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Radiotherapy, Bisphosphonates, and Other Supportive Therapies for Multiple Myeloma

Module 2: First-Line Treatment of Multiple Myeloma

Section 4: Radiotherapy, Bisphosphonates, and Other Supportive Therapies for Multiple Myeloma

Dr. David Roodman: The role of radiotherapy is an important treatment modality for myeloma. Radiotherapy is very useful in patients with isolated solitary plasmacytomas and to treat painful lytic lesions. However, multiple radiotherapy treatments at multiple sites can have adverse effects on hematopoietic function so that patients cannot receive systemic therapy. Therefore, I would caution physicians to use radiotherapy sparingly so that patients can receive systemic therapy when needed.

(Treatment of Bone Mestastases)

(Myeloma Bone Disease)

Radiotherapy also has a very important use in patients with spinal cord compression syndromes as an immediate treatment for this potentially devastating complication of myeloma.

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Dr. Robert Kyle: Curative radiation doses are indicated for patients with solitary plasmacytoma. Palliative radiation doses should be given to the patient with myeloma who has focal pain that does not respond to chemotherapy or to analgesics. Palliative radiation should be directed only to the area of pain. The radiation field should not be increased to include all apparent involvement because this often will result in the development of pancytopenia, which makes it difficult to give subsequent chemotherapy to these patients.

Dr. David Roodman: For patients who present with spinal cord compression and require radiation therapy, dexamethasone at high doses is routinely started to relieve the edema around the lesion as well as to treat the lesion. Both radiation therapy and dexamethasone are indicated in patients with spinal cord compression syndromes.

(Supportive Therapy for Myeloma)

Common complications in patients with myeloma include severe bone pain, pathologic fractures, anemia, infections, and shingles. Treating patients with severe bone pain requires systemic chemotherapy as well as aggressive analgesia.[View Reference] For patients who have lesions that do not respond to these therapeutic modalities, radiation therapy to a specific lesion should be initiated.

Pathologic fractures are a very common complication in these patients and, in combination with lytic lesions and osteopenia, occur in up to 50% of the patients at diagnosis. Patients who have large lytic lesions in weight-bearing bones may require orthopedic procedures as prophylaxis for fracture. This is especially common in the femur and other weight-bearing bones. [View Reference]

In addition, treating patients who have bone disease with intravenous bisphosphonates is an important therapeutic modality to control pain and prevent further bone loss. There are very good data demonstrating an analgesic effect of intravenous bisphosphonate therapy in addition to its capacity to block bone resorption. This is an important contribution to the total care of the patient. [View Reference]

In terms of anemia in patients, about 50% of patients with myeloma respond to erythropoietin therapy. Erythropoietin can be given either three times a week or once weekly, depending on the patient's and the physician's preference. Erythropoietin is routinely started between 30,000 and 40,000 units once a week, and, after 1 month, if there is no response, the dose can be increased to 60,000 to 70,000 units per week. Patients are then followed for another month, and, if there still is no response, erythropoietin probably should be discontinued because of the expense and the low probability of a subsequent response. [View Reference]

Patients who respond to erythropoietin should be followed, and once their hematocrits are above 30% to 32%, the dose can be tapered. The physician must make sure that patients are on doses that will maintain their hematocrit levels in that range.
Treatment of bone disease in patients with myeloma involves use of intravenous bisphosphonates. At present, only pamidronate has been approved for treatment of bone disease in patients with myeloma. Oral bisphosphonates in the United States should not be used because of problems with absorption. Adequate levels of these agents in patients with severe bone turnover problems, such as patients with myeloma, must be reached to see beneficial effects. Outside the United States, there are oral bisphosphonate preparations that have been reported to have good results when used in patients with myeloma; for example, clodronate in oral form has been used to treat patients with myeloma. This drug has been reported to be effective in these patients.

(Relative in vivo and in vitro Potencies of Bisphosphonates)

A new intravenous bisphosphonate may be available to patients in the future (zoledronicacid). It is more potent than pamidronate, which is approved for patients withmyeloma, and can be infused in patients over shorter periods of time. Zoledronicacid has just been approved by the FDA and should be available for patients inthe next 6 to 12 months.
Studies with zoledronic acid compared with pamidronate have shown equal efficacyin patients with myeloma bone disease. The advantage of zoledronic acid is thatit can be given over a much shorter period of time and at a lower dose than requiredfor pamidronate for similar results.[ViewReference]

How do you treat infections in patients with multiple myeloma?

Dr. Brian Durie: Infections are a particular problem for patients with multiple myeloma. The reason for this is multifactorial, but, predominantly, there is a reduced immune response against potential infectious agents, including both viral and bacterial infections. The particular risk for infection complications is during the first 3 months of induction therapy. Because of this and because of data indicating benefit, many clinicians will use prophylactic antibiotics for broad antibacterial coverage during this period.

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Dr. Durie: Because of the current therapies, including VAD for induction and subsequent high-dose therapy, broader antimicrobial therapy frequently is used in a preventive fashion. In addition to broad antibacterial coverage with such drugs as trimethoprim/sulfamethoxazole, antiviral therapy, antifungal therapy, and prophylaxis for PCP are used in this initial induction setting.

When patients are first diagnosed, there is a consideration of immunization against potential infections. Many clinicians routinely will use vaccination against pneumococcal infection as well as vaccination against influenza. However, it is important to note two aspects of such vaccination strategies. First, because of the compromised immunity in patients with myeloma, the level of benefit is not high. Second, various complications with the use of vaccination need to be balanced against reduced potential benefit in patients with myeloma.

Another type of therapy used to manage infections in myeloma is high-dose intravenous gammaglobulin. Although there are studies indicating benefit with this in a preventive setting, the inordinate expense makes use prohibitive except in cases of extreme recurrent infection. Intravenous gammaglobulin does have its value but mostly for the prevention of severe infections in a limited number of patients.

Are there particular ways to manage pain in patients with myeloma?

Dr. Brian Durie: Pain is a frequent complication of myeloma, particularly in the active phase of the disease. Acute pain can be the reason that a patient seeks medical attention. Therefore, management is a critical aspect of ongoing care for patients with multiple myeloma.

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Dr. Durie: Acute pain can be treated in a variety of ways. The most definitive way is to control the myeloma with overall systemic therapy. However, initially it may be important to give acute relief of pain using high doses of glucocorticoids, such as dexamethasone or even to give high-dose fractionated radiation, in an effort to relieve pain and alleviate pressure on the spinal cord or a nerve that is the source of pain.

On a more long-term basis, pain also can be an issue for many patients with myeloma, even when the disease is under control. This pain is associated with bone damage, which may be persistent even if the myeloma has been brought into remission. Pain may be secondary to chronic arthritic or degenerative problems, inflammation, irritation, or damage to nerves. This type of chronic pain can be particularly difficult to manage. Various options are available, ranging from the simpler to the more complex.

The simple therapies are anti-inflammatory agents. In this setting, we would typically use acetaminophen or low doses of aspirin but would avoid the whole category of nonsteroidal anti-inflammatory drugs (NSAIDs), particularly for patients who have renal compromise. Occasionally, a patient who has completely normal function could safely use an NSAID. However, we generally would recommend against that, just as a precaution.

If a patient has ongoing pain that requires management, it may be necessary to resort to narcotics: either oral opioids or perhaps in the form of a patch. Occasionally, it may be necessary to deal more aggressively with an area of focal pain that may require injection of steroids or a nerve block.

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Dr. Durie: If the pain is in the vertebral column, one way to reduce that pain is to use vertebroplasty or kyphoplasty. With this technique, liquid cement is injected into the area of a collapsed vertebra, for example. The most effective way to do this safely is to inject the liquid cement into a balloon in a procedure called balloon kyphoplasty. In this way, there can be reexpansion of the area of the collapsed vertebra, frequently with significant improvement in pain and some recovery of normal structure and function in that area.

Gabapentin sometimes can be helpful in the management of chronic pain in patients with myeloma. Gabapentin is an antiepileptic drug, but it can be helpful in patients who have pain related to postherpetic neuralgia or, for example, pain and discomfort following an episode of shingles, but also related to nerve compression from a variety of causes. It is important to escalate the dose to the level that is effective.

When should bisphosphonate therapy in patients with myeloma be initiated, and how long should it be continued?

View Topic Summary by G. David Roodman, MD, PhD

Dr. David Roodman: There are data that support starting bisphosphonate therapy in any patient who has lytic bone disease confirmed by x-ray film. There are no data suggesting that patients should be treated prophylactically with bisphosphonates. [View Reference]

In my practice, I treat every patient who has lytic bone disease with bisphosphonates, and I continue the therapy indefinitely. Other people have suggested stopping bisphosphonate therapy if the patient remains in complete remission for 2 years. [View Reference]

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Dr. William Bensinger: I frequently have recommended stopping bisphosphonates for patients who have had transplants and have shown no evidence of disease for 2 years. I agree that there are no data on the proper time interval or whether bisphosphonates should be discontinued, but if patients have stable bone disease for 2 years, have no evidence of active myeloma, and are in complete remission, discontinuation is reasonable.

Dr. David Roodman: My concern with that strategy is that once patients get below the fracture threshold with their bone disease, regardless of bisphosphonates, they'll continue to fracture. Maintaining their bone density above the fracture threshold is, therefore, extremely important. We all have seen patients who start breaking bones regardless of the therapy, whether they're in remission or not, because the bone disease can continue in the absence of overtly active myeloma.

Dr. Brian Durie: I think that is a particularly important point.

Dr. Robert Kyle: I also recommend continuing the bisphosphonate indefinitely. However, one should test for proteinuria or an increase in creatinine level in patients who are on bisphosphonates for long periods.

Dr. Brian Durie: Patients who have developed proteinuria or increased creatinine have mostly been using pamidronate either in a higher dose than 90 mg or dosing more frequently than once a month.

Dr. David Roodman: I think this is an important question that many physicians raise. For a patient in whom bone disease does not appear to be responding to standard-dose pamidronate, for example, should the dose be increased? Physicians frequently double the dose and shorten the interval from once a month to every 2 weeks or every 3 weeks. There are no clear data, except in Paget's disease, that there is a dose-response curve to bisphosphonate therapy in patients with bone disease. [View Reference]

The toxicity issues that have been raised are important ones when increasing the dose of bisphosphonate. I think that those considerations always must be taken very carefully before manipulating doses or intervals of bisphosphonate therapy.

Dr. Seema Singhal: What about patients with renal dysfunction? Do you advocate giving a lower dose?

Dr. David Roodman: No, I do not. This has been looked at carefully, and we know that patients given standard-dose bisphosphonates on dialysis can tolerate that dose without any further deterioration in their renal function. Therefore, I do not adjust the dose of bisphosphonates for patients on dialysis. I do not increase the dose either, but I do follow these patients very carefully. To my knowledge, there is no contraindication in renal dysfunction for bisphosphonates. It should not be administered rapidly to these patients; for that reason, I sometimes administer it over 4 hours rather than 2 hours, because the peak dose of bisphosphonate has the greatest impact on renal function.

Dr. Seema Singhal: Should patients with myeloma who do not have overt lytic lesions, but do have reduced bone density, be considered as candidates for bisphosphonate therapy?

Dr. David Roodman: That is a very difficult question because patients with myeloma tend to be elderly and can have osteoporosis independent of their myeloma. Postmenopausal osteoporosis and senile osteoporosis in men can occur, and patients with those conditions need to be treated. Whether or not they need to have intravenous bisphosphonate therapy is undetermined. I do not administer intravenous bisphosphonate therapy unless patients have identifiable lytic disease.

Dr. Brian Durie: If a woman with postmenopausal osteopenia also has myeloma but does not have a discrete bone disease associated with that, would you give that woman an oral bisphosphonate?

Dr. David Roodman: Yes.

Dr. Brian Durie: But you would not give her an intravenous bisphosphonate? Couldn't one make the argument that, as these patients have the two diseases, the intravenous bisphosphonate might be a good preventive strategy?

Dr. David Roodman: There are no data to indicate that preventive bisphosphonate therapy is a good thing for patients with myeloma. There are data on intravenous bisphosphonate therapy in patients with osteoporosis. It is administered for short periods of time at different doses and at different intervals. I have seen a patient with Paget's disease and myeloma. Is the bone disease coming from the myeloma, or is the bone disease coming from the Paget's disease? This can be determined by examining the alkaline phosphatase. For patients who have high alkaline phosphatase and myeloma, I treat their Paget's disease first.

Dr. Brian Durie: Would you say that there is proof of principle for the use of bisphosphonates in a prophylactic fashion for patients with osteoporosis or osteopenia, given that bisphosphonates used in a preventive or prophylactic fashion in patients with postmenopausal osteopenia reduce subsequent hip fracture? Would it not be reasonable to expect that benefit to translate to myeloma?

Dr. David Roodman: It is possible and reasonable to think it might occur, but there are no data to support that position. Pamidronate therapy is very expensive. Depending on what center you're in, the cost of a single dose of 90 mg of pamidronate once a month can range from $800 to $1500 per month. I think you need data before undertaking prophylactic bisphosphonate therapy at those dosages in patients with myeloma.

Dr. Brian Durie: But then aren't we left with the problem that such studies will never be done because of the difficulty and expense?

Dr. Seema Singhal: What about a postmenopausal woman with smoldering myeloma and reduced bone density? Would you prefer hormone replacement therapy or oral bisphosphonates?

Dr. David Roodman: I think hormone replacement therapy in postmenopausal women with myeloma is a controversial issue. Dr. Durie was the first to report estrogen receptors on myeloma cells. I do not know whether estrogen has any effect on the growth of myeloma cells. Bisphosphonates are very active in postmenopausal osteoporosis. Therefore, postmenopausal women with myeloma could receive treatment with bisphosphonates alone. Hormone replacement therapy would be used for other symptoms of hormonal deficiency. You can treat bone disease without hormone replacement therapy.

How is anemia treated in patients with multiple myeloma?

Dr. David Roodman: Treatment with erythropoietin for patients with myeloma should be started if hematocrit levels are less than 30%. (Indications for Therapy With Erythropoietin) They should have a trial of at least 2 months, starting at 40,000 units per week subcutaneously for the first month. If there is no response, doses should increase to 60,000 and 80,000 units per week for the second month. If there still is no response, I think erythropoietin should be discontinued.

Patients who respond should have their erythropoietin doses titrated to maintain their hematocrit levels in the 30% to 35% range. There is no reason to maintain hematocrit levels higher than 35%. There are also reimbursement issues associated with doses of erythropoietin that maintain hematocrit levels above 35%.

Dr. Brian Durie: I would just comment that the current reimbursement guidelines are quite frustrating. If one administers erythropoietin to the level of benefit and there is an increase to slightly above a 35% hematocrit, then erythropoietin must be discontinued. Before reinstating treatment, the hematocrit must drop below 30% again, and the process repeats itself. And so, there is a yo-yo process of administration: benefit, cancellation of reimbursement, development of anemia, requalification, and through the whole cycle again. It would be good if there would be some agreement reached that would make it a little smoother for the patient and the physician.

Dr. David Roodman: I agree.

Dr. Robert Kyle: Although erythropoietin is very expensive, one must keep in mind that blood transfusion is also expensive. I suspect that the cost of erythropoietin is no greater than that of repeated blood transfusions.

Dr. David Roodman: Plus the risks are markedly reduced.

Dr. Brian Durie: The risks of transfusions are significant.

Dr. William Bensinger: Do you think there is a role for measuring erythropoietin levels in selected patients?

Dr. David Roodman: The data for erythropoietin levels in patients with anemia of chronic disease due to cancer and AIDS have shown that patients whose erythropoietin levels are lower than 200 are more likely to respond to erythropoietin than those whose levels are above 200. [View Reference] Erythropoietin levels usually take quite a while to get back. You usually can see within the first month if the patient is responding by following the reticulocyte count.

Reimbursement issues can be influenced by the policies at specific hospitals: for example, whether or not the manufacturer resupplies the erythropoietin to the pharmacy if you discontinue therapy after a month.

Dr. Brian Durie: One of the most helpful and important baseline tests is to check for iron deficiency because hemoglobin levels are not going to improve in the absence of iron.

Dr. David Roodman: It is also important to follow serum ferritin levels after starting erythropoietin therapy because a relative iron deficiency will have impact upon the response to erythropoietin. Therefore, to continue to see a response, it is important to ensure that a patient has adequate iron stores while on erythropoietin. A clue that a patient is relatively iron deficient is when the hematocrit starts falling on the same dose of erythropoietin. The patient's iron stores should be checked at that time and replaced. It may not be at the iron-deficient level, but it is important to make sure that patients have adequate iron stores for their degree of erythropoiesis.

Dr. Brian Durie: Right.

Dr. Seema Singhal: In this context I wanted to mention B12 and folic acid as well. I had a patient who developed what was thought to be myelodysplastic syndrome (MDS) and very low counts. We performed a bone marrow test and discovered megaloblastic anemia. As it turned out, the patient was just getting repeated doses of chemotherapy without very good nutrition and had developed nutritional anemia.

Dr. David Roodman: You're right. Folate is important. It would take about 5 years for a patient to become B12 deficient, but folate deficiency is fairly rapid in patients who have poor nutrition, about 3 months according to the data Herbert showed. It takes 4 to 5 years before a patient with adequate B12 stores becomes B12 deficient.

Dr. Brian Durie: It is important to make sure that there is not another reason for anemia or lack of response to the erythropoietin.

Dr. David Roodman: Another problem with erythropoietin is when the patient develops a reticulocytosis and the mean corpuscular volume (MCV) increases. The physician must be careful when testing the MCV in patients on erythropoietin that the increased MCV is not simply due to a reticulocytosis rather than megaloblastic anemia.

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Overview of Treatment Options | Transplants | Thalidomide | Radiotherapy, Bisphosphonates, and Other Supportive Therapies for Multiple Myeloma

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