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A 62-year-old man with recently diagnosed multiple myeloma (MM) presented to clinic for follow-up. One month prior, he presented with fatigue and was found to have anemia and renal dysfunction.

His lab results showed a hemoglobin of 9.1 g/dL and hematocrit of 28 percent, serum creatinine of 2.8 mg/dL, albumin 3.5 g/dL, and a β-2 microglobulin of 4.5 mg/dL. Serum protein electrophoresis with immunofixation revealed a monoclonal IgG κ of 2.8 g/dL and serum-free κ light chain of 78 mg/L (κ/λ ratio of 52). Bone marrow demonstrated 15 percent plasma cells as well as normal cytogenetics and fluorescence in situ hybridization studies. Skeletal survey demonstrated no evidence of lytic lesions, and positron emission tomography revealed no evidence of bone involvement.

The patient was started on cyclophosphamide, bortezomib, and dexamethasone two weeks prior. He is then started on prophylactic antimicrobial therapy. Routine lab results revealed stable hemoglobin of 9.1 g/dL and serum creatinine at 2.8 mg/dL, with an estimated creatinine clearance of 34 mL/min.

In addition to his current therapy, which of the following therapies is most appropriate to add for this patient?

1. Denosumab 120 mg subcutaneously every four weeks
2. Zolendronic acid 4 mg intravenously every four weeks
3. Enoxaparin 1 mg/kg subcutaneously twice daily
4. Aspirin 325 mg orally daily
5. Rivaroxaban 10 mg orally daily

Answer: A

Patients with MM are at risk for significant disease- and therapy-related complications. These include infections, thrombosis, and skeletal-related events (SREs).¹

Thromboprophylaxis remains controversial in MM.^1,2 Patients on immunomodulatory agents such as lenalidomide and thalidomide are at higher risk of thrombosis. Guidelines suggest that these patients should be on full-dose aspirin or therapeutic anticoagulation depending on other risk factors. In this case, the patient is being treated with bortezomib, a proteasome inhibitor, and has no other clear risk factors requiring treatment with aspirin (choice D), therapeutic enoxaparin (choice C), or prophylactic dose rivaroxaban (choice E).

SREs are a major cause of morbidity and mortality in patients with MM.³ Patients at high risk for SREs are those with osteoporosis and/or lytic lesions. However, all patients starting antimyeloma therapy should be started on prophylaxis for SREs.

Bisphosphonates, zoledronic acid, and pamidronate have been the mainstay of therapy to prevent SREs for several years. In the Myeloma IX Trial⁴, zolendronic acid versus oral clodronic acid improved progression-free survival (PFS) by a median of two months and overall survival (OS) by a median of 5.5 months. Therefore, zolendronic acid has been the preferred agent of most clinicians. It is renally metabolized, and adverse events include osteonecrosis of the jaw and renal toxicity. In patients with pre-existing renal issues with creatinine clearance between 30 to 39 mL/min, zolendronic acid must be dose reduced to a maximum of 3 mg intravenously every four weeks. In the above case, zolendronic acid should be dose reduced (choice B). Dose-reduced pamidronate can be used in patients with renal dysfunction.

Denosumab is a fully human monoclonal antibody that binds and inhibits RANK ligand. RANK ligand is hypersecreted by myeloma cells and is a mediator of osteoclast formation and activation. Unlike bisphosphonates, denosumab is not cleared renally. In a phase III trial³, denosumab 120 mg subcutaneously every four weeks was compared to zolendronic acid 4 mg intravenously every four weeks. The study met its primary endpoint, which was noninferiority of denosumab versus zoledronic acid for time to first SRE. This subsequently led to its approval for use in MM. Additionally, PFS improved by 10.7 months in the denosumab arm compared to zolendronic acid (p=0.036) without a statistically significant difference in OS. Denosumab was associated with lower renal toxicity, with rates of creatinine greater than 2 mg/dL of 4 percent versus 7 percent. There was no difference in rates of osteonecrosis of jaw (4% vs. 3%), and denosumab was associated with higher rates of hypocalcemia (17% vs. 12%).

In patients with MM, denosumab is noninferior to zoledronic acid in preventing SREs. It is not metabolized by the kidney and is associated with lower renal toxicity; however, similar rates of osteonecrosis of the jaw and higher rates of hypocalcemia were observed. Of note, denosumab is also significantly more expensive with a severalfold difference in price.

Case study submitted by Arun Singavi, MD, of Medical College of Wisconsin, Milwaukee, Wisconsin.

Resources 

1. Snowden JA, Ahmedzai SH, Ashcroft J, et al. . Br J Haematol. 2011;154:76-103.
2. . NCCN. Last accessed July 23, 2018.
3. Raje N, Terpos E, Willenbacher W, et al. . Lancet. 2010;376:1989-1999.
4. Morgan GJ, Davies FE, Gregory WM, et al. . Lancet. 2010;376:1989-1999.