Vincristine, Doxorubicin And Dexamethasone Research Articles

Bortezomib promotes apoptosis of multiple myeloma cells by regulating HSP27

The aim of the present study was to investigate the effect of bortezomib on heat shock protein 27 (HSP27) in multiple myeloma (MM) and provide a potential new target for clinical treatment. Peripheral blood was collected from 50 normal subjects and 50patients with newly diagnosed MM and the expression of HSP27 was detected by ELISA. The changes of HSP27 after conventional vincristine, doxorubicin and dexamethasone (VAD) chemotherapy, and bortezomib plus VAD were compared. The effect of bortezomib on U266 cell proliferation and apoptosis was detected using a Cell Counting Kit‑8 assay and Annexin V‑FITC/propidium iodide double staining with flow cytometry. The content of HSP27 following bortezomib treatment was determined by ELISA. Western blot analysis and reverse transcription‑quantitative PCR were used to detect the mRNA and protein expression of HSP27, Bax and Bcl‑2. HSP27 expression was increased in patients with MM compared with healthy control subjects, and the expression was increased as the cancer progressed (P<0.05). Compared with the VAD chemotherapy group, the bortezomib plus VAD chemotherapy regimen significantly inhibited the expression of HSP27 (P<0.05), and the content of HSP27 was decreased in patients in which treatment was effective compared to those patients that exhibited disease progression (P<0.05). The efficacy of the treatment regimes was not associated with age or gender. Compared with the control group, bortezomib or OGX‑427 (HSP27 inhibitor) treatment inhibited U266 cell proliferation, promoted U266 cell apoptosis (P<0.05) and significantly decreased HSP27 expression (P<0.05). Furthermore, the expression of HSP27 and Bcl‑2 was significantly decreased, while the expression of Bax was increased by bortezomib and OGX‑427 (P<0.05). There was no significant difference between the bortezomib and OGX‑427 group in the invitro analysis. HSP27 was positively correlated with Bcl‑2 expression and negatively correlated with Bax expression in U266 cells. In conclusion, bortezomib promotes the apoptosis of MM cells, potentially by downregulating the expression of HSP27, providing a potential novel target for the clinical treatment of multiple myeloma.

Pretransplant hemoglobin and serum creatinine levels correlate with progression free survival in myeloma patients undergoing autologous stem cell transplantation.

e19532 Background: High dose melphalan and autologous stem cell transplantation (ASCT) significantly prolong survival for patients with multiple myeloma (MM). The purpose of this study is to assess the effects of hemoglobin (Hgb) and serum creatinine (Crea) values at the time of transplantation on the overall outcome of patients with multiple myeloma treated at our transplant center. Material &amp; Methods: This analysis included 247 consecutive patients who underwent ASCT for MM between 2010-2016. Hemoglobin was grouped as low or high relative to their sample median. Patients were also stratified according to serum Crea value at the time of transplantation ( &lt; 2 or ³2 mg/dl). Results: The median age was 57 (29-75) years and most patients were male (n = 151, 61.1%), IgG subtype (n = 124, 50.2%), and ISS stage 3 (n = 122, 49.4%). The interval from the time of diagnosis to ASCT was median 7 months and median follow-up from ASCT was 49 months (range, 3-198 months). The most commonly induction regimens included VAD (vincristine, doxorubicin and dexamethasone) and VCD (bortezomib, cyclophosphamide, dexamethasone), respectively. Since maintenance was not an approved treatment in myeloma most patients did not receive any. For the entire cohort, the median Hgb and Crea were 11.5 g/dL and 0.9 mg/dL respectively. No difference in progression free survival (PFS) was observed between a lower and higher Hgb (82 vs. 81 months, p = 0.96). However, the median PFS was significantly longer in patients with a lower Crea compared to those with a higher Crea (83 vs. 48 months, p = 0.01). Patients with both a lower hemoglobin and higher Crea experienced shorter PFS compared to those with a higher hemoglobin and lower Crea (45 vs. 82 months, p &lt; 0.001). We failed to demonstrate the impact of creatinin levels on time to neutrophil and platelet engraftment. There were no differences in OS according to lower vs. higher Hgb (58 vs. 52 months; p = 0.29, respectively) but in higher crea cohort worse OS was observed (41 months vs. 57 months; p = 0.02, respectively). Conclusions: We demonstrate that hemoglobin and creatinine represent important determinants of clinical outcomes after ASCT. A lower hemoglobin and higher creatinine, individually and when combined, were associated with shorter PFS. Therefore, further studies of larger randomized cohorts are required to clarify the impact of pre-transplant Hgb and Crea levels on ASCT outcomes.

A prospective comparative study of efficacy of lenalidomide plus dexamethasone combination therapy versus VAD (vincristine, doxorubicin and dexamethasone) regimen in the treatment of multiple myeloma

Background: Lenalidomide plus Dexamethasone (Len-Dex) and VAD (Vincristine, Doxorubicin and Dexamethasone) regimen are the two common drug therapies employed in the treatment of Multiple myeloma.Objectives: To compare the efficacy of Len-Dex versus VAD regimen based on complete remission achieved with treatment in newly diagnosed cases of multiple myeloma in a tertiary care hospital in Kerala.Methods: Eighty patients (forty in each group) of newly diagnosed cases of multiple myeloma, who were willing to give the informed consent, were included in the study. Patients were allocated by the treating physician to two groups; one group was given Len-Dex (lenalidomide + dexamethasone) regimen and the other VAD (Vincristine, Adriamycin, Dexamethasone) regimen. A total of six cycles were given for both groups. Their baseline investigations and follow up investigations were collected at regular intervals, based on these values, the outcome was classified as partial remission and complete remission and the results were compared and analyzed.Results: Among the forty patients in each group, 17 (38%) on VAD regimen and 28 (62%) on Len-Dex regimen achieved complete remission. The statistical analysis was done using chi square test (χ2= 6.13, df= 1, p= 0.01) which showed statistically significant difference.Conclusions: The study showed that the efficacy of Lenalidomide-Dexamethasone (Len-Dex) combination therapy is clearly higher than that of VAD regimen among the study population. The overall efficacy of Len-Dex combination is 70% and that of VAD regimen is only 42.5%.

Novel Agents Versus Conventional Drugs for the Treatment of Relapsed Multiple Myeloma Patients: Experience of a Single Center over the Last 25 Years

Background: New active classes of drugs such as proteasome inhibitors (e.g., bortezomib) and immunomodulatory drugs-IMiDs (e.g., thalidomide and lenalidomide) are nowadays the standard treatment for multiple myeloma (MM) patients, alone or in association with old agents. The achievement of deeper responses, using novel agents instead of conventional treatment, is a significant prognostic factor for the outcome of these patients, resulting in an improved overall survival (OS) and progression-free survival (PFS). Here, we report the single center real life comparison between the outcome achieved with old agents with that obtained with novel agents in young MM patients treated at first relapse over a 25-year period.Patients and Methods: We analyzed a cohort of 258 young (median age 55 years; range 19-69) newly diagnosed MM patients treated at our Center between August 1989 and November 2014. All patients received old or novel agents followed by autologous hematopoietic stem cell transplantation (single or tandem) as first line treatment. Of the 258 patients, 144 experienced a progression of disease after a median of 34 months (range 7-195) and received old or novel agents as second line therapy. Old agents used as first and second line treatment were prevalently vincristine, doxorubicin and dexamethasone (VAD), melphalan and prednisone (MP) or cyclophosphamide and dexamethasone (CD); novel agents included velcade-based or IMiD-based regimens. Our cohort was divided into four different groups: 1) 51 patients treated with old agents as first and second line therapy (35.4%);2) 79 patients treated with old agents as first line therapy and novel agents as second line therapy (54.8%);3) 2 patients treated with novel agents in induction therapy and subsequently with old agents as second line therapy (1.4%);4) 12 patients treated with novel agents both in first and second line (8.3%). Our analysis focused on groups 1 and 2; group 3 was not considered for the small number of patients and because the choice of treatment was based exclusively on a worsening of the clinical condition; group 4 was not included for the small number of patients and because of the short follow-up. Our aim was to compare the results obtained in patients treated only with old agents both as first and second line treatment with the outcome of patients who received old agents as first treatment and novel agents as second line treatment, to assess the impact of novel agents in real life MM patients' management.Results: The OS at 5 years for patients of group 2 was significantly higher than that of group 1 patients (41.6% vs 14.1%); even at 10 years, the OS was significantly better for group 2 (20.4% vs 2.4%, p<0.0001); median OS was 4.1 years for group 2 and 1.4 years for group 1. The PFS was superior for patients treated with novel agents as second line treatment both at 5 years (12% vs 6.9%) and at 10 years (10% vs 2.3%) (p=0.02); median PFS was 1.4 years for group 2 and 0.7 for group 1. PFS2, considered as the interval from the start of first line treatment to the date of second relapse, showed also significantly better results for group 2 patients compared to group 1 patients both at 5 (61.8% vs 33.3%) and 10 years (25.7% vs 9.2%). Median PFS2 was 6.8 years for group 2 and 3.7 years for group 1(p=0.0002).Conclusions: We analyzed the effect of the introduction of novel agents in a cohort of young MM patients treated at our Center over a 25-year period, between 1989 and 2014. Patients treated in the earlier years received old agents both as first and second line treatment, while in more recent years all patients who experienced a relapse were treated with novel agents as second line treatment. Our analysis underlines that patients receiving novel agents witnessed a significantly better OS and PFS compared to patients treated only with old agents. When focusing on PFS2, we could determine that the duration of response obtained with proteasome inhibitors and IMiDs was significantly longer than that obtained with conventional chemotherapy. This currently ongoing study and a longer follow-up in a larger number of group 4 patients will allow to conclusively define the true real life impact of novel agents when used both as first and second line treatment for the management of young MM patients. DisclosuresPetrucci:Celgene, Janssen-Cilag, Amgen, Mundipharma, BMS: Honoraria.

Outcome in Multiple Myeloma Patients Eligible for Stem Cell Transplantation: A Single-Center Experience

Autologous hematopoietic stem cell transplantation (ASCT) is the standard of care for selected patients with multiple myeloma (MM). Many data exist on ASCT in the era of novel agents. We retrospectively analyzed 189 patients (108 males and 81 females) with biopsy-proven MM, who had received ASCT after induction therapy with either conventional chemotherapy alone or in combination with novel agents at our department. The outcomes of both groups and the risk factors for shorter survival were investigated. The most commonly used induction chemotherapy prior to ASCT was VAD (vincristine, doxorubicin and dexamethasone, 42%), followed by PAD (bortezomib, doxorubicin and dexamethasone, 21%). One-hundred and twenty-nine patients (68%) received cyclophosphamide-recombinant human granulocyte colony-stimulating factor for stem cell mobilization. No differences were observed for progression-free survival in terms of the number of transplanted CD34+ cells (p = 0.261). A trend in improved overall survival (OS) was seen for the use of novel agents when compared to conventional chemotherapy (164.3 vs. 82.0 months; p = 0.046). The International Staging System stages had a significant (p = 0.036) impact on OS. The novel agents improved OS in our patients with MM undergoing ASCT when compared to conventional chemotherapy regimens. The number of transplanted CD34+ cells had no significant impact on hematopoietic reconstitution.

A case of primary (AL) amyloidosis with predominantly vascular amyloid deposition in the kidney.

We report a 70-year-old man with primary (AL) amyloidosis with predominantly vascular deposition of amyloid diagnosed by renal biopsy, who was successfully treated using two chemotherapy regimens. There was rapid elevation of the serum creatinine level without remarkable proteinuria or hematuria. Renal histological examination showed some thickened arterial walls with amyloid fibril accumulation, and only a small amount of amyloid deposition in the glomeruli. Immunohistochemical examination was positive for anti-kappa staining. Serum immunoelectrophoresis and immunofixation testing did not show monoclonal proteins, and urine immunoelectrophoresis did not show Bence-Jones proteins. Serum free light chain (FLC) analysis showed that the serum FLC level and FLC kappa/lambda ratio were abnormally high for his renal function. He received two courses of VAD (vincristine, doxorubicin, and dexamethasone), followed by BD (bortezomib and dexamethasone), resulting in a hematologic partial response. Renal amyloidosis with vascular-limited amyloid deposition has few urinary findings. Early diagnosis of this condition is challenging, because kidney biopsies are not usually performed in patients without significant urinary findings. We suggest several currently available methods of achieving earlier detection of this condition.

Clonal Evolution In Two Multiple Myeloma Patients and a Biclonal MGUS Patient

BackgroundMultiple myeloma (MM) and its benign precursor monoclonal gammopathy of undetermined significance (MGUS) are diseases characterised by the production of monoclonal immunoglobulins. Clonal heterogeneity in MM has become a well-accepted phenomenon; however dogma would suggest the proteins produced by these clones remain consistent. Free light chain (FLC) escape is one exception to this rule, but is comparatively poorly documented and to our knowledge has not been identified in MGUS patients. Here we report 2 cases of MM patients with intact immunoglobulin and FLC producing clones that have different sensitivities to treatment leading to escape. In addition we report an MGUS patient whose routine corticosteroid treatment for polymyalgia rheumatica (PMR) impacted on the intact immunoglobulin but not the FLC producing clones and led to an escaping FLC clone which was subsequently diagnosed as myelomic. MethodsSerum protein electrophoresis (SPE) and immunofixation electrophoresis (IFE) were performed using Hydrasys 2 apparatus (SEBIA). Serum free light chain (FLC) levels were measured nephelometrically on a Siemens BNTM II using polyclonal antisera assays, Freelite®(The Binding Site Group Limited, Birmingham, UK). ResultsTwo intact immunoglobulin MM patients (Patient 1 IgAκ: 14.4g/L, κ FLC: 1320 mg/L, age: 65, sex: male; Patient 2 IgAλ: 8g/L, λ FLC: 9510 mg/L, age: 48, sex: male) were monitored through the course of their disease for 762 and 1330 days respectively. Following cyclophosphamide, thalidomide and dexamethasone (CTD) treatment Patient 1 achieved a VGPR (∼90% reduction in IgAk and 65% reduction in FLC) which was stable for 270 days. Subsequently whilst only a trace of IgAκ was present, dFLC levels increased from 460mg/L to 15194mg/L. Patient 2 achieved a CR following treatment with vincristine, doxorubicin and dexamethasone (VAD) and autologous stem cell transplant (ASCT) which was stable for 330 days. As with Patient 1 relapse was characterised by a substantial increase in dFLC from 8.61mg/L to 3168mg/L. In both patients the velocity of change and sensitivity to treatment of the intact immunoglobulin and FLC suggested the presence of heterogeneous clones.A rare biclonal MGUS patient, IgGκ (3.9g/L) and λ FLC (316mg/L), was identified during routine laboratory investigations (age: 71, sex: female) and followed annually in accordance with local guidelines (low/moderate risk MGUS). 16 months following MGUS diagnosis the patient was started on oral methylprednisolone for PMR. The treatment resolved the PMR and coincidently caused a reduction in the IgGκ serum concentration (trace quantities) and a normalisation of the FLC κ/λ ratio. A year post steroidal treatment whilst the IgGκ monoclonal protein concentration remained stable, dFLC levels increased from 9.6 mg/L to 1052 mg/L (κ/λ ratio: 0.008), indicating the emergence of a λ FLC clone although the patient remained asymptomatic. 4 months later and almost 4 years following diagnosis, the patient progressed to symptomatic disease with severe renal impairment (creatinine 6.19 mg/dL; eGFR 7.03 ml/min/1.73m2) anemia (Hb 9.0g/dL) and 70% clonal plasma cells present in the bone marrow. The dFLC concentration had further increased to 9726 mg/L however the IgGκ monoclonal protein was no longer detectable by IFE indicating the biclonal MGUS had progressed to a λ light chain multiple myeloma. DiscussionRoutine monitoring of MM patients to detect FLC escape is recommended by international guidelines, in light of the MGUS patient FLC escape leading to MM, we suggest routine evaluation of FLC levels in MGUS may also be beneficial. Disclosures:Endean:The Binding Site Group Ltd: Employment. Harding:The Binding Site: Employment.

A Combination Regimen of Bortezomib, Cyclophosphamide and Betamethasone Gives Quicker, Better and More Durable Response than VAD/CyBet Regimens: Results from a Swedish Retrospective Analysis

Background: Induction therapy for multiple myeloma (MM) and remission status before high-dose treatment (HDT) have been shown to be prognostic factors for survival outcome, although the optimal induction therapy is yet to be defined. Methods: We conducted a retrospective analysis of the impact of induction therapy on survival outcome before and after HDT in MM patients. The study included 236 consecutive patients who underwent HDT. Results: One hundred and forty-two patients (62%) were treated with vincristine, doxorubicin and dexamethasone (VAD) or cyclophosphamide and betamethasone (CyBet) and 94 (38%) were treated with bortezomib, cyclophosphamide and betamethasone (VCB) as induction. Time to first and time to best response was faster in the VCB group than in the VAD/CyBet group, with 42 versus 75 (p < 0.001) and 54 versus 88 days (p < 0.001), respectively. After induction therapy, 49% of the patients in the VCB group and 38% in the VAD/CyBet group achieved a very good partial response or better. Multivariate analysis revealed younger age, lower International Staging System stage and induction treatment with VCB as variables associated with favourable time to progression. Conclusions: Outcome measured as response and time to progression before and after HDT in MM differs depending on type of induction treatment and suggests that VCB is a highly effective induction regimen that confers a post-HDT advantage.

The Response to Second-line Induction with Bortezomib and Dexamethasone is Predictive of Long-term Outcomes Prior to High-dose Chemotherapy with Autologous Stem Cell Transplantation for Multiple Myeloma

We retrospectively investigated the efficacy and predictive factors for the treatment outcomes of bortezomib plus dexamethasone (BD) as second-line induction therapy prior to high-dose chemotherapy supported by autologous stem cell transplantation (HDT/ASCT) in multiple myeloma (MM) patients. Sixty-six transplant eligible MM patients treated by the Kyoto Clinical Hematology Study Group between 2006 and 2011 were investigated. Conventional induction chemotherapy, including vincristine, doxorubicin and dexamethasone (VAD) and high-dose dexamethasone (HDD), was used as first-line induction therapy in all patients, seven (10.6%) of whom attained a very good partial response (VGPR). Of the 59 patients who did not attain VGPR with VAD or HDD, 33 were given BD as second-line induction therapy prior to HDT/ASCT. Patients not treated with BD induction showed an overall response rate (ORR, i.e., better than partial response) of 85.3% after induction therapy, while the ORR of patients treated with BD induction improved from 42.4% after conventional induction therapy to 84.8% after BD. The overall survival (OS) and progression-free survival (PFS) of patients not treated with BD induction were not significantly influenced by the response to induction therapy. Among the patients treated with BD, failure in attaining VGPR prior to ASCT was associated with a significantly shorter PFS and it also tended to show a shorter OS, while the disease stage and achievement of a complete response after HDT/ASCT had no impact on OS or PFS. The achievement of at least VGPR with second-line BD induction therapy is a prerequisite for attaining longer OS and PFS after HDT/ASCT.

A Rare Lung Nodule Consisting of Adenocarcinoma and Amyloid Deposition in a Patient with Primary Systemic AL Amyloidosis

A 60-year-old woman was found to have proteinuria and a lung nodule. The surgically resected left upper lobe contained a nodule, in which the adenocarcinoma was surrounded by a heavy deposition of amyloid. Subsequent renal and gastric biopsies demonstrated amyloid deposition with Aλ immunoreactivity. She was treated with 2 courses of VAD (vincristine, doxorubicin and dexamethasone), resulting in the disappearance of Bence Jones proteinuria. Her nephrotic syndrome has been improving during the subsequent 3 years. The rare lung nodule consisting of adenocarcinoma and amyloid deposition was a diagnostic clue in this primary systemic AL amyloidosis patient.

Amyloid myopathy: a therapeutic trial for the rare and underdiagnosed myopathy with bortezomib

A 69-year-old woman was referred to our clinic because of a 6-month history of progressive muscle weakness. Five years previously, when she was diagnosed as having nephrotic syndrome, the renal biopsy showed deposition of AL-amyloid. Subsequent investigations revealed multiple myeloma with k-type Bence-Jones protein at stage 3 according to the international staging system. A course of vincristine, doxorubicin and dexamethasone (VAD) and an additional course of cyclophosphamide were administered, followed by another course of melphalan (L-PAM) at age 67. The proteinuria slightly improved but persisted for 5 years, when proximal weakness developed. Neurological examination revealed proximally dominant weakness with MRC scale 4 in the deltoid and 3 in the iliopsoas muscles and she was unable to stand up from a full squat. Serum creatine kinase (CK) elevated to 3,399 U/L. Electromyography showed a myogenic pattern with small motor unit potentials, fibrillation potentials and early recruitment pattern. Muscle biopsy revealed a variation of fiber size, little infiltration of inflammatory cells, and homogeneous accumulations beneath the muscle membrane (Fig. 1a). Congo red-positive materials were noted both in vessel walls and in muscle fibers (Fig. 1b, c, d) with fluorescence for rhodamine, consistent with amyloid deposition, the hallmark of amyloid myopathy. We were not able to identify whether the deposits were located beneath the basal lamina or the plasmalemma due to lack of electron microscopic preparation. Five years ago, the serum CK value was 110 U/L (Fig. 2). Two years later, when her nephrotic syndrome deteriorated, the CK elevated to 2,336 IU/L without overt weakness. Interestingly, after she received L-PAM, the CK decreased to 120 U/L just 1 month after the treatment. When girdle weakness developed 6 months ago, the CK again soared to 3,378 U/L. The fluctuation of CK and the amyloid deposition in the muscle led us to the diagnosis of amyloid myopathy due to multiple myeloma. We then administered two consecutive courses of bortezomib (1.3 mg/m on days 1, 4, 8, and 11 for the first course and 1.0 mg/m on days 1, 4, 8, and 11 for the second course). The treatment reduced the proportion of myeloma cells from 16.8 to 1.2%. The CK started to fall a few weeks after the first course and eventually fell to 187 U/L 1 month after the second course, when she was able to rise from a sitting position more easily. However, multiple myeloma deteriorated in the following months and the CK again elevated to 694 U/L. She was not able to receive additional treatment because of her poor general status. Amyloid myopathy, a progressive myopathy in a proximally dominant fashion, is caused by a variety of primary amyloidoses, such as familial amyloidosis, AL-amyloidosis and multiple myeloma [1–3]. Postulated mechanisms include impaired muscle metabolism or failed electrical conduction by amyloid deposition beneath the muscle membrane [4, 5]. Therapeutic trials have included plasmapheresis, administration of corticosteroid, and high-dose K. Shiga (&) R. Mizutani R. Isayama T. Tokuda M. Nakagawa Department of Neurology, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Hirokoji-agaru, Kawaramachi-dori, Kamigyo-ku, Kyoto 602-0841, Japan e-mail: kenshiga@koto.kpu-m.ac.jp

High incidence of arterial thrombosis in young patients treated for multiple myeloma: results of a prospective cohort study

AbstractThis prospective study evaluated the risk of arterial thrombosis in 195 consecutive patients aged 18 to 65 years with newly diagnosed multiple myeloma (MM). All patients were treated with 3 cycles of VAD (vincristine, doxorubicin, and dexamethasone) or TAD (thalidomide-AD) or PAD (bortezomib-AD) in national trials, followed by high-dose melphalan and autologous stem cell transplantation. For a period of 522 patient-years, 11 of the 195 patients (5.6%) developed arterial thrombosis. The highest incidence was seen during induction chemotherapy courses. Median age at onset of arterial thrombosis was 59 years (range, 43-65 years). Hypertension and smoking were significantly associated with arterial thrombosis with a relative risk of 11.7 (2.23-61.2) and 15.2 (1.78-130), respectively. Factor VIII levels (FVIII:C) correlated significantly with age (P = .02) and higher International Scoring System (ISS) stage (P = .001). A higher FVIII:C was associated with arterial thrombosis (hazard ratio [HR] = 1.85; 95% confidence interval [CI] = 0.99-3.47) after adjustment for age, ISS score, and assigned treatment arm. MM patients have an increased risk for arterial thrombotic events during and after induction chemotherapy. Hypertension, smoking, and high factor VIII levels, possibly reflecting disease activity, contribute to the risk of arterial thrombosis.

The Newly Diagnosed Myeloma Patient – Therapeutic Approaches

The outcome for myeloma patients has significantly improved over the last decade, mainly due to the introduction of new drugs with a singular mechanism of action such as thalidomide and lenalidomide (revlimid), both immunomodulatory drugs (IMIDs), and the proteasome inhibitor bortezomib (velcade). In newly diagnosed young patients, induction regimens such as bortezomib–thalidomide or lenalidomide plus dexamethasone will replace vincristine, doxorubicin and dexamethasone (VAD), followed by high-dose melphalan. Maintenance with IMIDs may represent the new standard of care for young multiple myeloma (MM) patients. This approach is being challenged by continuous treatment with novel agents and the postponement of a transplant until relapse. Allogeneic transplant should be conducted within the context of clinical trials. In elderly patients or non-transplant candidates, new regimens based on melphalan–prednisone plus thalidomide, velcade or lenalidomide have become new standards. The reduction of side effects while maintaining efficacy of treatment is most important in the elderly population.

Toxic epidermal necrolysis following thalidomide and dexamethasone treatment for multiple myeloma: a case report

Dear Editor, Toxic epidermal necrolysis (TEN) is a life-threatening idiosyncratic adverse drug reaction characterized by fullthickness epidermal necrosis and eventual development of subepidermal bullae [1, 2]. Carbamazapine, phenytoin, and allopurinol are frequent causes of TEN in Asia [1]. Although thalidomide has been suggested as a cause of TEN, to the best of our knowledge, only two cases had been reported worldwide [3, 4]. We present the case of a 65-year-old male patient who was initially diagnosed with Immunoglobulin G-κ (IgG-κ) multiple myeloma stage IIIA, and had been treated with combination chemotherapies including a VAD (vincristine, doxorubicin, and dexamethasone) regimen as well as an MP (melphalan and prednisone) regimen. About 3 years after finishing MP treatment, the patient presented with bone pain and a serum monoclonal protein level of 4,170 mg/dl. We initiated treatment with 200 mg thalidomide per day for 12 days and 40 mg dexamethasone per day for 4 days, and the dose of thalidomide was then increased to 400 mg per day. Eleven days after the boost, the patient’s course was complicated by the development of sloughing from the periorbital and perioral regions. Three days after the onset of the initial event, the patient was admitted to the emergency department with fever, dysphagia, and itching. The same day, oral mucositis, angioedema of lips and eyebrow, and diffuse erythematous to purpuric patches and plaques appeared on the face, neck, trunk, and extremities. On the third day of hospitalization, a skin biopsy showed subepidermal bullous change with an infiltration of lymphocytes and polymorphonuclear cells in the epidermis which suggested TEN (Fig. 1). On the fifth day, the clinical course was complicated by the worsening rash over the entire trunk, and the patient was started on 400 mg/kg intravenous immunoglobulin (IV-Globulin S®, Green Cross Inc., Korea) per day for five consecutive days. In addition, the patient was intensively treated as a burn patient. On the sixth day, focal skin detachment was noticed and, after 2 days, was followed by generalized detachment from the face to the lower extremities. The patient’s severity-ofillness score for TEN (SCORTEN) was 4 with an expected W. K. Eo : S. H. Cheon : S. H. Lee : J. S. Jeong Integrative Cancer Center, Kyung Hee University, East-West Neo Medical Center, Seoul, South Korea

Retrospective Comparison of Bortezomib-containing Regimens with Vincristine-Doxorubicin-Dexamethasone (VAD) as Induction Treatment Prior to Autologous Stem Cell Transplantation for Multiple Myeloma

Patients with multiple myeloma (MM) achieving high-quality responses, defined as a complete response (CR) and a very good partial response (VGPR) after transplant, benefit from high-dose therapy followed by autologous stem cell transplantation (ASCT). Induction pre-transplantation treatment with vincristine, doxorubicin and dexamethasone (VAD) is currently being replaced by new targeted agents with high anti-myeloma activity. The use of these novel agents may increase the CR + VGPR rate before ASCT, which may improve post-transplantation responses and survival. We performed a retrospective analysis of 69 patients with MM who received bortezomib-containing regimens (n = 30) or VAD (n = 39) before collection of peripheral blood stem cells and ASCT. Objective response rate (at least a partial response) prior to ASCT was documented in 27 (90%) of 30 and 31 (81.6%) of evaluable 38 patients with bortezomib-containing regimens and VAD, respectively. The difference between the two groups was not significant (P = 0.494). However, the high-quality response rate with VGPR or more in the bortezomib group was significantly higher compared with the VAD group (66.7% vs. 34.2%, respectively, P = 0.006). The superiority of bortezomib-containing regimens in the high-quality response rate remained significant for only the newly diagnosed patients (n = 16, P = 0.008). The engraftment data as well as stem cell harvesting were comparable between the two groups. The major bortezomib-related toxicities were thrombocytopenias and peripheral neuropathies; toxicities of VAD were hematologic and infectious. After ASCT, the difference between the two groups did not reach the level of statistical significance with respect to progression-free survival and overall survival (P = 0.498 and 0.835, respectively). The results of this retrospective comparison of bortezomib-containing regimens with the VAD as induction treatment prior to ASCT for MM provided a demonstration of the superiority of bortezomib therapy in terms of achieving a high-quality response. However, survivals following ASCT did not differ according to the induction regimens.

High-Dose Therapy in AL Amyloidosis: A Prospective Phase II Study by the Dutch-Belgian Cooperative Group (HOVON)

Background: AL amyloidosis is generally caused by a kappa or lambda light-chain producing plasma cell clone in the bone marrow. High-dose melphalan (HDM) followed by autologous stem cell transplantation (ASCT) is effective in AL amyloidosis. Pretreatment of these patients with vincristine, doxorubicin and dexamethasone (VAD) may have a rapid and additive effect on the underlying plasma cell clone.Objective: To study the feasibility and efficacy of VAD followed by HDM and ASCT in AL amyloidosis.Patients and Methods: In a prospective multicenter phase II study, the Dutch-Belgian Hemato-Oncology Cooperative Group (HOVON) studied the effect of three courses of VAD followed by HDM with ASCT on hematological and clinical response rates and overall survival in AL amyloidosis. Untreated patients aged ≤ 65 years with proven AL amyloidosis and monoclonal gammopathy or multiple myeloma stage I were included. Patients with recent prior malignancy, other types of amyloidosis, and severe other diseases not related to AL amyloidosis were excluded. High risk was defined as cardiac septum ≥ 15 mm, cardiac ejection fraction ≤ 55%, creatinine > 177 μmol/L, or bilirubin > 34 μmol/L (Dispenzieri et al, J Clin Oncol 2001; 19:3350–6). All patients were treated with VAD or dose-modified VAD and after the third course re-evaluated. Patients were judged eligible for stem cell collection and ASCT if WHO performance status 0–2, NYHA class 1–3, cardiac ejection fraction >45%, and no severe other disease. Hematological response was defined as complete response (disappearance of monoclonal protein in blood and urine, and no clonal excess of plasma cells in bone marrow), partial response (greater than 50% reduction in serum and urine monoclonal proteins), persistence, and progression (doubling of monoclonal protein in serum or urine). Clinical response was defined as organ response, stabilization, or progression (Gertz et al, Am J Hematol 2005; 79:319–28).Results: Sixty-nine newly diagnosed patients with AL amyloidosis were included between September 2000 and January 2006: 37 men and 32 women with a median age of 55 years and WHO performance status 0–2. Organ involvement was renal in 58 (84%), cardiac in 32 (46%), hepatic in 12 (17%), and neuropathic in 18 (26%); 15 patients (22%) had involvement of 3 or 4 organs. Thirty-seven (54%) could be classified as high-risk patients. Forty-six patients (67%) could proceed to HDM (140–200 mg/m2) after VAD induction. The transplants were performed in tertiary referral centres. Median haematological recovery time of ANC > 1.0 × 109/L and platelets > 50 × 109/L was 17 and 21 days, respectively. End of survey was November 2007. Overall hematological response was 39% including 16% with a complete response. Overall clinical response was 26% and stabilization in 35%. In 43% of patients only the clinical response could be assessed. Overall survival of all patients was median 60 months and had not been reached for the transplanted patients (Figure). Nine patients died from TRM (11%), 7 during VAD and 2 following HDM. Side effects CTC grade ≥ 2 were recorded in 46% of patients during VAD induction and in 87% of patients after HDM; infections CTC grade ≥ 2 were recorded in 13% and 65%, respectively.Conclusions: VAD induction followed by HDM and ASCT for AL amyloidosis is feasible, has acceptable TRM, and results in a remarkable prolonged survival. This two-step approach of induction with non-intensive chemotherapy in all patients followed by HDM with ASCT in eligible patients is now recommended as standard treatment by HOVON for newly diagnosed patients with AL amyloidosis who are eligible for high-dose therapy. [Display omitted]

Nephrotic Syndrome Due to Primary Systemic AL Amyloidosis, Successfully Treated with VAD (Vincristine, Doxorubicin and Dexamethasone) Alone

We report 3 patients with nephrotic syndrome ascribed to primary systemic AL amyloidosis that were successfully treated with VAD (vincristine, doxorubicin and dexamethasone) alone. M-protein in serum disappeared soon after VAD, and nephrotic syndrome gradually improved in parallel with a decrease in daily protein excretion in urine. Long-term follow-up of these patients showed neither relapse of nephrotic syndrome nor reappearance of M-protein. High-dose melphalan followed by autologous stem cell support is a standard therapy for primary systemic AL amyloidosis, but in high-risk cases for this treatment, such as elderly patients and those with multiple organ involvement, VAD might be a therapeutic option.

Therapeutic Outcome of Cyclic VAD (Vincristine, Doxorubicin and Dexamethasone) Therapy in Primary Systemic AL Amyloidosis Patients

Intensive chemotherapy targeting plasma cell dyscrasia has been recently employed for the treatment of primary systemic AL amyloidosis. We prospectively studied the clinical usefulness of cyclic VAD (vincristine, doxorubicin and dexamethasone) in patients with primary systemic AL amyloidosis who were ineligible for high-dose melphalan with autologous stem cell support. Eight patients (mean age, 60.4+/-8.8 years) were treated with cyclic VAD until the disappearance of M-protein from both serum and urine. Of these, seven showed nephrotic syndrome before the start of VAD irrespective of a decrease in creatinine clearance. Serial follow-up studies after VAD evaluated hematological status and organ function. Four patients (50%) showed a marked decrease in abnormal plasma cells in the bone marrow and normalized kappa/lambda ratios of serum free light chain in conjunction with disappearance of M-protein after 1 to 3 courses of VAD. There were no serious adverse events, and nephrotic syndrome gradually improved with no hematological relapse in the follow-up period of 3 to 5 years. The remaining 4 patients showed worsening of congestive heart failure and/or systemic edema ascribable to dexamethasone, resulting in cessation of cyclic VAD before disappearance of M-protein. All of these patients died of multiple organ failure or required permanent hemodialysis within 1 year after the start of cyclic VAD. Cyclic VAD is a potent therapeutic option in primary systemic AL amyloidosis, but in patients with renal or cardiac dysfunction careful management for adverse events, especially body fluid retention, is necessary.

AL amyloidosis manifesting as systemic lymphadenopathy

We report three patients with AL amyloidosis manifesting as systemic lymphadenopathy, mainly in the cervical and supraclavicular regions. Histopathology of lymph nodes showed massive deposition of AL amyloid with no abnormal findings suggestive of lymphoproliferative disorders. Two of the patients were considered to be classifiable as primary systemic AL amyloidosis based on the presence of M-protein in serum and abnormal plasma cells or lymphoplasmacytoid cells in the bone marrow probably producing the precursor immunoglobulin, although no visceral organs were affected. The size of the involved lymph nodes in these two patients increased gradually, and one was treated with rituximab and VAD (vincristine, doxorubicin and dexamethasone) followed by high-dose melphalan with autologous peripheral blood stem cell transplantation (auto-PBSCT). The remaining patient showed no obvious change in the size of lymph nodes or detectable M-protein in serum. The prognosis of AL amyloidosis manifesting as lymphadenopathy is usually good as long as there are no hematological malignancies or rapid increases in the size of lymph nodes, but in cases of the systemic type, intensive chemotherapy, such as high-dose melphalan with auto-PBSCT, should be actively considered in order to avoid possible involvement of visceral organs.

Initial Cytoreductive Treatment with Thalidomide Plus Bolus Vincristine/Doxorubicin and Reduced Dexamethasone (T-bVAd) Followed by Autologous Stem Cell Transplantation (ASCT) for Multiple Myeloma.

High-dose chemotherapy supported by autologous stem cell transplantation (ASCT) after the combined chemotherapy with vincristine, doxorubicin and dexamethasone (VAD) is an effective therapy for newly diagnosed, multiple myeloma. Bolus vincristine/doxorubicin intravenous administration as an outpatient route is convenient and has acceptable efficacy and toxicity. Thalidomide has recently shown significant antimyeloma activity. We studied the efficacy and toxicity of the combination of bolus vincristine/doxorubicin and reduced-dose of dexamethaxone with thalidomide (T-bVAd), administered on an outpatient basis in previously untreated multiple myeloma. From August 2005 to December 2006, 26 patients were enrolled in a prospective study. All patients received T-bVAd, which consisted of vincristine 0.4 mg intravenously i.v., doxorubicin 9 mg/m2 i.v. administered as single bolus dose on days 1 to 4, and dexamethasone 20 mg per os daily for 4 days. Dexamethasone was also given on days 8 to 11, 15 to18 of the each cycle of treatment. The regimen was administered every 4 weeks for four courses. Thalidomide was given daily at a dose of 200 mg at bedtime. Response to treatment was evaluated after each cycle of treatment. After achieving response, the patients were allowed to proceed to high-dose chemotherapy with ASCT. On an intention-to-treat basis, 23 of the 26 patients (88.4%) responded to treatment. Sixteen patients (61.5%) achieved complete and seven (26.9%) partial response. Only three (11.6%) were rated as non-responders. Grade 3 or 4 toxicities consisted of neutropenia (9%), febrile neutropenia (6%), thrombocytopenia (4%) without significant nonhematologic events. Of the 23 patients who showed response, 9 proceeded to single ASCT and 7 tandem ASCT. Median event-free survival and median overall survival were not reached yet. As an induction therapy, T-bVAd administered as an outpatient regimen, seems to be efficient and well tolerated.