Non-Producing Multiple Myeloma (MM) Is a Distinct Subset Of Non-Secretory MM Characterized By High Cyclin D1 Expression and Decreased Progression Free Survival
Authors: Papanikolaou Xenofon , Zhang Qing , Heuck Christoph , Waheed Sarah , Atrash Shebli , Singh Zeba N , Alapat Daisy V. , van Rhee Frits , Chavan Shweta S. , Epstein Joshua , Barlogie Bart 
Published: October 2019

Abstract

Introduction
Non-Secretory Multiple Myeloma (NSMM) is a well described entity with an estimated prevalence of 3% characterized by typical morphological and pathological MM characteristics and the absence of an M-protein on immunofixation electrophoresis (BJH, 2003, 121:749-757). The serum free light chain (sFLC) assay can detect an abnormal serum free light chain level in up to two-thirds of cases, suggesting that many cases of NSMM are at least minimally secretory. Among the true NSMM cases there is a subset in which no cytoplasmic Immunoglobulin synthesis is detected. This entity of ‘’Non Producing’’ Multiple Myeloma (NPMM) though recognized three decades ago (J Clin Invest. 1985;76(2):765-769) has only been described in a small number of case reports. The purpose of this study is to confirm the existence of and subsequently systemically describe NPMM, through the interrogation of MIRT’s MM Data Base (MMDB).

Methods
MMDB was interrogated from January 2000 until January 2013. Clinical and laboratory data were systemically reviewed for the MM isotype classification.

Results
210 MM patients were identified as NSMM. Flow cytometry data on cytoplasmic immunoglobulin (cIg), performed at initial diagnosis, was available for 197 out of 210 patients. 19 cases revealed no cIg by flow cytometry thus identifying them as NPMM. Review of sFLC assay results revealed that in all cases but one, the free immunoglobulin light chain levels were low and the sFLC ratio was normal, confirming that the negative result of flow cytometry was not due to a technical failure. In one single case elevated sFCL levels were measured, which could be traced to grade 3 renal failure resulting in accumulation of FLC in the serum. The MM diagnoses were confirmed by chart review for each of the 19 cases, which revealed that all cases had symptomatic MM. The basic clinical/laboratory characteristics of the 19 NPMM cases are shown in table 1. Sixteen of the 19 cases had results on immunoglobulin In Situ Hybridization (ISH) and 5 were found to be positive for κ or λ light chains. In two cases a mixed population of light chain positive and negative plasma cells by ISH was identified. α and γ heavy chain positivity was found in 4 and 1 cases respectively. Thus in pathological terms, two categories of “minimally producing” and “ totally non producing” MM can be identified. There was no overlap between the cases with cytoplasmic heavy or light chain positivity by ISH. Osteolytic bone disease by X-rays was evident in 12/19 cases and active focal lesions were seen in 11/19 patients by PET and 16/19 by MRI. Metaphase cytogenetic analysis at initial diagnosis was abnormal in 10 out of 19 available samples, with the t(11;14) translocation found in 3 of them. Baseline Gene Expression Profiling (GEP) was available for 16 cases. 13 (81%) of them belonged to the CD1/CD2 subgroup, and all of them were characterized by markedly high cyclin D1 expression, the hallmark of the t(11;14) translocation in MM. In comparison, only 21% of patients enrolled in the Total Therapy 3 trial belonged to the CD1 or CD2 molecular subgroups (94/441, p<0.001) only 87 had a CCND1 gene expression above the FISH defined t(11;14) translocation threshold (p<0.001). With a median follow up of 68 months the median overall survival was not reached (6 deaths), and progression-free survival was only 8.9 months. To further delineate the pathophysiology of NPMM we performed a comparative genomic study of the GEP of the NPMM with the normally producing-secreting MM. The comparison revealed a list of 128 genes with a p value <0.0001 and a false discovery rate < 0.01. Ingenuity pathway analysis revealed that these genes were closely related with Cellular Development, Cellular Growth and Proliferation and Cellular Morphology.

Conclusion
NPMM is a very rare entity in MM. It is characterized by an increased expression of cyclin D1, suggesting that the t(11;14) translocation plays a role in its pathophysiology. Furthermore, while data on OS are yet inconclusive, it seems to exert a markedly decreased PFS implying a decreased sensitivity in MM therapy.

Disclosures:
No relevant conflicts of interest to declare.