Clonal plasma cells keep strange company

Multiple myeloma and other clonal plasma cell disorders have long been known to give rise to a diverse set of paraneoplastic phenomena. Some of the paraneoplastic effects are linked to cross-reactivity of the secreted monoclonal immunoglobulin, such as disturbances of Factor X or Von Willebrand Factor, leading to bleeding diatheses, or M-protein attachment to myelin sheaths producing peripheral neuropathy.[1–3] Other non-CRAB (hypercalcemia, renal insufficiency, anemia and bone disease) pathology associated with monoclonal plasma cell disorders, such as scleromyxedema, have idiopathic etiology.[4] Still other plasma cell disorders drive paraneoplastic phenomenon through pathologic alteration of cytokine production. The premier example of such is POEMS (peripheral neuropathy, organomegaly, endocrinopathy, monoclonal paraprotein and skin changes) whereby the signs and symptoms do not relate to the ongoing proliferation of malignant cells, but rather are cytokine driven by the paraneoplastic elevation of vascular endothelial growth factor and interleukin-6.[5] Multiple myeloma has also been linked to other malignancies, most notably second primary malignancies seen during coadministration of lenalidomide with oral melphalan alkylating chemotherapy or after autologous stem cell transplant.[6] Multiple myeloma also has been associated with concurrent hematologic, solid tumor and skin malignancies, independent of chemotherapy.[7]

Neutrophilia and plasma cell disorders are known to be associated, but the pathophysiology is protean. Case reports have described elevated levels of G-CSF (either secreted by the monoclonal plasma cells or surrounding stroma) driving neutrophilia, while others have shown that chronic neutrophilic leukemia and multiple myeloma can co-exist as two separate clonal processes.[8,9] Interestingly, in one case report, treatment of the clonal plasma cell disorder with concurrent therapy against chronic neutrophilic leukemia (CNL) led to therapeutic response; yet, could treatment of either the CNL or the myeloma alone have led to a similar result if the two disease are inter-related?[10]

In this issue of Leukemia and Lymphoma, Stevens et al. provide a case series of five patients with simultaneous neutrophilia and plasma cell disorder.[11] In depth molecular and cytokine analyses were performed in these patients, showing that there may be multiple mechanisms at play in the linkage of the two proliferative processes. In two patients, a SETBP1 mutation, which is associated with CNL, was seen thereby suggesting that the CNL and MM were derived from distinct clonal processes.[12] In the SETBP1 wild type patients, it appears that the clonal plasma cells themselves were the culprit in leading to overproduction of cytokines interleukin-6 and G-CSF and thereby driving a reactive neutrophilia, as confirmed by serum ELISA testing. Treatment of the plasma cell disorder led to improvement of the neutrophilia when no SETBP1 mutation was detected. The authors describe the failure of a patient’s neutrophilia to respond to dasatinib, despite a positive ex vivo drug screen on a primary marrow aspirate. This patient, who was negative for mutated SETBP1, had marked improvement of neutrophilia when given myeloma-directed therapy of bortezomib + dexamethasone followed by autologous stem cell transplantation. In those patients harboring mutated SETBP1, hydroxyurea was able to control the neutrophilia for a period of time, but these patients ultimately expired (one as a consequence of infections in the setting of 7 + 3 induction chemotherapy and the other opting for comfort care upon evolution to AML). Interestingly, another patient in the series who was negative for SETB1 mutation also had predicted sensitivity to dasatinib on ex vivo drug screen. This patient, in contrast to the other SETBP1 negative patient, responded well to dasatinib monotherapy not only clearing the neutrophilia, but also reducing the bone marrow plasma cell burden as well. These disparate findings support the author’s conclusions that plasma cell-associated neutrophilia may arise from different mechanisms which may guide therapy; however, some of the pathophysiology remains yet to be elucidated.

This excellent case review with correlative laboratory studies informs a practicing oncologist that indeed plasma cell disorders and neutrophilia can coexist and that directing treatment at the plasma cell neoplasm may be the most effective management strategy in some cases. Although, this report is limited by the small number of patients its retrospective nature, it is unlikely that intervention or prospective observational studies will ever be available to better describe or outline optimal treatment for the phenomena of plasma cell-associated (or contemporaneous) neutrophilia. Given the relatively low incidence of CNL, a thorough workup for underlying clonal plasmacytosis and associated myeloma, amyloidosis or POEMS should be undertaken before CNL-directed therapy is started, especially in the absence of mutations suggestive of primary CNL, such as SETBP1, JAK2 and CSF3R. We are now ready to add one more condition to the already long list of plasma cell disorder-related diseases and neoplastic syndromes: neutrophilia (multifactorial).

Potential conflict of interest

Disclosure forms provided by the authors are available with the full text of this article at http://dx.doi.org/10.3109/10428194.2015.1106539