Biological markers and treatment as prognostic factors in multiple myeloma
Author: Uttervall, Katarina
Date: 2015-08-28
Location: B64, Karolinska Universitetssjukhuset Huddinge, 141 86 Stockholm
Time: 09.00
Department: Inst för medicin, Huddinge / Dept of Medicine, Huddinge
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Thesis (6.667Mb)
Abstract
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.
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.
List of papers:
I. A combination regimen of bortezomib, cyclophosphamide and betamethasone gives quicker, better and more durable response than VAD/CyBet regimens: results from a Swedish retrospective analysis UTTERVALL K, Admasie J, Alici E, Lund J, Liwing J, Aschan J, Barendse M, Deneberg S, Mellqvist UH, Carlson K, Nahi H. Acta Haematol 2013;130(1):7-15.
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II. Improved survival in myeloma patients: starting to close in on the gap between elderly patients and a matched normal population. Liwing J, UTTERVALL K, Lund J, Aldrin A, Blimark C, Carlson K, Enestig J, Flogegård M, Forsberg K, Gruber A, Haglöf Kviele H, Johansson P, Lauri B, Mellqvist UH, Swedin A, Svensson M, Näsman P, Alici E, Gahrton G, Aschan J, Nahi H. Br J Haematol. 2014;164(5):684-93.
Fulltext (DOI)
Pubmed
View record in Web of Science®
III. The use of novel drugs can effectively improve response, delay relapse and enhance overall survival in multiple myeloma patients with renal impairment. UTTERVALL K, Duru AD, Lund J, Liwing J, Gahrton G, Holmberg E, Aschan J, Alici E, Nahi H. PLoS ONE [Internet]. 2014; 9(7):[e101819 p.].
Fulltext (DOI)
Pubmed
View record in Web of Science®
IV. Deletion of chromosome 8p21 confers resistance to bortezomib and is associated with upregulated decoy TRAIL receptor expression in patients with multiple myeloma. Duru AD, Sutlu T, Wallblom A, UTTERVALL K, Lund J, Stellan B, Gahrton G, Nahi H, Alici E. [Manuscript]
I. A combination regimen of bortezomib, cyclophosphamide and betamethasone gives quicker, better and more durable response than VAD/CyBet regimens: results from a Swedish retrospective analysis UTTERVALL K, Admasie J, Alici E, Lund J, Liwing J, Aschan J, Barendse M, Deneberg S, Mellqvist UH, Carlson K, Nahi H. Acta Haematol 2013;130(1):7-15.
Fulltext (DOI)
Pubmed
View record in Web of Science®
II. Improved survival in myeloma patients: starting to close in on the gap between elderly patients and a matched normal population. Liwing J, UTTERVALL K, Lund J, Aldrin A, Blimark C, Carlson K, Enestig J, Flogegård M, Forsberg K, Gruber A, Haglöf Kviele H, Johansson P, Lauri B, Mellqvist UH, Swedin A, Svensson M, Näsman P, Alici E, Gahrton G, Aschan J, Nahi H. Br J Haematol. 2014;164(5):684-93.
Fulltext (DOI)
Pubmed
View record in Web of Science®
III. The use of novel drugs can effectively improve response, delay relapse and enhance overall survival in multiple myeloma patients with renal impairment. UTTERVALL K, Duru AD, Lund J, Liwing J, Gahrton G, Holmberg E, Aschan J, Alici E, Nahi H. PLoS ONE [Internet]. 2014; 9(7):[e101819 p.].
Fulltext (DOI)
Pubmed
View record in Web of Science®
IV. Deletion of chromosome 8p21 confers resistance to bortezomib and is associated with upregulated decoy TRAIL receptor expression in patients with multiple myeloma. Duru AD, Sutlu T, Wallblom A, UTTERVALL K, Lund J, Stellan B, Gahrton G, Nahi H, Alici E. [Manuscript]
Institution: Karolinska Institutet
Supervisor: Nahi, Hareth
Issue date: 2015-08-10
Rights:
Publication year: 2015
ISBN: 978-91-7676-023-9
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