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What's New in Research - October 22, 2002

Report from ESMO: New Proteasome Inhibitors, Biphosphonates Evaluated in Multiple Myeloma
By David JE Candlish NICE, FRANCE -- October 20, 2002

New drugs, and new strategies with older drugs, may soon provide an improvement in outcome for patients with multiple myeloma, according to data presented here at the 27th annual meeting of the European Society for Medical Oncology (ESMO). Dr. Mario Boccadoro of the Divisione Universitaria di Ematologia, in Turin, Italy, described these promising developments in the treatment of multiple myeloma (MM), a disease that still remains fatal with conventional chemotherapeutic approaches. The current treatment approach, using melphalan and prednisone chemotherapy was first introduced in the 1960s and has changed little since then. Median overall survival rates rarely exceed three years with this approach. Clearly new drugs or new strategies with older drugs are needed to improve outcomes in this disease area. The new drugs being evaluated include proteasome inhibitors and third generation biphosphonates such as zolendronate. Thalidomide is also being reassessed for a possible new role in the treatment of multiple myeloma. A proteasome inhibitor, dipeptide boronic acid or PS-341, has been shown to induce apoptosis in tumour cells in vitro and to reduce tumour burden in mice bearing a PC-3 tumour. There may also be a synergistic effect with dexamethasone. Phase I safety studies look positive and Phase I-II studies have begun to evaluate PS-341 in refractory melanoma. Biphosphonates are currently the treatment of choice for hypercalcaemia due to osteolytic lesions as they are potent inhibitors of osteoclast-mediated bone resorption. A second-generation biphosphonate, pamidronate, has been shown to prolong survival in some MM patients, also reducing bone pain and analgesic requirements. Zolendronate is a more potent third-generation biphosphonate that has proved superior to pamidronate for hypercalcaemia and skeletal metastasis. Pre-clinical studies indicate it may also have anti-tumour activity in myeloma cell lines. This is currently being assessed in clinical trials. Since being banned for teratogenicity in 1962, thalidomide has been reintroduced to clinical use as an oral agent for malignancies such as MM. It directly inhibits the growth and survival of myeloma cells and inhibits tumour necrosis factor-a and interleukin-6 secretion. Its precise mode of action in MM is still uncertain, reported Dr. Boccadoro, but "ongoing biological studies will clarify this crucial point."

A combination of dexamethasone, cyclophosphamide, etoposide, and cisplatin is less toxic and more effective than high-dose cyclophosphamide for peripheral stem cell mobilization in multiple myeloma.
Alessandro Corso, Luca Arcaini, Sabrina Caberlon, Patrizia Zappasodi, Silvia Mangiacavalli, Angela Lorenzi, Chiara Rusconi, Daniela Troletti, Maria Angela Maiocchi, Cristiana Pascutto, Enrica Morra, Mario Lazzarino
Correspondence: Alessandro Corso, MD, Division of Hematology, Policlinico San Matteo, 27100, Pavia, Italy. Fax: +39.0382.502250.
Haematologica 2002; 87: 1041-1045

Background and Objectives.
The purpose of this study was to compare the efficacy and toxicity of two regimens for peripheral blood stem cell (PBSC) mobilization in multiple myeloma (MM) patients.

Design and Methods.
From 1995 to 2001, 116 patients were enrolled in two high-dose programs including autologous transplantation, adopting two mobilizing regimens: 61 patients were mobilized with high-dose cyclophosphamide (HD-Cy) at 4 g/m2 (group I), and 55 patients with DCEP (dexamethasone, cyclophosphamide, etoposide, and cisplatin) (group II), both followed by granulocyte colony-stimulating factor (G-CSF 5 mg/Kg/day) started 48 hours after chemotherapy.

The median number of CD34+ cells harvested was similar in the two groups (5.9 vs 5.82x106 cells/kg). The target of at least 4x106 cells/kg was reached in a higher percentage of patients in the DCEP group (75 vs 59%) (p=0.05). The proportion of poor mobilizers (<2x106 CD34+ cells/kg) was 21% with HD-Cy and 13% with DCEP (P=NS). In group I, 10 patients (16%) required packed red cell transfusions, 5 patients (8%) platelet support, and the majority of patients (87%) had a neutrophil count below 500/mL, whereas none did so in group II (p=0.0009, p=0.01, p=0.0009, respectively). Neutropenia-related fever occurred in 18% of patients in group I versus 0% in group II (p=0.0005). WHO grade >II extra-hematologic toxicities (microhematuria, cystitis, infections) were seen in 8 patients (13%) of group I vs 0 in group II (p=0.007).

Interpretation and Conclusions.
DCEP is a better tolerated and more effective regimen than HD-Cy for peripheral stem cell mobilization in MM patients assigned to high-dose therapy programs.

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Multiple myeloma: role of allogeneic transplantation.
Pandit S, Vesole DH.
Department of Medicine, Medical College of Wisconsin, Milwaukee 53226, USA.
Oncology (Huntingt) 2002 Sep;16(9):1268-74; discussion 1274-6

An estimated 14,600 new cases of multiple myeloma will be diagnosed in the United States in 2002. Multiple myeloma remains an incurable disease despite significant improvements in complete response rates and overall survival through the use of autologous stem cell transplantation. Allogeneic transplantation offers the advantage of a tumor-free graft and a graft-vs-myeloma effect but has been associated with a high mortality rate from transplant-related complications-primarily graft-vs-host disease (GVHD). As immunotherapy for patients with relapsed myeloma, donor lymphocyte infusion has resulted in response rates of over 50%, but many of these responses are not durable. In addition, donor lymphocyte infusion is associated with a significant risk of moderate-to-severe GVHD. In an attempt to decrease the high transplant-related mortality of conventional allogeneic transplants and to employ the proven efficacy of immunoreactive donor T lymphocytes, the use of nonmyeloablative transplants or "mini-transplants" is increasing. This approach has succeeded in significantly reducing transplant-related mortality but still may not be sufficient in producing long-term remissions or cures in myeloma patients. A combination of an autologous transplant (to achieve maximal cytoreduction) and a mini-transplant with donor lymphocyte infusion (for the immunoablative effect of alloreactive T lymphocytes) followed by maintenance therapy (thalidomide [Thalomid], steroids, cytokines, vaccines) for long-term immunomodulation is being investigated as a potential cure for this challenging disease.

Collection of peripheral blood stem cells in newly diagnosed myeloma patients without any prior cytoreductive therapy: the first step towards an 'operational cure'?
Powles R, Sirohi B, Kulkarni S, Treleaven J, Rudin C, Sankpal S, Goyal S, Horton C, Millar B, Saso R, Singhal S, and Mehta J.
Leukaemia and Myeloma Units, Royal Marsden Hospital and Institute of Cancer Research, Sutton, UK.
Bone Marrow Transplant 2002 Oct;30(8):479-484

We have shown that primary therapy with non-myeloablative (140 mg/m(2)) high-dose melphalan (HDM) without hematopoietic support results in high response rates in untreated myeloma and very long-term survival of some patients. This study was designed to see if sufficient CD34(+) cells can be harvested at presentation in newly diagnosed patients to administer myeloablative HDM (200 mg/m(2); HDM200) with autograft as primary therapy. This may improve outcome by rapid achievement of complete remission (CR) and possible avoidance of late myelodysplasia as a consequence of non-transplant induction chemotherapy. Thirty untreated patients received 1 g/m(2) methylprednisolone daily (days 1-6) and 12-16 &mgr;g/kg G-CSF daily (days 3-6), and underwent leukapheresis on days 6 and 7. The median CD34(+) cell yield was 1.31 x10(6)/kg (range, 0.23-5.63), and was >/=1 x10(6)/kg in 73%. Cell yields were significantly lower than in 82 historical controls apheresed after completion of induction chemotherapy (median 2.16 x 10(6)/kg), and improved in patients who were apheresed again after induction chemotherapy. Three patients received primary therapy with HDM200 and autograft using these cells and attained CR. We conclude that it is possible to harvest stem cells in three-quarters of untreated myeloma patients. Increasing the number of apheresis procedures is needed to improve the number of CD34(+) cells collected.

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