Background: Systemic mastocytosis (SM) is a rare clonal mast cell disorder that may co-occur with other hematologic neoplasms (SM-AHN). While most SM-AHN cases involve myeloid neoplasms, co-occurrence with plasma cell dyscrasias particularly smoldering multiple myeloma (SMM) or multiple myeloma (MM) is exceptionally uncommon. Given the rarity, prognostic impact, diagnostic complexity, and optimal management strategies remain poorly defined.

Aims: To describe the clinical, pathologic, and molecular characteristics of reported cases of SM/SM-AHN with concurrent plasma cell dyscrasias, and assess patterns in presentation, clonality, mutational status, and outcome.

Methods: A literature search of PubMed and Scopus was conducted through June 2025, identifying case reports and small series describing SM/SM-AHN with coexisting MM or SMM. Demographic, immunophenotypic, molecular, and outcome data were extracted and tabulated. One additional unpublished case from Qatar's National Cancer Center was included.

Results: A total of 13 previously published cases and 1 recent case) (N=14) were analyzed. The median patient age was approximately 64 years (range: 53–79), with a slight female predominance (8 females, 6 males). Nine patients had MM (including light-chain and non-secretory subtypes), while 5 had SMM. Plasma cell clones ranged from 14% to 40%, often with lambda light chain restriction.

All patients had SM or SM-AHN diagnosed by marrow histology and/or immunohistochemistry, with mast cell clusters expressing CD117, CD25, and in some cases CD2. Several cases fulfilled WHO 2022 criteria via multifocal clusters and KIT mutation positivity. Two had associated cutaneous involvement. The KIT D816V mutation was detected in 7 of 9 (78%) cases where testing was reported. One case also reported TET2 mutation.

Three patients had coexisting amyloidosis. Two were confirmed AL-type (lambda), consistent with plasma cell origin. In contrast, the case we added from our center featured ALECT-2 amyloidosis, unrelated to the clonal plasma cells, marking the first such report.

Most SMM-associated cases followed an indolent course with observation or conservative management. In contrast, MM-associated cases were more heterogeneous: two required cytoreductive therapy and FLT 3 inhibitors for SM progression, and three received myeloma-directed treatment with good control of both neoplasms. Only one case described aggressive SM with organ damage.

Conclusions: Systemic mastocytosis coexisting with plasma cell dyscrasias represents a rare but clinically relevant diagnostic entity. While most SMM/SM-AHN cases are indolent, MM-associated cases exhibit greater variability and may require tailored therapy depending on dominant clone behavior. The presence of KIT D816V mutations in most patients reinforces the clonal independence of mast cells in this context. Clinicians should maintain a high index of suspicion for dual pathology in patients with unexplained cytopenias, or marrow abnormalities.

Keywords: Systemic mastocytosis, Smoldering multiple myeloma, Plasma cell neoplasms

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2025
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