Bone marrow microenvironment: culprit and target 

Jorge J. Castillo, MD, Dana-Farber Cancer Institute, Boston, USA

Apart from factors such as genetic events that contribute to the malignant transformation in Waldenström’s macroglobulinemia (WM), the bone marrow microenvironment has been identified as a crucial player in WM disease progression [1]. Similarly, it appears to be essential for the emergence and ­progression of multiple myeloma (MM) and constitutes a significant reason why MM ­patients are not amenable to cure but inevitably develop relapses [2]. Delineation of malignant cell growth in the context of the bone marrow microenvironment has therefore moved into the focus of research approximately 15 years ago as it might enable the design of more efficient therapeutic strategies for both MM and WM.

According to our understanding, immuno­modulatory agents such as thalidomide and lenalidomide that are being used to treat MM patients exert effects by modifying the microenvironment. Likewise, I believe that ibrutinib, when used in patients with WM, not only works by inhibiting BTK, which is an important aspect, but also regulates the microenvironment to some degree. Observations we make in clinical routine support this assumption. For example, we would treat a patient with WM and 80 % infiltration of the bone marrow who is very anemic because the marrow does not provide sufficient space to produce an appropriate quantity of red cells. Three to 6 months into therapy, the patient’s hemoglobin is back to normal or much improved, and the IgM levels have decreased by 50 % or 70 %. However, when we perform another bone marrow biopsy on this patient, we find that the degree of infiltration is still 80 %. Therefore, we believe that a mechanism within the ­malignant cell uses the microenvironment to achieve a survival advantage. I feel that ibrutinib and many other medications work by suppressing the disease’s impact on the microenvironment. 

Much research is going on concerning the possibility of targeting the disease by targeting the microenvironment. From my perspective, this specific approach has been more successful in MM than it has been in WM, but I believe that we are on our way to identifying agents that can potentially help in this scenario. Hopefully, we can combine these with BTK inhibitors, Bcl-2 inhibitors and other agents to achieve more profound and long-lasting responses.

REFERENCES

1. Jalali S, Ansell SM, Bone marrow microenvironment in Waldenstrom’s macroglobulinemia. Best Pract Res Clin Haematol 2016; 29(2): 148-155
2. Mondello P et al., Bone marrow microenvironment is a crucial player for myelomagenesis and disease progression. Oncotarget 2017; 8(12): 20394-20409