Haematologica 2003 - Supplements
Haematologica 2003 - Supplements Haematologica 2003 - Supplements
MM cells digital camera detects bioluminescence emitted from luc+ MM cells when mice are injected i.v. with luciferin; c) combined use of both modalities (which is feasible due to lack of interference between signals emitted by GFP and luciferase). The marked visual contrast generated GFP+ and/or luc+ MM cells vs. non-fluorescent/non luminescent (GFP-/luc-) normal tissues, allowed us to characterize in detail the total number and size of MM lesions (even small lytic lesions which escape detection by X-rays) and to monitor, serially and non-invasively, their anatomic distribution in the skeleton, s.c. tissues, and visceral sites of potential tumor infiltration. The small size of Mmbearing mice results in limited attenuation of the GFP/luc signals, which are captured by digital cameras, for computerized quantification of MM tumor burden. Confirmatory studies in cohorts of >70 mice (for each of these imaging modalities) injected with MM cells (including RPMI-8226/S, MM-1S or MM-1R cell lines) expressing GFP+ and/or luc+ showed that long-term stable in vivo expression by MM cells of GFP and/or luc, which are functional (and thus detectable) only in live MM cells. Practically all mice (>98%) in these studies developed skeletal lesions, primarily in the axial skeleton, e.g. spine (>96 % of mice), skull and pelvis. BM homing of GFP+ MM cells was confirmed by flow cytometry (detection of cells expressing GFP+ and human CD38/CD138 markers in BM aspirates from tumor sites) and histopathological analyses. Extra-skeletal lesions were also formed (e.g. s.c. plasmacytomas in >50% of mice), but their presence did not Abstract of Presentation (Scientific Session: Mouse models for MM) significantly impact upon MM survival and quality of life, while visceral MM lesions in lung, liver, spleen or kidney developed only rarely (
9. Chemotherapy, maintenance treatment and supportive care P9.1 OPTIMAL CHEMOTHERAPY FOR INDUCTION AND MAINTENANCE Jan Westin, MD, PhD Department of Hematology, University of Lund, Sweden and the Nordic Myeloma Study Group Before therapy of a myeloma patient is started two important questions have to be answered. First, is the patient really in need of chemotherapy? If the answer is no, i.e. the patient has smoldering or stage I myeloma, he/she should be carefully watched but no active therapy given. There are no established means to delay the onset of symtomatic disease, but the results of ongoing trials using thalidomide and other drugs are awaited. Second, if the patient needs immediate therapy, next question to be raised is if he/she is a candidate for intensive therapy (usually high-dose melphalan with autologous stem cell support, given once or twice; or in a small minority of patients allogeneic bone marrow transplantation). This will today constitute the standard therapy for patients below the age of 60 (at least), 65 (in most places) or 70 years or more (at certain institutions). If the patient will undergo high-dose therapy with stem cell support up-front this decision influences the choice of initial chemotherapy. Melphalan should be avoided, since it may damage the hematopoietic stem cells and reduce the yield at the stem cell harvest. The standard pretransplant induction therapy has for many years been VAD (vincristine, adriamycin and dexamethasone), usually given as a continous 4-day infusion. This regimen is, however, both toxic and technically complex (indwelling catheter, pump, frequent hospital visits). Furthermore, neither vincristine nor adriamycin are potent antimyeloma drugs, showing minimal activitity when given as single drugs, and dexamethasone seems to be the most potent component of the drug combination. This has led to several ongoing trials, in which dexamethasone alone, dexamethasone plus thalidomide (e.g. Mayo Clinic, ECOG) or dexamethasone plus cyclophosphamide (NMSG) is compared to VAD as induction therapy before stem cell harvest and high-dose melphalan. A further advantage of a mainly dexamethasonebased induction regimen might be a shortening of the time from diagnosis/start of therapy to the high-dose melphalan (and hopefully subsequent good response). Negative might be that fewer patients would achieve a partial response on the induction therapy, but this fact does not preclude a good response to highdose melphalan. For the patients not considered for intensive therapy (and with a median age of 70 years in an unselected patient population this will still be the majority of cases) intermittent melphalan and prednisone (MP) has since more than 40 years been the therapy of choice. Since the absorption of melphalan is variable the dose should be stepwise escalated to achieve a moderate leuko- and thrombocytopenia between the courses (nadir reached 14- 21days). In patients with renal failure the dose should be reduced. High fluid intake is important. For patients with initial cytopenias, especially thrombocytopenia cyclophosphamide may be an alternative instead of melphalan. With MP a partial response can be demonstrated in 50-60 % of patients (but CR in less than 5 %), and the median duration of response is about two years. After a patient has entered a plateau phase continued MP therapy is generally considered of no value. Inspired by the dramatic effect multidrug cytostatic regimens was shown to exert in other B-cell neoplasms a very large number of clinical trials has been performed also in multiple myeloma, from the early 60-ies onwards, evaluating combination chemotherapy vs traditional MP therapy. A number of drug combinations have been investigated, most of them comprising vincristine, an anthracycline, one or two alkylating agents and corticosteroids. This led to many years of discussion regarding the advantages of different regimens, at least in certain situations, over MP. However, in the overview, performed by the Myeloma Trialists' Collaborative Group (1998), that included invididual data on 6623 patients from all known trials worldwide (n = 27), it was not possible to demonstrate that combination chemotherapy has an advantage in comparison to MP. It could neither be shown that multiagent chemotherapy conferred a survival benefit to poor-risk patients. Interferon alone was in the early 80-ies shown to induce responses in a certain fraction of newly diagnosed myeloma patients, but the addition of this drug to MP or combination chemotherapy did not convincingly increase the response rate and not the overall survival. Today several large clinical trials are ongoing, both in Europe and in the US, exploring the value of adding thalidomide and/or other drugs to the induction therapy, but no results are yet available. Patients responding to initial chemotherapy inevitably relapse after a period of varying length, months to years. Great interest has therefore been focused, and is focused today, on methods to prevent or delay relapse. Alfa-interferon has since the early 80- ties been used for this purpose in several trials, recently summarized in an overview performed by the Myeloma Trialists' Collaborative Group (2001), comprising 12 maintenance studies. Even if a significant advantage was demonstrated for interferontreated patients with regard to both time to progression and total survival (c:a 6 months), this moderate gain is by most physicians (and many patients) considered too small to upweigh the negative side-effects and the cost of the therapy. Today much interest is focused on a number of new drugs with activity in myeloma (immunomodulators, proteasome-inhibitors, arsenic compounds), and several of them are in different stages of clinical trial evaluation. Almost every clinical trial group is in one or other way including thalidomide maintenance in their running protocols. Some results from these studies may be availabe at this meeting. Other trials, in which prolonging the time in "remission" for myeloma patients with the help of chemotherapy has been explored, have not been successful. A number of options are still not fully examined, e.g. repeated post-remission chemotherapy, late intensification therapy, early treatment of "subclinical" relapses with the help of minimal residual disease status. However, it seems more realistic to believe that immunotherapy (in some form) rather than chemotherapy will be a practicable way to prolong remission or perhaps even cure myeloma patients with a heavily reduced tumor burden or a stable plateau phase. References The Myeloma Trialists' Collaborative Group: Combination chemotherapy versus melphalan plus prednisone as treatment for multiple myeloma: An overview of 6.633 patients from 27 randomized trials. J Clin Oncol. 16: 3832-3842, 1998. The Myeloma Trialists' Collaborative Group: Interferon as therapy for multiple myeloma: an individual patient data overview of 24 randomized trials and 4.012 patients. Brit J Haematol. 113: 1020-1034, 2001. S52
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MM cells digital camera detects bioluminescence emitted from<br />
luc+ MM cells when mice are injected i.v. with luciferin; c)<br />
combined use of both modalities (which is feasible due to lack of<br />
interference between signals emitted by GFP and luciferase). The<br />
marked visual contrast generated GFP+ and/or luc+ MM cells vs.<br />
non-fluorescent/non luminescent (GFP-/luc-) normal tissues,<br />
allowed us to characterize in detail the total number and size of<br />
MM lesions (even small lytic lesions which escape detection by<br />
X-rays) and to monitor, serially and non-invasively, their<br />
anatomic distribution in the skeleton, s.c. tissues, and visceral<br />
sites of potential tumor infiltration. The small size of Mmbearing<br />
mice results in limited attenuation of the GFP/luc signals, which<br />
are captured by digital cameras, for computerized quantification<br />
of MM tumor burden. Confirmatory studies in cohorts of >70<br />
mice (for each of these imaging modalities) injected with MM<br />
cells (including RPMI-8226/S, MM-1S or MM-1R cell lines)<br />
expressing GFP+ and/or luc+ showed that long-term stable in<br />
vivo expression by MM cells of GFP and/or luc, which are<br />
functional (and thus detectable) only in live MM cells. Practically<br />
all mice (>98%) in these studies developed skeletal lesions,<br />
primarily in the axial skeleton, e.g. spine (>96 % of mice), skull<br />
and pelvis. BM homing of GFP+ MM cells was confirmed by<br />
flow cytometry (detection of cells expressing GFP+ and human<br />
CD38/CD138 markers in BM aspirates from tumor sites) and<br />
histopathological analyses. Extra-skeletal lesions were also<br />
formed (e.g. s.c. plasmacytomas in >50% of mice), but their<br />
presence did not Abstract of Presentation (Scientific Session:<br />
Mouse models for MM) significantly impact upon MM survival<br />
and quality of life, while visceral MM lesions in lung, liver,<br />
spleen or kidney developed only rarely (