outcome. OS is significantly shorter in patients with high-risk cytogenetic abnormalities, increased LDH and time to HEMM <3 years. Further studies assessing best therapy in patients experiencing this complication are warranted. Figure 1. Figure 1. Disclosures Cohen: Neopharm Israel: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Medisson Israel: Consultancy, Honoraria, Research Funding. Garderet:Takeda: Consultancy; Celgene: Consultancy; Amgen: Consultancy. Niesvizky:Amgen Inc.: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Takeda: Consultancy, Research Funding. Castillo:Pharmacyclics: Consultancy, Research Funding; Beigene: Consultancy, Research Funding; Millennium: Research Funding; Genentech: Consultancy; Janssen: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding.

Extramedullary disease in multiple myeloma: a systematic literature review

“…In a retrospective study of 127 consecutive patients with hematogenous EM relapse [37], first treatments for EMD included PIs (50%), IMiDs (39%), monoclonal antibodies (10%), and chemotherapy (53%). ORR (≥ partial response) was 57% across all treatments and IMiDs were associated with higher ORR compared with PIs (HR 2.2, 95% CI 1.02-4.7; p = 0.04).…”

Expert review on soft‐tissue plasmacytomas in multiple myeloma: definition, disease assessment and treatment considerations

“…33 A multicentre study of 127 patients with EMD disease also showed dismal outcome. 78 The prognosis is particularly poor in patients with CNS involvement who have a median survival of <3 months, 38,39 and even when novel agents are used outcomes to date have been dismal. 41,79,80 Survival may be improved by the combination of radiation therapy (cranial or craniospinal) along with systemic plus intrathecal therapy, but this constitutes an area of exquisite unmet medical need.…”

Extramedullary disease in multiple myeloma

“…A few studies have reported association of high-risk cytogenetics like t(4;14), t(14;16), gain (1q21), and del(17p) in patients with EMD [2,24,25]. Studies have also identified del(17p13) and del(13q14) as markers for progression to EMD [2,26] and del(13) as risk factor for EM relapse. Gain (1q) was associated with inferior outcome [27].…”