Kooperativer Bibliotheksverbund

In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 3383-3383

Abstract: Background. The depth of Hypogammaglobulinemia has been related to adverse prognosis in myeloma for decades, but most importantly, it has been suggested that its recovery following treatment was associated with good outcome and prolonged survival. However, none of the traditional techniques has allowed a precise measurement of isotype-matched (i.e. concentrations of IgGκ in an IgGλ myeloma patient) hypogammaglobulinemia. Recently, a new test quantifying paired clonal and non-clonal immunoglobulins (heavy/light chains HLC i.e. IgGκ/IgGλ) in serum was developed. Here we aim to assess the new HLC assays as tools to measure Hypogammaglobulinemia, and potentially replace traditional techniques for the monitoring of patients with myeloma. Materials and methods. 107 (59 IgGκ, 29 IgGλ, 12 IgAκ, 7 IgAλ) myeloma patients treated with pomalidomide and dexamethasone in two IFM studies (IFM 2009-02 in end-stage RRMM, and IFM 2010-02 in del17p and t(4;14) RRMM ) were included. The criteria for selection were that patients had measurable intact immunoglobulin myeloma according to IMWG criteria (M spike ≥10g/L), using serum and/or urine protein electrophoresis, with exclusion of patients solely measurable on UPEP and sFLC. All sera were collected centrally before initiation of treatment and sequentially every cycle until progression. Hevylite® (HLC) was measured in the biology laboratory of CHRU of Lille (France). For each patient we have measured the clonal isotype HLC level, and the corresponding non-clonal paired isotype HLC level, e.g. for IgAκ myeloma, the IgAλ non-clonal paired isotype. (Normal ranges: IgGκ 3.84-12.07, IgGλ 1.91-6.74 and IgGκ/IgGλ 1.12-3.21; IgAκ 0.57-2.08, IgAλ 0.44-2.04 and IgAκ/IgAλ 0.78-1.94 g/L). Results. Overall, 98 (92%) patients had an abnormal suppressed uninvolved HLC level at baseline with suppression being more common in IgG than IgA patients (95% v 73%, p 〈 0.001), and 94 (87%) at the time the greatest response was reached (IgG 90% 〉 IgA 77%), meaning that the vast majority of patients had not recovered from hypogammaglobulinemia at the time of best response. The median uninvolved IgG and IgA HLC concentrations at baseline were 0.62 and 0.2 g/L respectively (range: 05-6.9; 0.01-5.6). At best, response levels reached were 0.53 and 0.24g/L respectively (0.01-5.6; 0.01-7.4). Interestingly, more patients had recovered in the IFM 2009-02 study compared to the IFM2010-02 study, essentially different in the number of prior lines of therapy (3 and 9, respectively). We then sought to understand the relationship with response to therapy. We noted that very few patients’ hypogammaglobulinemia levels normalized completely, nor did their uninvolved paired isotype HLC levels normalize. However, we found that 55% of responders (IMWG) had improved levels (by at least 20%) of the uninvolved paired isotype HLC compared to 18.5% of the non-responders (p=0.001). Similarly, an improvement of at least 50% in the levels of uninvolved paired isotype HLC was achieved by 35% of responders compared to 13% of non-responders, respectively (p=0.013); an improvement of 75% was reached by 22.5% of responders and 7.4% of non-responders (p=0.028). This data strongly correlated to the depth of response, since, for example, 75% of patients in VGPR or better had improved levels of uninvolved paired isotype HLC by 50% at the time of greatest response, compared to 31% for PR and 13% for SD (p=0.005). Similar correlations were seen for 20% (p 〈 0.0001) and 75% (p=0.16) recoveries. Conclusion. The mechanism of immunosuppression in myeloma patients is poorly understood. Here we have shown for the first time that isotype-matched hypogammaglobulinemia correlates to depth of response. Hypogammaglobulinemia is important to assess not only because of its greater risk of infectious complications, often severe in myeloma, but also as it plays a predictive role in occurrence of response and more importantly depth of response. Future studies are needed to unravel the relationship between debulking of tumor cells and correction of hypogammaglobulinemia; in other words, is repopulating of the marrow with normal B cells associated to better outcome, and how does this affect the homeostasis of the bone marrow in its ability to support tumour cells. Disclosures Stoppa: Celgene Jansen: Honoraria. Marit:Celgene, Janssen: Congress expenses Other.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V124.21.3383.3383

Language: English

Publisher: American Society of Hematology

Publication Date: 2014

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In: Blood, American Society of Hematology, Vol. 125, No. 9 ( 2015-02-26), p. 1411-1417

Abstract: Pom-Dex is active and well tolerated in adverse cytogenetic patients with early RRMM, particularly in those with del(17p). Pom-Dex prolonged OS in adverse cytogenetic patients with early RRMM.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2014-11-612069

Language: English

Publisher: American Society of Hematology

Publication Date: 2015

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detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 2021-2021

Abstract: Background. Protein electrophoresis and immunofixation in the serum (SPEP - SIF) and urine (UPEP – UIF) have been routinely used for decades for characterizing and quantifying the M protein in Multiple Myeloma (MM). However, these techniques are notoriously tarnished with inaccuracy, despite improvements in recent years. The most important breakthrough in the field in recent years was the discovery of the Serum Free Light Chain Assay (sFLC), a routine quantitative and automated assay that measures kappa and lambda sFLC, however this was added to / rather than replaced traditional tests in the diagnostic armamentarium of MM. Recently, a new test quantifying paired clonal and non-clonal immunoglobulins (heavy/light chains HLC i.e. IgGκ/IgGλ) in serum was developed. Here we aim to assess the new HLC assays as tools to replace SPEP / IFE during MM patient monitoring Materials and methods. 110 Myeloma treated with pomalidomide and dexamethasone in two IFM studies (IFM 2009-02 in end stage RRMM and IFM 2010-02 in del17p and t(4;14) RRMM ) were included. The criteria for selection were that patients had measurable intact immunoglobulin myeloma according to IMWG criteria (M spike ≥10g/L), using serum and/or urine protein electrophoresis, with exclusion of patients solely measurable on UPEP and sFLC. All sera were collected centrally before initiation of treatment and sequentially every cycle until progression. Hevylite® (HLC) was measured in the biology laboratory of CHRU of Lille, France and results compared to traditional measurements. Along with SPEP, SIF, UPEP, UIF, and sFLC, we have also measured IgA HLC (IgA k and IgA l) and IgG (IgG k and IgG l) and the corresponding difference (clonal - non clonal) and ratio (clonal/non clonal). Results. Overall, 80% were measurable on SPEP with a median serum level of 31g/L (CI95% 19;42), and the remaining also had UPEP measurable myeloma with a median serum level of 0.66g/24h (CI95% 0.4;1.3). The median involved HLC level was 29.7g/L (CI95% 17.6;43.3), the median involved HLC difference clonal - non clonal was 28.8g/L (CI95% 15.6;42.7), the median involved HLC ratio clonal / non clonal was 51.9 (CI95% 18.3;203.9). Since all patients had a measurable intact immunoglobulin-based disease according to IMWG criteria, we have first confirmed that patients had also a measurable disease by HLC. All patients had an abnormal HLC ratio but one patient, who was measurable with an abnormal IgG L involved HLC test. Approximately 32% of patients had an M-spike below 20g/L and/or an electrophoretic migration in beta region meaning in the range of lack of sensitivity of the techniques used, all of whom had a measurable disease using involved HLC level and/or a measurable HLC ratio. We then sought to study the response rate according to HLC, and for that purpose we applied the exact same criteria as to the sFLC-based response criteria recommended by IMWG (e.g. normal ratio is CR and if abnormal ratio, then 〈 50% reduction in the difference clonal – non clonal is SD, ≥50% - 〈 90% reduction is PR, 〉 90% reduction is VGPR). The ORR in the 2 studies as a whole using traditional measurements was 32%, including 29% PR rate, absence of CR, and 44% had SD (SD and MR). Using HLC, the ORR was 36%, including 26% PR rate and 4.0% CR, and 33% had SD (r² 0.823, p 〈 .0001). Interestingly, 7 patients classified as SD with regular techniques, were progressive disease using HLC, anticipating a progression of Myeloma. Similarly, 5 patients classified as SD with regular techniques, were ≥PR using HLC. Conclusion. HLC is a new routine quantitative and automated assay that measures Immunoglobulin heavy chain/light chain pairs immunoassay, allowing diagnosis, prognosis and precise assessment of the response to treatment and disease progression in all cases with Myeloma treated with pomalidomide and dexamethasone in 2 different clinical trials. Our study indicates that HLC may be used as a replacement for traditional tests and may offer greater sensitivity in some instances. Furthermore, obviating the need for interpretation may standardize assessments of patients during trials. Future studies might confirm this data analysis in larger trials. Disclosures Karlin: Janssen: Honoraria; celgene: Consultancy, Honoraria; Sandoz: Consultancy. Hulin:Celgene: Honoraria. Stoppa:Celgene Jansen: Honoraria. Marit:Celgene, Janssen: Congress expenses Other.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V124.21.2021.2021

Language: English

Publisher: American Society of Hematology

Publication Date: 2014

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In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 1971-1971

Abstract: Prognosis of relapses is severe in elderly multiple myeloma (MM). In recent studies, median survival at progression after 1st line therapy was between 9 and 13 months (T. Facon, Lancet 2007; C. Hulin, J Clin Oncol 2009). Bortezomib (V) plus dexamethasone (D) is a major regimen in the treatment of relapses. Bendamustine (B) demonstrated to be highly active in advanced MM. The IFM 2009-01 trial evaluates the combination of B, V and D in elderly patients with progressive MM on or after 1stline treatment. Methods Phase 2 IFM 2009-01 trial was dedicated to patients older than 65 years in 1st relapse or refractory to 1st line therapy. Inclusion criteria were measurable disease, PS ECOG 0-2, ANC 〉 1.5x109/l, platelets 〉 100x109/l, serum creatinine level 〈 250 mcmol/l, AST and ALT 〈 3xULN. Pts with prior exposure to bortezomib were excluded. Treatment regimen was B 70 mg/m2 day 1-8, V 1.3 mg/m2 day 1-8-15-22 and D 20 mg day 1-8-15-22 every 28 days. 6 cycles were administered. Responders were assigned to receive maintenance treatment with 6 additional cycles administered 1 month out of 2. Response was evaluated according to IMWG criteria. Response rate was the primary objective. Progression-free survival (PFS), overall survival (OS) and toxicity were secondary end-points. Results From 03/2010 to 07/2011, 73 pts were included. Median age was 75.8 years (range 66-86). Median time from diagnosis to inclusion was 29 months. All pts received only 1 prior line of therapy: Melphalan-Prednisone (MP) in 12, MP-Thalidomide in 42, Lenalidomide-Dexamethasone (LD) in 14, other IMiD-based regimen in 5. Median treatment cycles administered was 7 (1-12). 51 pts (69.8%) achieved at least partial response [best response CR: 10 pts (13.6%), VGPR: 12 pts (16.5%), PR: 29 pts (39.7%), MR: 4 pts (5.5%), SD: 5 pts (6.8%), progression: 12 pts (16.5%), unrelated early death: 1 pt (1.3%)]. Median PFS was 10.8 months (95%CI: 7-18.2 months) and median OS 23 months (15.4-27.5). Adverse prognostic factors for PFS were PS ECOG 2 (p=0.0002), beta 2 microglobulin level 〉 3.5 mg/l (p=0.0006) and del17p (p=0.01). 26 pts (35.6%) completed the planned 12 cycles of treatment. Cause of treatment discontinuation was progressive MM in 30 pts (41.1%), failure to achieve PR in 5 pts (6.8%), adverse event in 10 pts (13.6%), patient refusal and unknown 1 pt (1.3%) each. 37 pts (50.6%) had died at time of final analysis. Cause of death was MM in 30 pts, sepsis in 5 pts, renal failure in 1 pt and unrelated in 1 pt. Grade 3-4 adverse events were neutropenia: 14 pts (19.1%), thrombocytopenia: 8 pts (10.9%), sepsis: 14 pts (19.1%), gastro-intestinal: 6 pts (8.2%), anaphylaxis: 2 pt (2.7%). Grade 2 peripheral neuropathy occurred in 8 pts (10.%) and grade 3 in 3 pts (4.1%). Conclusions In this elderly population with poor prognosis MM, BVD combination provides a high overall response rate and manageable toxicity. These results compare favourably with those achieved with VD or LD. Disclosures: Roussel: CELGENE: Honoraria; JANSSEN: Honoraria. Leleu:CELGENE: Honoraria; JANSSEN: Honoraria. Cony-Makhoul:BMS: Honoraria. Avet-Loiseau:CELGENE: Honoraria, Speakers Bureau; JANSSEN: Honoraria, Speakers Bureau. Moreau:Janssen: Honoraria; Janssen and Millennium: Membership on an entity’s Board of Directors or advisory committees.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V122.21.1971.1971

Language: English

Publisher: American Society of Hematology

Publication Date: 2013

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In: Blood, American Society of Hematology, Vol. 118, No. 22 ( 2011-11-24), p. 5752-5758

Abstract: The Intergroupe Francophone du Myelome conducted a randomized trial to compare bortezomib-dexamethasone (VD) as induction before high-dose therapy (HDT) and autologous stem cell transplantation (ASCT) to a combination consisting of reduced doses of bortezomib and thalidomide plus dexamethasone (vtD) in patients with multiple myeloma. Overall, a total of 199 patients were centrally randomly assigned to receive VD or vtD. After 4 cycles, the complete response (CR) rate was the same in both groups (13% in the vtD arm, 12% in the VD arm, P = .74). However, the CR plus very good partial response (VGPR) rate was significantly higher in the vtD arm (49% vs 36%, P = .05). After ASCT, the CR plus VGPR rate was significantly higher in the vtD arm (74% vs 58%, P = .02). The reduced doses of bortezomib and thalidomide translated into a reduced incidence of peripheral neuropathy (PN): grade ≥ 2 PN were reported in 34% in the VD arm versus 14% in the vtD arm (P = .001). vtD, including reduced doses of bortezomib and thalidomide, yields higher VGPR rates compared with VD and can be considered a new effective triplet combination before HDT/ASCT. This study was registered with www.clinicaltrials.gov as #NCT00910897 and EudraCT as #2007-005204-40.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2011-05-355081

Language: English

Publisher: American Society of Hematology

Publication Date: 2011

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In: Blood, American Society of Hematology, Vol. 121, No. 11 ( 2013-03-14), p. 1968-1975

Abstract: Combination of pomalidomide with dexamethasone is highly active and can salvage end stage myeloma refractory to lenalidomide and bortezomib. Current data suggest pomalidomide 4 mg/day on days 1 to 21 per 28-days cycle with dexmethasone should be studied in future phase 3 trials.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2012-09-452375

Language: English

Publisher: American Society of Hematology

Publication Date: 2013

detail.hit.zdb_id: 1468538-3

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In: Blood, American Society of Hematology, Vol. 132, No. 23 ( 2018-12-06), p. 2456-2464

Abstract: MRD using NGS-identified patients with an excellent outcome in multiple myeloma. MRD should be assessed in every prospective trial, and is a candidate to become a primary end point.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2018-06-858613

Language: English

Publisher: American Society of Hematology

Publication Date: 2018

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In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 4359-4359

Abstract: Bortezomib (B) is an effective drug alone or in combination in naive and pretreated WM patients. The interest of high dose of dexamethasone (D) with bortezomib (B) has not been evaluated in WM patients and D is systematically added to bortezomib combination with or without Rituximab (R) (BD, BDR). However, D is responsible for side effects in elderly population. We tested in a phase II trial the efficacy and safety of the addition of D to B after 2 B cycles in patients with a stable or progressive disease (SD, PD). Patients and Methods Bortezomib was used at 1.3mg/m2 IV D1, 4, 8 and 11 every 21 days for 6 cycles. In no responding patients, D (20mg) was added at D1,2, 4, 5, 8, 9, 11 and 12 at Cycles 3 to 6. The main endpoint was the overall response rate (ORR) at two months before D adjunction; secondary outcomes were ORR at 4 and 6 months, response duration, overall survival (OS) and progression-free survival (PFS). Two interim analyses were scheduled and performed after the inclusion of 17 and 27 patients, respectively, using Bayesian estimation of ORR with stopping rules. Results Interim analyses did not allow stopping the trial, with probability of ORR above 35% below 0.9. Thus, a total of 34 patients (pts) were enrolled in the study in two years (2009-2011) in 17 centers. The median age was 70.2 (64.2-79.6).ECOG was ≥1 in 53% of the pts. The median of previous lines, hemoglobin, beta 2 microglobulin, IgM, and albumin was 1, 9.8g/dL, 4.35mg/L, 29g/L, 35 g/L respectively. At 2 cycles, there were 6 partial responses and 10 minor responses(group I), with estimated ORR at 44.1% (95%CI: 27.6-61.9%). D was added in 16/18 pts with stable or progressive disease (group 2). At 4 and 6 cycles, 22/28 and 20/26 pts were in response (12 and 8 in group 1, 10 and 12 in group 2), with resulting 4 and 6 cycles ORR estimated at 75% (95%CI: 47.4-91.7) and 50% (95%CI: 28.0-72.0) in group I and 62.5% (95%CI: 35.9-83.7) and 75% (95%CI: 47.4-91.7) in group 2. A total of 62 adverse events grade 〉 2 (first course: 11, second course: 18, subsequent courses: group 1: 14, group 2: 19) were observed in 38 courses. Of these 62 events (49 grade 3 and 13 grade 4), 52 (84%) consisted in hematological adverse events (18: platelets, 15: hemoglobin, 8: leucocytes, 1 lymphocytes, and 10 neutrophils); 3 neurological toxicities grade 〉 2 were observed, 1 after the second course and 2 after the third course in group 1. Otherwise, there were 26 peripheral neurological toxicities grade ≤2, namely 5 for the first 2 courses, 11 in group 1 and 10 in group 2. With a median follow up of 36 months, 23 pts experienced disease progression or died (18 had disease progression and 5 died in response). For patients who achieved at least a minor response, the 18-month progression rates were 31.9% in group 1 and 52.1% in group 2 (p=0.43) and WM unrelated death rates were 6.3% in group I and 16.7% in group 2 (p=0.79). The 2-year survival rate was 79.8% [IC95%: 64.7; 98.3]. The median progression free survival time was 16.8 months [IC95%: 13.0-23.6] . Conclusion We showed that addition of D to B in the elderly population was well tolerated and allowed reaching 6-month response in patients who did not respond to two courses of isolated B. Dexamethasone must be associated to bortezomib-based regimen. Disclosures: Leblond: Mundipharma: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Roche : Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Off Label Use: Bortezomib in Waldenstrom macroglobulinemi. Dilhuydy:Roche: Honoraria. Leleu:Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; LeoPharma: Consultancy, Honoraria; Onyx: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Amgen: Honoraria; Novartis: Honoraria. Tournilhac:MUNDIPHARMA: Consultancy, travel funding Other; GSK: Consultancy, travel funding, travel funding Other; Celgene: Consultancy, teaching, teaching Other.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V122.21.4359.4359

Language: English

Publisher: American Society of Hematology

Publication Date: 2013

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In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 393-393

Abstract: Background Induction therapy followed by autologous stem cell transplantation (ASCT) is the standard of care for patients with symptomatic multiple myeloma less than 66 years old. The quality of response to the induction treatment is an important prognostic factor and is predictive of progression free survival (PFS) following ASCT. The triplet combinations bortezomib-thalidomide-dexamethasone (VTD) and bortezomib-cyclophosphamide-dexamethasone (VCD) have demonstrated high response rates in prospective phase 2 and phase 3 clinical trials, they are 2 of the most commonly used induction regimens prior to ASCT, and are both recommended in the International guidelines. To date, no comparative data from prospective randomized trials of the safety and efficacy of VTD vs VCD are available. This provided the rationale for the phase 3 investigation of VTD vs VCD prior to ASCT in patients with de novo MM in this randomized multicenter study (NCT01564537). Methods Patients with de novo symptomatic MM less than 66 years old were prospectively randomized to receive either 4 cycles of VTD (arm A) or 4 cycles of VCD (arm B) followed by ASCT. The VTD regimen consisted of four 21-day cycles of bortezomib 1.3 mg/m²/d, subcutaneously (SC) D1, 4, 8 and 11, Dexamethasone 40 mg/d, PO D1 to 4, D9 to 12 and Thalidomide 100 mg/d, PO D1 to D21. The VCD regimen consisted of four 21-day cycles of bortezomib 1.3 mg/m²/d, SC D1, 4, 8 and 11, Dexamethasone 40 mg/d, PO D1 to 4, D9 to 12 and Cyclophosphamide 500 mg/m²/d, PO D1, 8, 15. Patients were stratified according to ISS (1-2 versus 3) and cytogenetics (high-risk defined by 17p deletion and t(4;14) versus other).The primary endpoint was very good partial response (VGPR) rate following 4 cycles. Response was assessed in a central lab according to the IMWG criteria. Assuming a VGPR rate of 60% in the VTD arm versus 45% in the VCD arm (15% difference), the possibility to detect a statistically significant difference required the enrolment of 340 patients overall (170 per arm). Adverse events were graded using the NCI CTCAE catalogue, version 4.0. Results From 11/2013 to 02/2015, 358 patients were enrolled into the study. 18 were screening failures, and 170 were randomized each to arm A (VTD) and arm B (VCD). The median age was 60 years (range, 26-65), 62% of the patients were male, and overall, the patient characteristics were well-balanced across the 2 arms of the study. The median number of induction cycles administered in both arms was 4 (1-4). On an intent-to-treat basis, the overall response rate ( 〉 partial response [PR]) was 92.3% in arm A, including a 10.7% complete response (CR) rate and a VGPR rate of 66.7%, while in arm B the overall response rate was 84%, with a 9.5% CR and a 56.2% VGPR rate. VGPR and PR rates were significantly higher in the VTD arm with p-values of 0.04 and 0.02, respectively. Seven patients died during induction therapy (2%), 3 in arm A from infections (2) and pulmonary embolism (1), and 4 in arm B from progression to extramedullary myeloma (2) and infections (2). Grades 3 / 4 peripheral neuropathy occurred in 4% and 2.2% in Arm A and B, respectively. Grade 3/4 neutropenia was seen in 11.9% vs 22.5% in Arm A and B, respectively. Conclusion This trial is the first prospective randomized comparison of 4 cycles of VTD versus 4 cycles of VCD administered as induction therapy prior to ASCT. VTD was shown to be significantly superior to VCD in terms of VGPR and PR rates. Neuropathy rates low in both arms, while neutropenia was more frequent with VCD. Disclosures Moreau: Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees. Hulin:Celgene Corporation: Honoraria; Janssen: Honoraria; Bristol Myers Squibb: Honoraria; Amgen: Honoraria. MACRO:celgene: Membership on an entity's Board of Directors or advisory committees; jansen: Membership on an entity's Board of Directors or advisory committees; millenium: Membership on an entity's Board of Directors or advisory committees. Garderet:Bristol-Myers Squibb: Consultancy. Stoppa:Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Facon:Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millenium: Membership on an entity's Board of Directors or advisory committees; Onyx: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Pierre Fabre: Membership on an entity's Board of Directors or advisory committees. Laribi:Hospira SAS: Research Funding. Avet-Loiseau:jansen: Membership on an entity's Board of Directors or advisory committees; onyx: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; millenium: Membership on an entity's Board of Directors or advisory committees; millenium: Membership on an entity's Board of Directors or advisory committees; celgene: Membership on an entity's Board of Directors or advisory committees; jansen: Membership on an entity's Board of Directors or advisory committees; onyx: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Attal:jansen: Honoraria; celgene: Membership on an entity's Board of Directors or advisory committees.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V126.23.393.393

Language: English

Publisher: American Society of Hematology

Publication Date: 2015

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detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 689-689

Abstract: Multiple myeloma with del(17p) and/or t(4;14) are characterized with short survival related to early relapse rate (median TTP 〈 4 months) and rapid development of mechanisms of resistance to multiple agents. Furthermore, RRMM to IMiDs® imunomodulatory agent and proteasome inhibitors (bortezomib) also display a shortened median survival of approximately 9 months. We and others have previously showed that pomalidomide plus low-dose dexamethasone has produced 30% to 40% response rate (ORR, PR and greater) with prolonged duration of response (DOR) and median time to progression (TTP) in RRMM who have progressed after multiple treatment options. However, the median TTP was much shorter 〈 4 months for patients with del17p and/or t(4;14) who have been previously exposed to a median of 5- 6 lines of therapies in those studies. We have designed a phase 2 multicenter, open-label study aimed to determine the efficacy and safety profile of pomalidomide in RRMM patients with del(17p) and/or t(4;14). Method This study enrolled patients with progressive RRMM that were relapsing but not necessarily refractory to lenalidomide (minimum two cycles). Del(17p) and/or t(4;14) was identified centrally by Pr. Avet-Loiseau using FISH on bone marrow plasma cells. The response was evaluated centrally in Lille according to IMWG criteria. The primary objective was to evaluate TTP using pomalidomide plus low-dose dexamethasone in RRMM with del(17p) and/or t(4;14). Pomalidomide was given orally at 4 mg daily on days 1–21 of each 28-days and dexamethasone orally at 40 mg daily on days 1, 8, 15 and 22 of each cycle. Venous thrombotic events (VTE) prophylaxis was mandatory. The primary analysis was conducted on the ITT population. An interim analysis is reported. Results 50 patients (gender ratio 1.5) were enrolled, the median age was 59 yrs (range, 30-80). The median time from diagnosis to enrolment was 3 years (IQ 2-4), 40% had ISS 3, and 60% high beta2m. All patients had loss of 17p (46%) and/or t(4;14) (64%). At entry into the trial, 30% had Hb 〈 10 g/dL, 12% platelet count 〈 100 G/L and 4% neutrophils 〈 1 G/L, 6% had circulating plasma cells and 10% presence of clinically plasmacytomas. The median number of prior lines of therapy was 3 (1-10). All patients had prior exposure to lenalidomide with 84% refractory, 96% had received a proteasome inhibitor with 54% that became refractory; 90% had got an alkylating agent, with 36% became refractory; 76% had an autotransplant and 2% an allotransplant. Overall, 76% were refractory to the last line of therapy prior to study entry. The overall response rate (ORR) was 20% (27% in del17p and 16% in t(4;14)), including 6% 〉 VGPR, and 54% had stable disease. The median duration of response was not reached, but the 6-months event-free survival (EFS) was 54%. With a median follow-up of 5 months (IQ 3-11), 66% have stopped treatment including 76% due to progression of MM, and 38% had died. The median OS for the cohort as a whole is 12 months (CI95% 5;nr), with a 8-months event-free survival rate of 59%. Interestingly, del(17p) patients benefited more from pomalidomide plus low-dose dexamethasone as median OS was not reached, with 63% 8-months OS, while 9 months (4.5;16) for t(4;14). The median TTP for the cohort as a whole is approaching 3 months (2-5), nonetheless longer for del17p, 8 months (3;nr) versus 3 months (2;4) for t(4;14). We then concentrated on RRMM with more than 2 cycles, and found a similar profile with a clear cut benefit for del17p as compared to t(4;14) treated with pomalidomide plus low-dose dexamethasone. Toxicity was manageable in these fragile RRMM patients with 40% of serious adverse events (SAEs) reported related to the studied treatment, 13% of which led to death and 21% to permanent drug discontinuation. An other 48% led to drug dose reduction. No occurrence or worsening of neuropathy was reported, and only 1 pulmonary embolism was noted. Conclusion Pomalidomide plus low dose dexamethasone is active and well tolerated in this RRMM population characterized with high and rapid development of a refractoriness state, particularly with del(17p). This study provides further evidence that IMiD® compound, including pomalidomide is active in patients with adverse FISH cytogenetic and that ongoing triplet-based combination should demonstrate improved response rates and survival in future studies. Updated results will be presented at ASH2013. Disclosures: Leleu: JANSSEN: Honoraria; CELGENE: Honoraria. Off Label Use: Pomalidomide. Karlin:Janssen: Honoraria; Celgene: Export board committee Other, Honoraria. Roussel:JANSSEN: Honoraria; CELGENE: Honoraria. Moreau:JANSSEN: Honoraria, Speakers Bureau; CELGENE: Honoraria, Speakers Bureau. Attal:JANSSEN: Honoraria, Speakers Bureau; CELGENE: Honoraria, Speakers Bureau. Avet-Loiseau:JANSSEN: Honoraria, Speakers Bureau; CELGENE: Honoraria, Speakers Bureau. Facon:JANSSEN: Honoraria, Speakers Bureau; CELGENE: Honoraria, Speakers Bureau.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V122.21.689.689

Language: English

Publisher: American Society of Hematology

Publication Date: 2013

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7