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


Disease

Multiple myeloma (MM) is a hematologic neoplastic disorder that results from proliferation of malignant plasma cells[1]. Plasma cells produce immunoglobulins (Ig), which are integral to the humoral immune response[1]. In MM, there is abnormal proliferation of malignant plasma cells, leading to overproduction of specific Ig lineages[1]. MM has multi-organ system manifestations and can present with multiple ocular symptoms and signs[2](including the eyelid, iris, cornea, retina, optic nerve and brain[3]).

Pathophysiology

MM results from an uncontrolled proliferation of plasma cells[1]. Normally, plasma cells are produced from B-lymphocytes, which produce Ig against infection[4]. Ig contain two heavy chains and two light chains[4]. There are five types of heavy chains: IgG, IgM, IgA, IgE or IgD[4]. Depending on which plasma cell is proliferating, one of the five heavy chains will be overproduced[1]. In multiple myeloma, IgG or IgA levels are usually elevated[1]. The light chain can either be kappa or lambda[1]. As MM progresses, the light chains are produced in excess relative to the heavy chains[1]. 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[1]. 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[5]. The combination of these genetic abnormalities is responsible for nearly 90% of MM[5]. There are two prominent hypotheses for the ocular manifestations of MM[6].The first mechanism is direct infiltration of the ocular tissues[6]. Neoplastic infiltration of the surrounding orbital tissue can lead to the development of mass lesions[6]. This can induce compression of the surrounding structures, leading to several of the pathologies indicated in Table 1[6]. The second mechanism is hyperviscocity from elevated Ig[6]. Gertz et al proposed that the primary determinant of viscosity levels in serum and plasma is protein (e.g., Ig) levels[2]. Poiseuille’s Law states that resistance to flow in a pipe is directly proportional to the viscosity of the liquid in the pipe[7]. When the viscosity of the blood rises beyond 4 centipoise, an ocular thrombotic event (e.g., central retinal vein occlusion) may occur[8].

Etiology

MM is a common hematological malignancy, accounting for nearly 10% of blood related malignancies[5]. The median age of diagnosis is between 65-70 years[5]. Ionizing radiation, benzene, and herbicides may increase the risk for MM[5].

Ocular Signs and Findings

Ophthalmic Symptoms: Ocular symptoms may include diplopia, pain or pressure in the eye, ptosis, proptosis, or loss of vision[6].

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

Anatomical Location Signs Findings
General Orbit
Proptosis

Elevated Intraocular Pressure[6]

Forwardly displaced eye. Possible Visual Disturbance[9]

Papillademea, Abducens (CN VI) Palsy[10]

Eyelid
Bilateral Eyelid Ecchymosis[6]

Cutaneous Xanthomatosis[6]

Easy bruising in the skin around the eyes[11]

Localized Lipid Deposits. Appear as yellowish papules, nodules, or plaques[12]

Conjunctiva Conjunctival Crystalline Deposits[6]
  1. Possible Visual Disturbance[13]
Cornea Corneal Deposits[6]

Subepithelial Amorphous Corneal Deposits[6]

Possible Visual Disturbance[13]

Possible Visual Disturbance[13]

Iris
Ciliary Body Cysts[6]
Usually asymptomatic. Rarely cause visual disturbances[13].
Retina Hyperviscosity Retinopathy[6]

Retinal Microaneurysms[6]

Retinal Detachment[6]

Central Retinal Vein Occlusion[6]

Vision Loss and Blurred Vision are two most common findings[14].

Painless, Progressive Loss of Vision[15]

Sudden, painless loss of vision. Can have floaters and flashes[16].

Subacute, painless loss of vision. Can have a Relative Afferent Pupillary Defect (RAPD)[17].

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[18]. Constitutional symptoms may be absent (A) or present (B). These “B symptoms” of MM include fever, weight loss, headache, and fatigue[18]. In more advanced stages of the disease, anemia and hypercalcemia are common[18]. Renal involvement of the disease may present with light chain nephropathy, light chain amyloidosis, and light chain deposition disease[18]. Patients with MM can have abnormalities in the following tests[18]:

• 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[18]:

• 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[18]

• 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[19]. While the hematologist is primarily responsible for the treatment plan, it is imperative that an ophthalmologist help co-manage the patient’s symptoms[19]. Not only should the ophthalmologist treat the ocular symptoms, but also be familiar with the routine hematological labs and treatments associated with this condition[19]. Asymptomatic cases of multiple myeloma may not require aggressive treatment[20]. 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[20]. For patients who are not deemed high risk, twelve cycles of melphalan, prednisone, or thalidomide are initiated followed by observation[20]. 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[20]. The following are commonly used drug combinations in MM[20]:

• 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[20].

Prognosis

The median survival time of MM is nearly seven years with treatment[5]. 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[5]. Patients with isolated tumors have an overall better chance of survival[21].

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 Selene, I.I., Jose, J.A., Khalil, M.J., Faisal, M.S., & Malik, M.N. (2019). Presentation Patterns, Diagnostic Markers, Management Strategies, and Outcomes of IgD Multiple Myeloma: A Sytematic Review of Literature. Cureus, 11(2), e4011. Https://doi.org/10.7759/curues.4011
  2. ↑ 2.0 2.1 Gertz, M.A. (2018). Acute hyperviscosity: syndromes and management. Blood, 132(12), 1379-1385. https://doi.org/10.1182/blood-2018-06-846816
  3. ↑ Omoti, A.E., & Omoti, C.E.  (2007). Ophthalmic Manifestations of Multiple Myeloma. Western African Journal of Medicine, 26(4), 265-268.
  4. ↑ 4.0 4.1 4.2 Stavnezer, J., & Schrader, C. E. (2014). IgH chain class switch recombination: mechanism and regulation. Journal of immunology (Baltimore, Md. : 1950), 193(11), 5370–5378.
  5. ↑ 5.0 5.1 5.2 5.3 5.4 5.5 5.6 Al-Farsi, K. (2013). Multiple Myeloma: an update. Oman medical journal, 28(1), 3-11. https://doi.org/10.5001/omj.2013.02
  6. ↑ 6.00 6.01 6.02 6.03 6.04 6.05 6.06 6.07 6.08 6.09 6.10 6.11 6.12 6.13 6.14 6.15 6.16 Omoti, A.E., & Omoti, C.E.  (2007). Ophthalmic Manifestations of Multiple Myeloma. Western African Journal of Medicine, 26(4), 265-268.
  7. ↑ Singh, S., Randle, L.V., Callaghan, P.T., Watson, C.J., & Callaghan, C.J. (2013). Beyond poiseuille: preservation fluid flow in an experimental model. Journal of transplantation, 2013, 605326. Https://doi.org/10.1155/2013/605326
  8. ↑ Dhakal, P., Bhatt, V., Upadhyay, S., Khanal, N., & Ganti, A. (2015). Exertional Chest Pain and Dyspnea from Hyperviscosity Syndrome Related to Marginal Zone Lymphoma. World Journal of Oncology, 5(4), 175-177.
  9. ↑ Topilow, N. J., Tran, A. Q., Koo, E. B., & Alabiad, C. R. (2020). Etiologies of Proptosis: A review. Internal medicine review (Washington, D.C. : Online), 6(3), 10.18103/imr.v6i3.852. https://doi.org/10.18103/imr.v6i3.852
  10. ↑ Wall M. (2010). Idiopathic intracranial hypertension. Neurologic clinics, 28(3), 593–617. https://doi.org/10.1016/j.ncl.2010.03.003
  11. ↑ Epperla N, Mazza JJ, Yale SH. (2015). A Review of Clinical Signs Related to Ecchymosis. WMJ,114(2):61-5. PMID: 26756058
  12. ↑ Zaremba, J., Zaczkiewicz, A., & Placek, W. (2013). Eruptive xanthomas. Postepy dermatologii i alergologii, 30(6), 399–402. https://doi.org/10.5114/pdia.2013.39439
  13. ↑ 13.0 13.1 13.2 13.3 Katahira, H., Kumakura, S., Hattori, T., & Goto, H. (2017). Corneal deposits associated with topical tosufloxacin following penetrating keratoplasty: a case report. International medical case reports journal, 10, 239–241. https://doi.org/10.2147/IMCRJ.S132531
  14. ↑ Whitehead, M., Wickremasinghe, S., Osborne, A., Van Wijngaarden, P., & Martin, K. R. (2018). Diabetic retinopathy: a complex pathophysiology requiring novel therapeutic strategies. Expert opinion on biological therapy, 18(12), 1257–1270.
  15. ↑ Ezra, E., Keinan, E., Mandel, Y., Boulton, M. E., & Nahmias, Y. (2013). Non-dimensional analysis of retinal microaneurysms: critical threshold for treatment. Integrative biology : quantitative biosciences from nano to macro, 5(3), 474–480. https://doi.org/10.1039/c3ib20259c
  16. ↑ Jalali S. (2003). Retinal detachment. Community eye health, 16(46), 25–26.
  17. ↑ Alasil, T., Lee, N., Keane, P., & Sadda, S. (2009). Central retinal vein occlusion: a case report and review of the literature. Cases journal, 2, 7170. https://doi.org/10.1186/1757-1626-2-7170
  18. ↑ 18.0 18.1 18.2 18.3 18.4 18.5 18.6 Jewell, S., Xiang, Z., Kunthur, A., & Mehta, P. (2015). Multiple Myeloma: Updates on Diagnosis and Management. Federal practitioner: For the health care professionals of the VA, DoD, and PHS, 32(7), 49S-56S.
  19. ↑ 19.0 19.1 19.2 Mordukowitz, S.  (2018). Ocular Signs of Multiple Myeloma. Clinical and Refractive Optometry, 29(3), 89-99. Retrieved from: https://digital.crojournal.com/publication/?m=55224&i=549980&p=6&ver=html5
  20. ↑ 20.0 20.1 20.2 20.3 20.4 20.5 Kyle, R.A., & Rajkumar, S.V. (2009). Treatment of multiple myeloma: a comprehensive review. Clinical lymphoma & myeloma, 9(4), 278-288. https://doi.org/10.3816/CLM.2009.n.056
  21. ↑ Shah, S. (2011). Will Eye Residents Case Series- Diagnosis and Discussion. Review of Ophthalmology. Retrieved from: https://www.reviewofophthalmology.com/article/wills-eye-residents-case-series-diagnosis-and-discussion-30299
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