Ocular Manifestations of Multiple Myeloma

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Article initiated by:

Arjun V Jogimahanti, Subahari Raviskanthan, MBBS

All contributors:

Andrew Go Lee, MD, Peter W. Mortensen, MD, Nagham Al-Zubidi, MD, Subahari Raviskanthan, MBBS

Assigned editor:

Nagham Al-Zubidi, MD

Review:

Assigned status Up to Date

 by Nagham Al-Zubidi, MD on May 16, 2024.

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Contributing Editors:	add

Disease

Multiple myeloma (MM) is a hematologic neoplastic disorder that results from proliferation of malignant plasma cells. Plasma cells produce immunoglobulins (Ig), which are integral to the humoral immune response. In MM, there is abnormal proliferation of malignant plasma cells, leading to overproduction of specific Ig lineages. MM has multi-organ system manifestations and can present with multiple ocular symptoms and signs(including the eyelid, iris, cornea, retina, optic nerve and brain).

Pathophysiology

MM results from an uncontrolled proliferation of plasma cells. Normally, plasma cells are produced from B-lymphocytes, which produce Ig against infection. Ig contain two heavy chains and two light chains. There are five types of heavy chains: IgG, IgM, IgA, IgE or IgD. Depending on which plasma cell is proliferating, one of the five heavy chains will be overproduced. In multiple myeloma, IgG or IgA levels are usually elevated. The light chain can either be kappa or lambda. As MM progresses, the light chains are produced in excess relative to the heavy chains. The rate of change of the light chains as a whole as well the kappa to lambda ratio can be monitored to detect disease severity. Cytogenetic changes in MM include activation of oncogenes (e.g., cyclin D1 on chromosome 11q13, cyclin D3 on chromosome 6q21, and maf-B on chromosome 20q11)5 and translocation of one of these oncogenes to the Ig heavy chain locus (located on chromosome 14).5 In addition to the proliferative changes, over-expression of BCL-2 has been implicated in MM due to the resultant decrease in rates of apoptosis. The combination of these genetic abnormalities is responsible for nearly 90% of MM. There are two prominent hypotheses for the ocular manifestations of MM.The first mechanism is direct infiltration of the ocular tissues. Neoplastic infiltration of the surrounding orbital tissue can lead to the development of mass lesions. This can induce compression of the surrounding structures, leading to several of the pathologies indicated in Table 1. The second mechanism is hyperviscocity from elevated Ig. Gertz et al proposed that the primary determinant of viscosity levels in serum and plasma is protein (e.g., Ig) levels. Poiseuille’s Law states that resistance to flow in a pipe is directly proportional to the viscosity of the liquid in the pipe. When the viscosity of the blood rises beyond 4 centipoise, an ocular thrombotic event (e.g., central retinal vein occlusion) may occur.

Etiology

MM is a common hematological malignancy, accounting for nearly 10% of blood related malignancies. The median age of diagnosis is between 65-70 years. Ionizing radiation, benzene, and herbicides may increase the risk for MM.

Ocular Signs and Findings

Ophthalmic Symptoms: Ocular symptoms may include diplopia, pain or pressure in the eye, ptosis, proptosis, or loss of vision.

Ophthalmic signs: Table 1 below demonstrates previously reported signs grouped by anatomic region:

Anatomical Location	Signs	Findings
General Orbit	Proptosis Elevated Intraocular Pressure	Forwardly displaced eye. Possible Visual Disturbance Papillademea, Abducens (CN VI) Palsy
Eyelid	Bilateral Eyelid Ecchymosis Cutaneous Xanthomatosis	Easy bruising in the skin around the eyes Localized Lipid Deposits. Appear as yellowish papules, nodules, or plaques
Conjunctiva	Conjunctival Crystalline Deposits	Possible Visual Disturbance
Cornea	Corneal Deposits Subepithelial Amorphous Corneal Deposits	Possible Visual Disturbance Possible Visual Disturbance
Iris	Ciliary Body Cysts	Usually asymptomatic. Rarely cause visual disturbances.
Retina	Hyperviscosity Retinopathy Retinal Microaneurysms Retinal Detachment Central Retinal Vein Occlusion	Vision Loss and Blurred Vision are two most common findings. Painless, Progressive Loss of Vision Sudden, painless loss of vision. Can have floaters and flashes. Subacute, painless loss of vision. Can have a Relative Afferent Pupillary Defect (RAPD).

Diagnosis

Multiple Myeloma: Patients with MM may be asymptomatic. In the early stages of MM, a precursor condition known as monoclonal gammopathy of undetermined significance (MGUS) may be present. Constitutional symptoms may be absent (A) or present (B). These “B symptoms” of MM include fever, weight loss, headache, and fatigue. In more advanced stages of the disease, anemia and hypercalcemia are common. Renal involvement of the disease may present with light chain nephropathy, light chain amyloidosis, and light chain deposition disease. Patients with MM can have abnormalities in the following tests:

• Basic Metabolic Panel

• Complete Blood Count and Peripheral Blood Smear

• Serum Protein Electrophoresis (SPEP) and Immunofixation

• 24-hour urine collection for Electrophoresis (UPEP) and Immunofixation

• Bone Marrow Biopsy

• Skeletal Survey

Diagnostic Criteria:

• Clonal bone marrow plasma cells>10%

• Biopsy proven plasmacytoma

• Evidence of end organ damage attributable to underling plasma cell disorder:

• Serum Calcium> 11.5mg • Renal insufficiency: serum creatinine>2mg/dL and or

• Anemia: hemoglobin<10 g/dL or >2g/dL below lower limit of normal

• Bone Lesions: Lytic lesions, severe osteopenia, pathological gestures

• If no end organ damage, then clonal plasma cells> 60%

Differential diagnosis

• Smoldering Myeloma

• Monoclonal gammopathy of undetermined significance (MGUS)

• POEMS Syndrome

• Solitary Plasmacytomas

• Plasma Cell Leukemia

• Amyloid light chain (AL) Amyloidosis

General treatment

An ophthalmologist who suspects MM should refer the patient to a hematologist for further evaluation. While the hematologist is primarily responsible for the treatment plan, it is imperative that an ophthalmologist help co-manage the patient’s symptoms. Not only should the ophthalmologist treat the ocular symptoms, but also be familiar with the routine hematological labs and treatments associated with this condition. Asymptomatic cases of multiple myeloma may not require aggressive treatment. Generally, the patients who are candidates for treatment will be subdivided into a high-risk and low-risk patients based upon genetic predisposition to adverse outcomes. For patients who are not deemed high risk, twelve cycles of melphalan, prednisone, or thalidomide are initiated followed by observation. For those deemed to be at high risk, the general plan is a non-alkylator-based induction regimen for 2-4 cycles and subsequent evaluation for bone marrow transplantation. The following are commonly used drug combinations in MM:

• Lenalidomide with Low-Dose Dexamethasone

• Thalidomide with Dexamethasone

• Bortezomib with Dexamethasone

• Bortezomib, Thalidomide, and Dexamethasone

• Vincristine, Doxorubicin, Dexamethasone

Additionally, patients should be prophylactically treated for potential complications of hypercalcemia, skeletal diseases, and infections.

Prognosis

The median survival time of MM is nearly seven years with treatment. Major advances have occurred over the years and continue to help patient outcomes. Infections, due to lack of antigenic diversity of the produced antibodies, and renal failure are among the most common causes of mortality from the disease. Patients with isolated tumors have an overall better chance of survival.