Introduction
Multiple myeloma (MM) is a plasma cell neoplasm, which is a terminally differentiated, mature B cell lineage neoplasm. Symptomatic MM requires therapy, which usually includes induction therapy with corticosteroids, proteasome inhibitors, and immunomodulatory drugs, followed by stem cell transplant and lenalidomide maintenance therapy. While treatment often leads to remission in MM, it is also associated with an increased risk of secondary hematologic malignancies. The majority of secondary malignancies following MM therapy are myeloid neoplasms, including acute myeloid leukemia and myelodysplastic syndrome. However, therapy-related B-lymphoblastic leukemia (B-ALL) has been increasingly recognized in recent years. Previous studies have suggested that therapy-related B-ALL occurs as an adverse effect of lenalidomide, a common myeloma maintenance therapy.1,2 Herein, we present a patient with treated MM who developed B-ALL with unusual surface light chain expression, a potential diagnostic pitfall. Cytogenetic and molecular studies indicated that the antecedent MM and B-ALL are clonally unrelated. These findings expand our knowledge of therapy-related B-ALL, a potentially emerging disease entity.
Case presentation
The patient was a 65-year-old male who presented with fatigue and fever. Complete blood count showed hemoglobin 11.0 g/dL, white blood cell 3.7 × 109/L, and platelet 88 × 109/L. He had a history of IgG lambda MM (Fig. 1), diagnosed three years prior to the current presentation. The myeloma was hyperdiploid with trisomy 17, classified as a standard-risk category at the time of diagnosis. The patient had received lenalidomide/bortezomib/dexamethasone chemotherapy, followed by an autologous stem cell transplant and monthly subcutaneous daratumumab/lenalidomide/dexamethasone therapy. His myeloma was well controlled, with low copies on the ClonoSEQ MRD (minimal residual disease) test (41 residual clonal cells per million nucleated cells). A bone marrow evaluation was performed and demonstrated sheets of blasts (Fig. 2). Flow cytometric immunophenotypic analysis showed the blasts were positive for CD19, CD22, CD79a, CD20 (small subset), CD10 (small subset), CD33 (subset), HLA-DR (not shown), CD123, TDT, and surface kappa light chain; negative for CD34, cytoplasmic myeloperoxidase, and all tested T-cell markers (Fig. 3). Additional immunohistochemical stains demonstrated that the blasts were positive for MYC and BCL-2, and negative for BCL6, MUM1, and Epstein-Barr virus in situ hybridization (Fig. 4). A repeated flow cytometric analysis on day 20 (pre-treatment), post-initial diagnosis, showed persistent surface kappa light chain expression in the blasts (Fig. 5). Additional ancillary studies were performed to further characterize the disease. A karyotyping study showed a normal male karyotype 46,XY[20], lacking hyperdiploid/trisomy 17, which had been identified in the preceding myeloma. Flurorescence In Situ Hybridization analyses revealed no evidence of common recurrent genetic abnormalities seen in B-ALL or rearrangement of MYC, BCL2/BCL6. Next-generation sequencing demonstrated two pathogenic mutations: KDM6A: p. Asn839Valfs*27 (variant allele frequency 64%) and KRAS: p. Gly12Asp (variant allele frequency 33%). ClonoSEQ MRD analysis revealed three dominant immunoglobulin sequences (2 IgH, 1 IgK) in 46–59% of total marrow cells. These clones were different from the dominant clone identified in the antecedent myeloma. In addition, a low level of antecedent myeloma dominant clonal sequences was identified (10 residual clonal cells per million nucleated cells). A diagnosis of B-lymphoblastic leukemia/lymphoma with unusual surface kappa light chain expression in a patient with previous myeloma treatment was made.
The patient was treated with mini hyper-CVAD (cyclophosphamide, vincristine sulfate, adriamycin and dexamethasone) + inotuzumab, followed by an allogeneic stem cell transplant. He has been in remission for approximately eight months after the completion of chemotherapy, with negative flow cytometric MRD studies for both B-ALL and myeloma.
Discussion
The patient received chemotherapy for MM and developed B-ALL three years after the diagnosis/treatment of myeloma. Therefore, it can be categorized as therapy-related B-ALL. Although therapy-related B-ALL has not been officially recognized by the World Health Organization (WHO) hematologic malignancy classification, previous studies indicate that there is an increased risk of B-ALL in patients receiving myeloma treatment, and the majority of these patients received a lenalidomide-containing regimen as induction, maintenance, or in combination with other agents.1–4 Parrondo et al.2 demonstrated that the median time to develop therapy-related B-ALL following lenalidomide maintenance was 61.2 months (range 16.9–123.4), which is significantly shorter than therapy-related B-ALL after non-myeloma treatment. Therefore, it is suggested that lenalidomide treatment is a risk factor for the development of secondary B-ALL in patients with myeloma. It is known that lenalidomide can cause the degradation of the transcription factor IKAROS, a product of the IKFZ1 gene. An IKFZ1 abnormality is considered one of the genetic drivers in B-ALL leukemogenesis.5 It has been hypothesized that lenalidomide-induced dysregulation of IKZF1 facilitates the development of therapy-related B-ALL. The time frame and treatment that the current patient received are in line with the diagnosis of therapy-related B-ALL. Previous studies also suggest that B-ALL and antecedent myeloma are clonally unrelated. Aldoss et al.6 analyzed six paired samples of B-ALL and antecedent myeloma using whole exome sequencing. A comprehensive somatic mutation and copy number alteration analysis showed that the two neoplasms were clonally unrelated. The present case used a different approach to address the clonal relationship. ClonoSEQ analysis of unique dominant clonal sequences was performed on the B-ALL and antecedent myeloma samples. It was found that the two neoplasms had different sets of dominant clones, indicating that B-ALL and the antecedent myeloma were clonally unrelated. Since ClonoSEQ is routinely performed on myeloma patients at certain medical centers, the identification of new dominant clones, in the absence of immunophenotypic or morphologic evidence of monotypic plasma cells, may suggest the emergence of a secondary B-cell neoplasm, such as B-ALL.
Another interesting observation is that the B-lymphoblasts showed surface light chain restriction. Surface immunoglobulin light chain restriction is usually a feature of mature B-cell neoplasms. Additionally, the blasts showed expression of MYC and BCL2. Therefore, a differential diagnosis of high-grade B-cell lymphoma with MYC/BCL2 translocation was raised. Although surface light chain expression in B-ALL is rare, it has been reported in the literature. Kansal et al.7 reported fifteen cases of B-ALL with surface light chain restriction, including both children and adults. The blasts can arise from the early, intermediate, and late stages of precursor B-cells and harbor variable cytogenetic abnormalities, with the exception of MYC rearrangement. Similar cases have been reported by others.8,9 Therefore, surface light chain expression alone cannot be used as a criterion for excluding B-ALL. In addition, Flurorescence In Situ Hybridization analysis in the current case showed no evidence of MYC or BCL2 rearrangements. Therefore, a diagnosis of high-grade B-cell lymphoma with MYC/BCL-2 rearrangement was excluded. The patient has been on monthly daratumumab treatment. Since daratumumab is an IgG kappa monoclonal antibody, the possibility of artifactual surface kappa light chain expression in blasts due to the binding of daratumumab is raised. A repeated flow cytometric analysis was performed twenty days after the initial diagnosis, and the demonstrated blast population showed surface kappa light chain expression with a higher mean fluorescence intensity (2,866) compared to the initial diagnosis (1,616). This result favors true surface light chain expression by the blasts, given that the subcutaneous daratumumab has a half-life of 20 days.
Conclusions
In summary, we present an interesting case of B-lymphoblastic leukemia with unusual surface light chain expression in a patient who has previously undergone myeloma treatment. This case represents therapy-related B-ALL. Although it has not been categorized as a WHO-recognized disease entity, our case provides additional evidence supporting that myeloma treatment, particularly lenalidomide therapy, is associated with secondary B-ALL. Furthermore, the ClonoSEQ test result in the current case indicates that therapy-related B-ALL is clonally unrelated to the preceding MM. The identification of new predominant clones in follow-up bone marrow samples of myeloma patients should alert clinicians to the possible emergence of a secondary B-cell neoplasm.
Declarations
Ethical statements
The study was performed following the ethical standards of the institutions to which we are affiliated and in accordance with the Declaration of Helsinki (as revised in 2013). Written informed consent was obtained from the patient for the publication of this case report.
Data sharing statement
As a case report, all data generated or analyzed are included in this article.
Funding
None.
Conflict of interest
The manuscript was submitted during Dr. Zhou’s term as an editorial board member of the Journal of Clinical and Translational Pathology. The authors have no other conflicts of interest to declare.
Authors’ contributions
Study design (JZ), data collection (AJC, JZ), manuscript drafting (AJC, TEI, JZ), and editing (AJC, TEI, JZ). All authors made significant contributions to this study and have approved the final manuscript.