Immunoglobulin D Multiple Myeloma - Symptoms, Diagnosis, and Treatment

Introduction

Plasma cells belong to a division of white blood cells that produce antibodies (immunoglobulins) to protect the body against infections. There are five types of heavy-chain immunoglobulins (Ig), namely, IgG, IgA, IgM, IgD, and IgE, and two light-chain variants (kappa and lambda). Malignancies of these plasma cells are termed multiple myeloma. In myeloma, there is excessive production of abnormal plasma cells in the bone marrow. These abnormal plasma cells produce the same types of antibodies, which are also called monoclonal proteins.

Multiple myeloma is classified according to the presence of M protein (monoclonal protein). IgG myeloma is the most common type, followed by IgA and light chain types. IgD multiple myeloma is a rare variant that is often missed in clinical practice due to a lack of scientific data. This article analyzes its clinical and laboratory findings, treatment strategies, and prognosis.

What Is Immunoglobulin D Multiple Myeloma?

Neoplastic growth and proliferation of plasma cells where a single clone producing only monoclonal immunoglobulin D (IgD) is termed immunoglobulin D multiple myeloma (IgD MM). IgD MM is a rare neoplasm that comprises only two percent of the total myeloma. IgD multiple myeloma is more prevalent in males than females, and it has been reported that young patients with an average age of 45 to 60 years are frequently affected by IgD MM. The predominant characteristics that differentiate IgD MM from other multiple myelomas are as follows,

• Rampant clinical course.

• Low frequency of occurrence.

• Increased incidence of renal failure.

• Increased prevalence in comparatively younger age groups.

• Failure to detect monoclonal proteins (due to decreased size or absence).

• Shorter median survival duration (18 to 24 months).

• Extremely poor prognosis.

What Are the Clinical Manifestations of IgD Multiple Myeloma?

Clinically patients report symptoms related to renal, cardiac, and hepatic dysfunctions. Individuals with IgD multiple myeloma (72 percent) experience severe bone pain and frequent fractures due to the increased activity of osteoclasts (cells that cause bone degradation). Reports suggest that nearly six percent of patients remain asymptomatic.

• Renal failure.

• Hypercalcemia (increased serum calcium levels in the blood due to osteoclastic activity).

• Bone pain (bones of the extremities and spine).

• Amyloidosis (deposition of abnormal proteins in the kidney, liver, and spleen).

• Weakness and fatigue.

• Extramedullary plasmacytoma (proliferation of abnormal plasma cells outside the bone marrow).

• Nerve root compression and extradural tumor (due to extramedullary tumor growth).

• Weight loss.

• Extraosseous lesions.

• Hepatomegaly (enlargement of the liver).

• Carpal tunnel syndrome (compression of nerves in wrists).

• Generalized lymphadenopathy.

• Hepatosplenomegaly.

• Macroglossia.

• Peripheral edema.

• Peripheral neuropathy (numbness of the skin and tingling sensation in hands and legs).

• Immunological deficiencies (prone to infections).

How Is IgD Multiple Myeloma Diagnosed?

The diagnostic challenges of IgD multiple myeloma are due to the rarity of the disease and limited scientific literature sources. However, clinicians and scientists are able to develop advanced diagnostic protocols through case reports and studies conducted in certain healthcare facilities. Detection of IgD MM is challenging since the IgD concentration is very minimal and escapes serum electrophoresis. The diagnostic criteria for IgD MM include the following strategies,

• Detection of increased abnormal plasma cells in the bone marrow or extramedullary sites (plasmacytoma).

• Presence of IgD monoclonal protein (M protein component) in the serum (with or without light-chain proteinemia or Bence Jones proteinuria).

• Osteolytic lesions and associated symptoms derived from plasma-cell proliferation.

Laboratory Findings - This includes complete blood count (CBC) and biochemical panel.

• Elevated creatinine value ( greater than 2.0 mg/dL) due to renal failure.

• Beta-2-microglobulin level (greater than six ng/mL).

• Serum protein electrophoresis to detect all the components of plasma proteins and to identify abnormal proteins produced in IgD MM.

• The serum monoclonal protein component is elevated (characteristic feature), showing a protein spike.

• Urinary protein and urinary monoclonal protein components are detected through immunoelectrophoresis.

• Patients with IgD MM have significantly increased urine M-protein excretion, serum creatinine levels, and serum calcium values which is a striking diagnostic feature that distinguishes IgD MM from other myelomas.

Bone Imaging Tests - These tests detect pathologies in the bone and also identify areas of myeloma activity.

• Conventional Bone X-Rays - Detect bone fractures and diffuse patches of osteolytic lesions.

• Bone Surveys - Help to identify asymptomatic areas of osteoclastic activities and help to diagnose underlying myeloma.

• Magnetic Resonance Imaging (MRI) - It is the most sensitive imaging technique to identify myeloma lesions and forthcoming fractures.

• Positron Emission Tomography (PET) - PET scanning is a nuclear medicine scanning technique where minuscule amounts of radioactively-labeled sugar are used to identify plasma cell tumors in the bones. It is sensitive and identifies responses to treatment and relapses. Its added advantage is that the entire bone system is analyzed.

Histopathological Findings

• Bone marrow aspirations and biopsies are examined to detect abnormal plasma cells and extramedullary involvement.

• Hematoxylin and Eosin-Stained Bone Marrow Biopsy - Show an increased number of plasma cells with interstitial distribution in cluster or sheet formations.

• CD138 Immunohistochemistry - Staining of bone marrow shows up to 90 percent interstitial infiltration by plasma cells.

• Flow Cytometry - It is performed to confirm the plasma cell percentage with total white blood cells.

• Chromosome analysis by cytogenetic techniques to detect abnormalities.

• FISH (fluorescence in situ hybridization) analysis of the bone marrow to help to assess the prognosis.

• Bone marrow aspirate sample is also stored in a tissue bank for further analysis and invention of novel treatment modalities.

What Are the Treatment Modalities of IgD Multiple Myeloma?

In recent decades, the development and use of novel therapeutics such as proteasome inhibitors and immunomodulatory agents in the treatment of IgD MM have resulted in a 50 percent increase in survival rate and better prognosis. The therapeutic interventions for IgD multiple myeloma include the following,

• Autologous stem cell transplantation (ASCT) is the cornerstone for IgD MM therapy.

• Drugs like Bortezomib (proteasome inhibitor) and Lenalidomide (immunomodulatory agent) are effective when combined with autologous hematopoietic stem cell transplantation (ASCT).

• Combination chemotherapy like Vincristine, Carmustine, Melphalan, Cyclophosphamide, and Prednisone with interferon alfa-2.

• Melphalan and Cyclophosphamide with Doxorubicin are used to achieve a better response.

• The anti-CD38 monoclonal antibody, Daratumumab, in combination with Dexamethasone, acts as a proteasome inhibitor and an immunomodulatory agent.

• Subcutaneous Daratumumab is administered in combination with Hyaluronidase.

• Anti-B-cell maturation antigen (BCMA) and a humanized immunoglobulin G antibody conjugated with microtubular disrupting agent monomethyl auristatin are used as an immunomodulator.

• Ciltacabtagene autoleucel (chimeric antigen receptor T-cell therapy) produces long-lasting and durable responses.

• Improved outcomes are reported in patients with IgD MM when treated with high-dose chemotherapy followed by ASCT.

What Is the Prognosis of IgD Multiple Myeloma?

The outcome of IgD multiple myeloma is improving with the use of new immunomodulators and ASCT in spite of its overall survival (OS) being lesser when compared with other myeloma types.

• Extramedullary disease progression, heart failure, and renal insufficiency are the major causes associated with poor prognosis.

• A complete response to therapy favors longer remission rates and increases overall survival percentage.

• Minimal residual disease (MRD) assessment is a sensitive cell-based sequencing assay done to detect the presence of any residual IgD myeloma cells in individuals who have reached complete remission.

Conclusion

Immunoglobulin D multiple myeloma is an aggressive neoplastic disease that usually faces diagnostic difficulties due to its rare occurrence. Specific laboratory diagnosis for IgD immunoglobulin component helps in early diagnosis. Intensive combination treatment strategies, which include chemotherapy, stem cell transplantation, and the use of novel immunomodulators, increase overall survival and improve treatment outcomes.