Total Therapy With Tandem Transplants for Newly Diagnosed Multiple Myeloma

Blood ◽  
1999 ◽  
Vol 93 (1) ◽  
pp. 55-65 ◽  
Author(s):  
B. Barlogie ◽  
S. Jagannath ◽  
K.R. Desikan ◽  
S. Mattox ◽  
D. Vesole ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Remission Induction ◽  
Comprehensive Treatment ◽  
High Dose ◽  
Newly Diagnosed ◽  
High Dose Therapy ◽  
Dose Therapy ◽  
Total Therapy ◽  
Macrophage Colony ◽  
Intent To Treat

Abstract Between August 1990 and August 1995, 231 patients (median age 51, 53% Durie-Salmon stage III, median serum β-2-microglobulin 3.1 g/L, median C-reactive protein 4 g/L) with symptomatic multiple myeloma were enrolled in a program that used a series of induction regimens and two cycles of high-dose therapy (“Total Therapy”). Remission induction utilized non–cross-resistant regimens (vincristine-doxorubicin-dexamethasone [VAD], high-dose cyclophosphamide and granulocyte-macrophage colony-stimulating factor with peripheral blood stem cell collection, and etoposide-dexamethasone-cytarabine-cisplatin). The first high-dose treatment comprised melphalan 200 mg/m2 and was repeated if complete (CR) or partial (PR) remission was maintained after the first transplant; in case of less than PR, total body irradiation or cyclophosphamide was added. Interferon--2b maintenance was used after the second autotransplant. Fourteen patients with HLA-compatible donors underwent an allograft as their second high-dose therapy cycle. Eighty-eight percent completed induction therapy whereas first and second transplants were performed in 84% and 71% (the majority within 8 and 15 months, respectively). Eight patients (3%) died of toxicity during induction, and 2 (1%) and 6 (4%) during the two transplants. True CR and at least a PR (PR plus CR) were obtained in 5% (34%) after VAD, 15% (65%) at the end of induction, and 26% (75%) after the first and 41% (83%) after the second transplants (intent-to-treat). Median overall (OS) and event-free (EFS) survival durations were 68 and 43 months, respectively. Actuarial 5-year OS and EFS rates were 58% and 42%, respectively. The median time to disease progression or relapse was 52 months. Among the 94 patients achieving CR, the median CR duration was 50 months. On multivariate analysis, superior EFS and OS were observed in the absence of unfavorable karyotypes (11q breakpoint abnormalities, -13 or 13-q) and with low β-2-microglobulin at diagnosis. CR duration was significantly longer with early onset of CR and favorable karyotypes. Time-dependent covariate analysis suggested that timely application of a second transplant extended both EFS and OS significantly, independent of cytogenetics and β-2-microglobulin. Total Therapy represents a comprehensive treatment approach for newly diagnosed myeloma patients, using multi-regimen induction and tandem transplantation followed by interferon maintenance. As a result, the proportion of patients attaining CR increased progressively with continuing therapy. This observation is particularly important because CR is a sine qua non for long-term disease control and, eventually, cure.

Total Therapy With Tandem Transplants for Newly Diagnosed Multiple Myeloma

Blood ◽  
1999 ◽  
Vol 93 (1) ◽  
pp. 55-65 ◽  
Author(s):  
B. Barlogie ◽  
S. Jagannath ◽  
K.R. Desikan ◽  
S. Mattox ◽  
D. Vesole ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Remission Induction ◽  
Comprehensive Treatment ◽  
High Dose ◽  
Newly Diagnosed ◽  
High Dose Therapy ◽  
Dose Therapy ◽  
Total Therapy ◽  
Macrophage Colony ◽  
Intent To Treat

Between August 1990 and August 1995, 231 patients (median age 51, 53% Durie-Salmon stage III, median serum β-2-microglobulin 3.1 g/L, median C-reactive protein 4 g/L) with symptomatic multiple myeloma were enrolled in a program that used a series of induction regimens and two cycles of high-dose therapy (“Total Therapy”). Remission induction utilized non–cross-resistant regimens (vincristine-doxorubicin-dexamethasone [VAD], high-dose cyclophosphamide and granulocyte-macrophage colony-stimulating factor with peripheral blood stem cell collection, and etoposide-dexamethasone-cytarabine-cisplatin). The first high-dose treatment comprised melphalan 200 mg/m2 and was repeated if complete (CR) or partial (PR) remission was maintained after the first transplant; in case of less than PR, total body irradiation or cyclophosphamide was added. Interferon--2b maintenance was used after the second autotransplant. Fourteen patients with HLA-compatible donors underwent an allograft as their second high-dose therapy cycle. Eighty-eight percent completed induction therapy whereas first and second transplants were performed in 84% and 71% (the majority within 8 and 15 months, respectively). Eight patients (3%) died of toxicity during induction, and 2 (1%) and 6 (4%) during the two transplants. True CR and at least a PR (PR plus CR) were obtained in 5% (34%) after VAD, 15% (65%) at the end of induction, and 26% (75%) after the first and 41% (83%) after the second transplants (intent-to-treat). Median overall (OS) and event-free (EFS) survival durations were 68 and 43 months, respectively. Actuarial 5-year OS and EFS rates were 58% and 42%, respectively. The median time to disease progression or relapse was 52 months. Among the 94 patients achieving CR, the median CR duration was 50 months. On multivariate analysis, superior EFS and OS were observed in the absence of unfavorable karyotypes (11q breakpoint abnormalities, -13 or 13-q) and with low β-2-microglobulin at diagnosis. CR duration was significantly longer with early onset of CR and favorable karyotypes. Time-dependent covariate analysis suggested that timely application of a second transplant extended both EFS and OS significantly, independent of cytogenetics and β-2-microglobulin. Total Therapy represents a comprehensive treatment approach for newly diagnosed myeloma patients, using multi-regimen induction and tandem transplantation followed by interferon maintenance. As a result, the proportion of patients attaining CR increased progressively with continuing therapy. This observation is particularly important because CR is a sine qua non for long-term disease control and, eventually, cure.

Delphi-Panel Analysis of Appropriateness of High-Dose Therapy and Bone Marrow Autotransplants in Newly Diagnosed Multiple Myeloma

1999 ◽  
Vol 33 (5-6) ◽  
pp. 511-519 ◽  
Author(s):  
Robert Peter Gale ◽  
Rolla Edward Park ◽  
Robert W. Dubois ◽  
Kenneth C. Anderson ◽  
William M. Audeh ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Delphi Panel ◽  
High Dose ◽  
Panel Analysis ◽  
Newly Diagnosed ◽  
High Dose Therapy ◽  
Dose Therapy

Clinical value of serum free ligh chain assay in Algerian newly diagnosed multiple myeloma undergoing high dose therapy

2015 ◽  
Vol 15 ◽  
pp. e123
Author(s):  
M. Yanis ◽  
M.C. Rahali ◽  
D. Bouchelouche ◽  
K. Bernine ◽  
N. Benfenatki ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Dose ◽  
Newly Diagnosed ◽  
High Dose Therapy ◽  
Clinical Value ◽  
Serum Free ◽  
Dose Therapy

scholarly journals Prognostic value of bone marrow angiogenesis in patients with multiple myeloma undergoing high-dose therapy

2004 ◽  
Vol 34 (3) ◽  
pp. 235-239 ◽  
Author(s):  
S Kumar ◽  
M A Gertz ◽  
A Dispenzieri ◽  
M Q Lacy ◽  
L A Wellik ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Prognostic Value ◽  
High Dose ◽  
High Dose Therapy ◽  
Dose Therapy

Genetic Polymorphisms Associated with Clinical Outcome in the Intergroup Trial S9321, Comparing High Dose Therapy with Standard Dose Therapy for Myelomaon, on Behalf of ECOG, SWOG, CALGB, and the Bank on a Cure.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1495-1495
Author(s):  
Rafael Santana-Davila ◽  
John Crowley ◽  
Brian Durie ◽  
Bart Barlogie ◽  
Philip Greipp ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
Genetic Polymorphisms ◽  
Median Survival ◽  
Dose Regimen ◽  
Standard Dose ◽  
High Dose ◽  
Newly Diagnosed ◽  
High Dose Therapy ◽  
Dose Therapy ◽  
Intergroup Trial

Abstract Genetic variations in patient populations likely contribute to disease progression and therapeutic outcomes. We have begun a systematic approach to examine the association of genetic variations (ie. functional, single nucleotide polymorhisms, SNPs) involved in myeloma growth promotion, metabolic events, drug responses, and DNA repair on clinical outcome in the intergroup trial S9321. This trial tested a single high dose regimen with autologous stem cell support against a conventional dose regimen, with further randomization of responders to maintenance with interferon or not, in newly diagnosed patients with multiple myeloma. ECOG, CALGB and SWOG enrolled 899 patients with newly diagnosed MM to receive VAD induction x 4 cycles followed by randomization to PBSC-supported high dose therapy (HDT) versus standard dose therapy (SDT) of VBMCP, using CTX 4.5 g/m2 + G-CSF for PBSC mobilization in all patients. Responders to VBMCP or HDT were randomized to IFN or no maintenance. Specimens were distributed through ECOG for biologic correlative studies, including candidate SNP analysis. SNP assays have been developed using the Sequenom Mass-extend platform for functional SNPs in IL-6, IL-1, IL-RA, IL-10, TNF, Lta, TGFb, MDR1, MPO, CYP3A4, GST (M, P, T), ERCC2 and XRCC1, and are being evaluated on 803 DNA samples prepared from patients enrolled in S9321. Preliminary findings (n=135) demonstrate functional genetic variants of IL-10 (position -1082), IL-1 (position +3953), TGFb (postion -509), and TNFa (position -308) are showing trends associated with differences in progression free survival; and variants in IL-6 (position -174) are associated with response. Median survival of the IL-10 variants was 31 months for A/A low producer alleles versus 19 months for the G/G high producer alleles (p=.5). For TNFa, 2 cases with the high producer A/A alleles died within a year, while the median survival for the lower producer G/G alleles was 2 years (p=.04). For patients with the high producer C/C/ allele of IL-1 (n=67), median survival was 2 years, versus 5 patients with the T/T low producer alleles that had a median survival greater than 5 years (preliminary p=.29). While these preliminary results are now only suggestive of trends in genetic polymorphisms associated with clinical outcome, completion of the full SNP panel on the entire sample base should provide a extensive association study, and analysis of potential differences in therapy arms of the trial. The full panel and association studies will be presented.ααββααα

Combination Chemotherapy with Cyclophosphamide, Thalidomide and Dexamethasone Achieves a High Response Rate in Patients with Newly Diagnosed, VAD-Refractory and Relapsed Myeloma.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1499-1499 ◽  
Author(s):  
Catherine D. Williams ◽  
Jennifer L. Byrne ◽  
Gamal Sidra ◽  
Sonya Zaman ◽  
Nigel H. Russell
Keyword(s):  
Stem Cell ◽  
Vascular Access ◽  
Response Rate ◽  
De Novo ◽  
High Dose ◽  
Newly Diagnosed ◽  
High Dose Therapy ◽  
Dose Therapy ◽  
Stem Cell Mobilisation ◽  
Relapsed Disease

Abstract The established first-line treatment for younger myeloma patients includes regimens containing high-dose pulsed steroids and a combination of intravenous cytotoxic drugs such as vincristine and adriamycin (e.g.VAD). Response rates of 60% are reported but some patients are refractory. Patients may have complications relating to the need for central vascular access. Oral treatments, such as thalidomide, have shown response rates of about 36% in refractory patients. In an attempt to improve on these results we have evaluated the efficiency and toxicity of a novel oral chemotherapy regimen containing pulsed cyclophosphamide, thalidomide and pulsed dexamethasone (CTD). This regimen consists of a four week cycle of oral cyclophosphamide 500mg, given on days 1, 8 and 15, daily oral thalidomide initiated at a dose of 100mg daily for the first two weeks, increasing to 200mg daily if tolerated, and oral dexamethasone 40mg daily on days 1–4 and 15–18. Patients were treated with 2–6 cycles depending on response. Response criteria were used according to the EBMT/IBMTR guidelines. Results are reported on 62 myeloma patients: 15 with newly diagnosed (de novo) disease, 29 with VAD-refractory myeloma and 17 with relapsed disease. Median age of the patients was 55 years (range 31–73). Isotype was IgG in 38 patients, IgA in 17, light chain in 6 and non-secretory (NS) in 1 patient. Of the 15 patients with de novo disease, a median of 5 courses of CTD were given(range 4–6). All patients responded with 12 achieving a PR and 3 a CR. Of the 29 VAD-refractory patients, 14 had either no response or progressive disease after 2 cycles of VAD and 14 had only a minimal response to VAD with < 50% reduction in paraprotein after 3 cycles. One patient with NS myeloma had <50% reduction in bone marrow plasmacytosis after 3 cycles. PR or CR was achieved in 24 of the 29 patients (83%), with the remaining five achieving < 25% reduction in paraprotein. Twenty nine of the 44 de novo and refractory patients were considered suitable to progress to high dose melphalan and underwent stem cell mobilisation with cyclophosphamide and G-CSF. The median CD34+ cell dose harvested was 5.22 x 106/kg (1.9–11.2). Only one patient failed to mobilise. Twenty eight of these patients have undergone high dose therapy of whom 10 (36%) have achieved a CR. The relapsed disease group included 17 patients of whom 16 had received previous high-dose therapy. The overall response rate (PR/CR) was 71% (12/17). Ten patients went on to receive maintenance thalidomide and 2 a PSCT. Median follow-up is 19 months and 10 of the 17 are still alive. Toxicity of the CTD regimen was minimal with most adverse affects being grade 1 or 2 by the WHO classification. One third of patients suffered constipation and, a quarter, somnolence due to the thalidomide. Dose reduction was rarely required. Peripheral neuropathy was reported by 9% of patients.Grade 3 toxicity was limited to 2 patients who had a DVT and 2 patients who developed febrile neutropenia. Overall, CTD is a highly effective regimen for patients with newly diagnosed myeloma, VAD-refractory disease or relapsed disease. It is well tolerated and does not impair stem cell mobilisation. As it is oral, compliance is good and complications related to vascular access are minimised. This regimen has now gone on to be tested in new patients in a Phase III setting as one arm of the current MRC Myeloma IX trial.

High-Dose Therapy and Autologous Peripheral Blood Stem Cell Transplantation in Multiple Myeloma: Up-front or Rescue Treatment? Results of a Multicenter Sequential Randomized Clinical Trial

Blood ◽  
1998 ◽  
Vol 92 (9) ◽  
pp. 3131-3136 ◽  
Author(s):  
Jean-Paul Fermand ◽  
Philippe Ravaud ◽  
Sylvie Chevret ◽  
Marine Divine ◽  
Véronique Leblond ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Peripheral Blood ◽  
Peripheral Blood Stem Cell ◽  
Blood Stem Cell ◽  
High Dose ◽  
High Dose Therapy ◽  
Dose Therapy ◽  
Rescue Treatment ◽  
Late Group

Results to date indicate that high-dose therapy (HDT) with autologous stem cell support improves survival of patients with symptomatic multiple myeloma (MM). We performed a multicenter, sequential, randomized trial designed to assess the optimal timing of HDT and autotransplantation. Among 202 enrolled patients who were up to 56 years old, 185 were randomly assigned to receive HDT and peripheral blood stem cell (PBSC) autotransplantation (early HDT group, n = 91) or a conventional-dose chemotherapy (CCT) regimen (late HDT group, n = 94). In the late HDT group, HDT and transplantation were performed as rescue treament, in case of primary resistance to CCT or at relapse in responders. PBSC were collected before randomization, after mobilization by chemotherapy, and, in the two groups, HDT was preceded by three or four treatments with vincristine, doxorubicin, and methylprednisolone. Data were analyzed on an intent-to-treat basis using a sequential design. Within a median follow-up of 58 months, estimated median overall survival (OS) was 64.6 months in the early HDT group and 64 months in the late group. Survival curves were not different (P = .92, log-rank test). Median event-free survival (EFS) was 39 months in the early HDT group whereas median time between randomization and CCT failure was 13 months in the late group. Average time without symptoms, treatment, and treatment toxicity (TWiSTT) were 27.8 months (95% confidence interval [CI]; range, 23.8 to 31.8) and 22.3 months (range, 16.0 to 28.6) in the two groups, respectively. HDT with PBSC transplantation obtained a median OS exceeding 5 years in young patients with symptomatic MM, whether performed early, as first-line therapy, or late, as rescue treatment. Early HDT may be preferred because it is associated with a shorter period of chemotherapy. © 1998 by The American Society of Hematology.

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