Case Study: Elevated LDL Secondary to Multiple Myeloma

Introduction

Elevated cholesterol is a well-known and modifiable risk factor for cardiovascular disease. Hyperlipidemia due to secondary causes is common and should be evaluated as part of treatment. Potential secondary causes include diabetes mellitus, excessive alcohol intake, cholestatic liver disease, hypothyroidism, chronic kidney disease, nephrotic syndrome and various classes of medications.(1)

Multiple myeloma is a malignant neoplasm characterized by proliferation of plasma cells producing a monoclonal gammopathy. Monoclonal proteins proliferate in the bone marrow and spill out into the urine or serum. Presenting symptoms frequently include weight loss, anemia, bone pain, hypercalcemia and renal impairment. Multiple myeloma can lead to the development of osteolytic lesions, hyperviscosity syndrome and renal failure. In most patients with multiple myeloma, the serum lipid levels are either normal or decreased.(2-4) Nevertheless, there are reports of multiple myeloma accompanied with hyperlipidemia, referred to as hyperlipidemic myeloma. The mechanisms leading to hyperlipidemia in patients with multiple myeloma are not well understood, although paraproteins appear to play an important role. Potential hypotheses include: decreased lipid degradation due to paraproteins complexing with lipoproteins, impaired lipolytic activity and paraprotein binding the LDL receptor inhibiting clearance.(5)

We describe a case of a patient presenting with marked increase in LDL as the initial sign of multiple myeloma, with subsequent improvement in lipids after diagnosis and treatment of multiple myeloma.

Case Presentation

The patient is a 72-year-old male with a past medical history of hyperlipidemia, hypertension, frequent premature ventricular contractions, osteoarthritis and hypothyroidism. Initial referral to lipid clinic was for marked increase in cholesterol over the course of one year. Prior to the presentation, the patient’s cholesterol had been monitored by his primary care physician without need for medical therapy. Historically, his total cholesterol (TC) ranged from 150-217 mg/dL (3.88-5.61 mmol/L) with low-density lipoprotein cholesterol (LDL-C) ranging from 87-133 mg/dL (2.25- 3.44 mmol/L) over a span of fifteen years.

Table 1. Patient’s lab results

As seen in Table 1, prior to referral to lipid clinic, LDL-C had increased from 133 mg/dL to 252 mg/dL in the span of one year, and a lipid panel rechecked two weeks later demonstrated similar elevations. TSH remained within normal limits at 0.326 uIU/mL. The patient denied any changes in medications, diet, illnesses or exercise habits. He was started on atorvastatin 80mg daily by his primary care physician. Labs were repeated after three months on atorvastatin, with a 55% reduction in LDL-C to 156 mg/dL. However, patient’s ALT increased from 40 to 127 U/L after initiation. Therefore, he was advised by his primary care physician to hold atorvastatin and he was referred to Lipid Clinic.

Physical examination was negative for xanthomas. The hepatic panel was repeated with improvement in ALT to 56 U/L. Given that ALT was less than three times the upper limit of normal at its peak, and his total bilirubin remained normal, atorvastatin 80mg daily was resumed in accordance with the NLA 2014 Statin Safety Task Force.(6) Additionally, ezetimibe 10mg daily was added to the regimen for additional LDL-C lowering based on previous patient response to atorvastatin. Concurrently, a right upper quadrant ultrasound and 24-hour urine were ordered to further assess for altered hepatic function and nephrotic syndrome. The right upper quadrant ultrasound revealed hepatic steatosis with no biliary ductal dilatation or obstruction. However, the 24-hour urine collection demonstrated 3g proteinuria, and the patient was referred to Nephrology.

Figure 1. Patient’s LDL cholesterol trends on medication therapy and during chemotherapy

The evaluation revealed predominantly non-albumin proteinuria, ultimately attributed to light chains. Urine electrophoresis demonstrated lambda band restriction, serum free light chains (1,474 mg/dL) and significantly elevated monoclonal lambda protein (2,073 mg/dL), concerning for multiple myeloma. The patient was subsequently referred to Hematology/Oncology. After further labs, positron emission tomography scan, and bone marrow biopsy, the diagnosis of IgG lambda multiple myeloma was confirmed and the patient was initiated on chemotherapy with seven cycles of bortezomib, lenalidomide and dexamethasone (VRD).  

He returned to Lipid Clinic after approximately two months of chemotherapy. In the interim, no changes were made to lipid lowering therapy. Most recent labs after reduction in paraproteins in response to chemotherapy demonstrated further improvement of his lipid panel: LDL-C 42 mg/dL, TC 106 mg/dL, high density lipoprotein cholesterol (HDL-C) 38 mg/dL, and triglycerides 131 mg/dL. Atorvastatin 80mg daily and ezetimibe 10mg daily were continued with a plan to discontinue ezetimibe at next visit if labs remained stable.

At his Lipid Clinic follow up visit six months later, the patient had completed induction chemotherapy (seven cycles of VRD) and remained on lenalidomide and dexamethasone maintenance therapy. Protein studies had normalized (Table
2) and patient’s lipid panel improved further: LDL-C 28 mg/dL, TC 90 mg/dL, HDL-C 44 mg/dL, and triglycerides 88 mg/dL. Ezetimibe was discontinued. See Figure 1 for a trend of the patient’s LDL-C cholesterol with medication therapy and during chemotherapy.

Discussion

Although patients with multiple myeloma typically present with a variety of systemic symptoms, elevated LDL is not known to be a common initial indicator of disease. Hyperlipidemic myeloma is a rare variation of multiple myeloma and little is known about its pathophysiology.

Misselwitz and colleagues published a case report and comprehensive review of 52 additional cases of hyperlipidemic myeloma. This report analyzed risk factors associated with hyperlipidemic multiple myeloma, as well as possible mechanisms for this rare presentation. They identified several commonalities in these patients as compared to multiple myeloma with a normal lipid panel. The majority of hyperlipidemic patients demonstrated IgA myeloma (53% vs. 21% with usual multiple myeloma) and these patients commonly present with cutaneous xanthomas (70%). Our patient presented with IgG lambda multiple myeloma and no cutaneous xanthomas. Of note, Misselwitz and colleagues reported that 42% of the hyperlipidemic cases included patients with IgG multiple myeloma, but when compared to 1,027 index cases of multiple myeloma, this incidence did not differ significantly from usual myeloma.(7) Additionally, it was noted that cholesterol levels were lower in IgG multiple myeloma than IgA.(5) For the majority of patients included within the case reports, the diagnosis of multiple myeloma preceded the diagnosis of hyperlipidemia, while in our patient the opposite occurred.

Table 2. Patient’s protein studies at baseline and during chemotherapy

Misselwitz and colleagues also noted “a striking correlation between paraprotein and lipid concentrations in their case, with improvement in lipids with successful anti-myeloma chemotherapy. Our patient demonstrated a similar response, with only modest improvement with a combination of maximum dose atorvastatin and ezetimibe. However, after seven cycles of VRD and normalization of monoclonal proteins, he achieved an additional 65% LDL-C reduction.

Many of the cases presented in the literature conducted further testing of hyperlipidemic multiple myeloma patients’ blood to determine potential mechanisms of this phenomenon. Physical binding of paraprotein to lipoprotein occurred in 24/32 cases tested. In another analysis of six patients, all samples demonstrated an extended half-life for lipoproteins. More detailed testing is not readily available at our institution, so the patient was unable to undergo further analysis.

Although multiple myeloma is not a common cause of hyperlipidemia, it is important to remain mindful that this could be a possibility with several different presentations, as seen in the literature and with this patient, and may require further workup in order to diagnose and treat this underlying cause. Our patient did achieve a moderate reduction in his lipids with standard medical therapy, with further subsequent improvement after treatment of his previously undiagnosed multiple myeloma.

Disclosure statement: Dr. Rabatin has no financial disclosures to report. Dr. Bartsch has no financial disclosures to report. Dr. Baddour has no financial disclosures to report. Dr. Mehta has no financial disclosures to report.

REFERENCES

1 Vodnala D, Rubenfire M, Brook RD. Secondary causes of dyslipid-emia. Am J Cardiol. 2012;110(6):823.
2 Fukudome K, Kato J, Ohashi T, Yamamoto Y, Eto T. Hyperlip-idemia associated with multiple myeloma. Intern Med. 1996 Apr;35(4):337-40.
3 Yim H, Ahn HJ, Park C, Cheon JY. Xanthoma of the liver in a patient with multiple myeloma associated with hyperlipidemia. A case re-port. J Korean Med Sci. 1995 Dec;10(6):453-6.
4 Rahman S, Kumar P, Mahto SK, Tonk RS, Taneja RS. Light Chain Myeloma induced Severe Hypertriglyceridemia. J Clin Diagn Res. 2017 Mar;11(3):OD01-OD03.
5 Misselwitz B, Goede JS, Pestalozzi BC, Schanz U, Seebach JD. Hyperlipidemic myeloma: review of 53 cases. Ann Hematol. 2010 Jun;89(6):569-77.
6 Jacobson TA, et al. NLA Task Force on Statin Safety - 2014 update. Journal of Clinical Lipidology 2014;8(3): S1-S4.
7 Kyle RA et al (2003) Review of 1027 patients with newly diagnosed multiple myeloma. Mayo Clin Proc 78(1):21–33.