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What's New In Research - March 6, 2003
CD34+ counts after etoposide and cyclophosphamide plus G-CSF mobilization versus G-CSF alone in multiple myeloma patients undergoing autologous transplantation
Pierce T. N., Scott L. M., White M., Agura E., Berryman R. B., Fay J. W., Vance E., Pineiro L.
Biology Blood Marrow Transplant February 2003 € Volume 9 € Number 2

There were 83 patients who had an autologous transplant for multiple myeloma. All patients had a myeloablative regimen with 26 (31%) receiving Melphalan, 55 (66%) received Melphalan/Total Body Irradiation (TBI). There was 1 patient who received ThioTepa/TBI and 1 who received Cyclophosphamide/ TBI as the conditioning regimen. Of the 83 pts, there were 58 (70%) who received mobilization with a continuous infusion of etoposide (2400mg/m2 over 34 hours) followed by cyclophosphamide 150 mg/kg followed by G-CSF at a dose of 5 mcg/kg/day. There were 25 patients (30%) that received mobilization with G-CSF only at a dose of 16 mcg/kg/day. For the patients who received chemotherapy mobilization, the average number of PBSC collections required was 1.8 (Range 1 to 7, median=1). Of the patients who received G-CSF mobilization, the average number of collections was 2.8 (Range 1 to 5, median=2). The average CD34+ collection was 31.9 ¥ 106/kg with the chemotherapy mobilization group and 6.7 ¥ 106/kg with the GCSF alone group. The target cell dose was 2.0 ¥ 106/kg. Chemotherapy with etoposide and cyclophosphamide is an effective means for mobilization of large numbers of CD34+ cells. This may offer an advantage over G-CSF mobilization alone in multiple myeloma patients who may benefit from receiving additional cytoreductive therapy.

Non-myeloablative stem cell transplantation (SCT) is safe and effective for patients with multiple myeloma
Moreb J., Cogle C. R.,Leather H., Wiggins L., Finiewicz K., Khan S. A., Reddy V.,Wingard J. R.,
Biology Blood Marrow Transplant February 2003 € Volume 9 € Number 2

Allogeneic SCT can be curative in multiple myeloma (MM), however the high transplant related morbidity and mortality (TRM) limit this therapy to young, low-risk patients.

Purpose: The purpose of this study was to determine safety and efficacy of non-myeloablative stem cell transplant (NST) for high-risk patients with MM. Patients and Methods: From September 1999 to June 2001, eight MM patients with a median age of 49 years (range, 44 to 62), received allografts from HLA-matched siblings (n=6) or unrelated donors (n=2). Prior to NST none were in complete remission (CR) and 4 had progressive disease (PD). Six patients had a prior autologous transplant. Median time from diagnosis to NST was 33 months (range, 5 to 64). The conditioning regimen included fludarabine, anti-thymocyte globulin and busulfan. Peripheral blood stem cell grafts were administered to all patients. Results: All patients had prompt myeloid and platelet engraftment. Acute graft versus host disease (GVHD) (three grade I, two grade III) occurred in 5 of 8 patients (62%), at a median time of 26 days (range, 11 to 106 days). Four patients (50%) developed chronic GVHD (2 limited, 2 extensive). Two patients with no GVHD and PD received donor leukocyte infusion (DLI) (1¥108 CD3/kg). One patient receiving DLI subsequently developed grade I acute GVHD. The conditioning regimen was well tolerated with no patients developing VOD or severe mucositis. During neutropenia, only one patient developed a line-associated gram positive bacteremia. While on immunosuppressants, seven patients developed opportunistic infections, including CMV and HSV colitis, cutaneous zoster, polyoma BK cystitis, mucocutaneous candidiasis, pulmonary aspergillosis and Strongyloides infection. Only one patient died of opportunistic infection. With a median follow-up of 13 months, three (38%) achieved CR, two (25%) PR, one MR, one SD, and one PD. All disease responses were observed after development of GVHD. Two patients (25%) died before 100 days: one of CNS failure secondary to possible FK506 toxicity and another due to opportunistic lung infection. One year EFS and OS are 50% and 75%, respectively.

Conclusions: NST with fludarabine, anti-thymocyte globulin and busulfan conditioning is well tolerated in high-risk patients with MM. In addition, a graft versus myeloma effect is observed.

Myeloablative conditioning with TBI/VP-16 with allogeneic stem cell transplantation for multiple myeloma: High response rate and prolonged progression free survival
Goldstein S. C., Perkins J., Field T., Janssen W.. Alsina M., Sullivan D., Fields K., Smith C.
H. Lee Moffitt Cancer Center and Research Institute at the University of South Florida, Tampa, FL.
Biology Blood Marrow Transplant February 2003 € Volume 9 € Number 2

Although High Dose Therapy with autologous peripheral blood stem cell transplantation has improved the complete response rates and overall survival for patients with Multiple Myeloma (MM), making it the standard of care for many patients (pts) with chemosensitive disease; autotransplantation has not demonstrated curative potential despite extensive evaluation with long-term follow-up. Despite the demonstration of an immunologic graft vs myeloma effect, the overall success of myeloablative conditioning with allogeneic transplantation for patients with MM has been limited by treatment related mortality (TRM) as well as relapse. Whereas novel strategies such as non-myeloablative conditioning may lower the early TRM, they have thus far have had only marginal success in long term disease control. Novel myeloablative conditioning regimens with acceptable toxicity carry the potential advantage of tumor cytoreduction and establishment of donor chimerism to improve long term disease control. We report the long term follow-up of 14 consecutive patients with MM who have undergone myeloablative conditioning with either BuCy2 (n=7) or TBI/VP-16 (n=7) followed by allogeneic bone marrow stem cell transplantation from HLA-identical sibling donors. Median age for all patients is 46 years. The probability of Overall Survival (OS) at 2.5 years for all patients, BuCy2 pts, and TBI/VP-16 pts is 36% (SE 13%), 14% (SE 13%), and 57% (SE 19%), respectively. The probability of Event-Free Survival (EFS) at 2.5 yrs is identical to the OS. Of note, the probability of Progression-Free Survival (PFS) at 2.5 years, in which treatment related deaths are censored, is 78% (SE 14%) for all pts, 50% (SE 25%) for BuCy2 pts, and 100% for TBI/VP-16 pts. Surviving patients after myeloablative conditioning have been followed without relapse for a minimum of 4 years. 100 day TRM for all pts was 28%. Although this analysis is limited by sample size, these results demonstrate prolonged disease free survival for pts with MM after myeloablative conditioning with high dose TBI/VP-16 followed by allogeneic stem cell transplantation. This regimen is well tolerated and warrants further investigation as a potentially curative strategy in young MMpatients with HLA-identical donors.

Thalidomide therapy in patients with refractory or relapsed multiple myeloma
[Article in Japanese]
Ochiai N, Shimazaki C, Uchida R, Fuchida S, Okano A, Ashihara E, Inaba T, Fujita N, Adachi Y, Nishio A, Nakagawa M.
Kyoto Prefectural University of Medicine, Second Department of Medicine.
Publication: Rinsho Ketsueki 2002 Dec;43(12):1045-9

We treated seven refractory or relapsed myeloma patients resistant to conventional chemotherapy with thalidomide. We started thalidomide at 100 mg daily and the dose was increased up to 300 mg if the patient could tolerate it. The patients were evaluated at four weeks and 12 mg of dexamethasone was added for four days when the patient failed to respond to thalidomide treatment. One patient was excluded from the study because of general fatigue. Two of the six patients responded to thalidomide alone and three of the remaining four patients responded to the combination with dexamethasone. The most common adverse effect was sleepiness which was seen in three patients. Two patients showed pancytopenia (Grade 3), constipation and skin eruption. Of the six patients four needed reduction of the thalidomide dose to 200 mg because of adverse effects. Plasma levels of TNF-alpha, IL-6, bFGF and VEGF were measured before and after four weeks. High plasma bFGF levels were seen in responding patients. In conclusion, treatment with thalidomide alone or in combination with dexamethasone is feasible and effective in refractory or relapsed myeloma patients. Further study is required to clarify the role of thalidomide in the therapeutic strategy for multiple myeloma.

Barriers to second transplant for multiple myeloma in a randomized autologous tandem trial
Wilson R. L., Gray M. L., Giralt S.
Biology Blood Marrow Transplant February 2003 € Volume 9 € Number 2
Blood and Marrow Transplantation, University of Texas M.D, Anderson Cancer Center, Houston, TX.

The objective of this analysis is to identify barriers to second transplant in multiple myeloma patients in a randomized tandem transplant setting. Patients were assessed from a current multiple myeloma trial at University of Texas M.D. Anderson Cancer Center. A total of 120 patients will be treated with an initial autologous transplant. All patients are randomized prior to initial transplant to receive a 2nd autologous transplant with a different regime vs. oral maintenance therapy if complete remission(CR) is not achieved by day 180. Those patients that achieve CR are not eligible to receive the assigned treatment. To date, a total of 49 patients have undergone initial transplant with 31 of those patients beyond 180 days post-initial transplant and evaluable to receive the assigned treatment. Seventeen of the 31 were randomized to the 2nd transplant and of these 17, 5 were in CR. The remaining 12 did not achieve CR and were eligible to receive the assigned 2nd transplant. Only 3 of the eligible 12 underwent second autologous transplantation. Reasons for not proceeding with the planned treatment are as follows: 5 patients refused, 2 were denied by insurance coverage, and 2 were disqualified from study due to external factors. One patient was disqualified due to interim treatment from the local physician. The final patient developed complications secondary to CMV pneumonia deeming him ineligible for second transplant. Regardless of the efforts made pretransplant to educate the patient of the protocol requirements, one could speculate the reasons for patient refusal for the 2nd transplant. This might include length of time between transplants, time away from home, financial burden, poor initial transplant experience or differences between the two transplants, the 1st can be outpatient, and the 2nd is inpatient. Further analysis is warranted to investigate potential reasons for patient declination, which make up the majority of this group at 55.56%. Insurance denials and disqualification account for 44.44% of non-2nd transplant participants. This analysis represents 25.83% of the total study population.

Non-myeloablative allogeneic peripheral stem cell transplantation in multiple myeloma: 2 years experience in a single center
Lie K., Liang R., Kwong Y., Chim C., Au W., Ma S. -- Queen Mary Hospital, Hong Kong, Hong Kong.
Biology Blood Marrow Transplant February 2003 € Volume 9 € Number 2

Multiple myeloma (MM) is considered incurable by chemotherapy alone and the role of standard allogeneic stem cell transplantation (allo-SCT) remains limited because of relatively high treatment-related mortality (TRM). Non-myeloablative allo-SCT is associated with satisfactory engraftment but less toxicity, which is essential in the heavily pretreated elderly patient with MM. We report our 2 years experience on 10 MM patients receiving non-myeloablative allogeneic PBSC transplantation using fludarabine 30 mg/m2 daily for 3 days plus total body irradiation 1.5 Gy daily for 2 days as conditioning. All patients received repeated courses of chemotherapy for active disease before SCT. Eight patients had full HLA-matched siblings donor, 1 had a one major HLA-antigen mismatched sibling and 1 had a HLA-matched daughter donor. All 10 patients had satisfactory engraftment before D21. No TRM was observed during the whole follow up period. Acute GVHD developed in 3 patients (2 at grade III and 1 at grade IV) and 7 patients had chronic GVHD (3 acute GVHD cases included). At a median follow up of 1 year, 2 patients had complete remission (CR), 3 patients had partial response (PR), 3 patients had no response (NR) and 2 patients were too early for assessment. No relapse was observed in the 2 patients with CR. Only one NR patients had donor lymphocyte infusion (DLI) and 2 NR patients had thalidomide. In conclusion, nonmyeloablative allo-SCT in multiple myeloma is effective with less toxicity and TRM. However, a longer follow up period and more cases are required before a definite conclusion can be reached.

The effect of glutamine on disease progression in multiple myeloma (MM) patients receiving high-dose melphalan
Crook J. L., Wasalenko J. K., Myhand R. C.--Walter Reed Army Medical Center, Washington, DC.
Biology Blood Marrow Transplant February 2003 € Volume 9 € Number 2

Mucositis, a frequent complication of high-dose therapy, is associated with major morbidity and mortality. Glutamine is one agent that has been shown to protect the gastro-intestinal epithelium from the toxic effects of chemotherapy. Although oral glutamine has been used successfully to prevent transplant related mucositis, the potential for glutamine mediated tumor protection has not been systematically investigated. In order to identify any possible tumor protective effect of glutamine in high-dose therapy, we performed a retrospective review of consecutive patients who received high-dose therapy with melphalan (200 mg/m2) for MM either with or without glutamine. Between July 1997 and August 2002, 41 patients were treated at our institution. The first 17 patients did not receive glutamine prophylaxis. In July 2000, we incorporated glutamine (10 gm po TID starting with the administration of the preparative regimen) standardly for mucositis prophylaxis. Twenty-four patients received glutamine. Eleven patients were lost to follow up (6 no glutamine, 5 glutamine). The response rate to transplant in the no glutamine group was 43%, compared with 47% in the glutamine group. In the no glutamine group, 8/11 patients (73%) were progression free at a median follow-up of 19 months, compared with 15/19 (79%) in the glutamine group at a median follow-up of only 9 months. Interestingly, of the patients who relapsed, the median time to relapse was 17 months in the no glutamine group and only 6 months in the glutamine group. Our observation is that glutamine at this dose may be associated with early relapse and poorer progression-free survival (PFS) in MM patients treated with high-dose melphalan. These data support the in vitro examination of glutamine in tumor cell lines to discern if glutamine abrogates the cytotoxic effects of chemotherapy. Future prospective trials should scrutinize response rates, PFS, and overall survival in glutamine and nonglutamine treated patients especially if higher-doses are utilized.

Monoclonal gammopathy of undetermined significance
[Article in French]
Chaibi P, Merlin L, Thomas C, Piette F. -- Service de Medecine Interne Geriatrique, Hopital Charles-Foix,
Ann Med Interne (Paris) 2002 Nov;153(7):459-66

Monoclonal gammopathy of undetermined significance (MGUS) is an asymptomatic disorder with serum monoclonal immunoglobulin less than 30 g/l. It preferentially affects elderly patients; MGUS prevalence is about 1% in the general population and about 10% in patients aged over 80 years. MGUS diagnosis is based on elimination of other causes of serum monoclonal immunoglobulin, particularly multiple myeloma. Within the 20 years following diagnosis of MGUS, about 25% of patients will evolve towards myeloma or other malignant lymphoproliferative disorder. No factor has been identified to date which can efficiently predict this evolution. Recent data concerning immunophenotype, cytogenetics and molecular biology of plasma cells demonstrate the link between MGUS and multiple myeloma. MGUS clearly appears now as a plasma cell monoclonal pathology with reduced malignity. Soon, new biological data would help to discriminate patients with MGUS who will remain asymptomatic life-long from those who will evolve towards malignant lymphoproliferative disorder.

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