Melphalan-prednisolone Research Articles

Long-Term Electrocardiographic Follow-Up of a Patient with Light-Chain Cardiac Amyloidosis

Amyloid light-chain (AL) cardiac amyloidosis can cause restrictive cardiomyopathy, which has a poor prognosis. Although electrocardiography (ECG) is useful for its diagnosis and management, there are few reports on the long-term follow-up of electrocardiographic changes in affected patients. The present patient was a 62-year-old woman who visited our hospital for assessment of palpitations and lower leg edema. A chest radiograph showed cardiac enlargement, and ECG revealed sinus rhythm, first-degree atrioventricular block, low QRS voltage in the limb leads and a pseudo-myocardial infarction pattern in the precordial leads. Echocardiography revealed left ventricular hypertrophy with systolic and diastolic dysfunction. Immunoelectrophoresis demonstrated M-protein (IgGλ), and bone marrow biopsy suggested IgGλ-type plasmacytoma. Myocardial biopsy findings were compatible with cardiac amyloidosis. On the basis of these findings, we diagnosed AL cardiac amyloidosis. Melphalan-prednisolone (MP) therapy was started in conjunction with treatment for non-sustained ventricular tachycardia and congestive heart failure. Two years and 4 months later, the sinus rhythm converted to atrial tachycardia. At a follow-up examination at 4 years and 8 months, right branch block appeared. After that, intraventricular conduction worsened, and the low voltage in the limb leads was not observed. Seven years after diagnosis, she was hospitalized for treatment of pneumonia and heart failure with tachycardia. On the seventh day of hospitalization, heart rhythm changed to atrial stand-still with escaped ventricular rhythm and she died of cardiac arrest. These ECG changes are valuable information regarding the pathophysiological changes that occur in AL cardiac amyloidosis.

Clinical Characteristics and Treatments Outcomes in Elderly Patients with Multiple Myeloma: A Multicenter Retrospective Study

Aim: Multiple Myeloma is an incurable fatal disease accounts for 1% of all the cancer and 10% of the haematological malignancies. Generally, it is seen in elderly population.The aim of the present study was to present our experience in 106 Multiple Myeloma patients aged 65 years or older and treated with different regimens during the 5 years term preceding the study. Method: In order to analyse the clinical characteristics and therapeutic outcomes of the Multiple Myeloma patients over 65 years, data were gathered retrospectively from 5 different centres in Turkey. Results: A total of 105 elderly Multiple Myeloma patients (aged 65 years or older) composed of 51 males and 54 females were evaluated retrospectively. Vincristine, Adriamisin, Dexamethasone (VAD), Bortezomib, Cyclophosphamide, Dexamethasone (VCD), Melphalan, Prednisolone (MP) Melphalan, Prednisolone, Thalidomide (MPT) regimens were given as the first line. 29 patients yielded complete responses and 18 of these patients underwent autologous stem cell transplantation. In 46 patients out of those not yielding a full response were treated with bortezomib, lenalidomide and thalidomide based second line treatments. 29 of those treated with a second line treatment yielded a complete response and 20 of these patients underwent autologous stem cell transplantation. 16 patients not responding to the first and second line treatments were treated with a third line treatment using a lenalidomide based (n=10) and thalidomide based (n=6) regimens. 5 patients were subjected to autologous stem cell transplantation due to remission status. Conclusions: An optimal treatment approach should make a productive, safe and high quality life possible while the aim should be to ensure a disease-free survival and prolong the general survival along with obtaining a full response. Key Words: Autologous stem cell transplantation , Elderly patients, Haematological malignancies, Multiple Myeloma, Optimal treatment.

How to treat patients with systemic amyloid light chain amyloidosis? Comparison of high-dose melphalan, low-dose chemotherapy and no chemotherapy in patients with or without cardiac amyloidosis

High-dose melphalan and autologous stem cell transplantation (HDM) is an effective treatment for systemic amyloid light chain (AL) amyloidosis but the eligibility criteria exclude many patients with this disorder. The aim of this study was to determine appropriate treatment strategies for systemic AL amyloidosis according to each patient's clinical condition in Japan. Historical cohort study. Fifty-three patients with systemic AL amyloidosis (those with malignancies were excluded) were treated in our hospital with HDM (15 patients), melphalan + prednisolone (MP) (17 patients), vincristine + adriamycin + dexamethasone (VAD) (11 patients), or supportive treatment (no chemotherapy, 10 patients). We compared the survival rates among these treatment groups. Mean survival was significantly longer in the HDM group than in the other three groups (P<0.01, log-rank test). This trend remained the same when patients were divided into those with and without cardiac amyloid involvement. Furthermore, in patients with heart involvement, survival in the VAD therapy group was significantly inferior to that in the MP therapy group (P<0.01 by log-rank test). Significant factors related to the survival rate included the presence or absence of heart involvement and treatment modality. HDM should be considered the treatment of choice in eligible patients with systemic AL amyloidosis even in the presence of cardiac amyloidosis. If HDM is not eligible, indications for VAD therapy should be carefully evaluated in patients with cardiac amyloidosis.

Incorporation of Bortezomib Into Frontline Treatment of Multiple Myeloma According to Risk Stratification Shifts the Most Significant Prognostic Indicator From Cytogenetics to the Quality of Induction Response

AbstractAbstract 3056 Introduction:Multiple myeloma (MM) is clinically heterogeneous and risk stratification is vital for prognostication and informing treatment decisions. As bortezomib is able to overcome several adverse features of MM, it has been incorporated into the induction algorithms of high-risk MM. We evaluate the survival data of MM patients managed in a single institution, overall, and with respect to treatment eras before (era 1) and after (era 2) the incorporation of bortezomib as frontline therapy for high-risk MM. Methods:From a comprehensive MM registry maintained in a tertiary institution, we study the survival data of 304 consecutive and previously untreated MM patients managed at our institution from 2000 to 2009. For induction therapy, transplant-eligible patients received.VAD chemotherapy from 2000 to 2004, and thalidomide/dexamethasone (thal/dex) combination from 2004 to 2009. Transplant-ineligible patients received VAD chemotherapy, thal/dex or melphalan/prednisolone (MP) combination from 2001 to 2004, and thal/dex or MP/thalidomide combination from 2004 to 2009. Patients < 65 years were eligible for high-dose therapy with autologous stem cell transplant (HDT/ASCT). Bortezomib became available for treatment of relapsed disease from 2004 and was incorporated into induction therapy in selected patients with high-risk MM from 2006. High-risk MM is defined by presence any adverse factors including stage III on the International Staging System (ISS), deletion 13, hypodiploidy, pseudo-diploidy or near-tetraploidy on metaphase karyotyping, or presence of deletion 17p, t(4;14) or t(14;16) on interphase florescence in-situ hybridization (FISH). As FISH was only available from 2004, the results of FISH will not be included in the survival analysis. Patient and disease characteristics, and survival data were evaluated overall, and with respect to treatment eras. Disease response was assessed by the IMWG criteria after induction treatment and after HDT/ASCT for transplant ineligible and eligible patients respectively.We applied multivariate Cox's regression modeling to determine what baseline parameters, along with the eventual induction response, significantly affected the OS in the respective eras. Results:The median age of all patients was 62 years. Overall, 35%, 40% and 25% of patients presented with ISS stages I, II and III respectively. Conventional karyotyping detected abnormalities in 49% (del 13 [17%], hypodiploidy [18%], hyperdiploidy [22%], pseudodiploidy [7%] and near tetradiploidy [2%]) of patients. Overall, the ISS, conventional cytogenetics, age (≤ or > 60 years), the presenting platelet count (≤ or > 140 × 109/L) and the induction response attained were discriminating of the overall survival (OS) (median= 5.2 yrs) on univariate analyses. Patients and disease characteristic and number of patients undergoing HDT/ASCT were comparable between the 2 eras. 33% of patients in era 1(N=182) were exposed to bortezomib predominantly in the relapse setting, while 52% (41% upfront, 59% during relapse) of patients were exposed to bortezomib (N=123) in era 2. Number of patients attaining ≥ very good partial response (VGPR) were significantly higher in era 2 compared with era 1 (48% vs 26%, p<0.001). The median OS of patients in era 1 and 2 were 5.1 and 6.0 respectively (P=0.06). On multivariate analysis stratified by era, the presence of an abnormal non-hyperdiploid karyotype was the most significant prognostic factor in predicting a worse outcome in era 1(median OS 2.7 years, hazard ratio 3.4, p=0.02), while the attainment of ≥VGPR emerged as the single most significant factor in predicting a favorable outcome in era 2 (median OS 8.1 years, hazard ratio 0.01, p<0.001). Conclusion:Our study suggests that bortezomib use in the frontline, rather than relapse setting may be better able to overcome the effects of adverse cytogenetics. Superseding the adverse effects of all other presenting clinical and laboratory parameters, the attainment of ≥VGPR emerged as the single most significant predictor of long-term survival in the era of novel therapy. Disclosures:No relevant conflicts of interest to declare.

High early mortality rate in elderly patients with multiple myeloma receiving a vincristine–doxorubicin–dexamethasone regimen

Treatment-related mortality (TRM) is not uncommon in patients after the first course of vincristine-doxorubicin-dexamethasone (VAD) chemotherapy,but quite rare after melphalan-prednisolone (MP). This motivated us to compare the rates of TRM after the first course of VAD with those after the first course of MP. We retrospectively assessed survival and TRM in 179 patients treated for multiple myeloma with either MP or VAD. Survival was similar in two groups (P 50.463 in log-rank test). However, TRM was significantly higher inpatients after the first course of VAD (11 in 100 patients, 11.0%) than that after the first course of MP (1 in 79, 1.3%; P 5 0.010). Poor performance status (P 5 0.004) and advanced age (P 5 0.009) before treatment were independent significant factors associated with TRM after the first course of induction therapy. Pyogenic infection was the major cause of TRM after VAD (9 in 11, 81.8%). We concluded that VAD should be cautiously used as induction therapy in multiple myeloma patients, especially in elderly and/or those with poor performance status.

下顎骨病的骨折を契機に診断し得た多発性骨髄腫の1例

A case of multiple myeloma of the in mandible is reported. A 67-year-old man presented to our hospital with discomfort caused by a denture in October 2005. There was a bony edge at the left molar region of the mandible, and radiographs showed a 6-cm osteolytic lesion and a fracture line in the left side of the mandible. Osteolytic lesions were also observed in the right side of the mandible and right temporal bone. A computed tomographic scan of the chest and abdomen revealed diffuse osteolytic changes and fracture lines in the spinal bones. There was increased uptake in the 9th and 12th thoracic vertebrae and the mandible on bone scintigraphy. However, little uptake was found in the region of the tumor. Laboratory tests revealed elevations of protein and IgG levels, accompanied by anemia. Renal failure and Bence-Jones proteinurea were not apparent. M-protein was positive in the urine. Bone marrow aspiration revealed 30 % plasma cells, and immunoelectrophoresis showed that an IgG band with a κ light chain. IgG-κ type multiple myeloma was diagnosed. In the department of hematological medicine, 2 courses of VAD (vincristine, adriamycin, dexamethasone) chemotherapy were administered, followed 20 courses of MP (melphalan, prednisolone) chemotherapy in the outpatient clinic. After chemotherapy, a complete response was achieved in the hematological findings, the fractured mandible healed, and the osteolytic lesions decreased. Tumor recurrence has not occurred for 2 years after VAD therapy.

Staged heart transplantation and chemotherapy as a treatment option in patients with severe cardiac light‐chain amyloidosis

The prognosis of advanced cardiac light-chain amyloidosis is poor. Heart transplantation might enable causative therapy and ultimately improve prognosis. Nineteen patients with cardiac amyloidosis but no obvious involvement of other organs were scheduled for heart transplantation. Four to 6 months later, high-dose melphalan chemotherapy and autologous stem cell transplantation (HDM-ASCT) was planned in patients not in complete remission. Seven of nineteen patients died while waiting for heart transplantation. The remaining 12 patients (complete remission, n = 4) underwent surgery. Chemotherapy in patients not in complete remission consisted of HDM-ASCT (n = 5/12; subsequent complete remission, n = 2; partial remission, n = 3) or melphalan-prednisolone (partial remission, n = 1). Two of twelve patients were ineligible for any chemotherapy. Three of twelve patients died [423.5 (105-2131) days] from progressive disease, relapse, or sepsis. The 1- and 3-year survival rates were 83 and 83%, respectively, similar to those of patients undergoing heart transplantation for standard indications. Corresponding survival rates stratified by haematological response were 100 and 100% for complete remission (partial remission, 100 and 100%; progressive disease, 0 and 0%). Heart transplantation in advanced cardiac amyloidosis is a promising approach to interrupting the vicious circle of ineligibility for potential curative chemotherapeutic treatment and extremely poor prognosis of cardiac amyloidosis without chemotherapy. Highly urgent heart transplantation combined with subsequent HDM-ASCT appears to offer a successful treatment option to improve the poor outcome of cardiac amyloidosis. However, it should be restricted to highly selected patients in specialized centres.

Thalidomide-dexamethasone compared with melphalan-prednisolone in elderly patients with multiple myeloma

AbstractWe compared thalidomide-dexamethasone (TD) with melphalan-prednisolone (MP) in 289 elderly patients with multiple myeloma (MM). Patients received either thalidomide 200 mg plus dexamethasone 40 mg, days 1 to 4 and 15 to 18 on even cycles and days 1 to 4 on odd cycles, during a 28-day cycle or to melphalan 0.25 mg/kg and prednisolone 2 mg/kg orally on days 1 to 4 during a 28- to 42-day cycle. Patients achieving stable disease or better were randomly assigned to maintenance therapy with either thalidomide 100 mg daily and 3 MU interferon α-2b thrice weekly or to 3 MU interferon α-2b thrice weekly only. TD resulted in a higher proportion of complete and very good remissions (26% vs 13%; P = .006) and overall responses (68% vs 50%; P = .002) compared with MP. Time to progression (21.2 vs 29.1 months; P = .2), and progression-free survival was similar (16.7 vs 20.7 months; P = .1), but overall survival was significantly shorter in the TD group (41.5 vs 49.4 months; P = .024). Toxicity was higher with TD, particularly in patients older than 75 years with poor performance status. The study was registered at ClinicalTrials.gov as NCT00205751.

Refractory Plasmablastic Type Myeloma with Multiple Extramedullary Plasmacytomas and Massive Myelomatous Effusion: Remarkable Response with a Combination of Thalidomide and Dexamethasone

A 74-year-old man with multiple myeloma was refractory to melphalan/prednisolone (MP), high-dose dexamethasone and VAD chemotherapy. He had the following poor prognostic factors: 1) multiple extramedullary plasmacytomas, 2) massive myelomatous effusion, 3) increasing immature myeloma cells with plasmablastic morphology, and 4) predominance of MPC1-CD49e-CD45+ phenotype immature myeloma cells. Combination therapy with thalidomide and dexamethasone resulted in a rapid response and a partial remission despite his multiple poor prognostic factors. The present case suggests that combination therapy with thalidomide and dexamethasone is still an alternative treatment regimen for resistant extramedullary plasmacytoma with a plasmablastic morphology.

Post-Marketing Surveillance of Bortezomib Treatment for Multiple Myeloma (MM) in Japan: Results of Interim Analysis by the Velcade Japan Proper Use Guideline Committee

[Background] Bortezomib (VELCADE® for Injection 3 mg) was approved in Japan on October 10, 2006 for the treatment of relapsed or refractory MM. As required for most oncology drug approvals in Japan, a special post-marketing surveillance program was implemented on December 1, 2006, enrolling all patients treated with bortezomib to assess its safety and efficacy from actual medical practice experience in Japan.[Patients and Methods] This surveillance is a prospective program designed to enroll patients before starting treatment with bortezomib. It included 1048 consecutive patients treated with bortezomib in the first year after the drug approval in Japan. This report summarizes the results of an interim analysis of safety and preliminary efficacy of the first two cycles of bortezomib in 525 patients. Patients are to be observed for 3 years at maximum. Observational items include: gender, age, medical history, prior therapies, administration of bortezomib, concomitant drug/therapy, laboratory testing, physical examination, clinical symptoms, anti-tumor effects, and adverse event (AE) collection. In addition, for AEs of special interest, such as lung disorder/interstitial lung disorder (LD/ILD), cardiac dysfunction, tumor lysis syndrome (TLS), peripheral neuropathy, hematotoxicity, pyrexia, skin disorder, hypotension and gastrointestinal disorder, heightened surveillance was conducted to capture onset, clinical course and outcomes.[Results] Males outnumbered females (55.8% [293/525] vs. 44.2% [232/525]). Patients elder than 50 years old accounted for 92.6% (486/525). Most of the patients were in stage III by both the International Staging System and Durie & Salmon system. More than half of the patients (59.1% [310/525]) had a duration of illness ranged from 1 to 5 years. Coexisting medical conditions were present in 62.3% (327/525) of patients; the most common was hypertension (17.5%). 7.6% and 10.5% of patients had coexisting medical conditions related to lung disease or heart disease, respectively. Most of the patients had received prior treatment for MM, which included MP (melphalan, prednisolone), thalidomide, dexamethasone, VAD (vincristine, doxorubicin, dexamethasone), and stem cell transplantation. The most commonly observed adverse drug reactions (ADRs) were abnormal changes in hematological laboratory tests (74.3%). Incidence of serious ADRs was 21.1% (111/525). The most frequent serious ADRs were low platelet count (5.3% [28/525]) and peripheral neuropathy (2.1% (11/525). LD/ILD was seen in 4.2% (22/525). TLS was observed in 5.0% (26/525). With regard to the preliminary analysis of anti-tumor effect, the overall response rate as determined by the investigator-based clinical evaluations was 50.2% (257/512). The overall response rate based on M-protein concentration was 41.8% (214/512). 12 (2.3%) patients died within 30 days after the final administration of bortezomib. Progression of disease was the most common cause of death, and worse performance status prior to initiating bortezomib was associated with early mortality.[Conclusion] Based on the interim analysis, this post-marketing surveillance reveals no new safety signals in Japanese patients with relapsed/refractory MM treated with bortezomib. The incidence rates of AEs of special interest were comparable to those observed outside Japan except for LD/ILD which was less than those initially reported for the Japanese population.

Newly Diagnosed Myeloma Pateints Are at Risk of Venous Thrombotic Events - High Risk Patients Need To Be Identified and Recieve Thromboprophylaxis: The MRC Experience.

Standard treatment for younger patients with presenting myeloma is VAD followed by high-dose melphalan with stem cell support. However this regimen requires a central venous catheter with risks of recurrent line infections and central venous thrombus. A number of oral alternatives have been used including dexamethasone (Dex), thalidomide (Thal) or combinations (Thal/Dex), although to date no randomized control trial has compared an intravenous with oral induction therapy. In older patients melphalan/prednisolone (MP) remains the standard approach. Thal combinations (MPT, CTD, DVdT) improve response rates and providing side effects can be managed effectively may also be appropriate for an elderly population. Patients with myeloma have an increased risk of venous thrombotic events (VTEs), and presenting patients receiving Thal may be at increased risk due to bulk disease. Combination with anthracyclines may also exacerbate this risk. The MRC Myeloma IX trial has been designed to address some of these issues. Younger patients are randomized to receive intravenous CVAD or an oral Thal containing regimen, CTD prior to autologous transplantation; older patients are randomized to MP or the Thal containing regimen, CTDa. At trial initiation (May 2003) physicians were advised that patients should start low-dose Thal (100mg od in the intensive and 50mg od in the non-intensive arm) and slowly dose escalate to 200mg. Patients at high risk of VTE should be considered for full anticoagulation with either warfarin or LMWH. As of Aug 2004 420 patients (239 intensive, 181 non-intensive) have been randomized and a total of 30 VTEs in 28 patients have been reported (22 intensive, 6 non-intensive). In the intensive arm there were 8 DVT, 9 PE and 7 line-related thromboses. In the non-intensive arm there were 4 DVT and 2 PE.CVADCTDCTDaMPDVT4.2%2.5%4.4%0%PE1.7%5.8%2.2%0%Line related5.0%0.8%NANATotal10.9%9.1%6.6%0%The median time from randomization to DVT/PE was 54.5 days (range 15–113). 4 patients were identified who had additional risk factors (2 immobility, 1 recent operation, 1 renal failure). Only 1 patient was receiving prophylaxis having previously suffered a DVT. There was one PE-related death. Importantly 2 PE and 5 DVT occurred in patients not receiving Thal therapy. All central thrombosis occurred in relation to the central line. In the non-intensive arm the addition of Thal increased VTE risk compared to MP. In conclusion myeloma patients have an increased incidence of VTE (5.9%–8.3%) although in this study so far patients on MP appear to have no excess thrombotic risk. Patients receiving infusional regimes are also at increased risk of line-related events (additional 5.0%). Using the combination of a slowly increasing Thal dose and thromboprophylaxis based on identification of high risk patients the addition of Thal marginally increased DVT/PE risk over and above the risk seen in patients with infusional regimens, but even in a large study such as this the number of events are too small to make firm recommendations. Currently our advice remains unchanged and ALL high risk patients should receive thromboprophylaxis.

Reduced bone marrow stem cell pool and progenitor mobilisation in multiple myeloma after melphalan treatment.

The content of stem cells was analysed in bone marrow samples from 75 multiple myeloma patients. In unstimulated bone marrow the percentage of CD34+ cells was significantly reduced in 11 patients previously treated with melphalan-prednisolone (MP)(median= 0.15%) compared to median 0.87% in 31 untreated patients (P=0.0001). The bone marrow cellularity in the two groups did not differ. There was no correlation between the number of courses or total dose of melphalan and content of CD34+ cells in the bone marrow. The clonogenicity as well as the ability to expand the marrow stem cell pool during growth factor treatment were also reduced in MP treated patients compared to untreated patients. Analysis of different subsets of CD34+ cells revealed no influence on the pre B cell compartment in the bone marrow by MP treatment, but the committed stem cells (CD34+CD38+) were reduced more than the uncommitted stem cells (CD34+CD38-) in the MP treated group compared to the untreated patients. Mobilisation to and harvest of total number of CD34+ cells from peripheral blood was also reduced in the MP treated group. There was, however, no difference in the distribution between CD34+CD38+ and CD34+CD38- populations in the leukapheresis products in the untreated and the melphalan-treated group, suggesting selective mobilisation of CD34+CD38+ cells and/or differentiation of CD34+CD38-cells during growth factor stimulation. We conclude that melphalan decreased the number of stem cells in the bone marrow, the ability to expand the stem cell pool and mobilise stem cells to the pheripheral blood.

Letter to the Editor: Low Dose Oral Idarubicin in Combination with Cyclophosphamide and Dexamethasone (CID) for Management of Melphalan-Prednisolone (MP) Resistant Myeloma

(1999). Letter to the Editor: Low Dose Oral Idarubicin in Combination with Cyclophosphamide and Dexamethasone (CID) for Management of Melphalan-Prednisolone (MP) Resistant Myeloma. Leukemia & Lymphoma: Vol. 33, No. 3-4, pp. 407-408.