Concomitant plasma cell myeloma and chronic myelomonocytic leukemia in elderly: diagnostic complexity, therapeutic challenges - case report and literature review.

Introduction

Chronic Myelomonocytic Leukemia (CMML) is a clonal hematopoietic stem cell disorder classified as a myelodysplastic/myeloproliferative neoplasm (MDS/MPN) overlap syndrome by the World Health Organization[ 1 ]. It is characterized by sustained peripheral blood monocytosis, bone marrow dysplasia, and features of both ineffective hematopoiesis and myeloproliferation[ 2 ]. CMML predominantly affects older adults, with a median age at diagnosis between 65 and 75 years and exhibits a male predominance[ 1 ]. The clinical presentation is heterogeneous, ranging from incidental laboratory abnormalities to symptomatic cytopenias, constitutional symptoms, splenomegaly, and progression to acute myeloid leukemia[ 3 ]. HIGHLIGHTS This case describes a rare dual hematologic malignancy involving both chronic myelomonocytic leukemia (CMML) and plasma cell myeloma in an elderly patient. Comprehensive diagnostic workup, including bone marrow morphology, immunophenotyping, and next-generation sequencing, was crucial to delineate both disease processes. The identification of NRAS and TET2 mutations provided molecular confirmation of CMML and guided therapeutic considerations. The patient’s clinical course was complicated by cytopenias and renal dysfunction, necessitating a careful balance between cytoreductive and anti-myeloma treatment strategies. This case underscores the importance of considering coexisting hematologic malignancies in elderly patients with overlapping laboratory and clinical features.

The diagnosis of CMML requires exclusion of reactive causes of monocytosis and other clonal myeloid malignancies such as chronic myeloid leukemia (CML) and MPNs[ 1 ]. Despite ongoing advances in understanding of CMML’s pathobiology, therapeutic options remain limited. Allogeneic hematopoietic stem cell transplantation is the only curative modality but is feasible in a minority of patients due to age and comorbidities[ 4 ]. Most patients receive supportive or palliative therapy, with treatment tailored to the disease phenotype – dysplastic or proliferative – and symptom burden. Hypomethylating agents (HMAs) such as azacitidine and decitabine represent the cornerstone of therapy for patients with higher-risk disease, though they have not been shown to alter disease course or prevent leukemic transformation[ 5 ]. Cytoreductive therapies – including hydroxyurea and, in selected cases, ruxolitinib – are employed in patients with proliferative features to control leukocytosis and splenomegaly[ 1 ].

Here, we present a diagnostically and therapeutically challenging case of an elderly female patient with coexisting plasma cell myeloma and CMML, complicated by significant cytopenias, hypercalcemia, renal dysfunction, and neurologic deficits. This case underscores the complexity of diagnosing and managing overlapping hematologic malignancies in older adults and highlights the critical role of integrated clinical, morphologic, cytogenetic, and molecular evaluation in guiding diagnosis and therapeutic decision-making.

This case report was drafted in accordance with the CARE Case Report Guidelines of 2013[ 6 ].

Case presentation

An 82-year-old Hispanic female with a history of cervical cancer status post-total hysterectomy and chemo-radiotherapy 50 years ago presented with 3 weeks of generalized weakness, progressive bilateral buttock pain, and difficulty walking. The burning pain radiated from her lower back to both thighs and gradually worsened, causing gait disturbance and urinary urgency. Initially, she needed wall support for ambulation and recently began using a cane, which was unusual for her baseline mobility. She denied weight loss, fever, chills, night sweats, numbness, tingling, weakness, dizziness, falls, trauma, or strenuous activity. She also denied smoking, alcohol, or illicit drug use, and her family history was noncontributory.

On physical examination, the patient was alert and oriented to time, place, and person. Her skin was warm and dry, and no rashes were noted. The conjunctivae were pale, and her pupils were symmetric and reactive to light. The cardiopulmonary examination was unremarkable, with S1 and S2 heart sounds without murmurs and clear lung fields. There was no lower extremity edema. The abdomen was soft, non-distended, and non-tender, with no hepatomegaly, splenomegaly, or palpable masses. Neurologically, cranial nerves II–XII were intact. Motor strength was 3/5 bilaterally in the lower extremities and 5/5 bilaterally in the upper extremities. Sensation was intact to both dull and sharp stimuli. Deep tendon reflexes were 2+ at the patella. The straight leg raise (SLR) test was negative. Musculoskeletal examination revealed mild tenderness in the sacral area, but there was no tenderness in the lumbar paravertebral muscles.

Initial laboratory findings are shown in Table 1 . Table 1 Lab parameters Parameter Day of admission Reference Range White blood cell count 85 × 10 3 /µl 4.0–11.0 × 10 3 /µl Neutrophils (%) 64.1% 40–60% Monocytes (%) 30.1% 2–8% Hemoglobin (Hb) 8.4 g/dl 12.0–16.0 g/dl Hematocrit (Hct) 26.3% 36–46% Mean corpuscular volume 88.1 fl 80–100 fl Platelet count 71 × 10 3 /µl 150–400 × 10 3 /µl Serum calcium 11.3 mg/dl 8.5–10.5 mg/dl Albumin 2.4 g/dl 3.5–5.0 g/dL Corrected calcium 11.8 mg/dl ≤ 10.5 mg/dl Blood urea nitrogen (BUN) 35 mg/dl 7–20 mg/dl Creatinine 1.92 mg/dl 0.6–1.3 mg/dl Serum protein gap 7.5 g/dl < 4 g/dl (approx.)

The patient presented with marked leukocytosis, hypercalcemia, anemia, acute kidney injury, and an elevated protein gap, prompting evaluation for both a myeloid malignancy and plasma cell dyscrasia. Clinically significant initial interventions included intravenous hydration, calcitonin, bisphosphonates, hydroxyurea, and allopurinol to treat hypercalcemia, hyperviscosity, and tumor lysis risk. Hematologic workup (BCR-ABL, flow cytometry, serum protein electrophoresis/ urine protein electrophoresis, serum immunofixation, and free light chains) was pursued given suspicion for CML, CMML, and multiple myeloma. Imaging identified multifocal osseous lesions and bilateral hydronephrosis without acute spinal cord compression. Neurology attributed bilateral leg weakness to multifactorial neuropathy; gabapentin and rehabilitation were initiated. Bone marrow biopsy demonstrated plasma cell myeloma (20–25% CD138 + cells) coexisting with a myeloid neoplasm consistent with CMML, supported by monocytosis, myeloid hyperplasia, MF-2 fibrosis, and NRAS/TET2 mutations.

During hospitalization, the patient experienced rapidly progressive leukocytosis requiring leukapheresis and escalation of hydroxyurea, followed by clinically significant pancytopenia necessitating repeated transfusions. Rising uric acid and new circulating blasts required further intensification of cytoreductive therapy. Bortezomib–dexamethasone was initiated for myeloma but contributed to worsening thrombocytopenia. After successful cytoreduction and resolution of leukocytosis, persistent neutropenia led to discontinuation of hydroxyurea and initiation of antibacterial prophylaxis.

Follow-up

Patient was discharged to a skilled nursing facility with neutropenic precautions and levofloxacin prophylaxis. Outpatient plans included lenalidomide–dexamethasone for plasma cell myeloma, weekly complete blood count monitoring, renal and uric acid assessment, and consideration of HMA therapy for recurrent CMML features. Supportive care focused on infection prophylaxis, transfusion support, bone health, and coordination with nephrology/urology for prior hydronephrosis.

Discussion

CMML (CMML), classified by the World Health Organization as an MDS/MPN overlap syndrome, is a hybrid hematological malignancy; characterized by clonal proliferation of hematopoietic stem and progenitor cell (HSPC) and exhibits overlapping features of both myelodysplastic syndromes (MDS) and MPNs[ 1 ]. The median age of diagnosis of the disease is 65 to 75 years with male to female ratio of (1.5 to 3.1):1[ 1 ]. Therapy-related CMML (t-CMML), which comprises approximately 10% of all CMML cases, arises as a consequence of prior cytotoxic chemotherapy or radiation exposure[ 7 ]. Analogous to therapy-related MDSs (t-MDS), t-CMML is typically associated with unfavorable clinical outcomes, including higher-risk disease features and reduced overall survival[ 8 ].

Many patients with CMML are asymptomatic at the onset, with the condition often being incidentally detected during routine blood work that shows mild anemia, neutropenia, monocytosis, and/or thrombocytopenia[ 9 ]. In other cases, CMML may emerge in individuals with a history of an underlying autoimmune disorder, such as rheumatoid arthritis, or another chronic inflammatory condition, which can obscure the diagnosis and delay clinical recognition[ 10 ].

Clinically, CMML is categorized into two subtypes: (1) dysplastic subtype, characterized by a white blood cell count <13 000/μl, and (2) proliferative subtype, defined by a WBC count >13 000/μl[ 11 ]. The dysplastic subtype is predominantly associated with the clinical consequences of cytopenias, such as fatigue, increased susceptibility to infections, and bleeding or bruising[ 12 ]. In contrast, the proliferative subtype of CMML is more commonly associated with constitutional symptoms such as weight loss, fever, night sweats, and hepatosplenomegaly[ 12 ], along with renal insufficiency potentially resulting from renal infiltration by monocytes and/or lysozyme secretion[ 13 ]. Additionally, it is possible for patients to present with a mixed clinical picture, exhibiting features of both dysplastic and proliferative subtypes, which can further complicate the diagnosis and management[ 14 ].

Exclusion of reactive etiologies of monocytosis is a critical initial step in the evaluation of persistent monocytosis prior to considering a diagnosis of CMML[ 15 ]. Monocytosis may be secondary to a spectrum of non-clonal conditions, including chronic infectious processes, autoimmune and granulomatous disorders, and inherited metabolic abnormalities[ 16 ]. Comprehensive clinical and laboratory assessment is necessary to differentiate reactive monocytosis from clonal hematopoietic disorders[ 16 ]. After reactive causes of monocytosis have been excluded, it is essential to consider molecularly defined clonal hematopoietic neoplasms. The foremost priority is to definitively rule out chronic myeloid leukemia (CML), which is characterized by the presence of the reciprocal translocation t(9;22)(q34;q11) that generates the BCR:ABL1 fusion oncogene[ 17 ]. Diagnosis requires thorough cytogenetic evaluation and sensitive molecular techniques, such as quantitative PCR or fluorescence in situ hybridization (FISH), to confirm the absence of this specific genetic abnormality. This step is critical for accurate differential diagnosis, as the molecular signature of CML distinctly differentiates it from CMML and other related myeloid malignancies[ 18 ]. Subsequently, assessment for rearrangements involving the platelet-derived growth factor receptor genes, PDGFRA and PDGFRB, should be undertaken[ 19 ]. Ultimately, the demonstration of bone marrow dysplasia in at least one hematopoietic lineage constitutes a fundamental diagnostic criterion[ 20 ]. However, in instances where dysplasia is absent or minimally apparent, a diagnosis of CMML may still be appropriately rendered if there is definitive evidence of clonal cytogenetic abnormalities or pathogenic molecular mutations characteristic of the disorder[ 1 ]. This acknowledges that clonal hematopoiesis can manifest prior to, or independently of, overt morphological dysplasia in CMML[ 21 ]. Diagnostic criteria of CMML as per International Consensus Classification versus World Health Organization is presented in Table 2 [ 22 , 23 ] . Table 2 Comparison of diagnostic criteria for CMML as per International Consensus Classification vs World Health Organization Criterion International Consensus Classification (ICC) World Health Organization 5th Edition WHO prerequisite criteria (all are required) Monocytosis Absolute monocyte count (AMC) > 500/μl with monocytes accounting for >10% of WBC differential count. Cytopenia At least one cytopenia; with Hemoglobin <13 g/dl in males, < 12 g/dl in females; absolute neutrophil count (ANC) < 1800/μl; Platelets <150 000/μl. - Blasts Blasts (myeloblasts, monoblasts, and promonocytes) constitute <20% of cells in blood and marrow. Exclusion of Other MPNs Exclude BCR:ABL1 or abnormalities associated with myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions (e.g., PDGFRA, PDGFRB). Not meeting diagnostic criteria for CML or other MPNs. Exclude myeloid/lymphoid neoplasms with tyrosine kinase fusions - Not meeting diagnostic criteria of myeloid/lymphoid neoplasms with tyrosine kinase fusions. WHO Supporting Criteria Clonality Abnormal cytogenetics and/or ≥1 myeloid neoplasm-associated mutation with ≥10% variant allele frequency (VAF). Acquired clonal cytogenetic or molecular abnormality. Diagnosis without clonality evidence AMC >1000/μl and >10% of WBC+ at least one of the following: - Increased blasts and promonocytes (≥5% in marrow or >2% in blood) Morphologic dysplasia Abnormal immunophenotype consistent with CMML Dysplasia - 2. ≥10 % morphologic dysplasia of cells of a lineage involving ≥1 myeloid lineages Monocyte repartition based flow cytometry - 3. Abnormal partitioning of peripheral blood monocyte subsets (e.g., increased classical monocytes >94% in the absence of active autoimmune diseases or inflammatory syndromes). Bone marrow aspirate and biopsy findings Hypercellular marrow, often with increased monocytes, lacking features of AML, MPNs, or other monocytosis-related conditions. - Clonal Monocytosis of Undetermined Significance (CMUS) Defined by AMC ≥0.5 × 10 9 /l with monocytes ≥10% of WBCs, no MDS-defining cytopenias, a myeloid-driver somatic mutation with VAF ≥2%, and no marrow morphologic findings of CMML. - According to the WHO classification, the diagnosis of CMML requires that all prerequisite criteria be fulfilled. If the absolute monocytosis is ≥1000/μl, at least one supporting criterion must also be met. If monocytosis is between ≥500/μl and <1000/μl, both supporting criteria 1 and 2 are required. In contrast, the International Consensus Classification mandates that all diagnostic criteria be present for a definitive diagnosis.

CMML (CMML) is characterized by significant genetic heterogeneity, with somatic mutations detected in more than 95% of affected individuals. The most commonly involved genes include TET2 (approximately 60%), SRSF2 (around 50%), ASXL1 (about 40%), and genes associated with the RAS signaling pathway (approximately 30%). Cytogenetic abnormalities are identified in nearly 30% of cases[ 1 ]. The disease is associated with an inherent risk of transformation to acute myeloid leukemia (AML), occurring in 15–30% of patients over 3–5 years[ 24 ].

The classification of CMML is predicated on the quantification of blasts and promonocytes within peripheral blood and bone marrow. CMML-1 is defined by ≤4 % blasts plus promonocytes in peripheral blood and ≤9% blasts in bone marrow. In contrast, CMML-2 encompasses cases exhibiting 5–19% blasts plus promonocytes in peripheral blood, 10–19% blasts in bone marrow, and/or the presence of Auer rods[ 25 ]. This stratification serves as a critical prognostic indicator, reflecting the disease burden and progression risk.

Several case reports and cohort studies underscore the clinical heterogeneity and complexity of CMML (CMML). Bochicchio et al described an 84-year-old patient with CMML-2 presenting with persistent anemia, monocytosis, and dysplastic myeloid morphology. Bone marrow evaluation confirmed the diagnosis, and next-generation sequencing identified both recurrent CMML-associated mutations and a rare germline variant linked to atypical hemorrhagic manifestations. The patient demonstrated a favorable response to azacitidine, with normalization of coagulation parameters[ 26 ]. Guastafierro et al documented a rare case of CMML harboring a CSF3R mutation, representing a distinct molecular subset with phenotypic overlap with chronic neutrophilic leukemia and atypical chronic myeloid leukemia, and a dismal prognosis[ 27 ]. Bernat et al reported a case of CMML with central nervous system involvement, manifesting as a chronic subdural hematoma overlying a hemorrhagic intra-axial lesion, with histologic evidence of leukemic infiltration – an exceedingly rare presentation associated with poor clinical outcomes[ 28 ]. Finally, Ma et al analyzed a real-world cohort of 156 Chinese patients with CMML, the majority of whom were elderly. HMAs constituted the most frequently administered therapy, while allogeneic transplantation was undertaken in a minority. Higher baseline hemoglobin levels and lower lactate dehydrogenase (LDH) were independently associated with improved survival, and therapeutic response was a strong predictor of favorable outcomes[ 29 ].

The management of CMML (CMML) is inherently risk-adapted and individualized, reflecting the disease’s biological heterogeneity, variable clinical course, and the current lack of disease-modifying pharmacologic therapies. Allogeneic hematopoietic stem cell transplantation remains the only potentially curative intervention and is typically reserved for patients with intermediate-2 or high-risk disease, as defined by molecularly integrated prognostic models such as the Mayo Molecular Model or the CMML-specific Prognostic Scoring System incorporating molecular data (CPSS-Mol) [ 30 , 31 ] . Transplant eligibility is further contingent upon patient-related factors, including performance status, comorbidity burden, and donor availability[ 32 ].

For patients who are not candidates for transplantation, therapeutic goals are primarily palliative, aiming to alleviate symptoms, reduce disease-related complications, and maintain quality of life. In patients with a myelodysplastic phenotype – characterized by cytopenias and relatively lower white blood cell (WBC) counts – supportive care remains foundational. This includes red blood cell transfusions for symptomatic anemia and consideration of erythropoiesis-stimulating agents in those with low serum erythropoietin levels and without excess blasts[ 33 ].

In contrast, patients with a myeloproliferative phenotype (typically defined by WBC ≥13 × 10⁹/l), splenomegaly, and systemic symptoms may benefit from cytoreductive therapy[ 5 ]. Hydroxyurea is the most commonly employed agent in this setting, providing effective control of leukocytosis and splenomegaly[ 34 ]. Ruxolitinib, a JAK1/2 inhibitor, may be considered in selected patients with refractory splenomegaly or constitutional symptoms, particularly those with prominent proliferative features and limited alternative options[ 31 ].

HMAs, including azacitidine, decitabine, and the oral decitabine/cedazuridine combination, constitute the therapeutic backbone for patients with higher-risk disease, excess blasts, or symptomatic cytopenias[ 35 ]. These agents are associated with overall response rates of 40–50% and complete remission rates ranging from 7 to 17%. However, they have not demonstrated a capacity to modify the underlying clonal architecture or natural history of the disease. The choice between HMAs and hydroxyurea in advanced or proliferative CMML should be individualized, informed by disease burden, molecular profile, patient comorbidities, and treatment goals[ 36 ]. Notably, emerging evidence suggests that overall survival may be similar between these approaches in high-risk proliferative CMML, despite higher response rates observed with decitabine[ 37 ].

Active surveillance may be appropriate for asymptomatic patients with low-risk disease lacking adverse prognostic features[ 12 ]. Given the absence of standard-of-care targeted therapies, clinical trial enrollment is strongly encouraged to access investigational agents and evolving therapeutic combinations aimed at altering the disease course or improving outcomes[ 1 ].

Limitations

This report describes a single patient, so the findings may not generalize or prove cause and effect. The overlap of CMML and myeloma, along with comorbidities, creates a risk of diagnostic misclassification despite extensive testing. We did not perform clonal lineage tracing or detailed serial molecular monitoring, so we cannot show a shared progenitor or track clonal dynamics over time.

Clinical takeaway

This case highlights that severe monocytosis, cytopenias, hypercalcemia, renal dysfunction, and an elevated protein gap should prompt evaluation for coexisting CMML and plasma cell myeloma. Early recognition by primary care clinicians and a comprehensive diagnostic approach is thus essential. Management must balance cytoreduction, low-intensity myeloma therapy, supportive care, and infection prophylaxis, with multidisciplinary coordination to address renal, neurologic, and functional complications.

Conclusion

This case highlights the diagnostic and therapeutic complexity of overlapping hematologic malignancies – coexisting plasma cell myeloma and CMML in an elderly patient. Nonspecific symptoms, progressive cytopenia, hypercalcemia, and neurologic deficits required comprehensive evaluation through morphologic, immunophenotypic, cytogenetic, and molecular analyses, revealing both a clonal plasma cell population and CMML features. Management was challenged by cytopenia, renal dysfunction, and proliferative leukocytosis, necessitating individualized use of cytoreductive therapy, leukapheresis, and targeted anti-myeloma treatment. The case emphasizes the importance of a multidisciplinary approach and highlights the need for further research to clarify the pathogenesis, prognosis, and optimal management of dual hematologic malignancies.

Acknowledgements

Not applicable.

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Declaration of AI usage

AI was not used in the research and manuscript development.

Ethical approval

Not required for case report.

Consent

Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.

Sources of funding

None.

Author contributions

D.K.R.: analyzed and interpreted the data, conceptualization, investigations, visualization, supervision, writing – review and editing; K.B.: data curation, writing – original draft, writing – review and editing; A.P.: data curation, writing – original draft, writing – review and editing; J.A.: data curation, writing – original draft, writing – review and editing; A.U.: data curation, writing – original draft, writing – review and editing; A.C.: data curation, writing – original draft, writing – review and editing; A.W.R.: data curation, writing – original draft, writing – review and editing; Z.T.: data curation, writing – original draft, writing – review and editing; N.F.: data curation, writing – original draft, writing – review and editing. All authors read and approved the final manuscript.

Conflicts of interest disclosure

None.

Research registration unique identification number (UIN)

Not applicable to case-report.

Guarantor

All authors are the guarantors.

Provenance and peer review

Not commissioned; externally peer reviewed.

Data availability statement

Not applicable to case-report.

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