A Rare Presentation of Multiple Myeloma as a Second Primary Cancer Sequential to Non-Hodgkin Lymphoma: Case Report.

Introduction

Diffuse large B-cell lymphoma (DLBCL) is the most common and aggressive subtype of non-Hodgkin lymphoma (NHL) arising from B-lymphocytes. It commonly presents with painless swelling of the lymph nodes, fever, night sweats, unexplained weight loss (B symptoms), and fatigue. Organ-specific symptoms such as pain abdomen (in case of gastrointestinal involvement) or neurological issues (if CNS is affected) can also occur. The standard treatment regimen for DLBCL is R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), which is usually effective for most patients. For high-risk or relapsed cases, more intensive therapies like R-EPOCH, CAR-T cell therapy or stem cell transplantation are used.

Patients treated for NHL have a significantly higher risk of developing second primary malignancies (SPMs), with an overall increased risk of 47% [ 1 ]. This evidence aligns with prior large-scale population studies. A Swedish registry-based analysis reported an incidence rate of 20.6 per 1,000 person-years for SPMs among NHL survivors, with multiple myeloma (MM) occurring at a lower incidence of 0.2 per 1,000 person-years and no significant elevation in risk (HR = 1.0; 95% CI: 0.7–1.4) [ 2 ]. Similarly, an Israeli national cohort study observed that 8.5% of NHL survivors developed SPMs. MM comprised 14% of all secondary hematological malignancies and contributed to an elevated standardized incidence ratio of 1.97 in men and 1.81 in women [ 3 ]. These findings reinforce the importance of long-term surveillance among NHL survivors, particularly for hematological malignancies such as MM.

Survivors of NHL including those treated with contemporary therapies such as anti-CD20 monoclonal antibodies (e.g., rituximab, obinutuzumab, ofatumumab) face the elevated risk of developing SPMs [ 4 , 5 ]. Evidence indicates that NHL patients treated with anti-CD20 therapies particularly rituximab, may have an increased risk for SPMs encompassing both solid tumors and hematologic malignancies viz. myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). While the mechanisms underlying this potential risk commands further probing, the contributing factors which were weighed include immunosuppression, damage to DNA and persistent lymphopenia. However, there are no conclusive studies establishing a direct link between rituximab and the development of SPMs [ 5 ].

MM is a malignant plasma cell disorder characterized by clonal expansion of plasma cells in the bone marrow, further causing the production of abnormal monoclonal immunoglobulins. MM presents with varied clinical manifestations, such as bone pain, anemia, and renal impairment. It is an incurable condition but can be managed with a combination of chemotherapy, immunotherapy, and stem cell transplantation.

NHL and MM are distinct B-cell-derived hematological malignancies with differing pathophysiological issues and clinical presentation. NHL particularly in its aggressive forms such as DLBCL, typically presents as a systemic lymphoproliferative disorder characterized by painless lymphadenopathy, and is often accompanied by constitutional “B” symptoms including fever, night sweats and unintentional weight loss [ 6 ]. Extra nodal involvement may also occur affecting the gastrointestinal tract, central nervous system, and/or bone marrow. In contrast, MM is a plasma cell malignancy primarily associated with monoclonal protein production and a clinical profile dominated by the CRAB features: hypercalcemia, renal impairment, anemia, and bone lesions. The bone lesions could manifest as bone pain, pathologic fractures, and vertebral collapse. Features such as recurrent infections and symptoms of hyperviscosity are also seen, given the immune dysfunction and high circulating paraprotein levels [ 7 ].

The sequential occurrence of these malignancies in the same patient is a rare phenomenon, and adds complexity to the diagnosis and management. This progression highlights the need for careful long-term monitoring and tailored therapeutic strategies, making this case a valuable addition to the literature. This case report highlights the clinical progression from NHL to the occurrence of MM in a patient, delineating the intricacies of diagnosis, treatment options, and the challenges posed by the evolving trajectory of the disease. The CARE checklist has been completed by the authors for this case report, which is attached as online supplementary material at https://doi.org/10.1159/000548795 .

Case Presentation

During November 2022, a 60-year-old male with a past history of hypertension for 20 years presented at Sammprada hospital, Bangalore, India, with complaints of fatigue since 2 months. Other complaints include shoulder pain, abdominal discomfort, anorexia, constipation, dry mouth, and feeling depressed. His medical history includes the diagnosis of DLBCL (stage-4 NHL) during 2015, for which he underwent 4 cycles of RVP and 8 cycles of R-CHOP chemotherapy regimens, followed by an autologous bone marrow transplantation during 2016. His surgical history includes a splenectomy and laparotomy performed during 2015 for the diagnosis of DLBCL. Additionally, he was diagnosed with tuberculosis during 2021 which was associated with lymphadenopathy and was managed with an 8-month course of anti-tubercular therapy (ATT).

Following investigations, the patient was found to have normocytic, normochromic anemia, thrombocytopenia, and leukocytosis with neutrophilia. Additionally, total protein and globulin levels were elevated with a low A/G ratio, which probably suggested a hematological disorder. The patient also presented with hypokalemia, hyperchloremia, hyperphosphatemia, hypercalcemia, elevated BUN, and serum creatinine, a low eGFR and hyperuricemia which indicates renal dysfunction, cumulatively rising the concern for tumor lysis syndrome. Further investigations done for establishing a definitive diagnosis include bone marrow biopsy, serum protein electrophoresis and imaging studies as depicted in Figure 1 .

The blood investigations revealed an elevated beta-2 microglobulin, kappa-free light chain, lambda-free light chain and significantly increased IgG levels as shown in Figure 2 . The bone marrow aspiration revealed normocytic, normochromic red blood cells, neutrophilic leukocytosis, and platelet clumps with giant platelets. Additionally, 14% plasma cells were noted. Based on the laboratory findings such as elevated beta-2 microglobulin, free light chains, IgG levels, plasma cell infiltration of the bone marrow, the associated renal dysfunction along with the radiologic findings, the patient was diagnosed with MM. Immunohistochemistry findings confirmed the plasma cell lineage as positive for CD138 and CD38. Light chain analysis showed negative staining for kappa and a strong positive staining for lambda which indicates a monoclonal, lambda-restricted plasma cell population. Table 1 represents the key laboratory investigations during November 2022 with observed values and their normal range, which eventually enabled the diagnosis of MM in this case.

Clinical Management

The patient had a 20-year history of hypertension, managed with a combination of telmisartan 40 mg and amlodipine 5 mg. In October 2015, the patient was diagnosed with DLBCL [ 7 ] following symptoms of fever, weight loss, and night sweats. Subsequent to splenectomy and laparotomy the diagnosis was confirmed as stage-4 NHL.

Initially, the patient received 4 cycles of rituximab 375 mg/m 2 , vincristine 1.4 mg/m 2 , prednisolone 60 mg/m 2 (RVP) but due to an inadequate response, the treatment was escalated to 8 cycles of the more intensive R-CHOP regimen (rituximab 375 mg/m 2 , cyclophosphamide 750 mg/m 2 , doxorubicin 50 mg/m 2 , vincristine 1.4 mg/m 2 , and prednisolone 60 mg/m 2 ). Following the completion of 8 cycles of R-CHOP regimen, the patient was found to achieve near complete remission. Subsequent PET-CT scan showed 1 lymph node area of residual disease. During August 2016, he underwent an autologous stem cell transplant (ASCT) for consolidating the remission and reducing the risk of relapse. After ASCT, the patient reached complete metabolic response and repeat PET-CT scan was normal. After NHL, the flow cytometry analysis of bone marrow biopsy did not show any observable clone of plasma cells ( Fig. 3 ).

The patient remained asymptomatic and in good health for 5 years, until the onset of new symptoms during November 2021. A clinical evaluation revealed enlarged lymph nodes, which prompted further investigation. A fine-needle aspiration cytology and subsequent biopsy of the lymph nodes confirmed the diagnosis as tubercular lymphadenopathy. The patient completed an 8-month course of ATT and was successfully cured of the infection. The onset of TB is a reflection of the underlying subtle immunosuppression related to NHL, chemotherapy, and transplantation.

During November 2022, the patient again presented with complaints of fatigue, bone pain, and weight loss since 2 months. The diagnosis of stage 3 MM was confirmed through key biomarkers, such as elevated beta-2 microglobulin (13.07 mg/L), free light chains (kappa: 43.35 mg/L, lambda: 7,500.00 mg/L), and increased IgG levels (7,813.86 mg/dL) as mapped in Figure 4 . A bone marrow biopsy showed 14% plasma cells, while imaging revealed osteolytic lesions and vertebral collapse which confirmed the advanced stage of disease. Classical karyotyping was not done. FISH analysis showed t (4,14) and it was not complex. Next generation sequencing (NGS) showed p53 mutation. Since electrophoresis was not performed during the course of treatment for NHL, we could not study the presence of monoclonal gammopathy of undetermined significance which could antecede MM. Following the diagnosis of MM [ 8 ] and the comorbid renal impairment of the patient as displayed in Figure 5 , the treatment regimen was formulated for six cycles. Molecular diagnostic tests for c-mic, CD 10, CD 2, CD 6 were done, but no cytogenetic studies were conducted.

Table 2 summarizes the chemotherapy regimen which includes three drugs for the first three cycles. In each cycle, the drugs were administered once weekly on days 1, 8, and 15 of each 21-day cycle, with a 7-day gap between doses. From the fourth cycle onwards, cyclophosphamide was changed to lenalidomide, and the six cycle regimen was completed. A customized approach was adopted for managing the drug regimen and dosage, with an intent to balance the efficacy of treatment and toxicity management.

Although the use of an anti-CD38 antibody was considered, it was deemed too expensive. Given the patient's renal dysfunction, immunomodulators were not currently indicated with a future plan to add either lenalidomide or pomalidomide following an improvement in the condition. Additionally, supplementary drugs such as erythropoietin and albumin were provided, and denosumab was included for managing the osteolytic lesions.

From the fourth cycle onwards, a new drug lenalidomide (25 mg) was added in response to the improvement in renal function. The dosage was adjusted in each cycle according to the response and tolerance of the patient. This tailored approach was aimed to optimize therapeutic outcomes while minimizing toxicity. The course of treatment was uneventful, with consistent monitoring for therapeutic response and adverse events. The patient was initiated on maintenance therapy, following the successful completion of chemotherapy and the ensued positive response. This includes lenalidomide 10 mg once daily, with the goal of prolonging remission and reducing the risk of relapse. In addition, denosumab 120 mg was recommended every 3 months for supporting the bone health and preventing skeletal-related complications.

Clinical profiling indicates a partial remission by July 2023, which progressed to complete remission by January 2024 as reflected by the stabilized biomarkers and clear radiological imaging [ 9 ]. Notably, the M protein (computed using IgG level) showed a reduction of approximately 80.03% which reflects a good therapeutic response. The patient is currently undergoing fracture management and radiation therapy as part of the treatment plan for addressing the skeletal complications and supporting the process of recovery.

Table 3 lists the monoclonal gammopathy of heavy chain IgG and an increase in light chains (kappa, lambda). Hypogammaglobulinemia is a result of suppressed polyclonal immunoglobulins (IgA, IgM) which in-turn predisposes the patient to infections. Given his previous history of cancer, a significant challenge in this patient was resistance to chemotherapy. For both the cancers, steroids were used in the treatment regimen which led to potential side effects. The chronic nature of MM coupled with frequent hospital visits and the associated risk of infection as well as an uncertain prognosis contributes to the significant psychological distress encompassing anxiety and emotional fatigue. These challenges underscore the complexities of managing MM in patients with a history of other cancers.

Discussion

This case illustrates the rare occurrence of MM as a second hematological malignancy post remission from DLBCL. The occurrence of SPMs in NHL survivors, particularly hematological malignancies, is well-documented and can be attributed to risk factors, such as chemotherapy and cumulative exposure, radiation therapy, older age, and genetic predisposition [ 1 , 4 , 5 ]. However, the progression to MM a distinct plasma cell disorder remains exceedingly rare. Identifying dual hematological malignancies requires careful evaluation due to the overlapping clinical features and their infrequent occurrence. Advanced diagnostics, such as cytogenetic studies, molecular studies, and clonality assessment, are pivotal in distinguishing these conditions.

This phenomenon may be influenced by a complex interplay of genetic and immunological factors [ 10 ]. Both NHL and MM arise from the B-cell lineage, although at different stages of maturation: NHL typically originates from mature B-lymphocytes within lymphatic tissues, whereas MM arises from terminally differentiated plasma cells in the bone marrow. This shared lineage raises the possibility of a common clonal origin at an earlier progenitor stage, which might over a period of time evolve into separate malignancies due to additional oncogenic events. The contributing factors may include preexisting clonal hematopoiesis, somatic genetic mutations, immune dysregulation, alteration in key cellular pathways regulating survival, proliferation, and signaling [ 2 ]. These interconnected mechanisms underscore the biological plausibility of sequential B-cell neoplasms arising in the same individual.

Zhao et al. [ 11 ] conducted a retrospective study analyzing the incidence and survival outcomes of MM as a SPM. Their findings indicate that MM accounts for 2% of SPM, with the affected patients experiencing significantly shorter survival compared to those with primary MM. The study also emphasized that treatment-related factors such as chemotherapy and immunomodulatory agents like lenalidomide contribute to the increased risk of developing MM as a SPM. Furthermore, genetic susceptibility, aging and improved overall survival following treatment of the primary cancer foster the rising incidence of SPM. These findings mandate the need for long-term surveillance and tailored therapeutic strategies for mitigating the risk of SPM in cancer patients.

Mahindra et al. [ 12 ] analyzed the biological relationship in a series of 7 patients with B-cell lymphoma and MM and concluded the biological independence of the two malignancies which conform to their distinct clonal origins. This was confirmed by clonality analysis, which proved that the SPM was not a result of transformation of the original tumor but an independent development [ 11 ]. These findings emphasize the complexity of B-cell malignancies and highlight the need for further research into genetic and environmental factors predisposing patients to multiple B-cell neoplasms.

Almeida et al. [ 13 ] describe the case of a 68-year-old woman who developed sequential MM following untreated B-cell NHL. Sequential changes observed in flow cytometry analysis of bone marrow biopsy suggested disease progression, with lymphoma cells differentiating into plasma cells eventually leading to plasmacytoma in the absence of therapy. Notably, a pathogenic TP53 variant (p.Leu188Trpfs*59) was identified which is associated with a poor prognosis in hematological malignancies. However, molecular evidence did not support the hypothesis that MM developed from NHL cells indicating that the two tumors arose independently [ 13 ].

The recognized risk factors for secondary hematological malignancies include prior chemotherapy and radiotherapy for NHL, while another established contributor is high-dose cytoreductive chemotherapy followed by ASCT [ 14 ]. In addition, procedures such as splenectomy and therapies such as rituximab or radioimmunotherapy with zevalin (ibritumomab tiuxetan) have also been significantly associated with an increased risk of developing MM as a SPM [ 3 ]. In the current case, rituximab was used in the treatment of NHL and evidence indicates its association with prolonged B-cell depletion and suppression of T-cell function. This immunosuppressive effect has been implicated in increasing the risk of SPM particularly hematological cancers [ 2 ].

A well-recognized mechanism for the development of secondary malignancies includes DNA damage induced by chemotherapy and radiotherapy. Additionally, T-cell suppression resulting from cytotoxic chemotherapy and corticosteroid use are known risk factors for increased susceptibility to the development of successive cancers. The present case report aligns with many of these findings and elucidates the need for long-term surveillance in survivors of lymphoma. The potential influence of surveillance bias toward the early detection of SPM should be considered, as it could be facilitated by extensive medical investigations and frequent health evaluations which follow the initial diagnosis and treatment of the primary malignancy.

Evidence shows the significantly poor survival among patients with MM occurring as a SPM compared to those with unique MM. Zhao et al.’s [ 11 ] retrospective cohort study from china reports a median overall survival (OS) of 24.5 months among patients with MM as a SPM, compared with 46.5 months among those without additional malignancies ( p = 0.04). Munker et al.’s [ 15 ] study reports that 14.7% of patients with MM had a preexisting cancer. The overall median survival of patients with MM without prior malignancy was 36.5 months when compared with 21.4 months for patients in whom MM succeeded the development of different cancers ( p ≤ 0.044). These observations indicate the potential impact of prior malignancies on the disease biology, tolerance to treatment and overall prognosis, thus reinforcing the need for an integrated care approach and early recognition of MM in cancer survivors.

This patient faced increased risk of infections such as pneumonia, herpes zoster and influenza which are commonly seen in MM due to the immune suppression (both due to the disease and its treatment). Additionally, B-cell deficiency and hypogammaglobulinemia tend to compromise the immune function rendering the patient more susceptible to infections [ 16 ]. The succession of MM after NHL in this case is rare but clinically significant, and its recognition is essential for optimizing patient management. This narrative highlights the importance of continuous monitoring, early detection and personalized treatment strategies for improving the outcomes in patients at risk of secondary hematological malignancies.

In the present case, the exact cause for the development of MM following remission of NHL is unclear. However, the likely combination of factors includes an aggressive treatment regimen, immunosuppression, and possible environmental exposures such as radiation, infection, and dietary factors, which might have contributed to the emergence of the second malignancy. Given the cost limitations, investigations such as clonality analysis have not been performed. Despite this, there is no definitive evidence to support a direct transformation of NHL cells to MM. The precise mechanisms linking these two malignancies are still not fully understood.

Conclusion

The case report annotates the diagnostic and therapeutic challenges associated with managing B-cell NHL and MM in-succession. It emphasizes the clinical and therapeutic challenges posed by sequential hematological malignancies and underscores the necessity for a thorough diagnostic approach. The report offers valuable clinical, pathophysiological, and molecular perspectives which contribute to a deeper understanding of the mechanisms underlying the co-occurrence of distinct B-cell neoplasms. Further research should explore the genetic, immune and environmental factors which predispose the development of multiple B-cell neoplasms, as well as investigate the potential biomarkers or pathways which assist in predicting or preventing such an occurrence.

Statement of Ethics

This study protocol was reviewed and the need for approval was waived by Sammprada hospital ethics committee. Written informed consent was obtained from the patient for publication of this case report and any accompanying images.

Conflict of Interest Statement

The authors declare that they have no conflict of interests.

Funding Sources

Funding support: Gangadhar R, Kaptronics pvt ltd, Bannerghatta road, Bangalore, India.

Author Contributions

P.G. drafted the initial version of the manuscript; G.D.V. revised the manuscript; V.R. revised the case report and presented the information in a critical manner; R.N. treated the patient and supervised the case report.

Data Availability Statement

The data that support the findings of this study are not publicly available due to privacy reasons but are available by emailing the corresponding author upon reasonable request.

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