Biological markers and treatment as prognostic factors in multiple myeloma

Sammanfattning: Multiple myeloma (MM) is an incurable disease with an increasing number of treatment options. The introduction of what are called novel drugs (bortezomib, lenalidomide and thalidomide) was an important step. These treatments have been well studied in clinical trials that involve selected patient groups and that focus on a specific treatment in a specific line of treatment. However, there is scarce information on the survival as a function of the entire treatment sequence. We wanted to clarify the effect of these treatments in a real-life setting. Furthermore, there are several well-known prognostic factors for MM, but the impact of those factors on survival in the era of novel treatment is not fully understood. In this thesis we aimed to: 1) understand in which order the treatments should be given, 2) define factors affecting prognosis, 3) increase the knowledge of cytogenetic abnormalities and their influence on prognosis and choice of treatment. In Paper I, we retrospectively analysed the outcome in high-dose treated (HDT) patients. The patients were divided according to induction therapy. 142 patients had received conventional chemotherapy with either vincristine, doxorubicin, dexamethasone (VAD) or cyclophosphamide, betamethasone (CyBet) and 94 patients had received bortezomib, cyclophosphamide, betamethasone (VCB). We found that the VCB patients had a quicker and better response than the VAD/CyBet group as well as a longer time to progression. In Paper II, we investigated 1 638 consecutive MM patients and compared their survival with that of a sex- and age-matched normal population. The use of novel agents as upfront treatment in non-HDT patients resulted in a significantly longer overall survival (OS) compared to those who received conventional chemotherapy. The OS was further improved by using novel agents in both first and second line of treatment and for these patients the OS approached the survival in the matched normal population. Paper III focused on MM patients with renal impairment at diagnosis. Previous studies have demonstrated the negative impact of renal impairment when conventional chemotherapy is used. We could confirm these findings. However, novel agents significantly improved the OS of non-HDT patients with renal impairment. Moreover, the difference in survival between those with and those without renal impairment vanished with the use of novel agents. Despite high response rates to novel treatment, approximately 20% of the patients do not respond to bortezomib therapy. In Paper IV, we demonstrated that changes associated with del(8)(p21) might be one explanation to bortezomib resistance. We found that MM cells without del(8)(p21) responded to bortezomib treatment by upregulating the pro-apoptotic TRAIL receptors, thus making the cells more sensitive to TRAIL/APO2L-mediated apoptosis. However, in cells with del(8)(p21) no upregulation was seen and the cells were largely resistant to TRAIL/APO2Lmediated apoptosis. These findings were also supported by clinical observations. To summarize, with these studies we could confirm that the survival benefits with bortezomib, lenalidomide and thalidomide that have been demonstrated in clinical trials are also seen in real life. Furthermore, we demonstrate a possible resistance mechanism to bortezomib.