Different aspects of thalidomide treatment and stem cell transplantation in multiple myeloma patients

Abstract

Multiple myeloma (MM) is an haematological malignancy caused by an unrestrained proliferation of plasma cells (monoclonally differentiated B-cells), and part of the white blood cell count. This proliferation infiltrates the blood forming skeletal bone marrow, producing osteoclastic factors, causing local bone destruction and bone resorption, causing bone pain as one of the major symptoms. The clonally transformed plasma cells all produce the same homogeneous immunoglobulin, the so called paraprotein or M-component. This paraprotein can be detected in urine and blood serum, can cause renal failure and is indicative for a malignant condition. These malignant cells are located the blood forming bone marrow and can be detected by a bone marrow biopsy. Anemia or hypogammaglobulinaemia (immunodeficiency) can be caused by bone marrow failure due to massive infiltration of the blood forming bone marrow. The diagnosis of multiple myeloma is based on a combination of radiological, laboratory and pathological findings. For the diagnosis of MM more than 30% bone marrow infiltration with plasma cells should be present according to the WHO classification of multiple myeloma. The types of plasma cell infiltration, the immunophenotype, the accumulating chromosomal abnormalities and the microenvironment are important for tumor survival and differentiation (chapter 2). After making the diagnosis a therapy should be started. The combination of melphalan and prednisone has been standard therapy for many years. Although not proven, the only possible curative option for multiple myeloma patients is chemotherapy followed by a stem cell transplantation (SCT). A SCT can be autologous (stem cells from the patient itself) or allogeneic (stem cells from a HLA-identical family member or a matched unrelated donor). The chemotherapy combination of vincristine, doxorubicin and dexamethason (VAD) is used in many cases. and applied to eliminate the malignant plasma cells. It also eradicates the patients own blood forming haematopoiesis, resulting in bone marrow failure with slow regeneration. The regeneration of the haematopoietic bone marrow depends on the type of conditioning pre SCT (non-myeloablative or myeloablative and the method of transplantation (allogeneic or autologous). It is important to be familiar with the normal regeneration of the blood forming bone marrow, but complications can occur during regeneration with characteristic bone marrow morphology and significant dyshaematopoiesis (chapter 3). During the pretransplant period and depending on the kind of pre-treatment there may be hypoplasia, residual disease and fibrosis. Also the presence of residual tumor cells in the bone marrow after the autologous or allogeneic stem cell transplantation is important, as their presence can indicate recurrent or refractory disease (chapter 4). On the other hand the presence of a low percentage of tumor cells after the transplantation can be cleared due to graft versus tumor response and no therapy is needed. Except for VAD therapy and melphalan, thalidomide is more and more used in multiple myeloma patients. A new active immunomodulatory and anti-angiogenic drug, with a long and impressive history. First synthesized as a sedative and tranquillizer, at that time called Softenon. In pregnant women it worked very well to treat morning sickness and help them sleep. It took more than four years to find out that the drug interfered with the development of the fetus and an epidemic of children followed, born with severe malformations of the limps, ears and internal organs. Thalidomide was at that time also tested on different kinds of cancer, but because it was consigned as one of the largest medical tragedies in history, it was not used anymore for many years. After more than 25 years thalidomide made a comeback and the drug is tested on many malignant tumors. The anti-tumor effect in multiple myeloma however is one of the most effective ones sofar. In the bone marrow the anti-angiogenic effect of thalidomide could be shown in bone marrow biopsies, taken at different time points during the treatment with VAD or TAD Although only a very small amount of patients, the anti-angiogenic effect of thalidomide on the microenvironment like the amount of vessels and the endothelial cells could be visualized in these bone marrow findings (chapter 5). As expected thalidomide treatment also has side effects, including sedation, constipation, dry skin, itching and others. Most important the combination of regular multi-chemotherapy with adriamycin, thalidomide and prednisone in multiple myeloma patients was reported to be associated with increased life threatening venous thromboembolism (deep venous thrombosis and lung embolism), being much higher than in patients receiving the more conventional chemotherapy. Although multiple pro-coagulating haemostatic alterations are known in MM patients, high levels of FVIII and von Willebrand factor (VWF) and a possible disturbance in fibrinolysis were likely to be of clinical importance. The plasma hypofibrinolytic activity,VWF and FVIII potential was measured in a large number of multiple myeloma patients at time of diagnosis, during chemotherapy with either vincristine or thalidomide in combination with adriamycin and doxorubicin, and after autologous stem cell transplantation, as the fibrinolysis of an already formed thrombus could be reduced. No evidence for hypofibrinolysis in myeloma patients at the time of diagnosis was observed (chapter 6). Although a significant increase in clot lysis time occurred during both types of chemotherapy, which may result in a higher risk of venous thrombosis, there was no extra increase due to thalidomide treatment compared to the more conventional VAD treatment. But besides the hypofibrinolysis also high levels of coagulation FVIII and von Willebrand factor were shown to be important, especially when thalidomide was combined with anthracyclines and/or dexamethasone. The levels of factor VIII and von Willebrand factor (VWF) were evaluated in the blood of a large series of patients, during consecutive treatment phases of MM patients, randomized to receive TAD (thalidomide, adriamycin, dexamethason) or VAD (vincristine), followed by high dose therapy (melphalan), and autologous stem cell transplantation. Levels of VWF and FVIII increased to a similar extent during both VAD and TAD treatment (chapter 7). This may explain the increased thrombotic risk during induction treatment, but also this does not explain the increased incidence of thromboembolic events during the thalidomide treatment. Although the cause of this elevated thromboembolic risk is not known, we know now that the extra thrombotic risk in practice can be prevented by using low dosed heparin during thalidomide treatment. Concluding we can say that thalidomide in combination with dexamethason followed by stem cell transplantation is an effective therapy for MM patients. The elevated thrombotic risk due to this treatment can cause life-threatening situations. Although we found that hypofibrinolysis, coagulation factor VIII and VWF are elevated in multiple myeloma patients, these factors do not explain the extra increased risk for this side effects during the thalidomide treatment, compared to the more conventional chemotherapy. Other explanations must be responsible for the increased risk of thrombo-embolic events in multiple myeloma patient treated with thalidomide therapy and are waiting to be investigated.