Abstract IA06: Intratumor heterogeneity and its role in therapeutic escape in multiple myeloma
Authors: Tiedemann Rodger E. 
Published: August 2018

Abstract
Multiple myeloma (MM) is a mature B cell neoplasm characterized by the accumulation of immunoglobulin-secreting plasma cells (PC) within the bone marrow. Despite treatment advances, MM remains incurable in the majority of patients and is over-represented in current cancer death rates. The lack of reliable cure in MM, despite the achievement of deep clinical responses with proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), and myeloablative melphalan, implicates the presence of intratumoral heterogeneity and the existence of drug-resistant cells with tumorigenic capacity. However, the molecular and cellular basis of this intratumoral heterogeneity remains only partially understood. Using sequential FACS and single-cell immunofluorescence-FISH or genomics strategies, we have identified clonal tumor progenitor subpopulations within the bone marrow of MM patients that recapitulate the physiologic maturation stages between post-germinal center B cells and plasma cells. These clonal MM subpopulations include tumor cells that resemble CD20+ CD27+ CD38- CD138- Irf4- Xbp1s- memory B cells, CD38+/- CD138- Irf4- Xbp1s- pre-plasmablasts, CD38+ CD138- Irf4+ XBP1s+ plasmablasts, and tumor-bulk CD38+ CD138+ IRF4+ Xbp1s+ plasma cells. Importantly, compared to tumor bulk plasma cells, early Xbp1s- tumor progenitor cells appear innately resistant to mainstay treatment with proteasome inhibitors (PI). Mechanistically, absence of Ire1-Xbp1 signaling in these primitive MM cells is associated with secretory immaturity; as Xbp1s- MM cells produce less secretory immunoglobulin, an important determinant of endoplasmic reticulum (ER) load in PCs, they experience less ER stress than Xbp1s+ cells and are thus less susceptible to induction of cytotoxic ER stress when ER-associated degradation (ERAD) is inhibited by PIs. Significantly, small numbers of Xbp1s- tumor cells can be detected in most MMs and as these progenitor cells are innately insensitive to PI-induced cytotoxic ER stress, these observations can conceivably account for a universal low level resistance that is inherent in the pathogenesis and residual progenitor structure of MM and that prevents PI-induced cure. While these findings may account for some clinical features of MM, at present it remains unknown whether or not Xbp1s- MM tumor progenitors are fully malignant or if they possess the capacity required to reinitiate MM disease. Plausibly, Xbp1s- pre-plasma cells in MM may instead represent a counterpart to the premalignant preleukemic stem cells identified in AML, CLL and HCL, or may alternatively represent dedifferentiated PCs. Although this heterogeneity in tumor cell maturation may contribute to therapeutic evasion, MM tumors also commonly contain multiple genetic subclones that show tidal dominance under therapeutic pressure that may also facilitate treatment escape. Such genetic heterogeneity is not mutually exclusive with diversity in tumor cell maturation. When MM genetic subclones with common recurrent secondary chromosomal structural abnormalities (such as del 13, del 17p, +1q or del 1p) are identified among tumor bulk PCs, similar subclones may also be identified amongst non-PC Irf4- Xbp1s- MM subpopulations; this suggests that tumor progenitor cells may play a role in the genetic evolution of tumors and may represent a reservoir for subclonal relapse. In support of a model in which MM PCs can be replenished from MM progenitor cells, primary Xbp1s- MM progenitors possess the ability to differentiate in vitro into mature Xbp1s+ MM plasma cells. Notably, however, in contrast to a model in which MM PCs are continuously replenished by MM progenitors, we have also identified some genetic events that appear to show restricted representation among tumor PCs, consistent with MM PCs comprising a self-sustaining tumorigenic population in its own right. Overall, these data support a model in which Xbp1s- progenitor subpopulations in MM represent a reservoir of innately PI-resistant cells that, following eradication of tumorigenic PCs, may give rise to clonally related clinical relapse via MM progenitor cell differentiation. Overall these findings imply that treatment strategies in MM need to better address Xbp1s- IRF4- tumor stem/progenitor cells, while also eradicating MM-bulk PCs, to achieve deeper treatment responses and cure for patients.
Citation Format: Rodger E. Tiedemann. Intratumor heterogeneity and its role in therapeutic escape in multiple myeloma [abstract]. In: Proceedings of the Second AACR Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; May 6-9, 2017; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(24_Suppl):Abstract nr IA06.