Xgeva (denosumab)

What Is Xgeva?

Xgeva® (denosumab) is a monoclonal antibody that prevents bone complications in myeloma patients. Our bodies have a delicate balance between cells that build bone (osteoblasts) and cells that break down bone (osteoclasts). For myeloma patients, signals sent by cancerous myeloma cells can disrupt this balance and lead to excess bone breakdown.

Xgeva is a bone-modifying agent (BMA); it is not the same as the monoclonal antibodies used to treat myeloma. The approval was based on data from the ‘482 clinical trial, a large (1,718-patient), international, randomized, double-blind, multicenter study that demonstrated the non-inferiority of Xgeva when compared to Zometa®. 

Xgeva binds to the cytokine RANKL, an essential factor in initiating bone breakdown by osteoclasts.¹ Like the bisphosphonates, Xgeva is an osteoclast inhibitor, but its mechanism of action, the way it is metabolized by the body, and its route of administration all differ from the bisphosphonates.

• Bisphosphonates bind to bone mineral tissue, where they are absorbed by mature osteoclasts, causing the osteoclasts to die. Xgeva does not bind to bone tissue; it blocks the ability of immature osteoclasts to mature, function, and survive.
• While bisphosphonates are excreted via the kidneys, and can cause kidney toxicity, Xgeva is not cleared by the kidneys, and produces a low level of kidney-related side effects when compared to the bisphosphonates. The ASCO guidelines indicate that Xgeva may be preferable to bisphosphonates in patients with kidney damage. 
• While bisphosphonates approved for myeloma in the U.S. are given as an IV infusion, Xgeva is given as a subcutaneous (SQ) injection. 

In the aforementioned study of 1,718 newly diagnosed myeloma patients, Xgeva provided approximately 23 months of prevention from bone complications²  Xgeva was found to be as effective at preventing bone lesions as another medication called zoledronic acid (Reclast®, Zometa)³. Taking Xgeva was also associated with a greater progression-free survival than zoledronic acid, suggesting Xgeva may also have an anti-myeloma effect.⁴

Who Is a Candidate for Xgeva?

Xgeva is approved to prevent bone-related events in adult patients with multiple myeloma. 

You cannot take Xgeva if you have severe, untreated hypocalcemia (low calcium levels in your blood). Xgeva can cause severe hypocalcemia, and fatal cases have been reported. If you have hypocalcemia, your doctors must treat this condition before starting Xgeva. 

Xgeva can cause loss of blood supply to the jawbone, also called osteonecrosis of the jaw. Therefore, you cannot take Xgeva if you have open or unhealed wounds from dental or mouth surgery. 

There are other reasons you may not be a candidate for Xgeva. Please see the package insert and ask your doctor for more information.

How Is Xgeva Given?

Xgeva is given as a subcutaneous injection (an injection under the skin), usually given once every 4 weeks. If you are taking Xgeva, your doctor may advise you to take calcium and vitamin D supplements to treat or prevent low calcium levels in your blood (hypocalcemia).

What Are Possible Side Effects of Xgeva?

Xgeva can cause severe side effects in some people. The most common side effects of Xgeva for multiple myeloma patients include:

• diarrhea,
• nausea, 
• low red blood cells (anemia), 
• low blood platelets (thrombocytopenia), 
• low levels of calcium (hypocalcemia), 
• back pain, 
• swelling of the lower legs or hands, 
• upper respiratory tract infections, 
• rash, 
• and headaches.
   

The most common serious side effect seen in clinical trials was pneumonia.⁵ 

The current ASCO guidelines warn that Xgeva should not be stopped abruptly because severe bone breakdown can occur in this situation. The Xgeva package insert warns of multiple vertebral fractures (MVF) following treatment discontinuation, and counsels the treating doctor to “evaluate the individual patient’s risk for vertebral fractures.” 

Females of reproductive potential and males with female partners of reproductive potential should discuss with their doctor the risk of embryo fetal toxicity and if the use of effective contraception is necessary before treatment with Xgeva begins, during treatment, and/or after the last dose of treatment is administered.

Other Possible Side Effects of Xgeva

Be sure to discuss with your doctor the possible side effects:

Osteonecrosis of the jaw

Osteonecrosis of the jaw (ONJ) is a problem that occurs in 3%–4% of patients with myeloma or other cancers who have been treated with either bisphosphonates or Xgeva. Before developing ONJ, a patient may have inflammation or an infection in the mouth, which produces pain, swelling, and bone damage around the tooth sockets in the jaws. Bone necrosis, or a loss of bone, may occur. This can lead to loose teeth, sharp edges of exposed bone, bone spurs, and the breaking loose of small bone spicules or dead bone. 

Symptoms may not be obvious at first, or may include pain, swelling, numbness, a “heavy jaw” feeling, or loosening of a tooth.

• Before treatment with any bone-modifying agent, such as Xgeva, all myeloma patients should undergo a dental evaluation, preferably by an oral surgeon or dental oncologist familiar with ONJ. Careful monitoring and follow-up are required.
• Prevention can help avoid or reduce issues related to ONJ. Inform your dentist if you are receiving treatment with a BMA. Also, maintain excellent oral hygiene and visit your dentist regularly.
• If an infection is present, an antibiotic treatment is recommended. The choice of antibiotic depends upon the type of infection. An oral rinse may be appropriate.
• Before starting treatment with a BMA, follow preventative dental care.
• If ONJ occurs, surgery is not the first step in management. Instead, a patient may undergo minor dental work to reduce sharp edges or remove injured tissue. A protective mouth guard may be helpful.
• Avoid tooth extraction and any elective jaw surgery, if possible. Stop BMA-therapy if dental surgery is recommended. Current data indicate poor healing with continued BMA therapy in surgical settings.
• If problems persist or if healing is slow, your healthcare team may consider stopping bisphosphonate therapy for 2 to 4 months to facilitate recovery.
• Dentures can be worn, but they may need adjustment. Dental implants appear to be contraindicated. Use of hyperbaric oxygen does not appear to be helpful.

Kidney dysfunction

All bisphosphonates are potentially toxic to the kidneys. Because myeloma can damage the kidneys through light chain proteins and elevated blood calcium levels, kidney-related side effects are a particular concern.

Before you begin treatment with a BMA such as Xgeva, ask your doctor if the BMA in combination with other medications you are receiving may be more likely to harm your kidney function. These therapies include ones to treat myeloma as well as nonsteroidal anti-inflammatory drugs (NSAIDs).

Atypical femur fracture 

Atypical fractures of the femur (thigh bone) have been reported in patients who received treatment with either a bisphosphonate or with Xgeva. AFFs can occur as a result of no or minimal trauma. AFFs are rare, and they can also occur in patients with no exposure to BMAs. The risk of atypical fractures is included in the “Warnings and Precautions” section of the package inserts
for all FDA-approved bisphosphonates, as well as for Xgeva.

AFFs can occur in one or both thighs and usually present as a dull aching pain weeks to months before a complete fracture occurs. Myeloma patients who were also receiving therapy with dexamethasone or another glucocorticoid (a class of corticosteroids) have reported atypical fractures. If you notice any new or unusual thigh, hip, or groin pain, report this to your doctor right away.

Fever

Pyrexia (medical term for fever) is defined as a temperature of 100.4°F (38°C) or higher. Fever may occur as an infusion-related reaction (IRR) associated with the use of bisphosphonates such as Xgeva. The fever is usually mild. Each treatment center has its own definition for “mild” temperature. You may experience a fever during your IV infusion or during the hours after. Such a fever may last for several hours. 

Typically, fever occurs with the first or second infusion. It may or may not occur with subsequent infusions. Patients who have severe recurrent fevers may not be able to tolerate IV bisphosphonates. As with other possible side effects, report your fever to your doctor right away.

Vein irritation

With IV infusions of bisphosphonates, mild phlebitis (vein irritation) can occur at the infusion site. It is usually mild, and patients typically recover within 1 to 2 days. To avoid any leakage of medication around the vein, your healthcare team must carefully monitor your veins.

A short infusion of saline at the end of the bisphosphonate infusion is recommended to clear the Xgeva from the area and reduce
the chance of phlebitis.

General aches and pains

These effects sometimes occur for a short time, along with fever, with infused bisphosphonates. Back pain has been reported in patients who are receiving therapy with Xgeva. Ask your doctor if receiving medication before your infusions may be beneficial for you.

Combining Xgeva with Myeloma Therapies

BMAs can generally be combined safely with most myeloma therapies. However, your doctor may avoid giving them on or near the same day as intravenous treatment. Because bisphosphonates can affect kidney function, confirm that your BMA is not combined with another drug that may also cause kidney toxicity. 

Insurance coverage

In the U.S., the Centers for Medicare & Medicaid Services (CMS), a federal agency that administers the Medicare program, rei burse for bisphosphonate therapy. Most other insurance programs in the U.S. also reimburse for bisphosphonate therapy. Xgeva is significantly more expensive than generic Aredia or Zometa, so unless there are medical reasons why a patient cannot receive bisphosphonate therapy (e.g., kidney disease), there may be insurance issues with receiving reimbursement for Xgeva. If you experience any problems with insurance coverage or reimbursement, speak with your healthcare team.

Since hospitals and clinics set up contracts for one product versus another, it’s important to double-check which agent, from which source, is being administered to you. Some patients may experience a new side effect or be intolerant of the solution into which the active ingredients are added. If this happens to you, be sure to find out what drug you received and which
company manufactured it, and report your side effects to your doctor.

For a complete list of side effects, please see the Xgeva package insert and consult the additional resources below.

Additional information on Xgeva

• The European Public Assessment Report (EPAR) on Xgeva
• FDA Label / Package Insert for Xgeva
• Amgen: Learn about Xgeva
• Denosumab versus zoledronic acid in bone disease treatment of newly diagnosed multiple myeloma: an international, double-blind, double-dummy, randomized, controlled, phase 3 study