Primary plasma cell leukemia: clinical and laboratory presentation, gene-expression profiling and clinical outcome with Total Therapy protocols

Abstract

To determine whether primary plasma cell leukemia (PPCL) remains a high-risk multiple myeloma feature in the context of contemporary therapy and gene expression profiling (GEP), we reviewed records of 1474 patients with myeloma who were enrolled in Total Therapy protocols or treated identically off protocol. 27 patients (1.8%) were classified as having PPCL. As a group, these patients more often had low hemoglobin, high beta-2-microglobulin, high lactate dehydrogenase, low albumin, and cytogenetic abnormalities. Among 866 patients with GEP results, the PPCL group more often had disease that was classified as high risk, and in CD-1 and MF molecular subgroups. Regardless of the therapeutic protocol, patients with PPCL had shorter median overall survival (1.8 years), progression-free survival (0.8 years), and complete response duration (1.3 years) than the remainder whose clinical outcomes had improved markedly with successive protocols. Multivariate analyses of pretreatment parameters showed that PPCL was a highly significant independent adverse feature linked to overall survival, progression-free survival, and complete response duration. In GEP analyses, 203 gene probes distinguished PPCL from non-PPCL; the identified genes were involved the LXR/RXR activation, inositol metabolism, hepatic fibrosis/hepatic stellate-cell activation, and LPS/IL-1-mediated inhibition of RXR function pathways. Different treatment approaches building on these genomic differences may improve the grave outcome of patients with PPCL.

Trends in survival of patients with primary plasma cell leukemia: a population-based analysis

“…5 Similarly, gene expression profiling suggests differential expression of genes in pPCL plasma cells that result in a myeloid-like differentiation during leukemic development when compared with MM plasma cells. 18 There are several limitations of this study, the first being that the SEER database does not contain information concerning the use of treatment types such as ASCT, chemotherapy, or novel agents; therefore, no direct assessment of a potential link between changes in therapy and superior survival results can be made. Because the use of novel agents upfront vs at relapse cannot be clearly distinguished in our study, we used various time periods as a surrogate for potential novel agent use in the upfront and relapsed setting based on the utilization of novel agents in the community.…”

“…21 Recent single-institution studies suggest an improvement in OS among pPCL patients when novel agents have been incorporated upfront in their treatment. [14][15][16][17][18] The wide availability of novel agents began in 2001; however, this was initially approved in the relapsed setting alone and it was not until 2006 that these agents began to gain approval for use in the first-line setting. Ramsingh et al assessed the outcomes of pPCL during 1973-2004 using the SEER 17 database but were unable to detect an improvement in OS with time.…”

“…1,[10][11][12][13] However, recent retrospective studies suggest that the incorporation of novel agents as well as ASCT in treating pPCL has improved the median OS to more than 24 months. [14][15][16][17][18][19] Given the lack of large, prospective studies evaluating the survival outcomes in pPCL because of its rarity, we used the Surveillance Epidemiology and End Results (SEER) program to evaluate the survival trends in pPCL patients in the US population during various time intervals based on the availability of ASCT and novel agent therapy.…”

Extramedullary disease portends poor prognosis in multiple myeloma and is over-represented in high-risk disease even in the era of novel agents

“…It may be postulated that EMD develops as a result of "bone marrow escape" of a MM subclone with either decreased cell adhesion or that acquires characteristics of the granulocytic lineage as observed in primary plasma cell leukemia. 21 There is further acquisition of mutations such as k-ras 22 and deletion 17p 23 in EMD-2 when comparing biological features with concomitant bone marrow at the time of disease relapse.…”

Heterogeneity of outcome with single-agent carfilzomib: all relapsed/refractory myelomas are not created equal

“…2 There has been a growing body of literature furthering the biological understanding of the disease. There is a clear recognition of both inter-patient and intra-patient genomic heterogeneity in multiple myeloma, 3 although the academic community is still trying to comprehend specific phenotypic presentations such as primary plasma cell leukemia 4 and extramedullary disease. 5 Even with effective upfront therapeutic strategies, which seemingly help a greater proportion of MM patients achieve a 'complete' remission by biochemical and pathology criteria, relapses do occur sooner or later that require subsequent lines of therapy.…”