Zometa, IGG's, and Physical Therapy, but Feeling Well

Ah, the long awaited doctor's visit. The white cells, although down a bit, are fine, red cells are up and platelets are way up. I received an IV of zometa today, which is a bone strengthening drug. Much more info on zometa is set forth below. The infamous IGG's are unfortunately trending UP, not Down. Went from 2440 to 3200. But my doctor was adamant that I should not concern myself with this, as there are way too many factors that could account for this...including the fact that my body is producing good immunoglobulins which could be counted in this number. He plans to do a much more definite and comprehensive blood test next visit (but not a bone marrow biopsy). Notwithstanding his dismissal of these numbers, I was disappointed as I know he would liked to have seen a downward, not upward trend. I did pull one of the nurses aside after I received the IV of zometa and grilled her a bit more on the numbers. She, who is a straight shooter, also told me they have many patients whose numbers don't move downward after transplant but they are able to control their myeloma with maintenance drugs. It would not surprise me to be put back on the steroid, dexamethasone, which was very effective in my early treatment in bringing the IGG's way down. I don't particularly like my body's response to the dex (shakes, and irritability), but it was quite effective. There is apparently a study by the French that shows this to be an effective measure following transplant. Ah, it is the acceptance of the fact that this is a long voyage that is so difficult at times. I am also going to start physical therapy for my back to relieve some of the stiffness and can return to the health club to try to get back into shape (staying out of the hot tub and pool). I also am likely to have my prostate surgery within the next month or so. Dr. Rifkin asked that I get back in touch with my urologist and get that going. He suggested we might try to do that around the same time as the restaging (bone marrow biopsy, etc.) So, it looks like the holidays may be busy. But I feel better every day and now that I can start working out and going to physical therapy I will probably start feeling even better. Today feels like one of those difficult days. But Susan refuses to be lead down the negative path--"I know you'll be fine and you can't pay attention to those numbers", she tells me. So, I will accept that approach--after a good night's sleep. Next visit is December 14th.


Zometa (zoledronic acid)
What It Is
Zometa® (zoledronic acid) is an intravenous, nitrogen-containing bisphosphonate marketed by Novartis Pharmaceuticals. It was initially approved in the US in 2001 for the treatment of hypercalcemia of malignancy (HCM), also known as tumor-induced hypercalcemia (TIH). It was approved in 2002 for the treatment of bone lesions in myeloma and patients with documented bone metastases from solid tumors, in conjunction with standard cancer therapy.

Zoledronic acid is 100-fold more potent than pamidronate. Because of this fact, the dose of zoledronic acid required is substantially lower and can be administered in a shorter period of time than pamidronate (15 minutes versus 2-4 hours).
What It Does
Zoledronic acid inhibits bone resorption, which is the breakdown of bone by osteoclasts. Although the exact mechanism of action is not completely understood, several things are thought to occur. In the laboratory, zoledronic acid inhibits osteoclast activity and induces apoptosis (programmed cell death) of osteoclasts. It also binds to bone and may block resorption. In addition, zoledronic acid inhibits the increased osteoclast activity and skeletal calcium release induced by various stimulatory factors released by tumors.
How It Is Administered
Zoledronic acid is administered as an intravenous infusion. The recommended dosage in patients with myeloma is 4 mg administered as a 15-minute infusion, given every 3 to 4 weeks. The optimal duration of therapy is not yet known. However, in clinical studies in myeloma, patients were treated for up to 12 months, and patients have received the drug for longer periods of time. Data from long-term administration (24 months of therapy) have been submitted to the regulatory authorities.


Patients receiving zoledronic acid should also take an oral calcium supplement of 500 mg and a multiple vitamin containing 400 IU of vitamin D daily.

Benefits in Myeloma
Zoledronic acid has been shown to be more effective than pamidronate in normalizing serum calcium levels in patients with hypercalcemia of malignancy. In 2 studies that were analyzed together, zoledronic acid (4 mg) normalized calcium by day 10 in 88% of patients compared to 70% with pamidronate. In addition, the median duration of response was significantly longer with zoledronic acid (32 days compared to 18 days). (Major et al. J Clin Oncol. 2001;19:558-567.)

In patients with myeloma, various studies have shown that zoledronic acid is as effective as pamidronate in treating bone lesions. For example
Zoledronic acid and pamidronate each reduced the number of skeletal events and the need for radiation therapy to bone in a study of patients with myeloma. (Berenson et al. Cancer. 2001;91:1191-2000.)
Results of a Phase III trial comparing zoledronic acid and pamidronate showed equal efficacy and tolerability of the drugs in the treatment of bone lesions in myeloma and breast cancer over the period of 1 year. (Rosen et al. Cancer J. 2001;7(5):377-387). Long-term (25 month) data from the study showed that both agents reduced the overall proportion of patients with a skeletal event. However, compared with pamidronate, zoledronic acid reduced the risk of developing skeletal complications (including hypercalcemia) as determined by multiple event analysis by an additional 16%. In patients with breast cancer, zoledronic acid was significantly more effective than pamidronate, reducing the risk of skeletal events by an additional 20% compared with pamidronate and by an additional 30% in patients receiving hormonal therapy. (Rosen et al. Cancer. 2003;98(8):1735-1744.)
Results of a small Phase II study in elderly patients with symptomatic refractory myeloma showed that the combination of zoledronic acid and targeted radiotherapy (Quadramet® [Samarium Sm-153 lexidronam], Cytogen) was an effective palliative option. For the eight patients in the study, one to three courses of therapy with these two agents was sufficient to produce long-term improvement in symptoms, particularly bone pain. (Iuliano et al. J Clin Oncol. 2004;22(14S). Abstract 6737.) Patients received a standard dose of 4 mg of zoledronic acid every 4 weeks and slightly more than half of the standard dose of Quadramet. No severe adverse effects were noted; two patients experienced transient grade 2 hematologic toxicity. Interestingly, M-protein levels decreased more than 25% in 4 out of the 8 patients and were still stable at 19 months follow up.
• Get more information on bone disease in myeloma
Guidelines for Use of Zometa in Myeloma
In September 2002, the American Society of Clinical Oncology (ASCO) published clinical practice guidelines for the use of bisphosphonates in the prevention and treatment of bone disease in myeloma. (Berenson et al. J Clin Oncol. 2002;20:3719-3736.) Upon review of published literature, the expert panel agreed that bisphosphonates reduce skeletal complications and provide a meaningful support benefit to myeloma patients with bone disease.

For patients who have bone lesions or bone loss, the guidelines recommend the use of intravenous zoledronic acid (Zometa) 4 mg infused over 15 minutes or pamidronate (Aredia®) 90 mg infused over 2 hours every 3 to 4 weeks. These bisphosphonates may also be used as part of a pain management strategy. The guidelines recommend that therapy, once started, be continued until the likely benefit is believed to be less than the inconvenience of receiving the treatment or until significant side effects are experienced.
• Get the complete summary of the guidelines for bisphosphonates
Potential Antitumor Effects
Zoledronic acid also appears to have several potential antitumor effects. For example,
It reduces the secretion of the growth factor interleukin 6 (IL-6) by myeloma cells grown in the laboratory. IL-6 is known to play an important role in the growth and survival of myeloma cells
In laboratory studies, zoledronic acid inhibited growth and induced apoptosis (programmed cell death) in human myeloma cell lines
Zoledronic acid exerted antimyeloma effects in mice that had implants of human myeloma cells growing in human bone fragments. (Yaccoby et al. Br J Haematol. 2002;116(2):278-290.)
When combined with dexamethasone in the laboratory, the effect of zoledronic acid on inhibiting growth and inducing apoptosis of myeloma cells was enhanced. (Tassone et al. Leukemia. 2000;14:841-844.)
The drug inhibited angiogenesis (the growth of new blood vessels) in an animal model. (Wood et al. Proc 36th ASCO Annual Meeting, New Orleans. 2000;19:664a.)
It is able to prevent the development of bone disease in a mouse model of myeloma. In this model, treatment with zoledronic acid was associated with a decrease in tumor burden and a significant increase in disease-free survival. (Croucher et al. J Bone Miner Res. 2003;18(3):482-492.)
Zoledronic acid appears to affect bone marrow stromal cells taken from patients with active myeloma, which could contribute to its antitumor effects. In the lab, the agent reduced bone marrow stromal cell proliferation, increased apoptosis, and modified the expression of adhesion molecules on their surface. (Corso et al. Blood. 2003;102(11). Abstract 1619.)
In blood cells taken from patients with myeloma, zoledronic acid induced anti-myeloma activity by activating a particular type of T cell. Zoledronic acid also enhanced the sensitivity of myeloma cells to killing by these T cells. (Mariani S et al. Leukemia. 2005 Mar 3. [Epub ahead of print])
However, it is not known whether zoledronic acid has the same effects in patients with myeloma.
Potential Side Effects
Zoledronic acid is generally well tolerated and the side effects are similar to those seen with pamidronate. Some patients may experience mild and transient side effects, such as fever, flu-like symptoms, fatigue, gastrointestinal effects, or anemia, which may be related to their underlying disease. Although rare, long-term use of the drug at higher doses or zoledronic acid infused in less than
15 minutes can affect the kidneys. For this reason, patients who receive zoledronic acid should have serum creatinine assessed prior to each treatment. In addition, serum calcium, electrolytes, phosphate, magnesium, and hematocrit/hemoglobin should also be monitored regularly.

Upon treatment initiation, dosage adjustments are recommended in myeloma patients with mild or moderate kidney impairment. (See How It Is Administered.) Treatment with zoledronic acid is not recommended in patients with severe kidney impairment because studies in this patient population have not been conducted. In myeloma, the risk of kidney dysfunction may be increased when it is used in combination with thalidomide or drugs known to affect kidney function (ie, nonsteroidal antiinflammatory drugs). There are animal data to suggest there can be a problem when bisphosphonates are administered during pregnancy. Therefore, zoledronic acid should not be used during pregnancy unless a physician feels the benefits outweigh the risks.

Long-term therapy with zoledronic acid appears to be safe. Results of a recent study of 22 patients who received intravenous zoledronic acid or pamidronate for up to 6 years found that prolonged therapy was well tolerated. No significant calcium, phosphorus, electrolyte, or WBC count abnormalities were seen. A clinically insignificant decrease in hemoglobin and platelet count and an increase in creatinine were observed. There were no stress fractures of long bones with prolonged therapy and the fracture rate beyond 2 years was no greater than during the first 2 years of treatment. (Ali et al. J Clin Oncol. 2001;19:3434-3437.)

A number of cases of painful exposed bone in the jaw (a condition called osteonecrosis of the jaw) have been reported in patients receiving intravenous bisphosphonates (pamidronate or zoledronic acid) for hypercalcemia of malignancy related to myeloma or breast cancer. (Marx RE. J Oral Maxillofax Surg. 2003;61:1115-1118.) However, cancer patients in general are at increased risk for this condition due to other therapies they may receive, such as radiation, chemotherapy, and medications such as steroids. (Tarassoff P. J Oral Maxillofax Surg. 2003;61:1238-1239.) Although no cause and effect relationship between bisphosphonates and osteonecrosis has been established, it is recommended that cancer patients take adequate steps to maintain their oral health. This includes practicing good oral hygiene and scheduling regular dental visits. Patients may want to complete major dental procedures before they begin treatment with bisphosphonates. If a dental problem does occur, the least invasive conservative management strategy is preferred.
Ongoing Clinical Trials
Trials are evaluating the use of zoledronic acid as an integral part of a treatment regimen for patients with early-stage or newly diagnosed myeloma to see if it can help prevent or delay the development of bone lesions. An additional trial is being conducted to determine the effect of zoledronic acid on the bone density of patients with bone loss with monoclonal gammopathy of undetermined significance (MGUS).

A study is also being conducted to investigate if lengthening the duration of infusion, in conjunction with increased volume of liquid the zoledronic acid is administered in, will provide renal protective effects.

The combination of zoledronic acid and the targeted radiotherapeutic Quadramet® (Samarium Sm-153 lexidronam, Cytogen) is being evaluated for the treatment of pain associated with metastatic bone disease in patients with recurrent or refractory myeloma.

Ongoing zoledronic acid clinical trials in myeloma are listed in the table below.


Ongoing Zometa Clinical Trials in Myeloma as of May 2005
Phase IV
A Multicenter, Open-Label, Randomized trial evaluating the duration of infusion of Zometa (zoledronic acid) 4 mg IV in Multiple Myeloma Patients with Bone Metastases
• View trial information
UARK 2004-43, A Multicenter, Open-Label, Randomized trial evaluating the duration of infusion of Zometa 4 mg IV in Multiple Myeloma Patients with Bone Metastases
• View trial information

Phase III
A Phase III Randomized Trial of Thalidomide plus Zoledronic Acid versus Zoledronic Acid Alone in Patients with Early Stage Multiple Myeloma
• View trial information

Phase II
First-line Treatment of Newly Diagnosed Multiple Myeloma with Combination of Low Dose Thalidomide, Zometa, and Dexamethasone
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Phase I/II
A Phase I/II Trial of Zometa in Patients with Monoclonal Gammopathy of Undetermined Significance (ZOMGUS-001)
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