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Combination Therapy With Doxil (Doxorubicin) Encouraging In Treating Newly Diagnosed Multiple Myeloma Patients BRIDGEWATER, NJ -- May 8, 2003 -- Results from a new study evaluating the combination of Doxil® (doxorubicin HCI liposome injection), vincristine and a reduced-dose dexamethasone, known as DVd, in patients with multiple myeloma were published in the November 15, 2002 issue of the journal Cancer. The study examined the efficacy, safety and convenience of the DVd regimen. Vincristine, a cancer chemotherapeutic, and dexamethasone are often given in combination with other drugs. The Phase II study, conducted at the Cleveland Clinic Myeloma Research Program of the Taussig Cancer Center, investigated the safety, tolerability and efficacy of the DVd combination regimen in 33 patients with newly-diagnosed multiple myeloma. In the study, patients received at least six cycles of the DVd regimen. During each cycle, patients were administered intravenous (IV) Doxil (40 mg/m2) and vincristine (2 mg) on the first day, and oral or intravenous dexamethasone (40 mg/day) for four days. This treatment regimen was repeated every four weeks. Eighty-eight percent (29 patients) responded to treatment with the DVd regimen. Of these patients, four (12%) achieved a complete response, defined as complete disappearance of myeloma protein from the serum and urine by immune fixation, a bone marrow biopsy demonstrating less than 3% plasma cells, the absence of monoclonal plasma cells by immune staining of the bone marrow on two occasions at least four weeks apart, and no evidence of progressive disease by any other parameters. Eighteen patients (55%) had a major response, defined as a 50 percent or greater decrease of myeloma protein from the serum and urine, while seven patients (21%) had a minor response, defined as a decrease in bone pain, an improvement of performance status by one grade, and a reduction in serum myeloma protein of 25 percent or greater. The median time to progression in the study was 23.1 months with two-year and three-year progression-free survival rates of 42% and 23%, respectively. The patient survival rate at three years was 67%. The most common Grade 3 or 4 toxicity reported in the study was palmar-plantar erythrodysesthesia (PPE) (a skin reaction that usually occurs on the palms of the hands and the soles of the feet). This occurred in five of the first nine patients enrolled; however, with improved patient education and prevention, only two of the remaining 24 patients enrolled experienced toxicity of this magnitude. Other Grade 3 and 4 toxicities reported were mucositis (inflammation and ulceration of the lining of the mouth, throat or gastrointestinal tract); neutropenia (low white blood cell count), anemia (low red blood cell count), and thrombocytopenia (low platelet count). No growth factors were necessary and no patients were hospitalized for neutropenic fevers or intravenous antibiotics. Six patients required packed red blood cell transfusions and one patient required a platelet transfusion. Only one patient experienced cardiotoxicity. Dose reductions were required in six patients and treatment was delayed due to adverse events in one patient. The incidence of Grade 1 and 2 adverse events was not reported by the authors in the publication. No patients discontinued treatment due to adverse events. Doxil, a pegylated liposomal formulation of doxorubicin, is an intravenous chemotherapy agent that has a longer half-life compared to doxorubicin. The advanced pegylated liposomal technology helps Doxil evade recognition and elimination by the immune system. This allows the pegylated liposomal doxorubicin to circulate in the body longer. The VAD [vincristine + Adriamycin (doxorubicin) + dexamethasone] combination is one of the standard regimens for the treatment of multiple myeloma. This study evaluated the DVd [Doxil + vincristine + a reduced dose of dexamethasone] regimen to determine whether this would improve the safety profile and convenience of the treatment regimen without compromising efficacy. "This phase II study evaluated DVd as an alternative to the VAD regimen. With DVd, Doxil is administered as a one hour infusion (compared to a 96 hour infusion with VAD, which also requires indwelling venous access), and vincristine as an IV push every 28 days. The results from this study are encouraging and further study of the DVd regimen in multiple myeloma is warranted," said Mohamad A. Hussein, M.D., Director of the Multiple Myeloma Research Program at the Cleveland Clinic Taussig Cancer Center, the lead investigator of the study. About Multiple Myeloma and Doxil There are more than 14,600 new cases of myeloma in the U.S. each year, representing 20 percent of blood cancers and 1 percent of all types of cancer. Multiple myeloma is a cancer of plasma cells. Plasma cells are normally present in the bone marrow and are responsible for antibody production in response to infection and other immune triggering events. In myeloma, a defective plasma cell (myeloma cell) gives rise to the much larger number of myeloma cells which build up in the bone marrow. This process disrupts the normal immune system as well as displacing the normal bone marrow cells.(1) Indication Doxil is indicated for the treatment of metastatic carcinoma of the ovary in patients with disease that is refractory to both paclitaxel- and platinum-based chemotherapy regimens. Refractory disease is defined as disease that has progressed while on treatment, or within 6 months of completing treatment. Doxil also is indicated for the treatment of AIDS-related Kaposi's sarcoma in patients with disease that has progressed on prior combination chemotherapy or in patients who are intolerant to such therapy. These indications are based on objective tumor response rates. No results are available from controlled trials that demonstrate a clinical benefit resulting from this treatment, such as improvement in disease-related symptoms or increased survival. How Doxil Works Doxil is an advanced form of doxorubicin, a liposomal formulation of doxorubicin, which means that doxorubicin is encapsulated by a fatty bilayer. The liposome is pegylated, which helps protect the drug from the immune system, resulting in the product circulating in the blood for a longer period of time. The longer circulation allows dosing once every four weeks. Administration Doxil is administered intravenously in the doctor's office or clinic. Treatment usually takes from 30 minutes to one hour, though the first treatment may be longer. * To manage adverse events such as PPE, stomatitis, or hematologic toxicity, the dose may be delayed or reduced; * Pretreatment with or concomitant use of antiemetics should be considered; and * Limited clinical experience exists in treating hepatically impaired patients with Doxil. Based on experience with doxorubicin HCl, it is recommended that Doxil dosage be reduced if the bilirubin is elevated as follows: Serum bilirubin 1.2 to 3.0 mg/dL give 1/2 normal dose, >3.0 mg/dL give 1/4 normal dose. Efficacy Doxil's refractory ovarian cancer indication was based on the results of three Phase II trials involving patients with metastatic ovarian cancer that was resistant to conventional chemotherapy. Most of the patients had been treated with two or more rounds of conventional chemotherapy, but the tumor was still progressing. In these studies, patients with refractory metastatic ovarian cancer treated with Doxil had a 13.8% (20/145) (95% CI 8.1% to 19.3%) combined response rate. The median time to response was 18 weeks, median duration of response was 39 weeks, and median time to disease progression was 16 weeks. Warnings In clinical trials, the most common side effects reported with Doxil therapy included reduced red blood cell count (anemia), reduced white blood cell count (neutropenia), nausea, hand-foot syndrome, mouth sores (stomatitis), weakness, vomiting, rash, mild hair loss, constipation, appetite loss, diarrhea, and tiredness. Some patients experienced infusion-related reactions and skin reactions. Hand-foot syndrome, also known as PPE, is characterized by symptoms of swelling, pain, redness and, for some patients, peeling of the skin on the hands and feet; in 17% of patients, these symptoms were moderate to severe. In some patients, heart-related side effects were reported, some of which were severe. Due to the serious, potentially permanent effects of some of these events, including the potential for bone marrow suppression, close monitoring is necessary. Experience with Doxil at high cumulative doses is too limited to have established its effects on the myocardium. Therefore, it should be assumed that Doxil will have myocardial toxicity similar to conventional formulations of doxorubicin HCI. Doxil should be administered to patients with a history of cardiovascular disease only when the benefit outweighs the risk. Acute infusion-associated reactions have occurred in up to 10% of patients treated with Doxil. Serious and sometimes life-threatening or fatal allergic/anaphylactoid-like infusion reactions have been reported. Medications to treat such reactions, as well as emergency equipment, should be available for immediate use. Severe myelosuppression may occur. Dosage should be reduced in patients with impaired hepatic function. Accidental substitution of Doxil for doxorubicin HCI has resulted in severe side effects. DO NOT SUBSTITUTE. The use of Doxil should be limited to physicians experienced in the use of cancer chemotherapeutic agents. Availability Doxil is available only by prescription and administered by a health care professional. It is marketed as Doxil in the U.S. by Ortho Biotech Products, L.P. and in Israel by Janssen-Cilag. It is marketed as CAELYX elsewhere by Schering-Plough. This study was supported by the Pastore Foundation, the Reisacher family and a grant from Ortho Biotech Products, L.P. For more information about Doxil, please visit http://www.Doxil.com. Full prescribing information for Doxil is available at http://www.doxil.com/05_shared_pages/01_prescribing_info.html.com. Reference: (1) International Myeloma Foundation Patient Handbook, Part 1. SOURCE: Ortho Biotech Products, L.P. E-mail this page to a friend or colleague! To print, use this version