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What's New In Research - December 3, 2002
11.27.02
OVERALL AND EVENT-FREE SURVIVAL ARE NOT IMPROVED BY THE USE OF MYELO-ABLATIVE THERAPY FOLLOWING INTENSIFIED CHEMOTHERAPY IN PREVIOUSLY UNTREATED MULTIPLE MYELOMA PATIENTS: A PROSPECTIVE RANDOMIZED PHASE III STUDY.
Segeren CM, IMF Scientific Advisor Sonneveld P, Van Der Holt B, Vellenga E, Crookewit AJ, Verhoef GE, Cornelissen JJ, Schaafsma MR, Van Oers MH, Wijermans PW, Fibbe WE, Wittebol S, Schouten HC, Van Marwijk Kooy M, Biesma DH, Baars JW, Slater R, Steijaert MM, Buijt I, Lokhorst HM.
Dutch-Belgian Hemato-Oncology Cooperative Study Group (HOVON), Erasmus Medical Center Rotterdam (Erasmus MC) and University Medical Center Utrecht (UMCU), The Netherlands.
Blood 2002 Nov 27; [epub ahead of print]

We compared the efficacy of intensified chemotherapy followed by myelo-ablative therapy and autologous stem cell rescue with intensified chemotherapy alone in newly diagnosed with multiple myeloma. 261 eligible patients with stage II/III multiple myeloma below 66 years were randomized after remission induction therapy with VAD to receive intensified chemotherapy, i.e., melphalan 140 mg/m(2) iv divided in 2 doses of 70 mg/m(2) iv (IDM) without stem cell rescue (n = 129) or the same regimen followed by myelo-ablative therapy consisting of cyclophosphamide, total body irradiation and autologous stem cell reinfusion (n = 132). Interferon-alpha-2a was given as maintenance. Seventy-nine percent of patients received both cycles of IDM and 79% of allocated patients actually received myelo-ablative treatment.

The response rate (CR plus PR) was 88% in the intensified chemotherapy group versus 95% in the myelo-ablative treatment group. CR was significantly higher after myelo-ablative therapy (13% versus 29%; P =.002). With a median follow up of 33 months (range: 8-65 months), the event-free survival (EFS) was not different between both treatments (median 21 months versus 22 months; P=.28). Time to progression (TTP) was significantly longer after myelo-ablative treatment (25 months versus 31 months; P =.04). The overall survival (OS) was not different (50 versus 47 months; P =.41). Intensified chemotherapy followed by myelo-ablative therapy as first line treatment for multiple myeloma resulted in a higher CR rate and a longer TTP when compared to intensified chemotherapy alone. However, it did not result in a better EFS and OS.


Bone marrow angiogenesis in multiple myeloma: effect of therapy.
Kumar S, Fonseca R, Dispenzieri A, Lacy MQ, Lust JA, Witzig TE, IMF Scientific Advisors Gertz MA, Kyle RA, Greipp PR, Rajkumar SV.
Division of Hematology and Internal Medicine, Mayo Clinic, Rochester, MN, USA.
Br J Haematol 2002 Dec;119(3):665-71

Recent studies have demonstrated that angiogenesis has a role in haematological malignancies, including multiple myeloma. Multiple myeloma is characterized by inevitable relapse after standard or high-dose chemotherapy. To study the effect of chemotherapy on bone marrow angiogenesis in patients with multiple myeloma, we used two methods to evaluate bone marrow angiogenesis in patients with newly diagnosed multiple myeloma, comparing these findings with those from bone marrow obtained after standard chemotherapy. Before therapy, an increased degree of bone marrow angiogenesis and a high bone marrow plasma cell labelling index (PCLI) were predictive of poorer survival. As estimated by microvessel density (MVD), the median survivals for patients with low-grade, intermediate-grade and high-grade angiogenesis were 77, 30 and 14 months respectively. After therapy, the MVD did not change significantly. However, when patients with at least a partial response were considered separately, they showed a decrease in MVD. Post-therapy PCLI was predictive of survival, but post-therapy MVD was not. There was good correlation between angiogenesis estimated by visual grading and that determined by MVD assessment. We conclude that the degree of bone marrow angiogenesis is a prognostic marker in patients with multiple myeloma and does not decrease significantly after therapy.


Imexon activates an intrinsic apoptosis pathway in RPMI8226 myeloma cells.
Dvorakova K, Payne CM, Landowski TH, Tome ME, Halperin DS, Dorr RT.
Departments of Microbiology and Immunology.
Anticancer Drugs 2002 Nov;13(10):1031-42

Imexon is a new antitumor agent with high activity in multiple myeloma. This drug induces apoptosis, oxidative stress and mitochondrial alterations. However, it was unknown whether imexon activates an intrinsic apoptotic pathway that is associated with activation of caspase-9 or an extrinsic pathway that is induced by receptor-mediated signals such as Fas ligand characterized by caspase-8 activation. In addition, we wanted to investigate the effect of imexon on Bcl-2 family proteins. In RPMI8226 myeloma cells, imexon activated caspase-9 and -3 in a time- and concentration-dependent manner. In contrast, cleavage of procaspase-8 was observed late and only after exposure to very high concentrations of imexon. Confocal microscopy confirmed that caspase-3 is also activated after treatment with imexon. High imexon concentrations activated caspase-3 and -9 at 12 h, while caspase-8 activation occurred only at 48 h. Imexon cytotoxicity was unchanged in three RPMI8226 cell lines with different levels (low, medium and high) of FAS expression. Similarly, the levels of Bcl-2, Bax and Bcl-x were unchanged in imexon-treated cells. However, Bcl-x was translocated to the mitochondria. These data suggest that imexon-induced oxidation activates the intrinsic or mitochondrial pathway of apoptosis, involving cytochrome release and activation of caspase-9 and -3.(L) (L)


Hepatocyte growth factor in myeloma patients treated with high-dose chemotherapy.
Seidel C, Lenhoff S, Brabrand S, Anderson G, Standal T, Lanng-Nielsen J, Turesson I, Borset M, Waage A; For the Nordic Myeloma Study Group.
Department of IMPI, Division of Pathology, Karolinska Institutet, Huddinge University Hospital, Stockholm, Unit of Haematology, Lund University Hospital, Lund, Sweden, The Institute of Cancer Research and Molecular Biology, Norwegian University of Science and Technology, Trondheim, Norway, Department of Medicine and Haematology, Aarhus University Hospital, Aarhus, Denmark, Department of Medicine, Malmo University Hospital, Malmo, Sweden, and Unit of Haematology, Norwegian University of Science and Technology, Trondheim, Norway.
Br J Haematol 2002 Dec;119(3):672-676

Hepatocyte growth factor (HGF) is a cytokine produced by myeloma cells. We examined serum HGF levels in a population of young myeloma patients (median age 52 years) treated with high-dose chemotherapy. Sera from 128 myeloma patients at diagnosis and serial samples from 16 patients were analysed. Compared with 62 healthy controls, HGF was elevated at diagnosis in 25% of patients (median 0.48 and 1.08 ng/ml respectively; P < 0.0001). The 95 patients who completed therapy were analysed for the impact of HGF on survival. Median survival was not reached after 77 months in the patient group with normal HGF values (< 1.7 ng/ml, n = 69). In the group with elevated HGF (>/= 1.7 ng/ml, n = 26), median survival was 63 months (P = 0.08). In 16 patients, serum was drawn at diagnosis and at the time of expected disease remission (6 weeks to 3 months after chemotherapy). HGF values declined after treatment in 14 of these patients, from a median of 0.9 ng/ml (0.49-1.65) to 0.42 ng/ml (0.32-0.73) (P = 0.005). Our results show that in young myeloma patients HGF is elevated, and that patients with higher levels had a trend towards poorer prognosis. Treatment with high-dose chemotherapy reduced HGF in the serum of the majority of patients.


A subset of multiple myeloma harboring the t(4;14)(p16;q32) translocation lack FGFR3 expression but maintain an IGH/MMSET fusion transcript.
Santra M, Zhan F, Tian E, IMF Scientific Advisor Barlogie B, Shaughnessy J.
Blood 2002 Nov 14 [epub ahead of print]

Previous studies have revealed that that approximately 10-15% of multiple myeloma (MM) are characterized by a reciprocal t(4;14)(p16;q32) translocation that activates expression of FGFR3 and creates an IGH/MMSET fusion transcript. Current data suggests that activation of FGFR3 is the oncogenic consequence of this rearrangement. Using a combination of microarray profiling, RT-PCR and interphase FISH we show that 32 of 178 newly diagnosed MM harbor the t(4;14)(p16;q32). Importantly, 32% of these cases lack expression of FGFR3, yet express MMSET and have an IGH/MMSET fusion transcript. Interphase FISH showed that whereas the IGH/MMSET fusion was present in greater than 80% of the clonotypic plasma cells in these novel cases, there was typically a complete loss of one copy of FGFR3. These data indicate that the t(4;14)(p16;q32) and loss of FGFR3 occurred very early and suggests that activation of MMSET, not FGFR3, may be the critical transformation event of this recurrent translocation.


A Phase II trial of pegylated liposomal doxorubicin, vincristine, and reduced-dose dexamethasone combination therapy in newly diagnosed multiple myeloma patients
Mohamad A. Hussein, M.D. *, Laura Wood, R.N., M.S.N., O.C.N., Eric Hsi, M.D., Gordan Srkalovic, M.D., Ph.D., MaryAnn Karam, R.N., Paul Elson, Ph.D., Ronald M. Bukowski, M.D.
Myeloma Research Program, Cleveland Clinic Taussig Center, Cleveland, Ohio
Cancer Volume 95, Issue 10, 2002. Pages: 2160-2168

ABSTRACT

BACKGROUND
Patients with multiple myeloma (MM) have increased bone marrow angiogenesis, a low plasma cell labeling index, and multidrug resistance (the primary cause of chemotherapy failure). MM patients receiving the vincristine, doxorubicin, and dexamethasone (VAD) regimen develop resistance and cardiac and steroid toxicity. Pegylated liposomal doxorubicin (Doxil®/CAELYXTM) could potentially extend the duration of malignant plasma cell exposure to therapeutic levels of doxorubicin. This Phase II study evaluates combination pegylated liposomal doxorubicin, vincristine, and reduced-dose dexamethasone in MM patients.

METHODS
Thirty-three newly diagnosed patients with MM received intravenous pegylated liposomal doxorubicin (40 mg/m2), vincristine (2.0 mg, Day 1), and oral or intravenous dexamethasone (40 mg per day for 4 days) every 4 weeks for six or more cycles and/or for two cycles after the best response.

RESULTS
The overall response rate was 88%: 4 (12%) patients achieved a complete response, 18 (55%) a major response, and 7 (21%) a minor response. Three patients (9%) had stable and one (3%) had progressive disease. The median time to progression was 23.1 months, with 2-year and 3-year progression-free survival rates of 42% and 23%, respectively. The patient survival rate at 3 years was 67%. No patients discontinued treatment due to adverse events. Myelosuppression was manageable. The most common toxicities were Grade 3 palmar-plantar erythrodysesthesia, mucositis, and neutropenia. Only one patient experienced cardiotoxicity.

CONCLUSIONS
Substituting pegylated liposomal doxorubicin for doxorubicin in the VAD regimen and reducing the dose of dexamethasone in patients with MM improve the safety profile and convenience of the treatment regimen without compromising efficacy.


Induction of kidney allograft tolerance after transient lymphohematopoietic chimerism in patients with multiple myeloma and end-stage renal disease.
Buhler LH, Spitzer TR, Sykes M, Sachs DH, Delmonico FL, Tolkoff-Rubin N, Saidman SL, Sackstein R, McAfee S, Dey B, Colby C, Cosimi AB.
Department of Surgery, Massachusetts General Hospital, Boston, MA.
Transplantation 2002 Nov 27;74(10):1405-9

BACKGROUND
Two patients with end-stage renal disease secondary to multiple myelomas were treated with combined kidney and bone marrow transplantation in an effort to achieve donor-specific allotolerance
through the induction of mixed lymphohematopoietic chimerism.

METHODS
Two female patients (55 and 50 years of age) with end-stage renal disease secondary to kappa light-chain multiple myelomas received a nonmyeloablative conditioning regimen that consisted of 60 mg/kg cyclophosphamide intravenously (IV) on days -5 and -4; 15 mg/kg equine anti-thymocyte globulin (ATGAM) IV on days -1, +1, and +3; and thymic irradiation (700 cGy) on day -1. On day 0, the recipients underwent kidney transplantation, followed by IV infusion of donor bone marrow (2.7x10 and 3.8x10 /kg nucleated cells, respectively) obtained from a human leukocyte antigen (HLA)-matched sibling. Cyclosporine A was administered IV at a dose of 5 mg/kg on day -1, then continued orallyat 8 to 12 mg/kg per day until days +73 and +77, respectively, after which no further immunosuppression was given. Donor leukocyte infusions (1x10 /kg CD3+ T cells) were administered in an attempt to enhance the graft-versus-myeloma effect (days +66 and +112 in the first patient and day +78 in the second patient). Hematopoietic chimerism was monitored weekly by microsatellite assays.

RESULTS
Multilineage lymphohematopoietic chimerism (5%-80% donor CD3+ or CD3- cells, or both) was first detected during the second posttransplant week and was maintained for approximately 12 weeks, after which there was a gradual decline to undetectable levels (<1% donor cells) after day 105 in the first patient and after day 123 in the second patient. In both recipients, the blood urea nitrogen and creatinine levels returned to normal within 3 days. No rejection episodes have occurred. Quantification of urinary kappa light chains revealed a decline from 28 mg/dL to undetectable levels (<2.5 mg/dL) within 29 days in the first case and from 99.8 mg/dL to <10 mg/dL within 50 days in the second case. Both patients continue with normal kidney function and sustained anti-tumor responses, while receiving no immunosuppression for nearly 4 years and 2 years, respectively.

CONCLUSIONS
This nonmyeloablative regimen followed by combined HLA-matched donor bone marrow and renal allotransplantation is the first example of an intentional and clinically applicable approach to inducing renal allograft tolerance and achieving potent and sustained antitumor effects in patients with multiple myeloma.


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