MM-associated anemia: more than “crowding out” HSPCs

In this issue of Blood, Bruns et al report that hematopoietic stem and progenitor cells are significantly decreased in the bone marrow of multiple myeloma (MM) patients. Based on their insightful findings the authors claim that hematopoietic suppression depends on cues (eg, the activation of TGFβ signaling pathways) within the MM milieu and is reversible in a MM-free bone marrow microenvironment.¹ 

Under physiologic conditions, the cellular and extracellular bone marrow (BM) compartments are highly organized and regulated by cell-matrix and cell-cell interactions within a liquid milieu and support normal hematopoiesis. In MM, the balanced homeostasis between these BM compartments is disrupted. Both MM cell adhesion to the extracellular matrix and stromal cells as well as cytokines and growth factors (eg, IL-6, VEGF, IGF-1, TGFβ) released from the malignant clone and stromal cells lead to alterations within the BM milieu. Besides providing selective supportive conditions for MM cell proliferation, survival, migration, and drug resistance, these alterations also induce lytic bone lesions, immune suppression, and enhanced microvessel density (MVD).² 

TGFβ is an important physiologic regulator of cell proliferation and differentiation generally leading to suppression of erythroid and myeloid cell proliferation.³  In MM, TGFβ is produced by tumor and stromal cells and induces secretion of the key growth and survival factor IL-6 as well as of the proangiogenic factor VEGF in the BM microenvironment.⁴  In addition, TGFβ plays a key role in MM-associated bone disease. Although TGFβ enhances the recruitment and proliferation of osteoblast (OB) progenitors, it also inhibits later phases of OB differentiation and maturation and suppresses matrix mineralization. Conversely, inhibition of TGFβ restores terminal OB differentiation to suppress MM growth.⁵ 

Approximately 60% of patients with MM present with anemia at time of first diagnosis and up to 90% develop anemia during therapy. To date few studies have addressed the underlying pathophysiology of MM-associated anemia. Physical replacement of hematopoietic stem and progenitor cells (HSPCs) by MM cells within the BM is widely considered to be the predominant cause of hematopoietic suppression. However, suppression of normal erythropoiesis also occurs in cases with low extent of malignant infiltration.⁶ 

Bruns et al show that HSPCs, megakaryocyte-erythrocyte progenitors (MEPs) in particular, are significantly diminished in the BM of MM patients not because of the impaction of the BM with tumor cells alone but as a result of functional impairment.¹  Specifically, using genomic profiling of distinct HSPC subsets derived from MM patients the authors indicate deregulation of TGFβ/Smad2, p38MAPK, and NFKB signaling pathways. Moreover, inhibition of TGFβ receptor (TβR)–I using SD-208 restores proliferation, cell cycling, and enhanced long-term self-renewal and clonogenic capacity of MM patient-derived HPSCs. Finally, transplantation of HSPCs derived from patients with MM into the BM of MM-free NOG mice shows enhanced engraftment and normal differentiation capacities. Similar to data presented here, previous studies have shown that TGFβ is associated with the induction of anemia in MDS and leukemia.^6,7 

This article will likely stimulate many additional studies. One could certainly postulate a therapeutic role of TGFβ inhibition in MM-associated anemia. Moreover, given that TGFβ also plays a key role in lytic bone lesions of MM, future clinical studies evaluating the potential therapeutic role of TβRI inhibitors are indeed of high interest. However, TGFβ has diverse and often conflicting roles. While TGFβ levels are increased in the MM BM milieu, surface expression of TβRI, TβRII, and TβRIII on MM cells is reduced.^4,8  Functionally, decreased levels of TGFβ receptors counteract the antiproliferative role of TGFβ on MM cells. Taken together, the development and clinical use of TGFβ inhibitors requires further investigation dependent on the context in which they act.

Another intriguing finding of this study is that MM-induced changes within the BM milieu can reversibly affect benign cells, HSPCs in particular. Specifically, transplantation of HSPCs derived from MM patients into the BM of MM-free NOG mice shows enhanced engraftment and normal differentiation capacities. These data are consistent with our clinical experience demonstrating rapid and sustained engraftment in the majority of MM patients after elimination of MM cells by high-dose therapy.⁹  Bruns et al hypothesize that increased engraftment might be due to a compensatory rebound of HSPCs after discontinuation of TGFβ-mediated inhibitory effects. Moreover, they speculate that increases of TGFβ secreted by stromal cells and tumor cells create a competitive advantage for clonal plasma cells over benign HSPCs. Future studies should explore whether the microenvironment can also irreversibly affect stromal cells and thereby induce a malignant phenotype. Already ongoing efforts aim to identify differences of stromal cells derived from the MM tumor microenvironment versus stromal cells derived from the BM microenvironment of healthy individuals. The existence of MM-specific endothelial cells, BM stromal cells, and mesenchymal stem cells (MSCs) has already been proposed.²  Indeed, one might speculate that the maintenance and expansion of the malignant plasma cell clone and thereby the transition of MGUS to MM depends on progressive supportive changes within the tumor microenvironment.

An unprecedented enhancement of our knowledge of MM cell biology and its interrelation with the BM microenvironment has led to the identification of novel targets. The development of derived therapies targeting both the tumor cell as well as the microenvironment that have fundamentally changed MM treatment strategies. The present study further extends our understanding of the impact of changes within the BM microenvironment in MM pathogenesis and provides new avenues for future investigations.