Oral melphalan pharmacokinetics--relation to dose in patients with multiple myeloma

The pharmacokinetics of melphalan have been studied after oral doses of 5, 10 and 20 mg, and 10 mg i.v. Seven patients with multiple myeloma received the drug on 4 consecutive days and the concentration of melphalan was determined by liquid chromatography. Melphalan was rapidly absorbed after p.o. administration. Absorption lag-time was less than 1 h. The median time for attaining the peak concentration was 1.12 h (97% confidence interval: 0.68-1.55), 1.21 h (0.85-1.43) and 1.08 h (0.84-1.29) after doses of 5, 10 and 20 mg. The bioavailability showed large interindividual variations, and was not significantly affected by the dose given. There was a significant decrease in bioavailability during the treatment course (P less than 0.05). Absorption of melphalan obeys first-order kinetics in the dose interval studied. The results indicate that it might be of benefit to administrate oral melphalan for fewer days than the usually used 4 day regimen, in an attempt to achieve a higher bioavailability.     

High-dose melphalan versus busulfan, cyclophosphamide, and etoposide as preparative regimens for autologous stem cell transplantation in patients with multiple myeloma

High-dose chemotherapy (HDC) with autologous stem cell transplant (ASCT) has improved response rates and survival for patients with multiple myeloma (MM). We report a single-institution experience using two conditioning regimens, busulfan, cyclophosphamide, and etoposide (BCV) or high-dose melphalan (HDM). Between July 1992 and August 2003, 110 patients with MM (median age=56.1) underwent HDC with ASCT using either BCV (n=62) or HDM (n=48) in sequential cohorts as the preparative regimen. Overall response rates, progression-free survival, and median overall survival were similar. BCV and HDM confer similar long-term outcomes with similar toxicity profiles as conditioning regimens prior to autologous stem cell transplant in patients with MM.     

High-risk multiple myeloma treated with high-dose melphalan.

PURPOSE: This study was undertaken to evaluate the efficacy and toxicity of high-dose melphalan (HDM) 140 mg/m2 in poor-risk multiple myeloma (MM). PATIENTS AND METHODS: Thirteen patients were previously untreated, and 13 had been pretreated with vincristine, Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), and dexamethasone (VAD) for refractory or relapsed MM. RESULTS: All 11 fully assessed, untreated patients responded, and six achieved a complete response. Remissions were of excellent quality, but response duration--a median of 16 months--was short. This was probably due to the high incidence of unfavorable prognostic signs, like a high beta 2-microglobulin (B2M) and/or a high plasma cell labeling index (LI). None of the nine pretreated patients with a measurable M component had more than 50% reduction of M component after HDM, indicating that intensive treatment has no effect on a residual tumor population. The relapse-free period after HDM in this group of patients (median, 9 months) was not better than in a historical control group of patients treated with VAD alone. The major complications due to the prolonged myelosuppression were severe infections. After primary HDM, median time to recovery to greater than 0.5 x 16(9) granulocytes was 30 days; in previously treated patients, the recovery period was even longer. There were three toxic deaths. Fulminant relapses with features of J-chain disease were frequently observed, indicating a dedifferentiated tumor, probably induced or selected by the HDM. CONCLUSIONS: HDM is an effective treatment resulting in good remissions for untreated MM. However, other therapy strategies should be explored first, focusing on the reduction of toxicity and prolongation of the relapse-free period, before HDM can be recommended as first-line treatment for the younger MM patient.     

Renal function in the elimination of oral melphalan in patients with multiple myeloma

Summary Pharmacokinetic studies in 11 patients with multiple myeloma were undertaken on the first and last days of one course of chemotherapy. The drug was administered PO in single doses of 6–14 mg daily. Melphalan concentrations were determined by high-performance liquid chromatography. The interpatient variability of pharmacokinetic parameters noted by other authors was observed. Regression analysis showed a significant positive correlation between the elimination rate constant for melphalan and renal function (P=0.003). The form of the line which describes the overall elimination rate constant for melphalan is given by the equation: K_el=5.67×10^-3+[4.90×10^-5xGFR]. There was also a significant negative correlation between renal function and the area under the plasma melphalan concentration/time curve (P=0.006). In vitro stability studies of melphalan in plasma at 37°C and pharmacokinetic data suggest that hydrolysis and renal clearance are the major mechanisms of melphalan elimination. This work shows quantitatively the relationship between renal function and drug elimination and how the data may be used in predicting melphalan half-life from creatinine clearance.The work described in this paper was supported by the Northern Ireland Leukaemia Research Fund     

High-dose cytosine arabinoside in multiple myeloma

In 14 patients with advanced refractory multiple myeloma, the effect of high-dose cytosine arabinoside (ara-C) administration was evaluated. There was one partial remission among 13 evaluable patients who received 2 g/m² intravenously over 2 hr every 12 hr, for a total of 2–8 g/m² per course, repeated every 3–4 weeks. Myelosuppression constituted the dose-limiting toxicity, causing two treatment-related deaths from infection and bleeding. Prior extensive therapy, a low percentage of cells in S phase and low levels of intracellular ara-CTP accumulation in the bone marrow could explain the resistance of myeloma to this treatment.     

High-dose chemotherapy with autologous hematopoietic stem cell transplantation in patients with multiple myeloma

Multiple myeloma, for all practical purposes, remains an incurable malignancy; however, 5-year survival has improved substantially during the past 30 years. A major contribution to improved outcome is the use of high-dose chemotherapy and stem cell transplantation. This multifaceted approach to therapy requires an understanding of appropriate induction therapy, techniques for stem cell mobilization, appropriate conditioning and supportive care. Also of importance are prognosis, features that predict outcome, the suitability of transplant candidates, and post-transplantation maintenance therapy.     

High-dose chemotherapy with autologous hematopoietic stem cell transplantation in patients with multiple myeloma

Multiple myeloma, for all practical purposes, remains an incurable malignancy; however, 5-year survival has improved substantially during the past 30 years. A major contribution to improved outcome is the use of high-dose chemotherapy and stem cell transplantation. This multifaceted approach to therapy requires an understanding of appropriate induction therapy, techniques for stem cell mobilization, appropriate conditioning and supportive care. Also of importance are prognosis, features that predict outcome, the suitability of transplant candidates, and post-transplantation maintenance therapy.     

High-dose busulfan in patients with myeloma.

PURPOSE: To evaluate the use of high-dose busulfan (HDB) with autologous bone marrow transplantation (ABMT) in patients with myeloma. PATIENTS AND METHODS: Fifteen patients received HDB (16 mg/kg), eight of whom received high-dose melphalan (HDM) but had experienced a short remission or progression-free interval. Two patients had received HDM on two previous occasions, one had no response to low-dose melphalan, and four had impaired renal function (edathamil clearance < 40 mL/min). All patients received induction chemotherapy before HDB. RESULTS: Two patients were in complete remission (CR) after induction chemotherapy before HDB. Of the remaining 13 patients, four (31%) achieved CR and two (15%) achieved a partial remission for an overall response rate of 46%. There were three treatment-related deaths, but the toxicity was otherwise predictable and manageable. CONCLUSIONS: In heavily pretreated patients, HDB results in a relatively high response rate. It can also be used safely in patients with renal impairment who are not suitable for HDM.     

High-dose melphalan with autotransplantation for refractory multiple myeloma: results of a Southwest Oncology Group phase II trial.

PURPOSE: To evaluate high-dose melphalan followed by autologous stem-cell transplantation in patients with refractory multiple myeloma. PATIENTS AND METHODS: Multiple myeloma patients with alkylating agent or vincristine/doxorubicin/dexamethasone-refractory disease were eligible for the phase II multi-institutional Southwest Oncology Group trial S8993. Patients up to age 70 years were enrolled between April 15, 1991, and May 1, 1996. Patients without prior stem-cell collection were primed with high-dose cyclophosphamide (HD-CTX; 6 g/m(2)) and granulocyte-macrophage colony-stimulating factor. After stem-cell procurement, patients received melphalan 200 mg/m(2) with autologous transplantation. Upon recovery from melphalan, patients were to receive interferon alfa-2b until relapse. RESULTS: Seventy-two patients were enrolled onto S8993; five were ineligible and one received no therapy. Of the 66 assessable patients, 56 patients underwent the transplant procedure; 54 were assessable for response and 56 for toxicity. The response to HD-CTX (n = 37) included three complete remissions (CRs; 8%) and five partial remissions (PR; 14%); response to melphalan (n = 54) included 16 CRs (30%) and 19 PRs (35%), for an overall CR and >/= PR (n = 66; intent-to-treat) of 27% and 58%, respectively. Toxicities included six treatment-related deaths: two during HD-CTX and four during transplantation. The median progression-free survival (PFS) and overall survival (OS) durations on an intent-to-treat basis from transplant registration was 11 months and 19 months (95% confidence interval, 14 to 29 months), respectively. The 3-year actuarial PFS and OS rates were 25% and 31%, respectively. CONCLUSION: High-dose therapy with melphalan 200 mg/m(2) is feasible with high response rates (58% overall) and an OS of 19 months in patients with refractory multiple myeloma.     

Bortezomib,melphalan, and prednisone in elderly patients with relapsed/refractory multiple myeloma

BACKGROUND:

In elderly patients with newly diagnosed multiple myeloma (MM), the addition of bortezomib to standard, combined oral melphalan and prednisone (MP) significantly increases the response rate and event‐free survival compared with MP alone.

METHODS:

In this phase 1/2 trial, the authors assessed the dosing, efficacy, and safety of a lower dose‐intensity MP schedule plus weekly bortezomib as salvage treatment for elderly patients with MM. To assess the maximum tolerated dose, 19 patients who had relapsed/refractory MM after 1 or 2 lines of treatment entered the first phase of the study. They received melphalan at a dose of 24 mg for 28 days; bortezomib 1.3 mg/m² on days 1, 8, 15, and 22; and prednisone at a dose of 50 mg every other day of a 28‐day cycle for a total of 9 cycles. At the end of the first phase, based on the good efficacy and acceptable toxicity of this combination, an additional 23 patients were enrolled.

RESULTS:

After a median follow‐up of 21 months, of 42 patients who relapsed, 24 (57%) obtained at least a partial response, 4 had stable disease, and 11 had progressive disease. The median time to progression was 18 months, and the median overall survival was 30 months. Grade 3 and 4 toxicity was observed in 16 of 42 patients (38%) and was more frequent during the early cycles.

CONCLUSIONS:

A weekly infusion of bortezomib associated with lower dose‐intensity MP induced a high proportion of responses and was well tolerated in elderly patients with relapsed/refractory MM. Cancer 2013. © 2012 American Cancer Society.     

Pegylated liposomal doxorubicin, melphalan and prednisone therapy for elderly patients with multiple myeloma

Melphalan & Prednisone (MP) is considered as the standard therapy for Multiple Myeloma (MM) patients not eligible for high-dose therapy. Here, we report the results of a phase I-II study to evaluate the feasibility and efficacy of the association of PLD to the conventional MP regimen during the first six cycles of the front-line therapy for untreated MM patients older than 70. Thirty patients were included in the study with a median age of 77 years (71-84) and a M/F ratio of 17/13. The phase I of the study demonstrated that the maximum tolerable dose of PLD in this setting was 30 mg/m(2), so it was the final dose evaluated in the study. Twenty-nine patients were valuable for response, which was: complete in 4 (14%) partial in 15 (52%) minor/no changes in 7 (24%) and progressive in 3 (10%). The median progression free survival (PFS) was 24 months. The median overall survival (OS) has not been reached yet, with a 3-year probability for OS and PFS of 52 and 37%, respectively. Haematological toxicity was frequent but usually weak/moderate (grades 1 & 2 of the WHO scale) and it was resolved only with dose delays. Infection was a relatively frequent event (30% of patients), but only in 4 cases it was of grade 3. No cases of palmar-plantar erythrodysesthesia were observed. In conclusion, pegylated liposomal doxorubicin can be safely added to the other chemotherapeutic drugs in the treatment of elderly MM patients, which can be very useful for patients in whom novel agents are not tolerated or inefficient.     

Pharmacokinetics of oral melphalan in relation to renal function in multiple myeloma patients

The impact of renal function on oral melphalan pharmacokinetics was studied in 15 patients with multiple myeloma. A two-fold interindividual variation in the plasma concentration-time curve (AUC) was found. An increase in AUC and melphalan mean residence time (MRT) was noted in patients with renal dysfunction. No correlation was found between GFR and the terminal plasma half-life time. We conclude from these results that renal dysfunction is associated with an increase in AUC and MRT of oral melphalan. A careful follow-up of hematological toxicity and possibly a dose reduction of melphalan are proposed for myeloma patients with renal impairment.     

肽胺哌啶酮联合MP化疗方案治疗多发性骨髓瘤的疗效观察

目的：观察肽胺哌啶酮联合MP方案，即马法兰＋泼尼松（强的松）治疗多发性骨须瘤的疗效及其毒副作用。方法：确诊的多发性骨髓瘤病人12例，肽胺哌啶酮－MP方案；肽胺哌啶酮自MP方案开始持续给药，每晚睡前口服，剂量从每天100mg开始，每周日剂量递增50mg，至病人不能耐受或最高至每日400mg;MP方案每月一个疗程。结果：部分缓解6例（50％），进步3例（25％）。总有效率为9／12（75．0），有效的病人中7例在4周内起效，肽胺哌啶酮每天100－400mg不等，中位剂量每天225mg，常见的副反应为皮疹，便秘，嗜睡、乏力、头昏，水肿等，结论：肽胺哌啶酮＋MP方案治疗多发性骨髓瘤副反应少，耐受性好，且反应率可能提高。     

High-dose therapy with peripheral blood progenitor cell transplantation in multiple myeloma

Background: The objective of our study was to evaluate the efficacyand toxicity of a high-dose melphalan-based (HD-Mel) therapy with or withouttotal body irradiation (TBI) followed by peripheral blood progenitor (PBPC)transplantation in patients with multiple myeloma (MM).Patients and methods: Between June 1992 and May 1996, 100 patients(67 males/33 females) with a median age of 51 years (range 30–65) weretransplanted at our centre. PBPC were collected during G-CSF-enhancedleukocyte recovery following high-dose chemotherapy. Fifty patients weretreated with TBI + melphalan 140 mg/m², while 50 patientsreceived melphalan 200 mg/m².Results: Following PBPC autografting, the median time to reachplatelets 20 × 10⁹/l and neutrophils 0.5 ×10⁹/l was 11 and 14 days with no difference between thetreatment groups. In the TBI group significantly longer periods of totalparenteral nutrition were required due to severe mucositis. Two patients fromthe TBI group died due to transplantation-related complications. Followinghigh-dose treatment, remission state improved in 43 out of 98 patients. Nostatistically significant advantage in reaching CR or PR was observed with TBI+ HD-Mel compared to the treatment with HD-Mel alone.Conclusion: Dose-escalated treatments, with particular regard to theinclusion or omission of TBI, should be prospectively investigated to find thebest high-dose regimen.     

Cost-effectiveness of a transplantation strategy compared to melphalan and prednisone in younger patients with multiple myeloma

High dose chemotherapy with autologous stem cell transplantation (ASCT) improves outcomes in patients 65 years of age or less with multiple myeloma. Survival and costs in a cohort of 16 patients who received melphalan and prednisone as part of a clinical trial were compared with those of 36 patients referred to our centre for consideration of ASCT. In the transplant group, survival and costs were extrapolated to match the period of observation in the melphalan and prednisone group. Patient-specific and average costs were calculated from the perspective of the Ontario Ministry of Health. Costs and survival were varied by 50% in the sensitivity analysis. Transplantation improved life expectancy by 19.3 months with a cost difference of $30,517 Canadian. The incremental cost-effectiveness of transplantation compared with melphalan and prednisone was $25,710 Canadian per life-year gained when additional pamidronate and follow-up costs were considered. Discounting costs and survival at 3 and 5% did not result in important differences. The sensitivity analysis resulted in best and worse case scenarios for transplantation compared with melphalan and prednisone of $13,049 and $63,954 per life-year gained respectively. In comparison with melphalan and prednisone, ASCT appears to be cost-effective in patients 65 years old or younger with myeloma.     

TAD方案加美法仑治疗多发性骨髓瘤18例

目的观察TAD方案（亚砷酸、维生素C、地塞米松）联合美法仑治疗多发性骨髓瘤（MM）的临床疗效。方法18例MM患者,男12例,女6例。采用TAD方案加美法仑（亚砷酸10mg,第1天至第5天,第8天至第12天;维生素C1．0g,第1天至第5天,第8天至第12天;地塞米松20mg,第1天至第4天,第8天至第11天;美法仑2mg,3次／d,第1天至第12天）治疗初治及难治复发性MM,观察18例患者中完全缓解（CR）、部分反应（PR）、微小反应（MR）、无改变（NC）比例。结果18例患者中CR3例（16．7％）,PR14例（77．7％）,MR1例（5．6％）。结论亚砷酸、美法仑、维生素C、地塞米松联合应用是一种有效且副作用小的治疗初治或难治性MM的方案。     

Dose intensity analysis of melphalan and prednisone in multiple myeloma

The average relative dose intensity (DI) of conventional oral melphalan and prednisone therapy received by 93 newly diagnosed multiple myeloma patients was correlated with survival and with percent reduction in M-protein. A survival advantage was shown with increasing average relative DI of melphalan and prednisone. Multivariate analysis showed survival to correlate with increasing DI of prednisone (P = .05) but not with the DI of melphalan (P = .93) nor with the percent decrement in M-protein (P = .10). These results suggest that the initial management of myeloma should be reassessed, with particular emphasis on more intensive therapy employing high-dose steroids.     

Intermediate dose of intravenous melphalan in advanced multiple myeloma.

Eighteen patients with advanced multiple myeloma resistant to VAD chemotherapy (vincristine, Adriamycin, dexamethasone) were treated with intravenous melphalan in a single-pulse dose of 50-70 mg/m2. Objective response (greater than or equal to 50% reduction of the monoclonal protein) was observed in 9 patients. The median duration of remission in the responding patients was 6 months and the median survival 11.5 months. The main toxicity noted was bone marrow suppression. We conclude that intermediate doses of intravenous melphalan are a useful therapeutic modality in refractory or relapsing myeloma patients.     

Intravenous melphalan and dexamethasone followed by lymphoblastoid alpha interferon in higher risk multiple myeloma patients

Intermittent courses of melphalan and prednisone is still the standard chemotherapy for the initial treatment of multiple myeloma (MM) in patients who cannot undergo high-dose chemotherapy/radiotherapy with either allogeneic or autologous stem cell transplantation. However, the absorption of the drug from the gastrointestinal tract is highly variable from patient to patient and therefore, different plasma levels of the drug are reached in the blood of individual MM patients. In order to overcome this limitation we decided to use intermediate dose (15-30 mg/m2, day 1) intravenous melphalan in resistant or relapsing MM patients as well as in untreated patients not eligible for a more aggressive protocol. Moreover, considering the good results obtained by other investigators using dexamethasone alone or associated with interferon in the treatment of resistant or relapsing MM patients, dexamethasone (40 mg total dose, day 1) and the lymphoblastoid alpha interferon (3 MU, 3 times a week x 3 weeks, from day 8 to day 26 of each course) were added to intravenous melphalan. Courses were repeated every 5 weeks for a total of 6 cycles. We treated 62 MM patients obtaining a response (defined as reduction > 25% of the initial monoclonal component value associated with disappearance of the clinical symptoms) in 38 out 62 evaluable patients (61%) and stable disease (defined as a decrease of < 25% in the base-line serum monoclonal component level with disappearance of all symptoms present at diagnosis) in 9 (14.5%) more patients. The overall median response duration was 14 months and the overall median survival duration (from the time of inclusion in this protocol) for the 62 patients entered into the study was 34 months. No severe (Grade 3-4 of the WHO) hematological as well as non hematological toxicities were observed. This lack of severe toxicity allowed us to administer the drugs on an outpatient basis. In conclusion, the overall response and the low grade of toxicity in this category of patients are encouraging and suggest that this protocol is both effective and safe treatment for high risk MM patients.