The Myeloma Alphabet Soup Handbook
Drugs Used To Treat Myeloma

Webmaster's note: This information has not been updated since 2001, and is presented here for reference only.

Adriamycin See Doxorubicin

Alkeran See Melphalan

Aredia See Pamidronate

Busulfan (byoo-SUL-fan)
Commonly used name: Myleran
Chemo: Alkylating agent
How given: By mouth

Special precautions: While you are using busulfan, your doctor may want you to drink extra fluids so that you will pass more urine. This will help prevent kidney and bladder problems and keep your kidneys working well.

Side effects needing medical attention as soon as possible: Fever, chills or sore throat; unusual bleeding or bruising; cough; side or stomach pain; joint pain; shortness of breath; swelling of feet or lower legs.

Side effects needing medical attention after you stop taking this medicine: Fever, cough, shortness of breath; unusual bleeding or bruising.

Carmustine (kar-MUS-teen)
Commonly used names: BiCNU, BCNU
Chemo: Alkylating agent
How given: By IV injection

Side effects needing immediate medical attention: If carmustine accidentally seeps out of the vein, it may damage some tissues and cause scarring. Tell the doctor or nurse right away if you notice redness, pain or swelling at the IV site.

Other side effects needing medical attention as soon as possible: Cough; fever, chills, or sore throat; shortness of breath; unusual bleeding or bruising; flushing of face; sores in the mouth and on the lips; unusual tiredness or weakness; swelling of the feet or lower legs; unusual decease in urination.

Side effects that affect the lungs: (for example, cough and shortness of breath) may be more likely if you smoke.

Side effects needing attention after you stop using this medicine: Cough; fever, chills or sore throat; shortness of breath; unusual bleeding or bruising.

Side effects that usually do not require medical attention: Nausea and vomiting (usually lasting longer than 4-6 hours); discoloration of the skin along the vein of injection; diarrhea; difficulty swallowing; difficulty in walking; dizziness; loss of appetite; loss of hair; skin rash and itching.

Cyclophosphamide (sye-kloe-FOSS-fa-mide)
Commonly used names: Cytoxan, Neosar
Chemo: Alkylating agent
How given: By mouth or by injection

Side effects needing medical attention as soon as possible: Dizziness, confusion or agitation; fever; chills or sore throat; missed menstrual periods; tiredness; cough; side or stomach pain; joint pain; shortness of breath; swelling of feet or lower legs; unusual bleeding or bruising; unusually fast heartbeat; black, tarry stools; sores in the mouth and on lips; unusually frequent urination; unusual thirst; yellow eyes and skin. If you are receiving this medication by injection, also check with your doctor if you notice redness, swelling or pain at the place of the injection. Check with your doctor immediately if you notice blood in your urine after you have stopped taking this medication.

Side effects that usually do not require medical attention: Darkening of the skin and fingernails; loss of hair; nausea or vomiting (unless severe).

Cytoxan See Cyclophosphamide

Decadron See Dexamethasone

Dexamethasone (Dex-a-METH-a-zone)
Commonly used names: Decadron, Dex
How given: By mouth

A steroid drug often given to multiple myeloma patients, usually along with other anticancer drugs. Dexamethasone can be used alone as a very effective treatment for myeloma. Dexamethasone is a steroid that is directly active against the myeloma cells.

Special Precautions: Your doctor may want you to follow a low salt and/or high potassium diet while using dexamethasone. Patients should avoid heavy smoking. Before having any kind of surgery (including dental surgery) or emergency treatment, tell the doctor in charge that you are taking dexamethasone.

Diabetic patients: This medicine may decrease the effectiveness of insulin or other antidiabetic drugs. If you notice a change in the results of your urine sugar test, or if you have any questions about your diabetes, check with your doctor.

Side effects needing medical attention as soon as possible: Swelling of the feet and ankles; muscle weakness; ulcers or stomach pain or burning; easy bruising; wounds which are slow to heal; dizziness; severe headaches; menstrual problems; blood-sugar problems; blurred or decreased vision or seeing halos around lights; sore throat and fever; depression; mood or mental changes.

For information on Dexamethasone: http://www.tirgan.com/decadron.htm

Dexrazoxane (Deks-ray-ZOKS-ane)
Commonly used names: Zinecard
How Given: IV
Use: Cardioprotective Agent

The Food and Drug Administration (FDA) has granted accelerated marketing approval for dexrazoxane injection (Zinecard/Pharmacia) to prevent cardiotoxicity that occurs in women receiving doxorubicin (Adriamycin/Pharmacia) for metastatic breast cancer. The drug is indicated for women who have already received a cumulative doxorubicin dose of 300 mg/m2 and who, in their physicians' opinion, stand to benefit from continued doxorubicin treatments. It is not recommended for use at the initiation of doxorubicin treatment.

Approval came after resubmission of a New Drug Application for Zinecard. The FDA had previously rejected the drug because of concerns that it might reduce the antitumor efficacy of doxorubicin. Full FDA approval will be granted only after trials are completed to determine whether the combination of dexrazoxane and doxorubicin after administration of 300 mg/m2 prolongs the time to tumor progression, reduces mortality, or (with respect to dexrazoxane) reduces the incidence of congestive heart failure.

Clinical experience has shown that anthracycline drugs such as doxorubicin, used in anticancer therapy, produce cumulative, dose- dependent, irreversible cardiomyopathy. This can result in congestive heart failure and death. The incidence of cardiotoxicity increases markedly when the total lifetime dose of anthracycline exceeds 550 mg/m2. Evidence suggests that the semiquinolone metabolite of doxorubicin produces superoxide anion and superhydroxide free radicals with iron as a cofactor. The heart muscle has only low concentrations of protective enzymes, so the free radicals cause lipid peroxidation, destroying the mitochondria in the myocardial cells. Apparently, dexrazoxane undergoes intracellular hydrolysis that opens one of its two ring structures. The resulting active molecule is a chelating agent that binds iron, thus blocking formation of free radicals by doxorubicin. (Seifert CF et al. Ann Pharmacother. 1994; 28: 1063-1072. Buss JL. Agents Actions. 1993; 40: 86-95.)

Chemically, dexrazoxane is a derivative of ethylenediaminetetraacetic acid (EDTA). Its pharmacokinetics are described by a two-compartment open model with first-order elimination. The mean peak plasma concentration is 36.5 mcg/mL at the end of a 15-minute infusion of 500 mg/m2 given 15 to 30 minutes before 50 mg doxorubicin/m2. Elimination half-life is 2.1 to 2.5 hours, plasma clearance 6.25 to 7.88 L/h/m2, renal clearance 3.35 L/h/m2, and volume of distribution 22.0 to 22.4 L/m2, depending on dosage (500 or 600 mg/m2). About 42% of a dose of dexrazoxane is eliminated in the urine. Dexrazoxane does not bind to plasma proteins, and it does not alter the pharmacokinetics of doxorubicin.

In three prospective, randomized clinical trials, dexrazoxane slowed the deterioration in myocardial function compared with placebo, as assessed from left ventricular ejection fraction (LVEF). Patients in the dexrazoxane and placebo groups received antitumor treatments consisting of fluorouracil, doxorubicin, and cyclophosphamide (FAC). A difference between active treatment and placebo became evident at a cumulative doxorubicin dose of 150 mg/m2 and became statistically significant in patients who received 400 mg/m2 or more. Retrospective historical analysis showed that the risk of congestive heart failure for patients receiving FAC plus dexrazoxane after six courses of FAC alone was significantly lower than that for patients who continued to receive FAC after the first six courses but did not receive dexrazoxane (hazard ratio approximately 1:13). By protecting against cardiotoxicity, dexrazoxane allowed a greater percentage of patients to receive extended doxorubicin therapy. Time to tumor progression was similar in both treatment groups, and survival time was at least as great with dexrazoxane as with placebo.

Adverse events in patients receiving FAC plus dexrazoxane have been similar to those in patients receiving FAC alone, except that pain on injection has been reported mainly in those receiving dexrazoxane.

Zinecard is supplied in single-use vials containing 250 or 500 mg dexrazoxane lyophilized powder. The product is reconstituted with sodium lactate solution for injection. It should be administered by slow intravenous push or rapid drip intravenous infusion from a bag. Administration of doxorubicin should begin within 30 minutes of the start of dexrazoxane infusion. The recommended dosage is a 10:1 ratio of dexrazoxane to doxorubicin (for example, 500 mg dexrazoxane/m2 with 50 mg doxorubicin/m2).

Doxorubicin (dox-oh-ROO-bi-sin)
Commonly used names: Adriamycin PFS, Adriamycin RDF, Rubex
Chemo: Antitumor antibiotic
How Given: By injection

Special precautions: While you are taking doxorubicin, your doctor will want you to drink extra fluids so that you will pass more urine. This will help prevent kidney and bladder problems and keep your kidneys working well. Heart tests are done before this drug is given and at certain times throughout the course of treatment. These tests are done to check heart function. A new drug Zinecard, helps to protect the heart from adriamycin. Avoid long exposure to sunlight. Use sunscreen and wear protective clothing outdoors. The medicine can be irritating to tissue if it leaks out of the vein. Tell the person giving this medicine if there is any burning or pain while the drug is being given. Doxorubicin causes urine to turn reddish in color, which may stain clothes. This is not blood. It is perfectly normal and lasts for only 1-2 days after each dose is given.

Side effects needing immediate medical attention: Unusually fast or irregular heartbeat; pain at the place of the injection; shortness of breath; swelling of the feet and lower legs; wheezing. If doxorubicin accidently seeps out ot the vein, it may damage some tissues and cause scarring. Tell the doctor or nurse right away if you notice redness, pain or swelling at the IV site. If there is a blister or scab, don't pop it or pick at it.

Other side effects needing medical attention as soon as possible: Fever, chills, or sore throat; sores in the mouth or on the lips; side or stomach pains; joint pain; unusual bleeding or bruising; skin rash or itching.

Side effects needing immediate attention after you stop using this medicine: irregular heartbeat; shortness of breath; swelling of the feet and lower legs.

Side effect that usually do not require medical attention: Loss of hair; nausea or vomiting (unless severe); reddish uring; darkening of soles, palms or nails.

Epoetin, EPO See Procrit

Etoposide (e-TOE-poe-side)
Commonly used names: VePesid, VP-16
Chemo: Plant alkaloid
How given: By injection

Side effects needing medical attention as soon as possible: Fever, chills or sore throat; difficulty walking; numbness or tingling in fingers and toes; pain at the site of injection; rapid heartbeat; shortness of breath or wheezing; weakness.

Side effects that usually do not require medical attention: Loss of appetite; loss of hair; nausea and vomiting; diarrhea; unusual tiredness.

Filgrastim See Neupogen

GM-CSF See Sargramostim

Idarubicin (Eye-dah-ROO-bah-sin)
Chemo:
Commonly used name: Idamycin (tm)
How given: By IV injection

This new orally active anthracycline offers an attractive alternative to Adriamycin for the treatment of myeloma. Its long half-life in vivo could confer a similar advantage as infused Adriamycin. There are also data suggesting that idarubicin may be less affected than daunorubicin by the MDR phenotype. Three studies using idarubicin either as a single agent or with prednisolone indicate a response rate of over 40 percent in relapsed and de novo patients. Preliminary data idarubicin in combination with dexamethasone (Z-Dex) indicate a high response rate with little toxicity other than that due to the dexamethasone. The Z-Dex protocol is now being used to achieve initial cytoreduction in de novo patients prior to intensive consolidation and then autologous transplantation. Idarubicin and dexamethasone in combination with CCNU for relapsed patients is currently being evaluated by the Riverside Haematology Group (UK).

Source: Multiple Myeloma
Edited by: Gahrton, Gosta & Durie, Brian G.
Page 121

Special Precautions: While you are using idarubicin, your doctor may want you to drink extra fluids so that you will pass more urine. This will prevent kidney and bladder problems and keep your kidneys working well.

Side effects needing medical attention as soon as possible: Irregular heartbeat; pain at the site of the injection; chest pain; severe bleeding - swelling of the feet and legs; shortness of breath.

If idarubicin accidently seeps out ot the vein, it may damage some tissues and cause scarring. Tell the doctor or nurse right away if you notice redness, pain or swelling at the IV site.

Other side effects needing medical attention as soon as possible: Fever, chills, or sore throat; sores in the mouth and on the lips; stomach pains; unusual bleeding or bruising, skin rash or itching or hives.

Interferon (in-ter-FEER-on)
Commonly used names: Alpha-interferon, Intron-A
Hormone, Cytokine

A cytokine (or hormone) which is produced normally in the body in response to virus infection. Produced by genetic engineering techniques, synthetic alpha-interferon is given as treatment for myeloma and is used primarily in the maintenance (or plateau phase) to block any re growth of myeloma and thus delays or prevents relapse.

Interferon in the Treatment of Multiple Myeloma: http://www.moffitt.usf.edu/pubs/ccj/v5n3/toc.html

Melphalan (MEL-fa-lan)
Commonly used names: Alkeran, L-PAM, phenylalanine mustard
Chemo: Alkylating agent
How given: By mouth, IV

Melphalan is absorbed erratically from the GI tract and food interferes with this absorption. For this reason, melphalan should be administered on an empty stomach, e.g., one hour before breakfast. Prolonged exposure to Melphalan depletes the stem cell pool, compromising the subsequent use of autologous BM or PBSC. Chronic exposure to alkylating agents increase the risk of secondary hematological malignancies, with the incidence of acute leukemia rising to 17.4% at 48 months.

Special Precautions: While you are using melphalan, your doctor may want you to drink extra fluids so that you will pass more urine. This will prevent kidney and bladder problems and keep your kidneys working well.

Side effects needing medical attention as soon as possible: Sudden skin rash and itching.

Other side effects needing medical attention as soon as possible: Black, tarry stools; fever, chills or sore throat; unusual bleeding or bruising; side or stomach pain; sores in the mouth and on the lips; swelling of feet or lower legs.

Side effects needing attention after you stop using this medicine: Fever, chills, or sore throat; unusual bleeding or bruising.

Side effects that usually do not require medical attention: Nausea and vomiting.

Good information site about alkeran: http://www.drugbase.co.za/data/pi/alkeran.htm

Neumega
Commonly used name: Oprelvekin, rhIL-11
Use: Stimulates platelet production.

November 25, 1997, the FDA gave Genetics Institute clearance for the marketing of oprelvekin. Oprelvekin is the first biologic drug that promotes the production of the body's platelet supply. Oprelvekin may prove to be useful in managing the severe hematologic side effects that are seen with the use of certain chemotherapeutic agents.

Oprelvekin stimulates the production of megakaryocytes and thrombocytes. Platelets that are produced in response to oprelvekin are morphologically and functionally normal. The platelets that are produced subsequent to oprelvekin therapy possess a normal life span. In addition, oprelvekin possesses non-hematopoietic properties. Oprelvekin has been shown to enhance the healing of gastrointestinal lesions, induce protein synthesis, inhibit adipogenesis, inhibit pro-inflammatory cytokine production by macrophages, increase production of osteoclasts, and stimulate neurogenesis.

Following administration, oprelvekin reaches peak plasma levels in about 3 hours with a terminal half-life of about 7 hours. The bioavailability of oprelvekin is greater than 80%. It has been shown that the clearance of oprelvekin decreases with age. The clearance of oprelvekin in infants and children is 1.2- to 1.6-fold higher than in adults and adolescents. In animal models, oprelvekin is eliminated via the kidney. However, only a very small amount of intact oprelvekin was recovered in urine suggesting that the drug is metabolized before it is excreted.

Oprelvekin has been shown to be superior to placebo in its hematopoietic effects. In patients who were receiving myelosuppressive chemotherapy, more patients in the oprelvekin group avoided platelet transfusions than those receiving placebo. Also, fewer patients who were in the oprelvekin group required platelet transfusions than those in the placebo group.

Oprelvekin should be administered cautiously to certain patients. Oprelvekin is known to cause fluid retention. For this reason, it is suggested that it should be used carefully in patients with clinically evident congestive heart failure, patients who may be predisposed to developing congestive heart failure, and patients who have a history of heart failure who are well compensated and receiving appropriate therapy.

Also, it is very important that fluid and electrolyte status be monitored closely in patients who are receiving concurrent diuresis. Death has been reported in patients who were receiving chronic diuresis concomitantly with oprelvekin.

It is also important to administer oprelvekin cautiously in patients who have cardiac arrhythmias. Oprelvekin is known to cause atrial arrhythmias and can worsen the condition of a patient who has an existing problem with arrhythmia.

Most adverse effects observed thus far have been mild to moderate in severity. These peripheral edema, dyspnea, tachycardia, and conjunctival redness. However, these adverse effects reversed upon discontinuation of the oprelvekin.

Oprelvekin may prove to be a much needed option in patients who are receiving myelosuppressive chemotherapy. Previously, clinicians waited for platelet nadirs to return to normal on their own before giving subsequent courses of chemotherapy. The other option would be to give the patient a platelet transfusion. However, oprelvekin can be used to replace both of these options. In addition, an individual will avoid the adverse effects and potential risks associated with a platelet transfusion. Also, the time between the courses of chemotherapy will not be prolonged secondary to a low platelet count. Oprelvekin may enable clinicians to adhere more consistently with their planned schedule of myelosuppressive chemotherapeutic agents.

If patients are self-administering this drug, this should be done only after careful training, especially with respect to dilution and preparation. The patient must understand concepts underlying aseptic technique. Special patient instructions are provided with each package of Neumega. Each dose should be given at about the same time each day. If a dose is missed, continue with the next scheduled dose. This drug may harm the fetus and pregnant women or those considering pregnancy should consult their physician about continuing oprelvekin use.

For More Information:
First Biologic Drug Licensed In U.S. To Boost Platelet Production: http://www.pslgroup.com/dg/4942a.htm
American Home Products Corporation: http://www.ahp.com/ahp/products/neumega.htm

Neupogen
Commonly used name: G-CSF
Ues: Stimulates white blood cell production (Neutrophils)

Dr. Hussein in Cleveland is using GM-CSF's in his trial for non-responding MMers. His theory is that some non-responders, especially those who are non-responders from the get go (as opposed to those with MDR) fail to respond because the chemo agents are looking for dividing cells, and their MM cells just aren't doing much dividing.

Neupogen Package Insert: http://wwwext.amgen.com/cgi-bin/genobject/neupogenIndications/tig6KUZhTTR


Oprelvekin See Neumega

Pamidronate (pa-mi-DROE-nate)
Commonly used name: Aredia
Bisphosphonate: Bone-resorption inhibitor
How given: IV
Pharmacodynamics/Kinetics
Onset of effect: 24-48 hours
Maximum effect: 5-7 days
Absorption: Poorly from the GI tract; pharmacokinetic studies are lacking
Half-life, unmetabolized: 2.5 hours
Distribution half-life: 1.6 hours
Urinary (elemination half-life: 2.5 hours
Bone half-life: 300 days

Source: NEJM 1996; 334:529-530

Management of Myeloma with Bisphosphonates

Osteolytic lesions are a hallmark of multiple myeloma. At the time of diagnosis, most patients have bone lesions whose extent is directly related to the mass of the tumor. About 30 percent of patients also have hypercalcemia. Bone lesions and hypercalcemia are major causes of morbidity in these patients, causing asthenia, cachexia, bone pain, fractures, compression of the spinal cord, and renal insufficiency. Thus, the diagnosis and treatment of bone disease are essential to the care of patients with multiple myeloma.

Unfortunately, the efficacy of treatment of the skeletal effects of multiple myeloma is very limited. Only patients who have complete remission of their disease have any healing of bone lesions, and only a few of those treated with standard chemotherapy (melphalan and prednisone) have complete remissions. Intensive regimens (using high-dose melphalan) are more effective, but only young patients can tolerate them, because of their toxic effects. Although the size of the tumor can be reduced with standard chemotherapy in about half of patients, such reductions are transient (lasting less than three years), and bone loss continues during the phase of disease control. The remaining patients are unresponsive to chemotherapy and have progressive destruction of bone. The limited efficacy of chemotherapy for multiple myeloma suggests that bone-sparing drugs could be of benefit in limiting bone loss and preventing hypercalcemia. The discovery that bone destruction in multiple myeloma is mediated by normal osteoclasts activated by myeloma cells strongly supports this view. Furthermore, the availability of potent inhibitors of bone resorption to control hypercalcemia has prompted interest in evaluating their ability to slow the progression of bone disease in patients with multiple myeloma.

Quantitative studies of bone histology have shown that multiple myeloma is characterized by excessive resorption of bone that occurs only in the vicinity of myeloma cells. Concurrently, bone formation is inhibited.

The formation of osteolytic lesions and the loss of bone are directly related to this imbalance between bone resorption and bone formation. Myeloma cells can stimulate all the phases of the normal mechanism of resorption -- specifically, the recruitment, differentiation, and resorptive activity of osteoclasts; the result is a large number of aggressive osteoclasts along bone trabeculae. This excessive resorption of bone can be detected histologically months or even years before bone lesions appear on radiography, a fact that supports the early use of antiresorptive therapy in patients with multiple myeloma. Since normal osteoclasts are stimulated locally by myeloma cells, there is no need to invoke systemic (endocrine) factors as having a role in this resorptive process. The autocrine-paracrine factors interleukin-1(beta), tumor necrosis factor (beta), and interleukin-6, which have important roles in normal bone remodeling and can induce hypercalcemia in vivo, are either produced directly by myeloma cells or induced in large quantities in the area around the tumor.

Although these are probably the major bone-resorbing factors involved in multiple myeloma, the possibility that myeloma cells produce other such factors cannot be ruled out. Furthermore, myeloma cells can inhibit bone formation directly. However, the cytokines mentioned above that are produced in excess in multiple myeloma all have this property also. It is important to note that interleukin-6, an essential growth factor for myeloma cells, is produced by bone cells themselves. Thus, there is evidence of a vicious circle involving myeloma cells and bone cells, with the former stimulating the latter to resorb bone through the action of factors that also support tumor growth. Inhibiting bone resorption could therefore limit the growth of myeloma cells, since they find what they need to survive inside bones.

Bisphosphonates are potent inhibitors of bone resorption. Three of them -- etidronate, clodronate, and pamidronate -- are now approved in Western countries for the treatment of hypercalcemia. All three have been used in the long-term care of patients with bone disease caused by multiple myeloma. In a large, double-blind, placebo-controlled study, oral etidronate added to standard chemotherapy did not reduce bone pain, loss of stature, progressive vertebral deformation, the frequency of pathologic fractures, or the frequency of hypercalcemia. The poor bioavailability of etidronate and its capacity to induce a defect of mineralization (in addition to that induced by myeloma) could explain these disappointing results. In another placebo-controlled study, adding oral clodronate to standard chemotherapy significantly reduced the progression of osteolytic lesions without lessening bone pain, decreasing the occurrence of fractures, or improving survival.

Pamidronate was 100 times more potent than etidronate and 10 times more potent than clodronate in preventing bone resorption when tested in vitro and is highly effective in treating hypercalcemia. In mice inoculated with plasmacytoma 5T2 cells, pamidronate prevents the occurrence of osteolytic lesions. In this issue of the Journal, Berenson et al. report the results of a trial of intravenous pamidronate, given every four weeks for nine cycles, in 392 patients with multiple myeloma who were stratified according to whether they were receiving first- or second-line antimyeloma treatment at entry into the study. Pamidronate reduced the proportion of patients who had any skeletal event (defined as a pathologic fracture, irradiation of bone or surgery on bone, or spinal cord compression), decreased the occurrence of new pathologic fractures, and prevented early hypercalcemia. Furthermore, it alleviated bone pain and improved the quality of life. No healing of bone lesions was observed, but bone mineral density was not measured. Finally, there was a trend toward increased survival among the patients who were receiving pamidronate. As compared with the previous results, the current ones are clearly promising and represent an important step toward better management of bone disease in these patients.

Considering the very early occurrence of bone resorption and bone loss in patients with multiple myeloma and the benefit bisphosphonates offer, even in patients who have no osteolytic lesions at the start of therapy, these results suggest that bisphosphonates should be used very early, probably in all patients -- not only because of their beneficial skeletal effects, but also because they may slow tumor growth. Indeed, bisphosphonates can inhibit the production by osteoblasts of interleukin-6, a growth factor essential to myeloma cells. Finally, the availability of other potent bisphosphonates (aminohexane bisphosphonate, risedronate, and alendronate) and other inhibitors of bone resorption besides the bisphosphonates (gallium nitrate and paclitaxel) opens new avenues for the much more efficient treatment of bone disease in patients with myeloma.

Regis Bataille, M.D., Ph.D.
Institute of Biology
44035 Nantes CEDEX, France


Advanced Multiple Myeloma Patients Reduces Skeletal Events

By James R. Berenson, Alan Lichtenstein, Lester Porter, Meletios A. Dimopoulos, Roldolfo Bordoni, Sebastian George, Alan Lipton, Alan Keller, Oscar Ballester, Michael Kovacs, Hillary Blacklock, Richard Bell, Joseph F. Simeone, Dirk J. Reitsma, Maika Heffernan, John Seaman, and Robert D. Knight for the Myeloma Aredia Study Group

Purpose: To determine the efficacy and safety of 21 monthly cycles of pamidronate therapy in patients with advanced multiple myeloma. Long-Term Pamidronate Treatment of Patients and Methods: Patients with stage III myeloma and at least one lytic lesion received either placebo or pamidronate 90 mg intravenously administered as a 4-hour infusion monthly for 21 cycles. At study entry, the patients were stratified according to whether they were to receive first-line (stratum 1) or second-line (stratum 2) antimyeloma chemotherapy. Skeletal events (pathologic fracture, radiation or surgery to bone, and spinal cord compression) and hypercalcemia were assessed monthly.

Results: The results of the first nine previously reported cycles are extended to 21 cycles. Of the 392 randomized patients, efficacy could be evaluated in 198 who received pamidronate and 179 who received placebo. After 21 cycles, the proportion of patients who developed any skeletal event was lower in the pamidronate-group (P = .015). The mean number of skeletal events per year was less in the pamidronate-group (1.3) than in placebo-treated patients (2.2; P = .008). Although survival was not different between the pamidronate-treated group and placebo patients overall, stratum 2 patients who received pamidronate lived longer than those who received placebo (14 v 21 months, P = .041). Pamidronate was safe and well tolerated during the 21 cycles of therapy.

Conclusion: Long-term monthly infusions of pamidronate as an adjunct to chemotherapy are superior to chemotherapy alone in reducing skeletal events in stage III multiple myeloma patients, and may improve the survival of patients on salvage therapy.

Address reprint requests to :
James R. Berenson, MD,
Division of Medical Oncology,
111H, West Los Angeles VA Medical Center
11301 Wilshire Blvd, Los Angeles, CA 90073
Email: berenson.james@ west-la.va.gov.

Source: Journal of Clinical Oncology (1998;16:593-602) http://www.jcojournal.org/abs16_2/v16n2p593.html



Aredia Best Buys
30 mg 4s. $829.02
60 mg. $408.54
90 mg. $597.84
Average Wholesale Price as of 9/23/97

Bisphosphonates as Anticancer Drugs http://www.nejm.org/content/1998/0339/0006/0398.asp


Novartis (Manufacture of Aredia)
Phone: 1 (800) 244-7668
Order: Aredia and Myeloma articles plus labeling information
Cost: No charge
Web Site: http://www.novartis.com/

Prednisone (PRED-ni-sone)
Commonly used names: Apo-prednisone, Detlasone, Liquid Pred;Meticorten, Orasone, Orasone5, Orasone10, Orasone20, Orasone50, Prednicen-M, Prednisone Intensol, Sterapred, Sterapred DS, and Winpred Hormonal
How given: By mouth

A steroid drug often given to multiple myeloma patients along with one or more anticancer drugs. Prednisone appears to act together with anticancer drugs in helping to control the effects of the disease on the body.

Special precautions: If you will be using prednisone for a long time, your doctor may want you to follow a low salt diet and/or a potassium-rich diet. Stomach problems are more likely to occur if you drink alcoholic beverages while you take this medicine. Do not drink alcoholic beverages unless you have first checked with your doctors. Before having any kind of surgery (including dental surgery) or emergency treatment, tell the doctor in charge that you are taking prednisone.

Diabetic patients: This medicine may decrease the effectiveness of insulin or other antidiabetic drugs. If you notice a change in the results of your urine sugar test, or if you have any questions about your diabetes, check with your doctor.

Side effects needing medical attention as soon as possible: Decreased orblurred vision; frequent urinations; increased thirst; skin rash; acne or other skin problems; back or rib pain; bloody or black, tarry stools; filling or rounding out of the face; irregular heartbeats; menstrual problems; depression; mood or mental changes; muscle weakness; nausea or vomiting; seeing halos around lights; sore throat and fever; stomach pain or burning (continuous); swelling of the feet or lower legs; unusual tiredness or weakness; wounds that do not heal.

There should be a gradual decrease in dosage prior to completing this medication. After you stop taking this medicine, your body may need time to adjust.

Side effects needing immediate medical attention after you stop taking this medication: Pain in the abdomen, stomach or back; dizziness or fainting; fever; loss of appetite (continuing); muscle or joint pain; nausea or vomiting; shortness of breath; frequent or continuing headaches; unusual tiredness or weakness; unusual weight loss.

Side effects that usually do not require medicals attention (unless prolonged or severe): Indigestion; false sense of well-being; increase in appetite; nervousness or restlessness; trouble in sleeping; weight gain.

American College of Rheumatology Announces First Guidelines for the Prevention and Treatment of Steroid-Induced Osteoporosis: http://www.rheumatology.org/press/announce.htm

Procrit
Commonly used names: EPO, Epoetin Alfa
Use: Stimulates red cell production

Procrit is a man-made version of the natural substance, erythropoietin (e- rith-ro-poy-e-tin), that your body needs to produce red blood cells. Procrit acts just like this natural substance to help your body make more red blood cells. Your other cells can then get the oxygen they need so you can start to feel better.

Procrit therapy should start to work within 4 to 8 weeks. Because each person has his or her own needs, your doctor may adust your dosage of Procrit to get the best results.

If you keep your own supply of Procrit, you will need to store it in a refrigerator. Procrit should be refrigerated but must not be frozen. Also, you should be careful never to shake Procrit. If you are planning a trip, ask your doctor how you can continue receiving Procrit therapy.

Most people tolerote Procrit therapy well. However, some patients have felt stinging from the injection of Procrit. Letting the vial warm up to room temperature (15 min) and putting ice on your skin before the injection can help this problem. You can also alternate the site of injection (arm, leg, etc.) If you still feel stinging, ask your doctor about the multidose vial for Procrit that contains an ingredient to help reduce stinging. Even though the risk is low, some people may experience increased blood pressure (hypertension), diarrhea, or bloating and swelling. Although hypertension is not a common problem, your doctor will regularly take your blood pressure and check your red blood cell count during the course of your Procrit therapy.

Call your doctor immediately if you believe you are experiencing any side effects. He or she can find the cause of your discomfort and take the proper measures to treat it.

PROCRITline (1-800-553-3851)

The Procritline is a tollfree number for all patients receiving Procrit. The Procritline makes it easy for you to get information on managing the cost of your Procrit therapy. A Procritline service representative trained to handle situations like yours will listen to your concerns and suggest reimbursement or financial assistance options.

Procrit Full Product Information: http://www.thebody.com/ortho/procrit/full.html

Sargramostim
Commonly used name: GM-CSF
Use: Stimulates white blood cell production

Dr. Hussein in Cleveland is using GM-CSF's in his trial for non-responding MMer's. His theory is that some non-responders, especially those who are non-responders from the get go (as opposed to those with MDR) fail to respond because the chemo agents are looking for dividing cells, and their MM cells just aren't doing much dividing. He's administering GM-CSF to get the MM cells dividing, then using cytoxan and vincristine. So far he's gotten good responses from 12 of 14 non-reponding or relapsed MMers'.

For More information:http://www.ccf.org/cc/mm/frames32.htm

Thalidomide (tha-LI-doh_mide)

How given: By mouth
Side effects that should be reported to your doctor:
More Common: Muscle weakness, tingling, burning, numbness, or pain in the hands, arms, feet, or legs.
Rare: Blood in urine, decrease in urination, fever, with or without chills and sore throat, irreggular heartbeat, lightheadedness, especially when stand up, skin rash.

Side effects that usually DO NOT require medical attention: These possible side effects may go away during treatment: however, if they continue or are bothersome, check with your doctor. Constipation, diarrhea, dizziness, drowsiness, nausea, stomach pain.

Warning: Thalidomide is known to cause nerve damage that may be permanent. Peripheral neuropathy is a common, potentially severe, side effect of treatment with thalidomide that may be irrevesible. Peripheral neuropathy generally occurs following chronic use over a period of months, however, reports following relatively short term use also exist. The correlation with cumulative dose is unclear. Symptoms may occur some time after thalidomide treatment has been stopped and may resolve slowly or not at all.

Patients should be examined at monthly intervals for the first 3 months of thalidomide therapy to enable the clinician to detect early signs of neuropathy, which include numbness, tingling or pain in the hands and feet. Patients should be evaluated periodically thereafter during treatment.

Antitumor Mechanisms of Action of Thalidomide:

Thalidomide has been shown to inhibit angiogenesis in a variety of ways. It reduced corneal neovascularization induced by bFGF in a rabbit model and by VEGF in a murine model. Recent studies suggest that the antiangiogenic effects may be mediated by the generation of hydroxyl radicals by this drug. In addition, it is clear that this agent has a number of other potential antitumor mechanisms of action. The drug reduces tumor necrosis factor-alpha (TNF-alpha) production by monocytes and macrophages. Its efficacy in erythema nodosum leprosum is associated with a drop in serum levels of this cytokine. This protein is thought to play a critical role in the development of myeloma and its most important clinical manifestation-bone disease.

Thalidomide has also been shown to alter the expression of adhesion molecules, especially members of the integrin-receptor family. Moreover, it has been shown to have effects on T-cell function. In vitro, the drug is a potent costimulator of T-cell responses, particularly in the CD8-expressing subset. However, the exact antitumor mechanisms of action of thalidomide remain an enigma. This is an important area for further studies, because elucidating the drug's mechanisms may lead to the development of other agents with enhanced antitumor activity and reduced toxicity.

The majority of myeloma patients respond to chemotherapy and/or glucocorticosteroid therapy, and complete responses can be achieved in 20% to 40% of patients following high-dose chemotherapy. However, all of these patients will ultimately relapse, with a paucity of therapeutic options available. Even in responding patients, antitumor effects are only of short duration. Thus, it is imperative that new agents be evaluated in these patients.

The recent pivotal report from the University of Arkansas demonstrating the antitumor activity of thalidomide in relapsing multiple myeloma patients has led to a dramatic change in the treatment of patients with relapsing disease. Most of the 84 patients in the initial report had relapsed following autologous peripheral blood stem-cell transplantation. The doses of thalidomide varied from 200 to 800 mg daily, with most (56%) of the patients receiving the maximum dose. Responses ( 25% reduction in paraprotein) were observed in nearly one-third of patients, within 2 months of initiation of therapy in most cases. However, side effects were observed in the majority of patients in a dose-related fashion and included somnolence, weakness, constipation, neuropathies, edema, and skin rash.

An update including an additional 85 previously treated patients continues to show a 25% paraprotein reduction in one-third of cases, many of whom had poor prognostic features (abstract #28). Consistent with other data evaluating prognostic factors among patients undergoing high-dose therapy at the University of Arkansas, loss of chromosome 13 was associated with a worse outcome. It is clear from many other reports that this agent has marked antimyeloma activity alone, even for patients with plasma-cell leukemia and extramedullary disease. Some of these reports show similar antimyeloma activity with lower doses that are better tolerated.

Single-Agent Thalidomide vs Combination

Therapy However, only a minority of patients respond to single-agent thalidomide. Moreover, the duration of response varies greatly and may last only a few months for some patients. Thus, it is clear that there is a need for improvement. Combining thalidomide with other drugs with known activity in myeloma is one possibility. The University of Arkansas has initiated a number of trials evaluating thalidomide with steroids alone or combination chemotherapy (abstract #28). Importantly, a number of studies suggest that the addition of thalidomide to other agents potentiates their antitumor effects. This has been demonstrated in animal models with combinations involving chemotherapeutic agents and nonsteroidal anti-inflammatory drugs. Previous in vitro studies suggested the synergistic antitumor effects of the combination of steroids with thalidomide on tumor cells from multiple myeloma patients.

The M. D. Anderson group showed that in relapsing myeloma patients failing to respond to single-agent thalidomide, the addition of oral dexamethasone at 40 mg for 4 days three times monthly led to responses in nearly an additional third of patients. In addition, a number of reports suggest that those patients unresponsive to both glucocorticosteroids and thalidomide as single agents may nonetheless have dramatic responses to the combination.

Durie previously presented findings suggesting that the macrolide antibiotic clarithromycin (Biaxin) may possess antimyeloma activity in a small study of previously relapsing patients. This led to the combination evaluated by Coleman and colleagues in patients with multiple myeloma and Waldenstrom's macroglobulinemia (abstract #27). Patients received oral clarithromycin at 500 mg twice daily; oral thalidomide at 50 mg/d, initially escalated by 50 mg/d biweekly to a maximum oral dose of 200 mg/d; and oral dexamethasone at 40 mg/wk. An update of the data presented at the 2000 American Society of Clinical Oncology meeting showed that 29 patients, most of whom had relapsed previously, were evaluated. All 21 evaluable patients responded to the combination, with complete remissions observed in three cases and most patients showing a 75% reduction in paraprotein levels. Moreover, the remissions were durable with no relapses observed to date in any of the 21 patients. Among the eight other patients considered not evaluable, five were too early in treatment and three died suddenly. These three latter patients had a history of prior cardiopulmonary disease.

JAMES R. BERENSON, MD, FACP
Cedars-Sinai Medical Center and UCLA School of Medicine
Los Angeles, California

Thrombopoietin
Commonly used name: Tpoietin
Use: Stimulates platelet production (In clinical Trials)
For More Information:http://www.oncolink.upenn.edu/conference/asco96/sun/abs2010.html

Vincristine (vin-KRIS-teen)
Commonly used names: Oncovin, Vincasar PFS, Vincrex
Chemo: Plant alkaloid
How given: By injection

Special Precautions: Vincristine frequently causes constipation and stomach cramps. Your doctor may want you to take a laxative and stool softener; however, do not decide to take these on your own without first checking with your doctor. While you are using vincristine, your doctor may want you to drink extra fluids so that you will pass more urine. This will prevent kidney and bladder problems and keep your kidneys working well.

Side effects needing medical attention as soon as possible: If vincristine seeps out of the vein, it may damage some tissues and cause scarring. Tell the doctor or nurse right away if you notice redness, pain or swelling at the IV site.

Other side effects needing medical attention as soon as possible: Blurred or double vision; constipation; difficulty walking; drooping eyelids; side or stomach pain; headache; jaw pain; joint pain; numbness or tingling in fingers and toes; pain in fingers and toes; pain in testicles; stomach cramps; swelling of the feet or lower legs; weakness; agitation; bed-wetting; confusion; convulsions; dizziness or lightheadedness when getting up from a lying or sitting position; hallucinations (seeing, hearing, or feeling things that are not there); lack of sweating; loss of appetite; mental depression; painful or difficult urination; seizures; trouble in sleeping; unconsciousness; unusual decrease or increase in urination; cough; fever, chills or sore throat; shortness of breath; sores in the mouth and on the lips; unusual bleeding or bruising. Nervous system effects are more likely to occur in older patients.

Side effects that usually do not require medical attention: Loss of hair; bloating, diarrhea, weight loss; nausea and vomiting; skin rash.

Vincristine has been known to cause peripheral neuropathy, the tingling, prickling and numbness sensation in the extremities. For information on peripheral neuropathy, call the Neuropathy Association at 800-247-6968 for a very informative bulletin covering this very annoying condition. http://www.neuropathy.org/



From: E. Loren Buhle, Jr. Ph.D.
Address: P.O. Box 218 Lansdowne, PA 19050
Phone: 610-622-4293
INTERNET: buhle@carelife.com
FAX: 610-622-1343

A recipe that I've used on individuals with peripheral neuropathy due to chemotherapy, diabetes and carpel tunnel surgery is: Vitamin B1 and B6...following the normal dosage on the bottle. If you can tolerate, add l-glutamine (some people get diarrhea with this). It may take 2-3 weeks of daily doses before you start to notice alleviation of the peripheral neuropathy.

I'm not sure how it works...and it doesn't work for everyone...but it is fairly safe and inexpensive (everything can be purchased at your local drugstore/health market...no specific brand)


Zinecard See Dexrazoxane

Zoledronate: (New in clinical trials)
Commonly used names: Zometa
Bisphosphonate: Bone-resorption inhibitor
How given:

Study for patients with multiple myeloma.

We are pleased to announce a new trial opening in July 1997 for patients with multiple myeloma with lytic bone lesions. This trial will be open at both UCLA and the VA Wadsworth Medical Centers. Patients will be treated in a double blind fashion with either Pamidronate 90 mg or Zoledronate (varying doses) monthly.

Zoledronate is a new biphosphonate which has been shown to be more potent than Pamidronate in preclinical studies. The preliminary objective of this trial is to determine if a dose-response relationship exists for Zoledronate. The secondary objectives are to assess the efficacy of Zoledronate therapy versus Pamidronate to prevent skeletal related events and improve bone mineral density and to assess the safety and tolerability of Zoledronate versus Pamidronate.

To participate, patients must fulfill the following criteria: Multiple myeloma with a previous skeletal related event:

* pathological fracture (includes vertebral compression fx)
* spinal cord compression
* surgery to bone lesion
* radiation to bone
* hypercalcemia

Patients who have failed first-line chemotherapy, and/or patients who have at least one lytic lesion which measures at least 1 cm in diameter will also be eligible for participation.

Patients will be excluded from participating if they fulfill any of the following criteria: Previous treatment (>4 doses) with a bisphosphonate or treatment with a bisphosphonate within 90 days.

Contact: Regina Swift, R.N., Study Contact
Address:VA Wadsworth Medical Center, Los Angeles, CA
Telephone: 310-478-3711 x 40028
email: SWIFT.REGINA@WEST-LA.VA.GOV

-----------------------
EAST HANOVER, N.J., Feb. 9 2000 /PRNewswire/ -- Novartis Pharmaceuticals
Corporation today announced Zometa(TM) (zoledronic acid for injection), an
investigational treatment for one of the most common metabolic complications
associated with cancer, has been designated for priority review by the U.S.
Food and Drug Administration (FDA).

The FDA grants priority reviews for products that may offer a significant
improvement compared to marketed products.  Actions taken on drugs given a
priority review generally are made within six months.  Under the priority
review process, the FDA is expected to rule on the approvability of Zometa by
June 21.  The new drug application for Zometa was submitted by Novartis on
December 21.

"We are extremely pleased that the FDA has designated Zometa for priority
review," said David Epstein, Chief Operating Officer, Novartis Pharmaceuticals
Corporation.  "Novartis has a long-standing commitment to the oncology
community and the priority review designation validates the potential
importance of our research in treating a frequently life-threatening
complication of cancer."

Zometa, currently the most potent intravenous (IV) bisphosphonate in
clinical trials, has been evaluated in clinical trials for the treatment of
tumor-induced hypercalcemia (TIH), a common and potentially life-threatening
disorder characterized by elevated serum calcium levels in patients with
cancer.



For More information on Drugs used to treat Myeloma:
Cleveland Clinic Multiple Myeloma Program Drug Information Page. http://www.ccf.org/cc/mm/frames32.htm

List of Other Chemotherapy Drugs: http://www.tirgan.com/chemolst.htm


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Last Updated: 06/21/2001