Updated Follow-up and Results of Subsequent Therapy in the Phase III VISTA Trial: Bortezomib Plus Melphalan–Prednisone Versus Melphalan–Prednisone in Newly Diagnosed Multiple Myeloma

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 650-650 ◽  
Author(s):  
Jesus F San Miguel ◽  
Rudolf Schlag ◽  
Nuriet K Khuageva ◽  
Meletios A Dimopoulos ◽  
Ofer Shpilberg ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Partial Response ◽  
Interim Analysis ◽  
Response Rates ◽  
Complete Response ◽  
Phase Iii ◽  
High Dose ◽  
End Point ◽  
Number Of Patients

Abstract Based on the results of the large, international, phase III VISTA trial in previously untreated MM patients ineligible for high-dose therapy with stem cell transplantation (HDT-SCT), bortezomib (VELCADE®) was approved by the US FDA for the initial treatment of multiple myeloma (MM). Data from VISTA showed that bortezomib plus melphalan–prednisone (VMP) was superior to melphalan–prednisone (MP) across all efficacy end points, including response rates (overall and complete response [CR] rates), time to progression (TTP), time to subsequent therapy (TTNT), and overall survival (OS). Patients (N=682) from 151 centers in 22 countries in Europe, North and South America, and Asia were randomized (1:1) to 54 weeks treatment with VMP (N=344) or MP (N=338). Patients received nine 6-week cycles of bortezomib 1.3 mg/m2 (days 1, 4, 8, 11, 22, 25, 29, 32 in cycles 1–4 and days 1, 8, 22, 29 in cycles 5–9) with melphalan 9 mg/m2 and prednisone 60 mg/m2 (days 1–4 in cycles 1–9), or melphalan plus prednisone, per the dose and schedule described above. The primary end point was TTP, with progression determined using European Group for Blood and Marrow Transplantation (EBMT) criteria. Median age was 71 years; 30% of patients were aged ≥75 years. At baseline, 34% of patients had Karnofsky Performance Status (KPS) ≤70%, 33% had β2-microglobulin >5.5 mg/L, and 34% had International Staging System (ISS) Stage III disease. An Independent Data Monitoring Committee recommended the trial be stopped based on a protocol-specified interim analysis as the statistical boundary for the primary end point had been crossed. VMP was well tolerated, with patients remaining on VMP therapy for a median of 46 weeks (8 cycles) versus 39 weeks (7 cycles) with MP; median total dose of bortezomib received was 38.5 mg/m2. Collection of tumor assessment data was stopped after presentation of the positive interim analysis. Collection of survival data, subsequent therapy data and safety/recovery data continued. Updated follow-up through April 25, 2008 confirms a statistically significant survival benefit for VMP versus MP (HR=0.64, P=0.0032) after a median follow-up of 25.9 months. Three-year survival rates were 72% versus 59%, respectively. TTNT and treatment-free interval (TFI) were also significantly longer in the VMP arm (TTNT 28.1 vs 19.2 months, HR=0.53, P<0.000001; TFI 16.6 vs 8.4 months, HR=0.54, P<0.00001). Fewer patients in the VMP versus MP arm (38% vs 57%, respectively) required subsequent therapy. Of the patients receiving subsequent therapy in the VMP and MP arms, 16% and 43% received bortezomib, 49% and 44% received thalidomide, and 19% and 6% received lenalidomide, respectively. Re-treatment with bortezomib was effective in the VMP arm (6% CR) (Table); a 10% CR rate was reported in the MP arm after bortezomib-based therapy. Peripheral neuropathy (PN) in the VMP treatment arm improved or resolved in 79% of events (median 1.9 months), with 60% of PN events resolving completely (median 5.7 months). VMP is an active and well-tolerated treatment option for previously untreated MM patients and significantly prolongs survival and time to subsequent therapy. Patients can be successfully treated with subsequent immunomodulatory-based combination therapy and can also be retreated with bortezomib, achieving high response rates with manageable toxicity. Table. Investigator-reported best responses with subsequent therapies per treatment arm VMP arm (n=129)* MP arm (n=194) Subsequent therapy and number of patients who received therapy* Complete response (%) Partial response (%) Complete response (%) Partial response (%) * Other agents were used as subsequent therapy including dexamethasone; patients could receive multiple-agent regimens Bortezomib or bortezomib combination (n=105) 6 33 10 45 Thalidomide combination (n=149) 4 44 3 52 Lenalidomide Combination (n=37) 4 52 0 55

Depth of response to isatuximab, carfilzomib, lenalidomide, and dexamethasone (Isa-KRd) in front-line treatment of high-risk multiple myeloma: Interim analysis of the GMMG-CONCEPT trial.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 8508-8508 ◽  
Author(s):  
Katja Weisel ◽  
Anne Marie Asemissen ◽  
Britta Besemer ◽  
Mathias Haenel ◽  
Igor W. Blau ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Partial Response ◽  
Interim Analysis ◽  
Response Rates ◽  
Complete Response ◽  
Induction Treatment ◽  
High Dose ◽  
Depth Of Response ◽  
Grade 3

8508 Background: High-risk (HR) multiple myeloma (MM) still has a significant impaired prognostic outcome. Addition of CD38 monoclonal antibodies to standard-of-care regimens significantly improved response rates and depth of response in newly diagnosed (ND) and relapsed/refractory MM patients (pts). Here, we report the prespecified end of induction interim analysis (IA) of the investigator-initiated GMMG-CONCEPT trial (NCT03104842), evaluating the quadruplet regimen isatuximab plus carfilzomib, lenalidomide and dexamethasone (Isa-KRd) in HR NDMM pts. Methods: 153 pts with HR NDMM are planned to be included into the trial. HR MM is defined by the presence of del17p or t(4;14) or t(14;16) or > 3 copies 1q21 and ISS 2 or 3 stage disease. Pts receive 6 cycles of Isa-KRd induction, 4 cycles of Isa-KRd consolidation and Isa-KR maintenance. Transplant eligible pts (arm A) undergo high-dose therapy. Transplant ineligible pts (arm B) receive 2 additional cycles of Isa-KRd induction. The primary endpoint is MRD negativity measured by next-generation flow after consolidation. This IA reports on overall response rates (ORR) after induction. Additional MRD analysis will be presented. Results: 50 pts (46 arm A, 4 arm B) were included in the IA population for ORR. HR MM was defined by del17p in 52%, t(4;14) in 38%, t(14;16) in 12% and > 3 copies 1q21 in 42%. 39/46 pts in arm A and 4/4 pts in arm B completed induction treatment. ORR was 100%, with 5 pts (10.0%) showing partial response (PR), 22 (44.0%; including 4 in arm B) very good partial response (VGPR) and 23 (46.0 %) complete response (CR). Median stem cell yield was 6.6 × 106CD34+ cells/kg. Grade 3/4 treatment-emergent adverse events (≥ 10%) with Isa-KRd included neutropenia (34.0%), leukopenia (26.0%) and thrombocytopenia (14.0%). Main non-hematologic toxicities grade 3/4 were hypertension (12.0%) and infection (8.0%). Conclusions: To the best of our knowledge, we report for the first time on a trial investigating solely HR NDMM and Isa-KRd quadruplet treatment. Isa-KRd induction induces deep responses in HR MM pts. The overall safety profile of Isa-KRd is expected and consistent with previous reports. The study is ongoing, with pts continuing to be included. Clinical trial information: 03104842 .

Thalidomide in Multiple Myeloma - A Community Hospital Experience.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5140-5140 ◽  
Author(s):  
Homayoun Leon Daneschvar ◽  
Hamed Daw ◽  
Asif Chaudhry ◽  
Harris Taylor ◽  
Manmeet Ahluwalia ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Side Effects ◽  
Partial Response ◽  
Community Hospital ◽  
Response Rate ◽  
Complete Response ◽  
M Protein ◽  
Newly Diagnosed ◽  
Number Of Patients

Abstract Multiple Myeloma accounts for 10% of malignant hematologic neoplasms. For the past 30 years, a combination of melphalan and prednisone has been the standard treatment for this disease. Nonetheless, it remains an incurable malignancy with a median survival that does not exceed three years. Recent evidence suggests that angiogenesis is increased in multiple myeloma and has prognostic value. Because of its anti-angiogenic properties, thalidomide has been employed as therapy and several trials show that thalidomide alone is active in 25% to 35% of patients with relapsed and refractory myeloma. Among previously untreated patients with more advanced and symptomatic disease, the combination of thalidomide-dexamethasone doubled the response rate to 72 % (in comparison to thalidomide alone) and induced remissions more rapidly. Objectives: To evaluate the efficacy and side effects of thalidomide in combination with glucocorticoid in previously untreated (newly diagnosed) and treated (refractory to other chemotherapies) multiple myeloma patients in a community hospital setting. Patients and Methods: We retrospectively identified eighty-four consecutive patients with multiple myeloma treated between September 1999 and October 2004 at the Cleveland Clinic Center at Fairview Hospital. The sixteen of eighty-four patients (Table 1) who had received thalidomide were selected for further study. The median starting dose was 150 mg/d. The maintenance dosage was 50–100 mg/d in accordance with tolerability. In addition to thalidomide all sixteen patients were receiving dexamethasone. All provided written informed consent prior to receiving treatment. The primary end point of the study was response rate, defined as complete (undetectable monoclonal M protein in the serum) or partial (greater than 50% reduction in serum monoclonal M protein level) Results: Three patients achieved a partial response in the refractory group and 2 in the newly diagnosed group. One patient achieved a complete response in the refractory group and four in newly diagnosed patients. Sixty percent of the patients in the refractory group and 100% of the newly diagnosed patients survived the follow up time (Table 2). Major side effects included sedation in four (25%), deep venous thrombosis in three (18.7%), neuropathy in three (18.7%) and constipation in two (12.5 %) of the patients. Conclusion: The combination of thalidomide and dexamethasone appears to show promising activity in patients with newly diagnosed and possibly with refractory MM. The combination induced a high frequency of response, rapid onset of remission, and low incidence of serious irreversible toxicity. However, ongoing randomized trials are still needed to define further the role of thalidomide with dexamethasone in the treatment of multiple myeloma. Table 1 Patients Characteristics Refractory patients Newly diagnosed patients Number of patients 10 6 Age (years) 66.3 60.5 Sex 7 male, 3 female 1 male, 5 female IgA type 3 3 IgG type 6 2 Biclonal 1 1 Table 2 Refractory patients Newly diagnosed patients Partial response 3 2 Complete response 1 4 No response 6 0 Median follow up (months) 25.2 11.3 Median progression free survival (months) 7.5 10 Diagnosis to start of thalidomide (months) 18.7 2.5 Time on thalidomide (months) 14.2 11.2 Number of deaths (during follow up time) 4 0

Unexpected Response to Erythropoietin Therapy in Intermediate-Low IPSS Myelodysplastic Syndromes.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4867-4867 ◽  
Author(s):  
M. Kwon ◽  
M. Ballesteros ◽  
I. Perez ◽  
V. Echeverria ◽  
M. Calderon ◽  
...  
Keyword(s):  
Partial Response ◽  
Myelodysplastic Syndromes ◽  
Therapeutic Response ◽  
Response Rates ◽  
Complete Response ◽  
Initial Therapy ◽  
High Rate ◽  
Number Of Patients ◽  
Transfusion Requirements

Abstract INTRODUCTION: The myelodysplastic syndromes (MDS) are clonal hematopoietic disorders characterized by dysplasia and cytopenias, especially anemia. There is no widely accepted standard therapy for MDS. Exogenous erythropoietin (EPO) seems to be able to raise Hb levels and/or decrease transfusion requirements in patients with MDS, with reported responses rates of 25–30%. In our center, EPO has been used since 1999, based on the published recommendations, assessing the therapeutic response after 12 weeks of therapy. OBJECTIVE: To analyze retrospectively the therapeutic response to EPO in 45 patients with MDS and anemia. PATIENTS AND METHODS: 45 consecutive patients with MDS and calculable IPSS score, showing low or intermediate-1 risk, were treated with EPO from 1999 to 2006. From the initial 45 patients, 5 were excluded from the analysis because of lack of follow-up. The 40 selected patients belonged to the following FAB subgroups: AR 20 (50%), ARS 12 (30%), AREB 3 (7%) and LMMC 5 (12%). Other criteria for treatment were Hb levels &lt;10 g/dL or transfusion requirements ≥ 2U/month and/or serum EPO levels &lt;500 U/L. Different commercially available EPO were used: 31 (77%) of the patients received EPO-alfa/beta (30,000 U/week sc) and 9 (23%) darbepoetin (150μg/week sc). Erythroid response criteria followed those of the International Working Group: complete response (CR) with a &gt;2 g/dL Hb increase or transfusion independence, and partial response (PR) with a 1–2 g/dL Hb increase or 50% decrease in transfusion requirements. Sixteen patients with no response after 12 weeks of therapy, continued with double EPO dose for a median of 10 weeks. RESULTS: From the 40 patients selected, 22 (55%) were female with a median age of 76 years old (47– 86). Mean baseline Hb level was 8,4 g/dl (5,8–11). Serum EPO levels were measured in 33 patients: 23 (70%) presented &lt;200 U/L and 10 (30%) between 200 and 500 U/L. Unexpectedly, as much as 19 (47,5%) of the 40 patients responded to treatment. 16 patients (40%) responded after twelve weeks: 7 of them (44%) showed CR and 9 (56%) PR. From the 24 patients who did not respond initially, 16 continued with double EPO dose and 3 (18%) of them responded after 8 weeks. Response rates in different FAB subgroups are shown in table 1. Median duration of all responses was 9 months (1–42 months), 12 months for CR and 5,5 months for PR. Interestingly, none of the subgroup with pretreatment EPO levels ≥200 responded (p=0,006). After an overall follow-up of 81 months, 7 selected patients died (3 due to blastic transformation and 4 due to causes not related to the disease). CONCLUSIONS: The response to EPO therapy of MDS-related anemia in our center was unexpectedly high (47,5%). Patients who do not show response after 12 weeks of initial therapy, seem to improve from switching to higher EPO doses since 18% of patients treated with this scheme responded. In our study, ARS subgroup showed an unexpected high rate of response (66%), although they were treated without association of granulocyte-stimulating colony factor. Remarkably, pretreatment serum EPO levels &lt;200U/L seems to be a valuable predictor of response since none of the patients with levels ≥200 U/L and &lt;500 U/L responded in our study. Table 1. Response rates in different FAB subgroups; N, number of patients; GR, global response; CR, complete response; PR, partial response FAB N GR (%) CR (%) PR (%) AR 20 35 20 15 ARS 12 66 16 50 AREB 3 33 33 0 LMMC 5 60 20 40

scholarly journals Bortezomib Plus Melphalan and Prednisone Compared With Melphalan and Prednisone in Previously Untreated Multiple Myeloma: Updated Follow-Up and Impact of Subsequent Therapy in the Phase III VISTA Trial

2010 ◽  
Vol 28 (13) ◽  
pp. 2259-2266 ◽  
Author(s):  
Maria-Victoria Mateos ◽  
Paul G. Richardson ◽  
Rudolf Schlag ◽  
Nuriet K. Khuageva ◽  
Meletios A. Dimopoulos ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Response Rates ◽  
Phase Iii ◽  
High Dose ◽  
First Line ◽  
Agent Based ◽  
Risk Of Death ◽  
Clinical Benefits ◽  
The Impact

PurposeThe purpose of this study was to confirm overall survival (OS) and other clinical benefits with bortezomib, melphalan, and prednisone (VMP) versus melphalan and prednisone (MP) in the phase III VISTA (Velcade as Initial Standard Therapy in Multiple Myeloma) trial after prolonged follow-up, and evaluate the impact of subsequent therapies.Patients and MethodsPreviously untreated symptomatic patients with myeloma ineligible for high-dose therapy received up to nine 6-week cycles of VMP (n = 344) or MP (n = 338).ResultsWith a median follow-up of 36.7 months, there was a 35% reduced risk of death with VMP versus MP (hazard ratio, 0.653; P < .001); median OS was not reached with VMP versus 43 months with MP; 3-year OS rates were 68.5% versus 54.0%. Response rates to subsequent thalidomide- (41% v 53%) and lenalidomide-based therapies (59% v 52%) appeared similar after VMP or MP; response rates to subsequent bortezomib-based therapy were 47% versus 59%. Among patients treated with VMP (n = 178) and MP (n = 233), median survival from start of subsequent therapy was 30.2 and 21.9 months, respectively, and there was no difference in survival from salvage among patients who received subsequent bortezomib, thalidomide, or lenalidomide. Rates of adverse events were higher with VMP versus MP during cycles 1 to 4, but similar during cycles 5 to 9. With VMP, 79% of peripheral neuropathy events improved within a median of 1.9 months; 60% completely resolved within a median of 5.7 months.ConclusionVMP significantly prolongs OS versus MP after lengthy follow-up and extensive subsequent antimyeloma therapy. First-line bortezomib use does not induce more resistant relapse. VMP used upfront appears more beneficial than first treating with conventional agents and saving bortezomib- and other novel agent–based treatment until relapse.

Aprepitant, Granisetron, and Dexamethasone for Prevention of Chemotherapy-Induced Nausea and Vomiting After High-Dose Melphalan in Autologous Transplantation for Multiple Myeloma: Results of a Randomized, Placebo-Controlled Phase III Trial

2014 ◽  
Vol 32 (30) ◽  
pp. 3413-3420 ◽  
Author(s):  
Thomas Schmitt ◽  
Hartmut Goldschmidt ◽  
Kai Neben ◽  
Anja Freiberger ◽  
Johannes Hüsing ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Multiple Myeloma ◽  
Rescue Therapy ◽  
Autologous Transplantation ◽  
Nausea And Vomiting ◽  
Phase Iii ◽  
High Dose ◽  
Phase Iii Trial ◽  
End Point

Purpose The optimal regimen to prevent chemotherapy-induced nausea and vomiting (CINV) for patients undergoing high-dose chemotherapy and autologous stem-cell transplantation (ASCT) is unclear. To evaluate the effect of aprepitant in addition to a standard regimen, we conducted this randomized, placebo-controlled phase III trial. Patients and Methods Patients with multiple myeloma were randomly assigned at a one-to-one ratio to receive either aprepitant (125 mg orally on day 1 and 80 mg orally on days 2 to 4), granisetron (2 mg orally on days 1 to 4), and dexamethasone (4 mg orally on day 1 and 2 mg orally on days 2 to 3) or matching placebo, granisetron (2 mg orally on days 1 to 4), and dexamethasone (8 mg orally on day 1 and 4 mg orally on days 2 to 3). Melphalan 100 mg/m2 was administered intravenously on days 1 to 2. ASCT was performed on day 4. The primary end point (complete response) was defined as no emesis and no rescue therapy within 120 hours of melphalan administration. Quality of life was assessed by modified Functional Living Index–Emesis (FLIE) questionnaire on days −1 and 6. Results Overall, 362 patients were available for the efficacy analysis (181 in each treatment arm). Significantly more patients receiving aprepitant reached the primary end point (58% v 41%; odds ratio [OR], 1.92; 95% CI, 1.23 to 3.00; P = .0042). Absence of major nausea (94% v 88%; OR, 2.37; 95% CI, 1.09 to 5.15; P = .026) and emesis (78% v 65%; OR, 1.99; 95% CI, 1.25 to 3.18; P = .0036) within 120 hours was increased by aprepitant. Mean total FLIE score (± standard deviation) was 114 ± 18 for aprepitant and 106 ± 26 for placebo (P < .001). Conclusion The addition of aprepitant resulted in significantly less CINV and had a positive effect on quality of life.

Long-Term Follow-Up of a Randomized Phase III Multicenter Study Comparing a Standard Versus an Intensified Conditioning Regimen for High-Dose Chemotherapy in Patients with Multiple Myeloma.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 945-945
Author(s):  
Roland Fenk ◽  
Peter Schneider ◽  
Martin Kropff ◽  
Ali-Nuri Huenerlituerkoglu ◽  
Ulrich Steidl ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Conditioning Regimen ◽  
High Dose Chemotherapy ◽  
Phase Iii ◽  
Study Endpoint ◽  
Primary Study ◽  
High Dose ◽  
Significant Difference

Abstract High-dose chemotherapy (HDT) improves the outcome of patients with multiple myeloma (MM) in comparison to conventional chemotherapy. Dose-escalating strategies including tandem HDT are currently evaluated to further improve remission rates and survival of patients. Therefore we conducted a randomized multicenter trial to compare an intensified conditioning regimen with the current standard high-dose melphalan. The primary study endpoint was response rate, with overall survival (OS), event-free survival (EFS) and toxicity analysed as secondary endpoints. Between 1997 and 1999 a total of 56 patients with stage II and III disease, who were matched for age (median 56 years), number of previous therapies (median time from diagnosis to transplant 7 months) and different risk factors (beta2-microglobulin, LDH, CRP, cytogentic abnormalities, chemoresistant disease, IgA-subtype, renal impairment), were randomized. All patients received 2 courses of oral idarubicine/dexamethasone and 2 courses of intravenous cyclophosphamide/adriamycine in combination with G-CSF followed by peripheral stem cell collection. Thirty patients were treated with melphalan 200mg/m2 (HD-M) whereas 26 patients received idarubicine 42mg/m2, melphalan 200mg/m2 and cyclophosphamide 120mg/kg (HD-IMC) followed by autologous blood stem cell transplantation. Acute toxicity was higher with HD-IMC, including 5 (20%) treatment-related deaths due to infections versus none (0%) in the HD-M group. This lead to early termination of the study. Severity of mucositis (grade III-IV 19 vs. 8 pts., p=0.001), CRP (20 vs. 7 mg/dl, p<0.001), days of fever (11 vs. 3, p<0.001), days with iv-antibiotics (13 vs. 4, p<0.001), number of erythrocyte-transfusions (6 vs. 2, p<0.001), number of platelet-transfusions (16 vs. 4, p<0.001) and days to granulocyte engraftment (18 vs. 11, p=0.007) were significantly higher after HD-IMC. After a follow-up of 5 years analysis restricted to patients surviving the first 30 days after HDT showed a trend to higher response rates (CR+vgPR: 47% (95%CI 24–72%) vs. 35% (95%CI 18–56%), PR 37% (95%CI 17–63%) vs. 48% (95%CI 29–68%) and time-to-progression (median 31 vs. 15 months, p=0.1) in the HD-IMC treatment arm in comparison to HD-M, but there was no significant difference in EFS and OS (median 22 vs. 30, p= 0.31 and 66 vs. 66 months, p=0.8, respectively). Univariate analysis demonstrated that LDH levels > 200 U/L (p=0.04) and chemoresistant disease (p=0.05) were a bad prognostic factor for EFS. Beta2-Microglobulin levels > 5mg/dl (p=0.01), abnormal conventional cytogenetics (p=0.02) and LDH levels > 200 U/L (p=0.03) were predictive for an inferior OS. In conclusion intensified conditioning for HDT had an intolerable high treatment-related mortality and did not improve EFS and OS in patients with multiple myeloma.

Holmium-166 (166Ho)-DOTMP Skeletal Targeted Radiotherapy (STR™) with Melphalan and Autologous Peripheral Stem Cell Transplant (PBSCT) for Multiple Myeloma (MM).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 922-922 ◽  
Author(s):  
Mark Goodman ◽  
William I. Bensinger ◽  
Sergio Giralt ◽  
Donna Salzman ◽  
Katherine L. Ruffner ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Hemorrhagic Cystitis ◽  
Conditioning Regimen ◽  
Complete Response ◽  
Phase Iii ◽  
High Dose ◽  
Cell Transplant ◽  
Red Marrow

Abstract Background: 166Ho-DOTMP is a beta-emitting radiophosphonate that localizes specifically to the bone surfaces and can deliver high dose radiation both to the bone and bone marrow. Follow-up data from 3 clinical trials with STR as conditioning for patients with MM undergoing autologous PBSCT are presented. Methods: In 2 Phase I/II dose-escalation trials, 83 patients received a dose of 166Ho-DOTMP STR calculated to deliver 20, 30, or 40 Gy to the red marrow; 82 pts received melphalan (140 or 200 mg/m2) ± 8 Gy TBI (n=25), followed by PBSCT. As of June, 2004, 77 subjects have been followed for at least 48 months. In a separate Phase II dosimetry trial, 12 patients received two 30 mCi tracer doses of 166Ho-DOTMP STR to determine the reproducibility of biodistribution and pharmacokinetics (PK). All pts received a 25 Gy therapy dose with concurrent IV hydration and continuous bladder irrigation, followed by 200 mg/m2 melphalan and PBSCT. These patients have been followed for at least 18 months. Results: Up to 2.3 Ci/m2, 166Ho-DOTMP STR was given in the Phase I/II trials; 29/83 (35%) patients achieved complete response (CR) and overall response rate (CR + PR) was 64% (7 pts not evaluable). The Kaplan-Meier estimate of median survival is 5.2 years for all 83 patients. In patients who are at least 4 years post transplant who achieved a CR, the survival is 74% (n=27). In patients who achieved less than a CR at least 4 years ago, the survival is 34% (n=44). Dose-related radiation-induced kidney toxicity presented in some patients more than 6 months post-therapy. The dose of 166Ho-DOTMP STR in the Phase II dosimetry trial was 550 to 860 mCi/m2, 166Ho-DOTMP. Currently, 18 months of follow-up reveals no occurrence of hemorrhagic cystitis or > Grade 2 elevated creatinine. A CR rate of 17% with an overall survival of 92%, was observed. In 10 patients who received 166Ho-DOTMP STR 750 mCi/m2 ± 10% in the Phase I/II trial, the CR rate was 40%, and the 4-year survival was 70%. Monitoring for safety and duration of response is ongoing in all 3 trials. Conclusion: Follow-up from the Phase I/II trials confirms that 166Ho-DOTMP STR provides favorable efficacy and safety as part of the conditioning regimen for patients with MM undergoing PBSCT. A Phase III, randomized multicenter study is now open to enrollment, comparing the safety and efficacy of 166Ho-DOTMP STR plus melphalan to melphalan alone as conditioning for PBSCT in subjects with primary refractory MM who have failed to respond to induction therapy, including high-dose dexamethasone, and are within 18 months of diagnosis.

Combination of Bortezomib and Dexamethasone (VD) or Bortezomib, Adriamycine and Dexamethasone (PAD) Followed by High Dose Therapy and Peripheral Blood Stem Cell Transplantation in First-Line Treatment of T(4;14) Multiple Myeloma : a Prospective Study of the MAG Group.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3408-3408
Author(s):  
Lionel Karlin ◽  
David Ghez ◽  
Marie-Olivia Chandesris ◽  
Sylvain Choquet ◽  
Margaret Macro ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Partial Response ◽  
Peripheral Blood Stem Cell ◽  
Induction Treatment ◽  
High Dose ◽  
High Dose Therapy ◽  
Free Survival ◽  
Blood Stem Cell Transplantation

Abstract Abstract 3408 Poster Board III-296 The t(4;14)(p16.3;q32), leading to the ectopic expression of two potential oncogenes, the Multiple Myeloma Set Gene (MMSET) and the Fibroblast Growth Factor 3 (FGFR3), is found in 15% of patients with multiple myeloma (MM) and is associated with a very poor prognosis. We previously shown in patients under 65 years of age that High Dose Therapy followed by Peripheral Blood Stem Cell Transplantation (HDT-PBSCT) provides a high response rate (RR) but a very short median relapse-free survival of only 11 months. In addition, relapses are often aggressive and chemoresistant. Thus, more effective regimen is urgently needed. We prospectively studied 23 t(4;14) MM patients treated with 3 or 4 cycles of a combination of Bortezomib and Dexamethasone (VD) (n=4) or of Bortezomib, Adriamycine and Dexamethasone (PAD) (n=19) as induction treatment before HDT-PBSCT (Melphalan 200 mg/m2). T(4;14) was detected using real time quantitative PCR searching for IGH/MMSET and FGFR3 transcripts. RR, event-free survival (EFS) and overall survival (OS) were evaluated. Median age at diagnosis was 51 years (range, 33-64). Isotype was IgA in 12 (52%) patients. All patients had stage II or III MM. An elevated serum β2m level (>3.5 mg/L) was found in 14 (61%) patients, and a low haemoglobin (Hb) level (<10 g/dL) in 10. Four presented with renal failure and 5 with hypercalcemia. Three (16%) of 19 patients had a t(4;14) without expression of FGFR3. After induction treatment with VD or PAD, PBSC were successfully harvested with granulocyte-colony stimulating factor only (n=15) or following a cycle of high-dose cyclophosphamide (n= 7). RR after induction treatment was complete response (CR) in 6 (26%) patients, very good partial response (VGPR) in 9 (39%), partial response (PR) in 3. Five patients had refractory or progressive disease (PD), including 1 who died before stem cell mobilization. RR after HDT was CR in 11 (48%), VGPR in 4 (17%) and PR in 4 (overall RR of 82%). Three had PD. With a median follow-up of 18 months (range, 3-32), 9 (39%) patients are alive without relapse, including 4 with a 19, 27, 30 and 32 months follow-up respectively. Twelve (52%) patients relapsed. Two patients died in the first month post HDT from PD. We found a median EFS and OS from initiation of therapy of 14.7 and 30.9 months respectively. EFS was not influenced by Hb and/or serum β2m level. However, we found a significantly longer OS in patients with low β2m (median non reached) as compared to patients with high β2m (median=23.1 months, p=0.04). These preliminary results illustrate the heterogeneity of this disease and indicate that some t(4;14) MM patients seem to benefit from bortezomib containing regimen as induction treatment before HDT in term of EFS and OS. A larger series with a longer median time of follow up will be presented. Disclosures: No relevant conflicts of interest to declare.

Comparison of Autologous and Allogeneic Transplantation As Therapy of First Relapse in Patients with Multiple Myeloma - Long-Term Follow up Analysis,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4124-4124
Author(s):  
Ute Hegenbart ◽  
Stefan O Schonland ◽  
Axel Benner ◽  
Christina Wunder ◽  
Thomas M. Moehler ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Multivariate Analysis ◽  
Chronic Gvhd ◽  
High Dose ◽  
Two Stage ◽  
Hematopoietic Stem ◽  
Number Of Patients ◽  
First Relapse ◽  
First Diagnosis

Abstract Abstract 4124 BACKGROUND: Most patients (pts) undergoing high-dose therapy with melphalan 200 mg/m2 (HDM) and autologous transplant for multiple myeloma (MM) develop disease recurrence. The optimal salvage treatment including autologous (auto-) and allogeneic (allo-) hematopoietic stem cell transplantation (SCT) as consolidation therapy for these patients is not yet defined. METHODS: We performed a retrospective analysis of 116 pts with MM treated in our institution between 1999 and 2005. Inclusion criteria were relapse after auto-SCT (n=88) or failure of induction treatment (n=28) and age ≤ 65 years. Re-induction was performed with TCED (thalidomide, cyclophosphamide, etoposide and dexamethasone (Möhler et al, Blood 2001). Seventy-one pts (median age, 59 yrs) received auto-SCT (auto-group) after HDM followed by maintenance therapy with thalidomide or interferon-alpha in 42 pts. Forty-five pts (allo-group, median age, 53 yrs) underwent a reduced-intensity allo-SCT (related in 24 pts), mostly using conditioning with 2 Gy total body irradiation and fludarabine. Thirty-eight pts received an auto-allo-tandem-SCT (Maloney, Blood 2003) and 7 pts have been directly transplanted after TCED. Statistical analysis was done using the two-stage test of Qiu & Sheng (JRSS Ser. B 2008) to compare two possibly crossing survival curves. Extended Cox proportional hazards regression models were applied to allow for time-varying differences between the two SCT groups. RESULTS: Estimated median follow-up after start of TCED was 95 months. All pts received a median number of 3 TCED cycles for re-induction therapy. 64 of 116 pts (55%) showed at least a PR after TCED chemotherapy (CR in 3 pts). TRM was 17% after 2 years in the allo-group and differed significantly from the auto-group (3%, p=0.02). More CR were achieved after allo-SCT compared to auto-SCT (17 vs. 4 pts., p<0.001). Median overall survival (OS) was 26 months for the auto group and 23 months for the allo group (Figure 1, p=0.16). Median progression-free survival (PFS) was 12 months for both groups but crossing hazards were observed (Figure 2, p=0.03, two-stage test of Qiu & Sheng). The results of multivariate regression analysis for OS and PFS including age at relapse-SCT, response to TCED, time between first diagnosis until first relapse-SCT and primary progression are shown in table 1. In the allo group, there was no OS or PFS difference between related and unrelated donors (multivariate analysis). Cumulative incidence of chronic GvHD was 73% (53% extensive). Patients with chronic GvHD showed a better OS and PFS than pts without (univariate analysis, both p<0.01). CONCLUSIONS: To our knowledge, this is the first analysis in a large number of patients with a long follow-up comparing allo with auto SCT in 1st myeloma relapse which were treated uniformly with TCED therapy for re-induction. Main problem was MM recurrence. However, younger pts with disease response after TCED and longer time from first diagnosis to first SCT after relapse profit best from TCED and this transplant approach. Most interestingly, disease control is better after allo compared to auto SCT in univariate and multivariate analysis leading to a PFS of about 20% after 4 years. In our opinion, allo SCT is a valuable clinical option for patients with 1st relapse after HDM and auto SCT. Disclosures: No relevant conflicts of interest to declare.

Prevalence of Oligoclonal Bands in Multiple Myeloma Patients Who Achieved Better Results Than Very Good Partial Response after Treatment with Standard or High Doses Chemotherapy-Final Analysis

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4210-4210
Author(s):  
Luiza soares Vieira ◽  
Edvan de queiroz Crusoe ◽  
Manuella de S. Sampaio Almeida ◽  
Lais Sousa ◽  
ana Lucia Perez ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Partial Response ◽  
Conflicts Of Interest ◽  
Progression Free Survival ◽  
Final Analysis ◽  
Complete Response ◽  
High Dose Chemotherapy ◽  
Oligoclonal Bands ◽  
High Dose ◽  
Good Partial Response

Abstract Introduction - Oligoclonal bands (OB) are monoclonal proteins distinct from those originally identified in the multiple myeloma (MM) diagnosis. Some authors consider that appearance of these bands confers a better prognosis and may be linked to immune reconstitution. There is no data of the exact prevalence of OB emergence in patients with very good partial response (VGPR) or better after different treatment schedules. Objectives - To determine the prevalence of OB in MM patients treated with or without high-dose chemotherapy that obtained at least VGPR and its prognostic value. Methods- This is a retrospective and prospective cohort study. Data were collected from records of patients that achieved at least VGPR to identify the OB emergence. Subsequently, new sample collections from the positive patients were made in order to monitor the progress and duration of the maintenance of these bands. Results-Median follow-up was 42m and 101 patients were included. Median age was 58y (29-87) and 55% were male. IgG was the most frequent component (60%). Durie-Salmon IIIA/B was identified in 92% of the population; ISS was 33% in stage I, 30% in stage II, and 31% in stage III. The prevalence of OB identified by SPE and IF was 50.5% (51 cases), with a higher prevalence in those who underwent transplantation and those who achieved complete response (p=0.00139 and p=0.0368, respectively). Progression free survival (PFS) was longer in the OB group (45.4m x 34.7m p = 0.0075). Conclusion - The OB prevalence in this population was 50.5% and oligoclonality resulted in a longer PFS. Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.

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