High-dose melphalan in patients with multiple myeloma

Since 1983 an increasing number of clinical trials have used high-dose melphalan with or without autologous stem cell support in patients with multiple myeloma. It has been shown that high-dose therapy including high-dose melphalan may be considered as the treatment of choice in newly diagnosed patients. The purpose of this report is to review and summarize the clinical information on IV high-dose melphalan in patients with multiple myeloma and to examine potential areas of future investigation.     

Oral dosage of melphalan and response to treatment in multiple myeloma

Forty-nine consecutive patients with multiple myeloma were analysed for treatment response in relation to dose of orally administered melphalan (induction therapy). All patients were given at least six courses of melphalan-prednisone. Treatment response, defined as a reduction of the myeloma protein of > 50%, was seen in 26 patients while 23 were non-responders. When treatment response was related to the dosage of melphalan given by mg/kg of body weight, the numbers of responding and non-responding patients were similar in the group of patients without dose reduction as well as in that with dose reduction. Drug-induced suppression of white blood cell and platelet count was similar in the responding as well as in the non-responding group indicating that the reason for non-response is not simply explained by deficient drug absorption. When the cumulative dose of melphalan given during the induction therapy was analysed, however, a positive correlation (r = 0.47, P < 0.001) was seen between the cumulative dose and the degree of response. Thus, the cumulative dose of melphalan given during induction therapy seems to be of importance for the response, but other factors as intrinsic differences in cell sensitivity may also explain the individual responsiveness.     

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.     

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.     

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-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.     

Oral melphalan, prednisone, and thalidomide for newly diagnosed patients with myeloma

BACKGROUND: Thalidomide is an immunomodulatory drug with strong antimyeloma activity. It is an effective treatment for multiple myeloma at disease recurrence and at diagnosis, both as a single agent and in combination with steroids or chemotherapy. No data are available on the association of thalidomide with oral melphalan and prednisone, still considered the standard treatment for elderly patients. METHODS: The feasibility and efficacy of the combination of melphalan, prednisone, and thalidomide (MPT) have been valuated in 49 newly diagnosed patients with multiple myeloma. RESULTS: According to European Bone Marrow Transplantation/ International Bone Marrow Transplantation Registry (EBMT/IBMTR) criteria, 18% of patients achieved immunofixation-negative complete disease remission (CR), 6% achieved immunofixation-positive near CR, 4% achieved a very good partial response, and 45% achieved a partial response, with a 50-89% reduction in monoclonal paraprotein. Six percent did not respond and 10% showed progressive disease. The median time to maximum response was 4 months. The Kaplan-Meier estimates of event-free survival and overall survival at 2 years were 64% and 91%, respectively. The major acute adverse events (National Cancer Institute Common Toxicity Criteria Grade III-IV) included thrombosis (20%), infections (12%), constipation (6%), and hematologic (22%) and neurologic (8%) toxicities. One patient died of pulmonary thromboembolism. CONCLUSIONS: These data suggested that MPT induced rapid and durable tumor responses with CR rates similar to those observed after autologous transplantation. Administration of prophylactic anticoagulant was required to prevent thromboembolism. MPT merits further investigation in randomized clinical trials.     

High dose melphalan or intermediate dose melphalan can be well tolerated and result in good response rates in selected elderly patients with myeloma

We have used two strategies for treating myeloma patients aged 65-75 years. Those fit enough underwent Cyclophosphamide mobilisation and PBSCT using melphalan 200mg/m(2) (HDM) (n=15, median 67 years). Those less fit were mobilised with G-CSF and received melphalan 70mg/m(2) (IDM) (n=15, median 69 years). Where possible sufficient PBSC were collected so that patients not in CR after their first IDM, underwent a second IDM procedure (n=6). The treatment was well tolerated with zero day+100 TRM. Median cell dose was 4.85x10(6)CD34+cells/kg and 2.7x10(6) in the HDM and IDM groups, respectively. Neutrophil engraftment was faster in the HDM group but despite this there was a trend to earlier discharge in the IDM group (13 days versus 15 days) and lower antibiotic and anti-fungal usage, suggesting better tolerability. Response rates were similar with CRs achieved in 7/15 patients receiving HDM and 9/15 receiving IDM (6 after the first and 3 after the second procedure). Three patients did not undergo a second IDM due to insufficient cells. In the IDM group 11/15 remain alive at a median follow up of 14 months with 5 in CR, whilst in the HDM group 12/15 are alive with 5 in CR at a median follow up of 15.5m. We conclude both approaches have comparable efficacy but that IDM may be better tolerated in an older age group.     

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。     

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.     

Low dose thalidomide in patients with relapsed or refractory multiple myeloma

Remarkable results of the treatment of refractory multiple myeloma with thalidomide have been reported. In most preceding studies, the given thalidomide dose was escalated to a maximum tolerated dose of up to 800 mg/d. The frequency of adverse effects correlates with dose intensity. Since a significant gain of therapeutic effects could not be observed as thalidomide dosage was escalated, the optimal dose of thalidomide remains to be determined. We report the results of a study with low dose thalidomide (median administered dose 100 mg/d, range 50-400 mg/d). Twenty-four relapsed (n=19) or resistant (n=5) multiple myeloma patients were included in the study. Twelve patients (50%) received thalidomide as monotherapy, 8 patients (33%) received a combination of thalidomide and dexamethasone (every 4 weeks 40 mg/day for 4 days) and 4 patients (17%) who were resistant to vincristine, doxorubicin, dexamethasone (VAD) received VAD combined with thalidomide. Overall, a response was observed in 12 patients (50%). Of the 12 patients treated with low dose thalidomide alone 5 (42%) responded, of the 8 patients who received a combination of thalidomide and dexamethasone 5 (63%) responded and of the 4 patients who had thalidomide in addition to VAD 2 patients (50%) responded. In 3 patients, thalidomide treatment had to be discontinued because of side effects and 1 patient died before response could be assessed. We conclude that low dose thalidomide is an effective and safe rescue therapy in relapsing or refractory multiple myeloma. Response to thalidomide might be dependent on prognostic parameters and tumor burden. To answer these questions larger prospective studies are necessary.     

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.     

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。     

Repeat administration of high dose melphalan in relapsed myeloma.

At a median time of 20 months following high dose melphalan for myeloma, 29 patients relapsed and were treated with induction chemotherapy to maximum response followed by a second course of high dose melphalan. The majority (90%) of patients received 200 mg m-2 with an autologous bone marrow transplant. Sixteen (55%) patients achieved complete remission and 11 (38%) a partial response. The median duration of remission was 17 (4-42) months. The median survival has not been reached, with 50% of patients alive at 58+ months after presentation. The period of neutropenia was similar during both first and second high dose procedures, but the duration of thrombocytopenia was longer in patients receiving melphalan for a second time (median 22 (16-56) days and 41 (18-69) days respectively). There was one treatment-related death due to thrombocytopenic haemorrhage. Repeated administration of high dose melphalan is a feasible approach for patients with relapsed myeloma.     

Oral mucositis and outcomes of autologous hematopoietic stem-cell transplantation following high-dose melphalan conditioning for multiple myeloma

The purpose of this study was to assess the relationship between oral mucositis (OM) and adverse clinical and economic outcomes of autologous hematopoietic stem-cell transplantation (HSCT) following high-dose melphalan (Alkeran) conditioning in patients with multiple myeloma. A retrospective study of 115 consecutive autologous HSCT recipients with multiple myeloma who received high-dose melphalan conditioning before transplantation was undertaken at a single academic center. OM severity was assessed twice weekly using a validated scale beginning 3-4 days following conditioning and continuing until hospital discharge or day 28, whichever occurred first. OM was graded, based on presence/extent of erythema/ulceration across eight oropharyngeal sites, as follows: 0 = no erythema or ulceration; I = erythema but no ulceration; II = ulceration, 1 site; III = ulceration, 2 sites; IV = ulceration, 3 sites; and V = ulceration, > or = 4 sites. Analyses examined the relationship between worst OM grade and selected clinical and economic outcomes, including days with fever, days of total parenteral nutrition (TPN),days of parenteral narcotic therapy, incidence of significant infection, and inpatient days and charges. The mean age of study subjects was 54 years; 19 patients (17%) received total-body irradiation, and 55 patients (48%) experienced OM grade > or = II (ie, ulceration). The worst OM grade was significantly (P < 0.05) associated with numbers of days of TPN and parenteral narcotic therapy, length of hospitalization, and total inpatient charges. Worst OM grade was not associated with the number of febrile days or the risk of significant infection. OM is associated with worse clinical and economic outcomes in multiple myeloma patients undergoing autologous HSCT following high-dose melphalan conditioning.     

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.     

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.     

Oral ixazomib maintenance therapy in multiple myeloma

Continuous therapy has proven to be an effective therapeutic strategy to improve the outcome of both young and elderly multiple myeloma patients. Remarkably, lenalidomide and bortezomib showed to play a crucial role in this setting due to their safety profile allowing long-term exposure. Ixazomib, the first oral proteasome inhibitor to be evaluated in multiple myeloma, exerts substantial anti-myeloma activity as a single agent and particularly in combination with immunomodulatory drugs and it may be an attractive option for maintenance therapy. Here we address the issue of maintenance therapy as part of a therapeutic approach of multiple myeloma patients focusing on the potential role of ixazomib.