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N Raje

Publications and source records attributed to N Raje.

At least 37 records · Page 2Linked to original sources
PubMed1999

RAFTK/PYK2-dependent and -independent apoptosis in multiple myeloma cells.

Related Adhesion Focal Tyrosine Kinase (RAFTK; also known as Pyk2), is a member of the Focal Adhesion Kinase (FAK) subfamily and is activated by TNF alpha, UV light and increases in intracellular calcium levels. However, the function of RAFTK remains largely unknown. Our previous studies demonstrated that treatment with dexamethasone (Dex), ionizing radiation (IR), and anti-Fas mAb induces apoptosis in multiple myeloma (MM) cells. In the present study, we examined the potential role of RAFTK during induction of apoptosis in human MM cells triggered by these three stimuli. Dex-induced apoptosis, in contrast to apoptosis triggered by anti-Fas mAb or IR, is associated with activation of RAFTK. Transient overexpression of RAFTK wild type (RAFTK WT) induces apoptosis, whereas transient overexpression of Kinase inactive RAFTK (RAFTK K-M) blocks Dex-induced apoptosis. In contrast, transient overexpression of RAFTK K-M has no effect on apoptosis triggered by IR or Fas. In Dex-resistant cells, Dex does not trigger either RAFTK activation or apoptosis. Finally, interleukin-6 (IL-6), a known survival factor for MM cells, inhibits both activation of RAFTK and apoptosis of MM.1S cells triggered by Dex. Our studies therefore demonstrate Dex-induced RAFTK-dependent, and IR or Fas induced RAFTK-independent apoptotic signaling cascades in MM cells.

Apoptosis↗
PubMed1999

Functional interaction between retinoblastoma protein and stress-activated protein kinase in multiple myeloma cells.

Previous studies have demonstrated that gamma-irradiation (IR)-induced apoptosis in multiple myeloma (MM) is associated with activation of stress-activated protein kinase (SAPK). In the present study, we examined the molecules downstream of SAPK/C-Jun N-terminal kinase (JNK), focusing on the role of retinoblastoma protein (Rb) during IR-induced MM cell apoptosis. The results demonstrate that IR activates SAPK/JNK, which associates with Rb both in vivo and in vitro. Far Western blot analysis confirms that SAPK/JNK binds directly to Rb. IR-activated SAPK/JNK phosphorylates Rb, and deletion of the phosphorylation site in the COOH terminus domain of Rb abrogates phosphorylation of Rb by SAPK/JNK. Taken together, our results suggest that Rb is a target protein of SAPK/JNK and that the association of SAPK/JNK and Rb mediates IR-induced apoptosis in MM cells.

Apoptosis↗
PubMed1999

Detection of Kaposi's sarcoma herpesvirus DNA sequences in multiple myeloma bone marrow stromal cells.

Whether Kaposi's sarcoma herpesvirus (KSHV) is associated with multiple myeloma (MM) remains controversial. We assayed for KSHV DNA sequences in long-term bone marrow stromal cells (BMSCs) from 26 patients with MM and 4 normal donors. Polymerase chain reaction (PCR) using primers which amplify a KSHV gene sequence to yield a 233-bp fragment (KS330233 within open reading frame 26) was negative in all cases. Aliquots of these PCR products were used as templates in subsequent nested PCR, with primers that amplify a 186-bp product internal to KS330233. BMSCs from 24 of 26 (92%) patients with MM and 1 of 4 normal donors were KSHV PCR+. DNA sequence analyses showed interpatient specific mutations (2 to 3 bp). Both Southern blot and sequence analyses confirmed the specificity of PCR results. The presence of the KSHV gene sequences was further confirmed by amplifying T 1.1 (open reading frame [ORF] K7) and viral cyclin D (ORF 72), two other domains within the KSHV genome. Immunohistochemical studies of KSHV PCR+ MM BMSCs demonstrate expression of dendritic cell (DC) lineage markers (CD68, CD83, and fascin). Serological studies for the presence of KSHV lytic or latent antibodies were performed using sera from 53 MM patients, 12 normal donors, and 5 human immunodeficiency virus (HIV)/KSHV+ patients. No lytic or latent antibodies were present in sera from either MM patients or normal donors. Taken together, these findings show that KSHV DNA sequences are detectable in BMSCs from the majority of MM patients, but that serologic responses to KSHV are not present. Ongoing studies are defining whether the lack of antibody response is caused by the absence of ongoing infection, the presence of a novel viral strain associated with MM, or underlying immunodeficiency in these patients.

Bone Marrow Cells↗
PubMed1999

Bone marrow and peripheral blood dendritic cells from patients with multiple myeloma are phenotypically and functionally normal despite the detection of Kaposi's sarcoma herpesvirus gene sequences.

Multiple myeloma (MM) cells express idiotypic proteins and other tumor-associated antigens which make them ideal targets for novel immunotherapeutic approaches. However, recent reports show the presence of Kaposi's sarcoma herpesvirus (KSHV) gene sequences in bone marrow dendritic cells (BMDCs) in MM, raising concerns regarding their antigen-presenting cell (APC) function. In the present study, we sought to identify the ideal source of DCs from MM patients for use in vaccination approaches. We compared the relative frequency, phenotype, and function of BMDCs or peripheral blood dendritic cells (PBDCs) from MM patients versus normal donors. DCs were derived by culture of mononuclear cells in the presence of granulocyte-macrophage colony-stimulating factor and interleukin-4. The yield as well as the pattern and intensity of Ag (HLA-DR, CD40, CD54, CD80, and CD86) expression were equivalent on DCs from BM or PB of MM patients versus normal donors. Comparison of PBDCs versus BMDCs showed higher surface expression of HLA-DR (P =.01), CD86 (P =. 0003), and CD14 (P =.04) on PBDCs. APC function, assessed using an allogeneic mixed lymphocyte reaction (MLR), demonstrated equivalent T-cell proliferation triggered by MM versus normal DCs. Moreover, no differences in APC function were noted in BMDCs compared with PBDCs. Polymerase chain reaction (PCR) analysis of genomic DNA from both MM patient and normal donor DCs for the 233-bp KSHV gene sequence (KS330233) was negative, but nested PCR to yield a final product of 186 bp internal to KS330233 was positive in 16 of 18 (88.8%) MM BMDCs, 3 of 8 (37.5%) normal BMDCs, 1 of 5 (20%) MM PBDCs, and 2 of 6 (33.3%) normal donor PBDCs. Sequencing of 4 MM patient PCR products showed 96% to 98% homology to the published KSHV gene sequence, with patient specific mutations ruling out PCR artifacts or contamination. In addition, KHSV-specific viral cyclin D (open reading frame [ORF] 72) was amplified in 2 of 5 MM BMDCs, with sequencing of the ORF 72 amplicon revealing 91% and 92% homology to the KSHV viral cyclin D sequence. These sequences again demonstrated patient specific mutations, ruling out contamination. Therefore, our studies show that PB appears to be the preferred source of DCs for use in vaccination strategies due to the ready accessibility and phenotypic profile of PBDCs, as well as the comparable APC function and lower detection rate of KSHV gene sequences compared with BMDCs. Whether active KSHV infection is present and important in the pathophysiology of MM remains unclear; however, our study shows that MMDCs remain functional despite the detection of KSHV gene sequences.

Adult↗
PubMed1999

Muc-1 core protein is expressed on multiple myeloma cells and is induced by dexamethasone.

Monoclonal antibodies (MoAbs) that selectively identify Muc-1 core protein (MoAbs DF3-P, VU-4H5) determinants were used to identify the Muc-1 glycoform present on 7 multiple myeloma (MM) cell lines, 5 MM patient plasma cells, 12 MM patient B cells, as well as 32 non-MM cell lines and normal hematopoietic cells. Flow cytometry studies demonstrated that all MM cell lines, MM patient plasma cells, and MM patient B cells expressed Muc-1 core protein epitopes. Circulating B cells from 4 normal donors also expressed Muc-1 core protein. In contrast, Muc-1 core protein was absent on 28 of 32 non-MM neoplastic cell lines, 17 of which expressed Muc-1. Splenic and tonsillar B cells, CD34(+) stem cells, resting T cells, and bone marrow plasma cells obtained from normal donors both lacked Muc-1 glycoforms. We next studied the effects of estrogen, progesterone, and glucocorticoid receptor agonists and antagonists on Muc-1 expression, because consensus sequences for the response elements of these steroids are present on the Muc-1 gene promoter. These studies showed that dexamethasone (Dex) induced Muc-1 expression on MM cell lines, as determined by both flow cytometry and Western blot analyses. Dex also induced upregulation of Muc-1 on prostate and ovarian cancer cell lines. Time and dose-response studies demonstrated that Dex induced maximal cell surface Muc-1 expression by 24 hours at concentrations of 10(-8) mol/L. Dex induced Muc-1 upregulation could be blocked with a 10-fold excess of the glucocorticoid receptor antagonist RU486, confirming that Dex was acting via the glucocorticoid receptor. No changes in Muc-1 expression were observed on MM cells treated with estrogen and progesterone receptor agonists and antagonists or with RU486. These studies provide the framework for targeting Muc-1 core protein in vaccination and serotherapy trials in MM. In addition, the finding that Muc-1 expression on MM cells can be augmented by Dex at pharmacologically achievable levels suggests their potential utility in enhancing treatments targeting Muc-1 in MM.

Dexamethasone↗
PubMed1999

Complete remission rate and outcome after intensive treatment of 177 patients under 75 years of age with IgG myeloma defining a circumscribed disease entity with a new staging system.

Because the presence of IgG paraprotein in the blood is clear cut, it makes IgG myeloma a more circumscribed disease than myeloma as a whole in which to study treatment efficacy, particularly relating to complete remission (CR). Between May 1989 and December 1997, 177 consecutive patients with IgG myeloma who were <75 years old were seen, of whom 153 entered a sequential therapy (ST) programme of initial courses of C-VAMP infusional chemotherapy (IC), high-dose treatment (with or without stem cell rescue) (119 patients) and maintenance interferon (87 patients). 74/153 (48.4%) patients entered CR. Median overall survival (OS) and event-free survival (EFS) were 4.9 and 2.1 years, respectively. Multivariate analysis at presentation showed OS was significantly prolonged for beta2M <2.7 mg/l and age 8.5 g/dl predicted for longer EFS. For CR patients, age <median 51 years, absence of Bence-Jones proteinuria (BJP), male sex and white blood cells (WBC) <7 x 109/l predicted for a longer OS. Longer length of first CR was predicted by absence of BJP at presentation (P = 0.03) and fewer than five courses of IC (P = 0.02) to attain CR. We have therefore been able to refine the use of ST in IgG myeloma, redefine CR as a 'macro' endpoint, and propose a new staging system for IgG myelomas. Analysis of 41 comparable IgA patients showed IgG to be a distinct entity.

Adult↗
PubMed1999

Oral idarubicin as a single agent therapy in patients with relapsed or resistant multiple myeloma.

The established treatment for multiple myeloma (MM) comprises induction with infusional chemotherapy, high dose chemotherapy (HDC) and autologous transplantation followed by maintenance interferon. On relapse, patients (pts) are reconsidered for this however some are unsuitable and in this situation the therapeutic options are limited. Between June 1995 and May 1997, 14 pts with previously treated relapsed or refractory MM were recruited. Using a prospective database, the tolerability and efficacy of chronic low dose oral idarubicin was evaluated. The median age of pts was 63 years. All had received previous anthracycline in the form of infusional cVAMP chemotherapy. 11/14 had received previous HDC. Median time from diagnosis to commencing idarubicin was 77 months. 10 mg idarubicin was administered 3 times/week for 3 weeks of a 5 week cycle. The maximum number of courses was 6. Three pts completed 6 courses, 5 pts 3 courses, 2 pts 2 courses and 4 pts 1 course. The reasons for stopping treatment were death due to progressive disease (PD) in 7 pts, persistent thrombocytopenia in 2 pts, PD in 1 pt and 1 pt suffered a cerebral infarction not considered to be related to the idarubicin therapy. Two pts showed evidence of response, neither amounting to a partial response. One had stabilisation of paraprotein with a reduction in bone marrow infiltration (47% to 7% plasma cells), the other had a reduction in bone marrow infiltration after 3 course but an increase after 6 courses. In total forty-one courses of treatment were administered. Grade 3/4 haematological toxicities were noted in a minor fraction of cases and were as follows: anaemia 6/41, neutropenia 10/41 and thrombocytopenia 11/41. Our data therefore shows a minor response in 2/14 (14%) of heavily pretreated patients with MM, without evidence of severe toxicity. It provides the rationale for using oral idarubicin as either single agent or in combination therapy for patients earlier on in their disease course especially if they are unsuitable for standard therapy.

Adult↗
PubMed1998

A randomized trial of maintenance interferon following high-dose chemotherapy in multiple myeloma: long-term follow-up results.

High-dose chemotherapy (melphalan) with autologous marrow stem cell support (AMSCS) results in high response rates in multiple myeloma (MM), with up to 50% of patients achieving complete remission. However, these remissions are generally not durable. As the cytokine interferon alpha has been shown to prolong partial response following conventional chemotherapy, this trial was conducted to evaluate its role following high-dose chemotherapy. 85 patients were randomly assigned to maintenance treatment with interferon alpha, 3 x 10(6) units/m2 subcutaneously three times weekly until relapse or no further treatment following recovery from high-dose chemotherapy (melphalan 140-200 mg/m2 or busulphan 16 mg/kg) combined with AMSCS. At 5.8 years following the accrual of the last patient in this trial, 38 patients had died, 17 in the interferon arm and 21 in the control arm. The median progression-free survival (PFS) in the 42 patients randomized to interferon alpha was 46 months versus 27 months in the controls. Both overall survival and PFS, which were highly significant at median follow-up of 52 months, have now ceased to be significant, because most patients have ultimately succumbed to their disease. Interferon was tolerated by the majority of patients with very good compliance. Toxicity consisted mainly of flu-like symptoms and malaise which were usually self-limiting. The results of such a pilot study should be carefully interpreted and the benefits of interferon should be confirmed in larger multicentre studies in the setting of minimal residual disease following autologous transplantation.

Adult↗
PubMed1997

Comparison of marrow vs blood-derived stem cells for autografting in previously untreated multiple myeloma.

Sixty-three new untreated patients with multiple myeloma under the age of 70 years received C-VAMP induction treatment followed by high-dose intravenous melphalan (200 mg m(-2)) and autologous stem cell transplant, either with marrow [autologous bone marrow transplants (ABMT), n = 26] or with granulocyte colony-stimulating factor (G-CSF)-mobilized stem cells from the blood [peripheral blood stem cell transplants (PBSCT), n = 37]. This was a sequential study and the two groups were not significantly different for all known prognostic variables. The complete remission (CR) rate after high-dose treatment was the same for both groups [ABMT 84% and PBSCT 70%; P = not significant (NS)]. Neutrophil recovery to 0.5 x 10(9) l(-1) occurred at a median of 22 days in the ABMT patients compared with 19 days for the PBSCT patients (P = NS). Platelet recovery to 50 x 10(9) l(-1) was significantly faster in PBSCT patients (19 days vs 33 days; P = 0.0015), and the PBSCT patients spent fewer days in hospital (median 20 vs 27 days; P = 0.00001). There was no difference in the two groups with respect to starting interferon (58 days for ABMT vs 55 days for PBSCT), and tolerance to interferon was identical. The median overall survival (OS) and progression-free survival (PFS) for the PBSCT patients has not yet been reached. The OS in the ABMT patients at 3 years was 76.9% (95% CI 60-93%) compared with 85.3% (95% CI 72-99%) in the PBSCT patients (P = NS), and the PFS at 3 years in the ABMT patients was 53.8% (95% CI 34-73%) and in the PBSCT patients was 57.6% (95% CI 34-81%) (P = NS). The probability of relapse at 3 years was 42.3% in the ABMT arm compared with 40% in the PBSCT patients (P = NS). Thus, PBSCT patients had a faster engraftment and a shorter stay in hospital than ABMT; the survival outcome and probability of relapse was the same for both groups.

Adult↗
PubMed1997

Outcome assessment of a population-based group of 195 unselected myeloma patients under 70 years of age offered intensive treatment.

A single centre series of 195 consecutive newly diagnosed untreated myeloma patients under 70 years, seen between September 1986 and March 1994, were analysed to assess the impact of current intensive treatment methods upon remission rate, response rate and subsequent outcome. They were predominantly an unselected population based group of patients (other than by age) that could be used by purchasers of health care as a model for outcome assessment. All patients were scheduled to receive a care plan which included a sequential package of treatment consisting initially of courses of infusional chemotherapy using vincristine, adriamycin and methyl prednisolone (VAMP) and 90 of these also received cyclophosphamide (C-VAMP). Thirty-eight patients received verapamil in addition to C-VAMP(V-C-VAMP). After VAMP all patients were planned to receive high-dose treatment with melphalan and an autograft (marrow or blood) and 112 received this treatment; a further 29 patients received modified high-dose treatment with melphalan alone (23) or busulfan (6) and 54 (28%) did not proceed to high-dose treatment because of refusal, resistant disease, poor performance or treatment-related death. The patients who received melphalan or busulfan alone instead of high-dose melphalan/autografts did so because of increasing age (P = 0.001) and a raised creatinine (P = 0.05). The complete remission rate was 53% for the whole group and 74% for those receiving high-dose melphalan and an autograft. From July 1988, the sequential therapy package included continuous three times weekly interferon (IFN) after high-dose treatment as maintenance therapy, initially as part of a controlled randomised trial and then for all suitable patients. Fifty-seven patients received IFN. The median overall survival (OS) and progression-free survival (PFS) from first treatment for the whole group of 195 patients is 4.5 years and 25 months, respectively. The 112 patients receiving the melphalan autografts fared significantly better than the rest of the patients with OS and PFS (from high-dose treatment) of 6.6 years and 27 months, respectively (P < 0.005), and the 57 patients also receiving IFN have a OS yet to reach a median at 8 years and a PFS of 44 months, significantly better than non IFN high-dose patients (P < 0.0036). However, although we showed benefit for selected patients in studies and trials (particularly with IFN) during the 8-year period of the series, this did not translate into overall PFS benefit in our study for unselected cohorts of patients for 1986-1988 (64 patients) 1989-1992 (100 patients) and 1992-1994 (34 patients) in spite of progressive increases in the proportion of patients receiving IFN (respectively 6, 35 and 58%). This is likely to be due to the dilution of benefit to specific patients by the overall number of patients involved. Outcome data from unselected patients are now expected by purchasers and presented in this way, help qualify the activity impact of advances made from research trials for the treatment of population-based cancer problems.

Adult↗
PubMed1997

A comparison of vincristine and doxorubicin infusional chemotherapy with methylprednisolone (VAMP) with the addition of weekly cyclophosphamide (C-VAMP) as induction treatment followed by autografting in previously untreated myeloma.

In a sequential nonrandomized study, 204 consecutive unselected patients aged < 70 years received induction chemotherapy with infusional vincristine and adriamycin with oral methyl prednisolone (VAMP: n = 75) or with additional cyclophosphamide, C-VAMP (n = 129). 38/129 C-VAMP patients also received verapamil during induction as part of a controlled trial with the aim to overcome drug resistance. A median of five courses (range 1-11) of chemotherapy were required before maximal response was attained and this was similar in both groups. An over-all response rate of 71% was noted at the end of induction. The complete remission (CR) rate with C-VAMP was 24%, which was significantly higher (P = 0.04) than the CR rate with VAMP alone (8%). The addition of verapamil did not alter the response rate of C-VAMP. Compliance to VAMP was overall 83% and not affected by the addition of cyclophosphamide. The proportion of patients going on to receive high-dose chemotherapy and an autograft was the same for VAMP and C-VAMP treated patients (71%). The median overall survival (OS) and progression-free survival (PFS) for the whole group were 4.4 years and 2.0 years and no difference in outcome was observed between the different treatment groups. Therefore the addition of weekly cyclophosphamide to VAMP induction therapy has significantly improved the response rates of previously untreated myeloma patients. C-VAMP was not more toxic and did not compromise the chances of receiving an autograft. Verapamil was without influence on any parameters in this study.

Adult↗
PubMed1996

Comparison of interferon tolerance after autologous bone marrow or peripheral blood stem cell transplants for myeloma patients who have responded to induction therapy.

Interferon (INF) has been incorporated as part of maintenance therapy after high dose treatment in order to make remissions more durable. In this study we have compared peripheral blood stem cell transplant (PBSCT) versus autologous bone marrow transplant (ABMT) with respect to INF tolerance. Thirty nine PBSCT patients have been compared to 37 ABMT patients for INF tolerance. This is followed by a comparison of 15 PBSCT patients versus 21 ABMT patients for engraftment details, response and survival. INF was started at a median of 61 days in the PBSCT and 58 days in the ABMT patients (P = NS). It was well tolerated in both groups without a significant difference in toxicity in the two arms. Engraftment was more rapid in the PBSCT patients with platelet recovery being significantly faster. Response and survival showed a favourable trend for ABMT patients though statistical significance was not reached and the cost of PBSCT was 12% cheaper. We were thus able to conclude that PBSCT grafts were as durable and could tolerate INF just as well as ABMT. Engraftment was more rapid and the procedure of PBSCT was also cheaper. Further studies with a larger group of patients will be required before comments on the efficacy of treatment can be made.

Adult↗
PubMed1996

Role of CD34+ cells in engraftment after high-dose melphalan in multiple myeloma patients given peripheral blood stem cell rescue.

During the period December 1992 to June 1995, 95 patients were treated with high-dose melphalan (HDM) with peripheral blood stem cell rescue (PBSCR). Sixty-five had received previous treatment and 28 had relapsed. Among patients who had relapsed 21/28 had received HDM previously including one who received HDM twice during the course of the study. Seventy-five patients were given HDM/PBSCR for the first time. Comparisons have been made between engraftment times for platelets and neutrophils among patients who received less than or greater than 2 x 10(6) CD34+ cells at rescue. Analyses have also been done to evaluate the effect of previous HDM on recovery. Mobilization of progenitor cells was done with granulocyte colony-stimulating factor (G-CSF). Patients received only PBSCR. No growth factors were given to the PBSCR recipients during the recovery period. The percentage of patients from whom the number of CD34+ cells mobilized was > 2 x 10(6)/kg was similar in patients who received HDM for the first time (23%) compared with those who had had it previously (19%). The yield of CD34+ cells correlated with the number of granulocyte-macrophage colony forming units (CFU-GM). Although the number of CD34+ cells infused was < 2 x 10(6)/kg in 77% of patients, all engrafted for neutrophils to > 0.5 x 10(9)/l. This was delayed in patients who had had previous HDM (P < 0.02). Platelet recovery to > 25, 50 and 100 x 10(9)/l was delayed in all patients who received < 2 x 10(6) CD34+ cells/kg infused (P < 0.02). In patients who had had previous HDM both neutrophil (P < 0.05) and platelet recovery (P < 0.007) were delayed compared with recovery in patients who had not had HDM. In patients who had had previous HDM and received < 2 x 10(6) CD34+ cells/kg infused only 3/17 regained platelets to > 100 x 10(9)/l compared with 3/4 who had > 2 x 10(6) CD34+ cells/kg infused (P < 0.05 Fisher's exact test). There was no evidence that low numbers of CD34+ cells in the PBSCR were associated with early death. The data show that previous treatment with HDM had adverse effects on the subsequent engraftment of platelets among patients given HDM/PBSCR. The data suggest that additional measures are needed to achieve platelet reconstitution in these heavily pre-treated patients.

Antigens, CD34↗
PubMed1996

An economic evaluation of peripheral blood stem cell transplantation as an alternative to autologous bone marrow transplantation in multiple myeloma.

Autologous peripheral blood stem cell transplantation (PBSCT) is increasingly being utilised as an alternative to autologous bone marrow transplantation (ABMT) in the treatment of malignant diseases. We have performed a pharmacoeconomic study using cost-minimisation analysis to evaluate the two techniques in a population of multiple myeloma patients undergoing PBSCT (n = 37) or ABMT (n = 14). In the PBSCT group, the time to > 0.5 x 10(9)/l neutrophils was significantly shorter (16 vs 22 days; P = 0.0019) as was the time to > 50 x 10(9)/l platelets (19 vs 27 days; P = 0.0019). The faster haematopoietic recovery resulted in a reduced period of intravenous antibiotic therapy (12 vs 19 days; P < 0.0001), reduced requirements for platelet transfusions (12 vs 31.5 units; P = 0.0005), and ultimately, a significant reduction in duration of hospitalisation (19 vs 27.5 days; P < 0.0001). These clinical benefits translated into economic benefits such that the total cost in the PBSCT group was 27.5% less than in the ABMT group (< Pounds 7995 vs < Pounds 11026; P = 0.0001). We conclude that the use of PBSCT as an alternative to ABMT in patients with multiple myeloma is associated with demonstrable economic advantages in addition to clinical benefits.

Adult↗
PubMed1995

Maintenance therapy for remission in myeloma with Intron A following high-dose melphalan and either an autologous bone marrow transplantation or peripheral stem cell rescue.

Eighty-four patients with myeloma were randomized to receive maintenance Intron A (Schering-Plough, Suffolk, UK), 3 mega units/m2 s.c. three times weekly or no treatment following induction therapy with cyclophosphomide, vincristine, doxorubicin, methyl prednisolone (C-VAMP), consolidated with high-dose melphalan (HDM) 200 mg/m2 + autologous bone marrow transplantation (ABMT). The patients have been followed up for a median of 52 months. Overall, median progression-free survival (PFS) from HDM was 27 months in the control group and 46 months in the Intron A group (< 0.025). For the 65 patients who achieved complete remission (CR) with HDM, there was a significant prolongation of remission (p = 0.02) for those who received Intron A and 49% of these patients remained in remission four years after high-dose treatment. However, for partial responders (PR) and nonresponders to HDM there was no significant prolongation of PFS. Overall, survival was also significantly better for the Intron A group, with 5 deaths versus 14 deaths in the control group (p = 0.006). Subsequently, 54 consecutive patients received the same HDM followed by rescue with peripheral blood stem cells after induction chemotherapy which included C-VAMP. Intron A was started in 45 of these patients at a median of 62 days which was comparable to the ABMT arm. The overall response rate in these patients was 79.62% (43/54-CR+PR) and the probability of survival at 18 months was 74.2% by the Kaplan Meier method.(ABSTRACT TRUNCATED AT 250 WORDS)

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1995

Kinetics of paraprotein clearance after autografting for multiple myeloma.

The kinetics of paraprotein clearance after autografting for multiple myeloma have not been described. We studied 33 myeloma patients in plateau phase with detectable paraprotein (3-34 milligrams, median 10 milligrams) at the time of ABMT who received melphalan (200 mg/m2) and methylprednisolone (1.5 g x 5) for conditioning. Fifteen patients received interferon-alpha post-transplant as part of a randomized study. Twenty-four of 33 (72.7%) patients eventually cleared the paraprotein at a median of 47 days (range 5-783) post-transplant. The probability of clearance was lower (46.7 vs 94.4%, P = 0.004) and the time taken to clear paraprotein longer (142 vs 29 days, P = 0.003) in patients with a higher level (> 10 milligrams) at the time of the transplant. However, clearance occurred within 6 months in 23 of 24 (95.8%) patients who ultimately cleared the paraprotein. Interferon-alpha did not influence the clearance of paraprotein. We conclude that after autografting for myeloma, the time taken to clear paraprotein is longer and the probability of clearance lower with higher levels at the time of ABMT, and most patients who eventually clear the paraprotein do so within 6 months. Because the probability of clearing paraprotein (and thus attaining remission) in patients with detectable paraprotein 6 months post-transplant is low, a decision about further treatment may be made at this point.

Adult↗