Carfilzomib, Cyclophosphamide and Dexamethasone Is Well Tolerated in Patients with Relapsed/Refractory Multiple Myeloma Who Have Received One Prior Regimen

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1840-1840 ◽  
Author(s):  
Kwee L Yong ◽  
Sarah Brown ◽  
Samantha Hinsley ◽  
Louise Flanagan ◽  
Neil Rabin ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Pulmonary Embolism ◽  
Research Funding ◽  
Induction Treatment ◽  
Published Data ◽  
Interim Assessment ◽  
Treatment Pathways ◽  
Dose Modification ◽  
Infusion Reactions ◽  
Grade 3

Abstract Introduction. Carfilzomib-containing doublet and triplet regimens demonstrate high response rates both in the relapsed and frontline settings and will soon enter the treatment pathways for multiple myeloma (MM). While the phase 3 studies, ENDEAVOUR and ASPIRE provide information on combinations with dexamethasone with or without lenalidomide, there are limited data on other combinations, especially with alkylating agents. Aim. To describe the safety and toxicity of Carfilzomib, cyclophosphamide and dexamethasone in patients at first relapse of MM, based on an interim assessment of the MyelomaUKfive (MUKfive) study. Methods. MUKfive is a randomised phase 2 study comparing carfilzomib with bortezomib, in triplet combination with cyclophosphamide and dexamethasone for patients who require treatment after one prior regimen, in a 2:1 randomisation, target 300 patients. Patients receive 6 months of induction treatment with six 28-day cycles of carfilzomib (20/36 mg/m2 in stepped up dosing d1, 2, 8, 9, 15, 16 by IV infusion over 30 minutes), oral cyclophosphamide (500 mg d1, 8, 15) and oral dexamethasone (40mg d1, 8, 15, 22) or eight 21-day cycles of bortezomib (1.3mg/m2 SC d1, 4, 8, 11) by SC or IV, cyclophosphamide (500 mg d1, 8, 15) and dexamethasone (40mg d1, 8, 15). The primary endpoint for this part of the study is ≥VGPR rate. The study opened in 2013, and we have carried out an interim assessment of safety data on the first 69 patients randomised to the Carfilzomib arm, with toxicities graded by CTCAE V4.0. Results. Median age was 67.6 years (range 35-85), 62.3% were male, and ISS stage as follows: 32 patients ISS 1, 22 patients ISS 2, 15 patients ISS 3. Median GFR was 78ml/min (range 30-243) and ECOG performance status as follows: 43 patients PS 0, 20 patients PS 1, 5 patients PS 2, 1 patient missing PS. Sixty-seven patients received at least one dose of trial treatment and are evaluable for safety. In cycle 1, the commonest treatment-related toxicities of any grade (adverse reactions, ARs) were anaemia (89.6%), thrombocytopenia (67.2%) neutropenia (29.9%), nausea (14.9%), diarrhoea (11.9%), vomiting (10.6%), constipation (9%), infections (4.5%) and infusion reactions (4.5%). During induction treatment (all cycles), the most common ARs of all grades were anaemia (97%), thrombocytopenia (83.6%) neutropenia (58.2%), nausea (47.8%), diarrhoea (37.3%), infections (29.9%) vomiting (22.4%), constipation (22.4%), hypotension (4.5%) and infusion reactions (4.5%). Haematologic grade ≥3 ARs included anaemia (19.4%), neutropenia (12%), and thrombocytopenia (10.5%), while non-haematological grade ≥3 ARs were infections (20.9%), vomiting (4.5%), nausea (3%), diarrhoea (3%), infusion reactions (3%). Treatment emergent neuropathy was reported by 18 patients (26.9%), all G1 except for 1 patient (G2). Three patients had thromboembolic ARs: one each of pulmonary embolism (G3), thrombophlebitis (G2) and brachial vein thrombosis (G1). Serious AEs were reported in 29 patients (43.3%). A total of 47 SAEs were reported, of which 31 (66%) were treatment related (28 related to carfilzomib). Treatment related SAEs included 22 infections (noted above, of which 15 were respiratory infections), 2 gastrointestinal, 1 acute kidney injury (G2) and 1 worsening of renal function (G1), 2 endocrine (1 each of hypo- and hyperglycemia), and 1 hepatobiliary. Two G3 SUSARs were reported, one cardiomyopathy, one extensive pulmonary embolism. In 87.2% of SAEs, patients had recovered or were improving. In cycle 1, 19 patients (28.4%) had at least one dose modification; carfilzomib dose was modified in 14, cyclophosphamide in 7 and dexamethasone in 11. The majority of these were dose omissions. Across all cycles, 54 patients (80.6%) had dose modification/s, 47 to carfilzomib, 32 to cyclophosphamide and 40 to dexamethasone. Of carfilzomib modifications, 53.3% were omissions, while the rest were reductions (24.6%) or delays (22.1%). Of carfilzomib dose reductions, the majority (72.9%) were due to haematological toxicity. Five patients (7.2%) stopped treatment due to toxicity after a median of 3 (range 1-4) cycles. There were no treatment related deaths. Conclusion. The triplet regimen carfilzomib, cyclophosphamide and dexamethasone is well tolerated in this patient group, with toxicity profile that is as expected from published data on carfilzomib. Acknowledgments: This trial a Myeloma UK Clinical Trial Network study Disclosures Yong: Autolous: Consultancy; Novartis: Consultancy; Janssen: Honoraria; Takeda: Honoraria; Amgen: Honoraria; BMS: Honoraria. Off Label Use: Carfilzomib with cyclophosphamide and dexamethasone as therapy in relapsed myeloma. Ramasamy:Celgene: Honoraria; Amgen: Honoraria; Takeda Millenium: Honoraria. Cavenagh:Celgene: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau. Owen:Celgene: Honoraria, Research Funding; Janssen: Honoraria. Kaiser:Chugai: Consultancy; Janssen: Honoraria; BristolMyerSquibb: Consultancy; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria. Williams:Amgen: Honoraria; Janssen: Honoraria.

Velcade, Intravenous Cyclophosphamide and Dexamethasone (VCD) Induction for Previously Untreated Multiple Myeloma (German DSMM XIa Trial).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 131-131 ◽  
Author(s):  
Hermann Einsele ◽  
Peter Liebisch ◽  
Christian Langer ◽  
Martin Kropff ◽  
Hannes Wandt ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Induction Therapy ◽  
Research Funding ◽  
Response Rate ◽  
Induction Treatment ◽  
High Dose ◽  
Prognostic Impact ◽  
Short Period ◽  
Grade 3 ◽  
High Dose Melphalan

Abstract Abstract 131 Introduction. Autologous stem cell transplantation (ASCT) after cytoreductive induction is considered standard of care for younger patients (pts) with multiple myeloma (MM). The previous standard of induction, the Vincristin-Adriamycin-Dexamethasone (VAD) combination, achieves inferior results compared with induction regimens which combine the proteasome inhibitor Velcade (V = Bortezomib) with Dexamethasone (D)(=VD) and a cytostatic drug such as Doxorubicin (PAD = VD plus Doxorubicin). Velcade-based induction therapy was shown to translate into better myeloma control after high dose melphalan and to lead to prolonged progression-free survival. In order to find a more efficacious and safer drug combination for induction therapy in MM, we tested the combination of Velcade with Cyclophosphamide and Dexamethasone (VCD). Methods. This trial was designed as an open, prospective, multi-center, uncontrolled, combined phase II/III study. As previously reported (Kropff M et al., Ann Hematol 2009), in the first 30 pts the optimal dose of iv Cyclophosphamide in combination with V and D was defined as 900 mg/m2 on d1. Between 03/2006 and 03/2009 we enrolled an additional 370 pts up to 60 years of age with untreated MM to receive three 3-week cycles of induction treatment with V 1.3 mg/m2 iv d1,4,8,11; D 40 mg/d orally d1,2,4,5,8,9,11,12; and C 900mg/m2 iv d1 before scheduled high dose melphalan and ASCT. The primary endpoint of the study is response rate on day 63 after 3 cycles of VCD according to EBMT and IMWG criteria. Results. Final data from 400 pts from 39 German centers will be presented at the meeting. In the currently evaluable 300 pts (mean age 52.3 years; 1.7% stage I, 21.3% stage II, 77.0% stage III) molecular cytogenetic analysis showed a prevalence of 13q- in 38%, of t[4;14] in 13% and of 17p- in 12% of pts (no changes in 35%). All 300 pts (88.3% of whom completed three cycles) were included in the intent-to-treat analysis. Overall response rate (ORR = CR+PR) was 84%, with 10% CR and 74% PR, 5.7% MR, 7.3% NC and 2.3% PD. The negative prognostic impact of 13q- or t[4;14] was abrogated (ORR normal 87.3%, 13q- 83.7%, t[4;14] 90.0%), the unfavorable influence of p53 loss in the 17p- subgroup was still detectable (ORR 69.2%) but this did not reach statistical significance. VGPR rates will be reported at the meeting. Serious adverse events were documented in 78/300 (26.0%) patients. Death rate was remarkably low (1.3%, of which one was not related to the trial medication). 155/300 (52%) of pts experienced grade 3/4 non-serious AEs and of these leucopenia (93/300 pts= 31%), thrombocytopenia (7%), neutropenia (6%), anaemia (5%) were the most frequent events. 80 AEs grade 3 or 4 and 45 SAEs were of infectious origin and occurred in 47/300 pts. 80/130 SAEs (61.5%) were at least possibly related to Velcade. 101/300 pts (34%) developed episodes of peripheral neuropathy. PNP was grade 1 in 62/300 pt (20.7%), grade 2 in 31/300 pt (10.3%) and grade 3 in 7/300 pts (2.3%). Conclusion. This analysis demonstrates that proteasome inhibition by Velcade in combination with Dexamethasone and iv Cyclophosphamide (VCD) is an induction regimen for newly diagnosed MM which is highly effective in a short period of time, has a rather low toxicity profile and is feasible for administration in an outpatient setting. Based on these characteristics, VCD qualifies to become a new standard for MM induction therapy. Disclosures: Einsele: OrthioBiotech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: Bortezomib is licensed as monotherapy for use in relapsed/refractory MM and in combination with melphalan/Prednisone in the first-line treatment of MM pts ineligible for HD-MEL and ASCT. . Liebisch:OrthoBiotech: Consultancy, Honoraria. Langer:OrthoBiotech: Consultancy. Kropff:OrthoBiotech: Consultancy, Honoraria. Kröger:OrthoBiotech: Honoraria. Ostermann:OrthoBiotech: Honoraria. Mügge:OrthoBiotech: Honoraria. Wolf:OrthoBiotech: Honoraria. Gramatzki:OrthoBiotech: Consultancy, Honoraria. Maschmeyer:OrthoBiotech: Travel Grant. Sezer:OrthoBiotech: Consultancy, Honoraria. Heidemann:OrthoBiotech: Honoraria. Jäger:OrthoBiotech: Honoraria. Dechow:Celgene: Research Funding. Simon:OrthoBiotech: Honoraria. Straka:OrthoBiotech: Consultancy, Honoraria, Research Funding. Fingerle-Rowson:orthoBiotech: Employment. Knop:OrthoBiotech: Honoraria.

scholarly journals Characterization of Cardiovascular Adverse Events and B-Type Natriuretic Peptide Levels in Patients with Multiple Myeloma Who Are Treated with Carfilzomib

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1956-1956
Author(s):  
Hang Quach ◽  
Khue Minh Nguyen ◽  
Matthew Ku ◽  
Ali Bazargan ◽  
Robin J Filshie ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Dose Reduction ◽  
Natriuretic Peptide ◽  
Research Funding ◽  
Published Data ◽  
Cardiac Enzymes ◽  
Cardiac Enzyme ◽  
Cardiovascular Assessment ◽  
Significant Difference ◽  
Grade 3

Abstract Background Carfilzomib (K), a second generation proteasome inhibitor that is approved for patients (pts) with relapsed refractory multiple myeloma (RRMM) is associated with increased cardiovascular (CV) adverse effects (AE), in particular hypertension (HTN), dyspnea and cardiac failure (CCF), based on the ENDEAVOR (Dimopoulos, MA. et al. Lancet 2016) and ASPIRE studies (Stewart, K.et al. NEJM 2015). The clinical characteristic and underlying mechanism of K induced CVAE have been poorly elucidated, and the limited published data on the utility of cardiac enzymes as biomarkers have not been revealing. We conducted a retrospective single centre review of K-treated pts who have undergone systemic serial cardiovascular and cardiac enzyme assessment, to profile the nature of CVAE and patterns in cardiac enzymes that might have predictive utility in K-induced CVAE. Method: Between January 2016 to June 2018, all pts who were treated with K (D1,2,8,9,15,16 in a 28 day cycle)-based regimen for RRMM at St.Vincent's Hospital Melbourne underwent systematic cardiovascular assessment including documentation of baseline cardiac risk factors (RF) and transthoracic echo (TTE). Serial troponin, creatinine kinase (CK) and B-type Natriuretic Peptide (BNP) were performed at baseline (C1D1 or 2), mid cycle (D8 or 9) and end of treatment (D16) of every cycle. Repeat TTE was done at physicians' discretion. Systematic documentations of CVAEs (graded according to CTCAEv5) were retrieved from medical records. The incidence and severity of CVAE was collated and correlated with serial cardiac enzyme levels, the association of which was tested using Student's t-test. Results 76 pts (67% male; median age 66(46-86) years) with RRMM who received a median of 6 cycles (1-26) of K-based treatment were included in this analysis. At baseline, 16 pts (21%) had at least 1 CVRF including HTN, history of ischaemic heart disease, hyperlipidaemia, diabetes or smoking. The incidence of HTN prior to treatment was 39%. On treatment, the incidence of HTN was 85% (28% grade≥3). 17% of pts required the addition of antihypertensive medications and 11% had K dose reduction due to HTN. K-related dyspnea occurred in 53% of pts (28% grade≥3), 52% of who required K dose reduction/interruption. CCF occurred in 14.5% (grade≥3, 13%) that all necessitated K interruption/dose reduction. 69 pts had baseline TTE that showed a median RVSP (right ventricular systolic pressure) of 32mmHg (range 20-48). On treatment, 38 pts had repeat TTE, mainly driven by dyspnea with a median RVSP of 41(20-93mmHg). Of the 18 pts with grade≥3 dyspnea who had repeat TTE, 83% had RSVP ≥39mmHg and 33% had RVSP≥50mmHg, compared to 70% with RSVP ≥39mmHg and 10% RVSP≥50mmHg in the group with grade 1-2 dyspnea. Troponin_I and CK level did not change significantly throughout K-treatment. However BNP level rose and fell within each cycle, typically with peaks at mid cycle (D9 and D16) and troughs at the beginning of a new cycle (D1 or 2). 87.1% of pts had at least one elevated BNP (>100ng/L) with a median maximal level of 300ng/L (range 114-2320ng/L). There was a significant difference in the incidence of grade ≥3 CVAEs (mainly HTN) in pts whose mid cycle BNPs (D9 or 16) were elevated in ≥50% of measurements during the first 4 cycles of K compared to the rest (65.5% vs. 25.0%, p=0.0084). In pts with dyspnea, persistent rise in mid cycle BNPs that does not normalise prior to next treatment cycle trended towards an increased incidence of raised RVSP of ≥39mmHg (21.7% vs. 7.9%, p=0.0543). Conclusion. The incidence of CVAEs in pts treated with K is higher in the real-world setting compared to that reported in the Endeavor and ASPIRE studies. Dyspnea is frequent, the degree of which correlates with the degree of raised RVSP, thus indicating pulmonary hypertension as a contributor to dyspnea in the setting of K treatment. BNP level typically peaks during mid cycle and troughs at the beginning of next cycle, indicating a temporal relationship to K infusions. In pts with dyspnea, the association of persistent rise in mid-cycle BNP (rather than troponin or CK) with raised RVSP and HTN perhaps indicate transient endothelial dysfunction as the mechanism for K-induced CVAE rather than myocyte injury. Disclosures Quach: Amgen: Consultancy, Research Funding; Sanofi Genzyme: Research Funding; Janssen Cilag: Consultancy; Celgene: Consultancy, Research Funding. Tam:Roche: Honoraria; AbbVie: Honoraria, Research Funding; Pharmacyclics: Honoraria, Travel funding; Beigene: Honoraria, Other: Travel funding; Pharmacyclics: Honoraria; Gilead: Honoraria; Janssen: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Beigene: Honoraria, Other: Travel funding; Gilead: Honoraria; Roche: Honoraria.

scholarly journals Carfilzomib Thalidomide and Dexamethasone Is Safe and Effective in the Treatment of Relapsed/Refractory Multiple Myeloma: An Open Label Phase II Australasian Leukaemia and Lymphoma Group (ALLG) MM 018/ Asian Myeloma Network (AMN) 002 Study

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 39-40
Author(s):  
Hang Quach ◽  
Simon J Harrison ◽  
Je-Jung Lee ◽  
Nichloas Murphy ◽  
Jae Hoon Lee ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Adverse Events ◽  
Board Of Directors ◽  
Phase Ii ◽  
Primary Endpoint ◽  
Research Funding ◽  
Open Label ◽  
Advisory Committees ◽  
Open Label Phase ◽  
Grade 3

Background: The combination of carfilzomib with immunomodulatory drugs (IMiDs) and dexamethasone is active in multiple myeloma (MM). Carfilzomib, thalidomide, and dexamethasone (KTd) has been studied in upfront MM treatment but has not been studied in the setting of relapsed/refractory myeloma (RRMM). The ALLG MM018/ AMN002 is an open-label phase II study of KTd in patients with RRMM. This study was conducted across 16 sites across Australia, New-Zealand, Singapore, South Korea and Taiwan. Method: Patients with RRMM with 1-3 prior lines of treatment were given carfilzomib [K: 20mg/m2 IV cycle 1 days 1 and 2, 56mg/m2 (36mg/m2 for patients age ≥75 years) from cycle 1 day 8 onwards], thalidomide (T: 100mg po nocte) and dexamethasone [dex: 40mg (20mg for patients age ≥75 years) po weekly], in a 28-day cycle. After 12 cycles, T was omitted, and K was given on days 1,2,15,16 and dex days 1,15 every 28-day cycles for a further six cycles. The primary endpoint was PFS. Secondary endpoints were ORR, overall survival, adverse events, and quality of life (QoL). The study had an 80% power to detect a ≥70% PFS at 6.5 months compared to historical ≤50% PFS at 6.5 months expected with Td (Kropff, M. et al. Haematologica 2012), at a significance level of 0.05. Results: This study has completed accrual. Eighty-three patients [median age of 66 years (42-85)] were enrolled with a median follow up of 15.9 (0.9-26) months. ORR rates were 86.4% (≥VGPR 70.2%). Median PFS was 20m (95% CI 15.9-26m). PFS at 6.5 months was 76.2% (95% CI 73.6-84.9%). Median OS has not been reached, and was 75% at 20 months. The most common grade ≥3/4 AEs were peripheral neuropathy (16%), upper respiratory tract infections (12%), dyspnoea (14%), and hypertension (10%). Grade ≥3/4 cardiac AEs occurred in 6%. The median carfilzomib dose that was delivered was 70.7% (32.8-92.6%) of the target dose. Thus far, 41% of patients have completed the intended 18 cycles of treatment. 21% of patients ceased therapy early. The most common reason for early treatment cessation was disease progression (30%) and adverse events (15%). Fifteen patients (18%) have died, 11 were due to MM, two from infection, one from an ischaemic cardiac event, and one from a traffic accident. QoL, as measured by the EQ-5D-5L instrument, remained stable throughout treatment. Conclusion: The ALLG MM018/AMN 002 study has met its primary endpoint. The KTd schedule as outlined in this study is efficacious in patients with RRMM, resulting in a prolonged PFS and a safety profile in line with previous reports for each of carfilzomib and thalidomide. KTd is an active option in jurisdictions where the cost of other IMiDs prohibits regulatory funding. Comparisons of efficacy and adverse events between the Caucasian and Asian populations will be presented at the meeting. Disclosures Quach: Celgene: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Glaxo Kline Smith: Consultancy, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Janssen Cilag: Consultancy, Honoraria; Sanofi: Consultancy, Research Funding. Harrison:Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria; CRISPR Therapeutics: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Patents & Royalties: wrt panobinostat; Haemalogix: Consultancy. Augustson:Roche: Other: Support of parent study and funding of editorial support. Campbell:Amgen, Novartis, Roche, Janssen, Celgene (BMS): Research Funding; AstraZeneca, Janssen, Roche, Amgen, CSL Behring, Novartis: Consultancy. Soo:Hanmi: Research Funding. Durie:Amgen, Celgene, Johnson & Johnson, and Takeda: Consultancy.

Phase I-II Trial of Oral Cyclophosphamide, Prednisone and Lenalidomide (Revlimid®) (CPR) for the Treatment of Patients with Relapsed and Refractory Multiple Myeloma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1874-1874 ◽  
Author(s):  
Donna E. Reece ◽  
Esther Masih-Khan ◽  
Arooj Khan ◽  
Saima Dean ◽  
Peter Anglin ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Dose Level ◽  
Research Funding ◽  
Overall Response Rate ◽  
Response Rate ◽  
Oral Cyclophosphamide ◽  
Refractory Multiple Myeloma ◽  
Grade 3

Abstract Abstract 1874 Poster Board I-899 Lenalidomide (Revlimid®) and dexamethasone is an effective regimen in relapsed/refractory multiple myeloma (MM) patients (pts), with an overall response rate of 60.6% and median time to progression (TTP) of 13.4 months (Dimopoulos MA, et al, Leukemia 2009 Jul 23 [Epub ahead of print]). Oral cyclophosphamide and prednisone is an older regimen with excellent patient tolerance, and we sought to enhance the efficacy of lenalidomide by adding oral cyclophosphamide and prednisone in this phase I-II trial. The CPR regimen consisted of cyclophosphamide on days 1, 8 and 15; lenalidomide on days 1–21; and prednisone 100 mg every other day in a 28 day cycle. ASA 81 mg/day was given to all pts as DVT prophylaxis. Three dose levels were evaluated using a 3 by 3 dose escalation design. Between 11/2007–07/2009, 31 pts with relapsed/refractory MM who had not previously received lenalidomide were entered onto study. Median age was 61 (40–78) years and 61% were male. Immunoglobulin subtype was IgG in 19 pts (61%), IgA in 8 pts (26%) and light chain only in 4 pts (13%). Median number of prior regimens was 2 (1–5) and 28 pts had undergone previous ASCT, including double transplants in 6 pts. Prior therapy included thalidomide in 9 (29%) and bortezomib in 15 (48%). FISH cytogenetics were available in 13 pts; one had 13q deletion but none had t(4;14) or p53 deletion. At the time of protocol entry, median β 2-microglobulin level was 246 (92–767) nm/L, albumin 39 (34–48) g/L, creatinine 83 (50–126) μmol/L, platelet count 230 (75–337) × 109/L and ANC 2.5 (1.1–6.1) x 109/L. Protocol treatment is summarized in Table 1. Dose limiting toxicity was not observed during cycle 1 at any dose level. Grade 3–4 toxicities included thrombocytopenia in 5 pts (16%) and neutropenia in 9 pts (29%). These were managed with dose reduction and/or growth factor support. Four episodes of febrile neutropenia occurred. Other grade 3–4 non-hematologic toxicities included abdominal pain/bacteremia in 1 pt in cohort 1; hypokalemia in 1 pt in cohort 2; and DVT in 2 pts, dizziness in 2 pts and fatigue in 1 pt in cohort 3. Using the International uniform response criteria (Durie BG, et al, Leukemia 2006; 20:1467–1473), the best response was documented at a median of 6 (1–5) cycles and included the following: dose level 1 (1 CR, 2 PR); dose level 2 (1 VGPR, 2 PR); dose level 3 (5 CR, 9 VGPR, 9 PR, 1 MR and 1 stable disease). At a median follow-up (F/U) of 12 (8–21) months, 20 pts remain on study, 2 have withdrawn and 9 pts have progressed at a median of 9 (4–13) months; only 1 one has died (due to MM). We conclude: 1) the combination of full doses of the agents in CPR can be given in a 28 day cycle with minimal toxicity; 2) the overall response rate (CR + VGPR + PR) in 31 pts to date is 93%; 3) at a median F/U of 1 year, only 9 pts (29%) have progressed; 4) longer follow-up is required to assess the TTP and survival of the CPR regimen. Disclosures: Reece: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Off Label Use: Lenalidomide in combination with drugs other than dexamethasone. Anglin:Celgene: Honoraria. Chen:Celgene: Honoraria, Research Funding. Kukreti:Celgene: Honoraria. Mikhael:Celgene: Honoraria. Trudel:Celgene: Honoraria.

A Phase I Study of Bendamustine Combined with Lenalidomide and Dexamethasone in Patients with Refractory or Relapsed Multiple Myeloma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1856-1856 ◽  
Author(s):  
Suzanne Lentzsch ◽  
Amy O’Sullivan ◽  
Silvana Lalo ◽  
Carrie Kruppa ◽  
Diane Gardner ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Partial Response ◽  
Board Of Directors ◽  
Dose Level ◽  
Research Funding ◽  
Advisory Board ◽  
Clinical Activity ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Grade 3

Abstract Abstract 1856 Poster Board I-882 Background: Lenalidomide is an analog of thalidomide that has shown significant clinical activity in patients with relapsed or refractory multiple myeloma (MM), both as a single agent and in combination with dexamethasone. Bendamustine is a bifunctional alkylating agent that is approved for the treatment of chronic lymphocytic leukemia and indolent non-Hodgkin's lymphoma that has progressed during or relapsed within 6 months following a rituximab-containing regimen. Bendamustine combined with lenalidomide may be an effective treatment option for MM patients, particularly those with preexisting or bortezomib-induced neuropathy. Our primary objective was to determine the maximum tolerated dose (MTD) and safety profile of bendamustine and lenalidomide when administered with dexamethasone for patients with relapsed or refractory MM. Methods: Patients aged ≥18 years with confirmed, measurable stage 2 or 3 MM that was refractory to or progressed after 1 or more prior therapies, including lenalidomide, received bendamustine by intravenous infusion on days 1 and 2, oral lenalidomide on days 1–21, and oral dexamethasone on days 1, 8, 15, and 22 of each 28-day cycle. Treatment was continued until a plateau of best response, as determined by the IBMTR/ABMTR, was reached. Study drug doses were escalated through 4 levels (Table), with 3–6 patients enrolled at each level depending on the rate of dose-limiting toxicity (DLT). After determining the MTD, up to an additional 12 patients will be enrolled in an MTD expansion arm to better evaluate toxicity and clinical activity. Secondary endpoints included preliminary efficacy, as evidenced by objective response, time to disease progression, and overall survival. Results: To date, 11 patients have been enrolled, with a median age of 63 years (range, 38–75 years). The MTD of bendamustine and lenalidomide has not been identified at this point; currently, patients are enrolling on dose level 3 with 100 mg/m2 bendamustine and 10 mg lenalidomide. Thus far, DLT included 1 grade 4 neutropenia at dose level 2. Nine of 11 patients are currently eligible for response assessment. A partial response was observed in 67% of patients, including 1 very good partial response and 5 partial responses (PR). Two patients experienced stable disease and 1 exhibited progressive disease. Grade 3/4 adverse events included grade 3 neutropenia, thrombocytopenia, anemia, hyperglycemia, and prolonged QTC, and 1 grade 4 neutropenia. Conclusions: Bendamustine, lenalidomide, and dexamethasone form a well-tolerated and highly active regimen even in heavily pretreated MM patients, with a PR rate of 67%. Additional updates on response and MTD will be available at the time of presentation. Disclosures: Lentzsch: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cephalon: Consultancy, Membership on an entity's Board of Directors or advisory committees. Off Label Use: Bendamustine is not FDA approved for the treatment of multiple myeloma in the USA. Burt:Millennium: Honoraria; Celgene: Honoraria. Mapara:Resolvyx: Consultancy, Research Funding; Genzyme: Membership on an entity's Board of Directors or advisory committees; Gentium: Equity Ownership; Celgene: Spouse is consultant , has received research funding, and participates on advisory board; Cephalon: Spouse has received funding for clinical trial and participates on advisory board. Redner:Biogen: Equity Ownership; Wyeth: Equity Ownership; Glaxo-Smith-Kline: Equity Ownership; Pfizer: Equity Ownership; Genzyme: Membership on an entity's Board of Directors or advisory committees. Roodman:Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy; Acceleron: Consultancy. Zonder:Amgen: Consultancy; Pfizer: Consultancy; Cephalon: Consultancy; Millennium: Consultancy, Speaking (CME only); no promotional talks.

A Phase I Study of Vorinostat, Lenalidomide, and Dexamethasone In Patients with Relapsed or Relapsed and Refractory Multiple Myeloma: Excellent Tolerability and Promising Activity In a Heavily Pretreated Population

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1951-1951 ◽  
Author(s):  
Paul Richardson ◽  
Donna Weber ◽  
Constantine S. Mitsiades ◽  
Meletios A. Dimopoulos ◽  
Jean-Luc Harousseau ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Board Of Directors ◽  
Research Funding ◽  
Phase I Study ◽  
Response Rate ◽  
Advisory Board ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Grade 3

Abstract Abstract 1951 Background: Although novel treatment combinations for multiple myeloma (MM) have improved outcomes, the disease remains incurable and new drug combinations are urgently needed. Vorinostat is an oral histone deacetylase inhibitor approved in the United States for treatment of patients (pts) with advanced cutaneous T-cell lymphoma who failed prior therapies. Vorinostat alters gene expression and protein activity, promoting MM cell death through multiple pathways, and has been shown in preclinical studies to synergistically enhance the anti-MM activity of bortezomib and immunomodulatory drugs, including lenalidomide, with or without dexamethasone. Aims: The primary objective of this Phase I study was to determine the maximum tolerated dose (MTD) of vorinostat plus lenalidomide and dexamethasone in pts with relapsed or relapsed and refractory MM. Secondary objectives included overall safety, tolerability, response rate, duration of response, and time to progression (TTP). Methods: Pts in this Phase I multicenter open-label study were sequentially enrolled into 1 of 5 escalating doses of the combination regimen using a standard 3 + 3 design for ≤8 cycles. Pts who tolerated treatment and experienced clinical benefit were eligible for enrollment in an extension phase. Toxicity was evaluated using the National Cancer Institute Common Terminology Criteria (version 3.0). Response was assessed using the modified European Group for Blood and Marrow Transplantation criteria and International Myeloma Working Group Uniform Criteria. Safety and efficacy data were analyzed using summary statistics, except for TTP, which was estimated by the Kaplan-Meier method. Results: As of July 15, 2010, 31 pts were treated and evaluable for toxicity; 4 pts remain on study. Most pts had received prior thalidomide (n=22; 71%), bortezomib (n=20; 65%), or lenalidomide (n=14; 45%), with a median of 4 prior therapies (range, 1–10). The patient population contained both high-risk and low-risk pts, based on cytogenetic and/or fluorescence in situ hybridization analyses. Most adverse events (AEs) were mild or moderate in severity. The most common grade ≥3 treatment-related AEs, experienced by 19 (61%) pts, were neutropenia (26%), thrombocytopenia (16%), diarrhea (13%), anemia (10%), and fatigue (10%); 8 pts discontinued due to toxicity. One dose-limiting toxicity (grade 3 diarrhea lasting >48 h) was observed at the maximum assessed dose (level 5), but MTD was not reached (Table) and there were no treatment-related deaths. Among 30 pts evaluable for response, the median TTP was 32 weeks (5 mo), and 4 pts remain on study as of the data cutoff date; 26 of 30 pts (87%) have achieved at least stable disease (SD). Best single responses included 2 complete responses, 3 very good partial responses (VGPR), 11 partial responses (PR), and 5 minimal responses (MR), with 5 pts achieving SD and 4 developing progressive disease, resulting in an overall response rate (ORR; PR or better) of 53%. Of 13 evaluable pts who had previously received lenalidomide, a best single response of SD or better was observed in 9 (69%; 2 VGPR, 3 PR, 1 MR, 3 SD), resulting in a 38% ORR. Notably, SD or better (2 PR, 1 MR, 3 SD) was observed in 60% of 10 evaluable pts who were relapsed, refractory, or intolerant to previous lenalidomide-containing regimens. Conclusions: Preliminary data from this Phase I study suggest that vorinostat plus lenalidomide and dexamethasone is a convenient and generally well-tolerated regimen with promising activity for relapsed or relapsed and refractory MM. The MTD for this combination was not reached. Importantly, responses were observed in pts who had received prior lenalidomide, bortezomib, and thalidomide. Further evaluation of this regimen is planned in future trials. Disclosures: Richardson: Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Vorinostat, Lenalidomide, and Dexamethasone for treatment in Multiple Myeloma. Weber:Novartis-unpaid consultant: Consultancy; Merck- unpaid consultant: Consultancy; Celgene- none for at least 2 years: Honoraria; Millenium-none for 2 years: Honoraria; Celgene, Millenium, Merck: Research Funding. Mitsiades:Millennium: Consultancy, Honoraria; Novartis Pharmaceuticals: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Merck & Co.: Consultancy, Honoraria; Kosan Pharmaceuticals: Consultancy, Honoraria; Pharmion: Consultancy, Honoraria; Centrocor: Consultancy, Honoraria; PharmaMar: Patents & Royalties; OSI Pharmaceuticals: Research Funding; Amgen Pharmaceuticals: Research Funding; AVEO Pharma: Research Funding; EMD Serono: Research Funding; Sunesis: Research Funding; Gloucester Pharmaceuticals: Research Funding; Genzyme: Research Funding. Dimopoulos:MSD: 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. Harousseau:Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Houp:Merck Research Laboratories: Employment. Graef:Merck Research Laboratories: Employment. Gause:Merck Research Laboratories: Employment. Byrne:Celgene Corporation: Employment, Equity Ownership. Anderson:Millennium Pharmaceuticals: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Onyx: Consultancy; Merck: Consultancy; BMS: Consultancy; Acetylon: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Siegel:Celgene and Millennium: Advisory Board, Speakers Bureau; Merck: Advisory Board.

Phase I-II Trial of Oral Cyclophosphamide, Prednisone and Lenalidomide (Revlimid®) (CPR) for the Treatment of Patients with Relapsed and Refractory Multiple Myeloma

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3055-3055
Author(s):  
Donna E. Reece ◽  
Esther Masih-Khan ◽  
Arooj Khan ◽  
Saima Dean ◽  
Sharon Fung ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Dose Level ◽  
Research Funding ◽  
Response Rate ◽  
Objective Response ◽  
Median Number ◽  
Prior Therapy ◽  
Best Response ◽  
Level 3 ◽  
Grade 3

Abstract Abstract 3055 Lenalidomide (Revlimid®) and dexamethasone is an effective regimen for relapsed/refractory (rel/ref) multiple myeloma (MM) patients (pts) with an overall response rate of 60% and median time to progression of 13.4 months (Dimopoulos ME, et al. Leukemia 2009; 23: 2147-52). We combined lenalidomide with the alkylating agent combination of cyclophosphamide and prednisone—an older regimen with minimal cumulative myelosuppression and good activity as second or third line therapy (Trieu Y, et al, Mayo Clin Proc 2005; 80: 1582). The CPR regimen consisted of cyclophosphamide (CY) on days 1, 8, and 15, lenalidomide on days 1–21 and prednisone 100 mg q 2 days in a 28-day cycle. ASA 81 mg/day was given as DVT prophylaxis. Three dose levels were evaluated using a 3 × 3 dose escalation design. Thirty-two pts were entered between 11/2007-06/2009; median age was 64 (42-80) yrs, 60% were male, and immunoglobulin isotype was IgG in 19 (62%), IgA in 8 (25%) and light chain in 4 (13%) pts. Median β2-microglobulin level was 257 (92-767) nm/L, albumin 39 (34-48) g/L, creatinine 83 (50-126) μmol/L, platelet count 355 (75-479) × 109/L and ANC 2.5 (1.1-6.1) × 109/L. The median number of prior regimens was 2 (1-5). Prior therapy included: ASCT (single in 91%; double in 19%), thalidomide (28%) and bortezomib (50%). FISH cytogenetics were available in 13 pts; 1 had del 13q but none had t(4;14) or del p53. Table 1 summarizes protocol treatment delivered. Table 1. Dose level N Cyclophosphamide dose (mg/m2) Lenalidomide dose (mg) Prednisone dose (mg) Median # cycles given 1 3 150 15 100 12 (12–34+) 2 3 150 25 100 10 (9–23) 3 26 300 25 100 17 (5–28+) 1–3 (All) 32 150–300 15–25 100 19 (5–34+) Dose limiting toxicity was not observed during cycle 1 at any dose level. Grade 3–4 toxicities during the trial included: thrombocytopenia in 7 (22%) and neutropenia in 9 (29%), managed with dose reduction and/or growth factors; five episodes of febrile neutropenia occurred, all at dose level 3. In cohort 3, other grade 3–4 non-hematologic toxicities included 1 episode each of abdominal pain/bacteremia, hypokalemia, fatigue, sick sinus syndrome, cardiac amyloidosis, perforated diverticulum and 2 episodes of DVT. Two heavily pretreated pts developed 2° MDS, including 1 previously treated for lymphoma, 43 and 190 mos after the diagnosis of MM. The best response using modified EBMT criteria was documented at a median of 7 (1-26) cycles and included the following: dose level 1 (1 CR, 2 PR); dose level 2 (1 VGPR, 2 PR); dose level 3 (4 CR, 14 VGPR, 11 PR, 1 MR and 1 stable disease). At a median F/U of 16 (5-34) months, 13 pts remain on study and 18 have progressed at a median of 10 (2-23) mos; 1 was lost to F/U and 9 have died of progressive MM. The 1-year actuarial OS and PFS rates are 93% (95% CI 76–98%) and 78% (95% CI 60–89%), respectively. We conclude: 1) the combination of full doses of the agents in CPR can be given in a 28 day cycle with an acceptable safety profile; 2) the objective response rate (CR + PR + MR) in all 32 pts to date is 94%; 3) the 1-year OS of 93% and PFS of 78% compare favorably with other 3-drug combinations in rel/ref MM pts; 4) further evaluation of this regimen in newly diagnosed pts would be of interest. Disclosures: Reece: Celgene: Honoraria, Research Funding. Off Label Use: Combination of lenalidomide and cyclophosphamide and prednisone in relapsed and refractory myeloma patients. Chen:Celgene Corporation: Consultancy, Honoraria, Research Funding. Kukreti:Celgene: Honoraria.

ARRY-520 Shows Durable Responses in Patients with Relapsed/Refractory Multiple Myeloma in a Phase 1 Dose-Escalation Study

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1860-1860 ◽  
Author(s):  
Jatin J Shah ◽  
Jeffrey Zonder ◽  
Adam Cohen ◽  
Robert Z. Orlowski ◽  
Raymond Alexanian ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Febrile Neutropenia ◽  
Dose Escalation ◽  
Safety Profile ◽  
Research Funding ◽  
Phase 1 ◽  
Phase 1 Study ◽  
Acceptable Safety Profile ◽  
Heavily Pretreated ◽  
Grade 3

Abstract Abstract 1860 Background: ARRY-520 is a potent, selective inhibitor of kinesin spindle protein (KSP, eg5) which is required for cell cycle progression through mitosis. Treatment with ARRY-520 arrests cells in mitosis with subsequent induction of apoptosis due to degradation of survival signals during mitotic arrest. Cancers, such as multiple myeloma (MM), that depend on the short-lived survival protein Myeloid cell leukemia (MCL)-1 are highly sensitive to treatment with ARRY-520 in preclinical MM models, providing a strong rationale for its clinical investigation in this disease. Methods: This Phase 1 study was designed to evaluate the safety, pharmacokinetics (PK), preliminary efficacy and biological activity of ARRY-520 administered intravenously on Days 1 and 2 every 2 weeks without/with granulocyte colony-stimulating factor (G-CSF) support. Eligible patients (pts) had relapsed or refractory MM with ≥ 2 prior lines of therapy (including both bortezomib [BTZ] and an immunomodulatory [IMiD] agent), unless refusing or ineligible for this therapy. Cohorts were enrolled in a classical 3+3 dose escalation design. Results: Enrollment in this Phase 1 study is complete. Thirty-one pts have been treated, with a median age of 60 years (range 43–79) and a median of 6 prior regimens (range 2–16). All pts received a prior proteasome inhibitor (30 pts BTZ, 4 pts carfilzomib) and an IMiD-based agent (28 pts lenalidomide, 23 pts thalidomide). Twenty-four pts had an autologous stem cell transplant. The maximum tolerated dose (MTD) was determined to be 1.25 mg/m2/day without G-CSF. As neutropenia was the dose-limiting toxicity (DLT), dose escalation with G-CSF support was conducted and the MTD for ARRY-520 with G-CSF was determined to be 1.5 mg/m2/day. At the MTD, 1 of 7 pts had a DLT of febrile neutropenia. At doses above the MTD, additional DLTs of Grade 3 mucositis and Grade 3 corneal disorder were observed. ARRY-520 demonstrated an acceptable safety profile. The most commonly reported treatment-related adverse events (AEs) included hematologic events (anemia, leukopenia, neutropenia, thrombocytopenia), as well as anorexia, blurred vision, diarrhea, dizziness, fatigue, febrile neutropenia, mucositis, nausea and rash. No treatment-related AEs of neuropathy or alopecia were reported at the MTD. ARRY-520 has been dosed over extended periods of time (to date, median 7 cycles [range 1–44]), with no evidence of cumulative toxicity. The plasma concentrations of ARRY-520 were determined over a 7-day period during Cycle 1 following the Day 1 and 2 infusions of ARRY-520. The preliminary noncompartmental PK parameter estimates in this population were similar to those observed in prior oncology studies. The PK was characterized by low clearance (CL = 2.2 L/hr/m2) and a large volume of distribution (Vss = 232 L/m2). The t1/2 of elimination was very long (67 hrs). Concentrations were typically maintained above the in vitro IC50 for KSP inhibition for ≥ 7 days suggesting therapeutically active concentrations of drug were maintained in pts for sustained periods. Further analyses of PK relative to safety and activity are on-going. ARRY-520 showed activity as a single agent across a range of doses in this heavily pretreated population (31 evaluable pts) with 3 confirmed partial responses (PR) and 1 confirmed minimal response (MR) per International Melanoma Working Group (IMWG) and European Group for Blood and Marrow Transplantation (EMBT) criteria. PRs had a median of 7 prior therapies (range 2–8). Responses were durable; to date, the durations of responses for PRs were 3.4+ months (mos), 11.9+ mos and 12.0 mos, respectively. Of interest, the time to response with ARRY-520 was prolonged, with a median time to PR of 3.7 mos (range 3.7–8.1). Notably, responses were observed in pts refractory to multiple standard-of-care agents. In addition, 4 pts experienced a best response of stable disease (SD) lasting ≥ 10 mos. To date, 5 pts remain on study, including 2 of 3 PRs. Conclusions: In this Phase 1 study, ARRY-520 shows promising evidence of clinical activity, with a long duration of response and an acceptable safety profile in heavily pretreated MM Patients. A Phase 2 portion of the study is ongoing to obtain additional information on the efficacy, safety and biological effects of ARRY-520 at 1.5 mg/m2/day with G-CSF support. Disclosures: Shah: Array BioPharma: Consultancy, Research Funding; Celgene: Consultancy; Onyx: Consultancy, Research Funding. Off Label Use: ARRY-520. Zonder:Millenium: Consultancy, Research Funding, Speakers Bureau; Celgene: Speakers Bureau; Medtronics: Honoraria; Amgen: Consultancy. Cohen:Celgene: Consultancy, Honoraria; Millenium: Consultancy, Honoraria; Onyx: Consultancy, Honoraria. Orlowski:Array BioPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees. Alexanian:Array BioPharma: Research Funding. Thomas:Array BioPharma: Research Funding; Centecor: Research Funding; Novartis: Research Funding; Immunomedics: Research Funding; Celgene: Research Funding; Millenium: Research Funding. Weber:Array BioPharma: Research Funding. Kaufman:Keryx: Consultancy; Celgene: Research Funding; Merck: Research Funding. Walker:Array BioPharma: Employment, Equity Ownership. Litwiler:Array BioPharma: Employment. Karan:Array BioPharma: Employment. Hilder:a: Employment. Ptaszynski:Array BioPharma Inc.: Consultancy. Lonial:Millenium: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Bristol Myers Squibb: Consultancy; Onyx: Consultancy; Merck: Consultancy.

Lenalidomide (Revlimid), Bortezomib (Velcade) and Dexamethasone (RVD) for Heavily Pretreated Relapsed or Refractory Multiple Myeloma

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2936-2936
Author(s):  
Victor H Jimenez-Zepeda ◽  
Donna E. Reece ◽  
Suzanne Trudel ◽  
Christine Chen ◽  
Vishal Kukreti
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Research Funding ◽  
Clinical Characteristics ◽  
Phase 1 ◽  
Prior Exposure ◽  
Rank Test ◽  
Continuous Variables ◽  
Previously Treated ◽  
Grade 3

Abstract Abstract 2936 Almost all patients (pts) with multiple myeloma eventually relapse and remission duration decreases with each regimen. The median Progression Free Survival (PFS) and Overall Survival (OS) in pts with relapsed myeloma refractory to lenalidomide (len) and bortezomib (btz) is poor at 5 and 9 months respectively. A phase 1 study of len plus btz in pts with relapsed or relapsed, refractory MM (RRMM) demonstrated favorable toxicity and promising response and survival further confirmed in a phase 2 study with len, btz and dexamethasone (dex) [RVD]. In this retrospective study, we assessed the efficacy and toxicity profile of RVD therapy for pts with advanced RRMM. We retrospectively reviewed the records of all pts with RRMM treated with RVD at Princess Margaret Hospital between 03/09 and 05/11. Relapse was defined according to the Uniform International Criteria. Pts were given RVD therapy as previous described by Anderson et al and must have completed at least one cycle of RVD therapy. Primary endpoints were response rate (RR), PFS, OS, and toxicity. Pts discontinued therapy if they experienced PD, no additional benefit or unacceptable toxicity. Definitions of response and progression were used according to the EBMT modified criteria with a category of very good partial response (VGPR). To examine variables independently prognostic for PFS and OS, multivariate Cox analysis was performed. Differences in continuous variables between groups were compared using Mann-Whitney or Kruskal-Wallis tests. Survival curves were constructed according to the Kaplan-Meier method and compared using the log rank test. Thirty pts with RRMM received RVD therapy. Clinical characteristics are seen in Table 1. Median age at RVD initiation was 57 yrs (37–76 yrs), and 46.7% were male. Pts received a median of 3 prior therapies (1–6). In many instances, pts previously treated with len had len added to btz + dex at progression (n=6), or pts previously treated with btz had btz added to len + dex, at progression (n=5). Thalidomide (thal), len and btz containing regimens were previously used in 60%, 73.3% and 80% of pts respectively. PR or better was observed in 46.6%. After a median of 4.6 cycles (1–14), VGPR was seen in 4.8%, PR in 33% and SD in 14%. Pts who achieved PR or better experienced a significant improvement in PFS. There was no difference in terms of RR between those pts according to prior exposure to either btz or len (p=0.7 and 0.9 respectively). Eight pts experienced non-hematological grade 3/4 adverse events (26%), including muscle weakness, sepsis and pneumonia but there was no worsening of peripheral neuropathy. Grade 3–4 neutropenia and/or thrombocytopenia were commonly seen in 70% of pts (n=21). Disease progression was seen in 19 pts at a median of 3.9 months. Median PFS for pts previously exposed to len was 2.3 months vs 2.9 months for those with no prior exposure (p=0.75). On the other hand, median PFS for pts previously exposed to btz was 2.1 months vs 3.4 months for those with no prior exposure (p=0.9) In addition, median PFS for pts who achieved at least PR was significantly better at 5.9 vs 2.0 months for those who did not (p<0.005). (Figure 1) FISH cytogenetics studies were available in 19 out of 30 patients at relapse: 5 -normal, 4–13q deletion, 3-p53 deletion and 2 - t(4, 14). High-risk MM pts had a median PFS significantly lower of 0.6 months (CI 95%, 0–1.99) vs 4.7 months for those without high-risk features (CI 2.5–7.0) (p=0.008) (Figure 2) At the time of submission, 13 pts are alive (43.3%) and 7 pts (23%) continue on RVD therapy.Table 1.Clinical characteristics of patients with RRMM treated with RVDClinical characteristic N=30MedianRange%Age5737-76Male46.7%Female53.3%Hemoglobin (g/L)10571-155Creatinine (mmol/L)99.936-383Beta-2 microglobulin (mmol/L)280119-1440Lactate dehydrogenase (U/L)18189-255IgG56.6% (17)IgA23.3% (7)IgM3.3% (1)Light Chain16.6% (5)Kappa (mg/L)4005.3-346063.3% (19)Lambda (mg/L)5145.1-530036.7% (11)KappaLambda*BMPC57%6-95%M-spike serum (g/L)300-77M-spike urine (g/d)0.890-7.9Prior therapies31-6ASCT83.3% (25)Thal60% (18)Len73.3% (22)Btz80% (24)*BMPC, Bone marrow plasma cells In conclusion, RVD is active and well tolerated in pts with RRMM, including pts who have received prior len, btz, thal and ASCT but PFS is short at 3.9 months in this highly advanced disease group of patients. We question whether response is dependent on recognized risk factors such as adverse cytogenetics. Disclosures: Jimenez-Zepeda: J & J: Honoraria. Reece:Bristol, Meyers, Squibb: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Johnson&Johnson: Research Funding; Merck: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Millennium: Research Funding; Amgen: Honoraria. Kukreti:Celgene: Honoraria.

Escalated Dose Bortezomib Once Weekly Combined with Lenalidomide and Dexamethasone (eVRD) Followed by Lenalidomide Maintenance in First Relapse of Multiple Myeloma (MM). the HOVON 86 Phase 2 Trial

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1853-1853
Author(s):  
Pieter Sonneveld ◽  
Okke de Weerdt ◽  
Mark-David Levin ◽  
Wendimagegn Ghidey ◽  
Edo Vellenga ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Partial Response ◽  
Dose Escalation ◽  
Research Funding ◽  
Phase 2 ◽  
Level 3 ◽  
First Relapse ◽  
Grade 3 ◽  
Dose Levels

Abstract Abstract 1853 Background: Bortezomib (1.3 mg/m2) combined with Lenalidomide (10–25 mg) and Dexamethasone (VRD) is effective in newly diagnosed and relapsed multiple myeloma (MM). Reported data on the effect of these drugs in relapse/refractory MM are available from the APEX and MM-009/MM-010 trials, respectively. These trials, however, were performed in patients with 2–8 prior regimens. Aim: This investigator sponsored two-step phase 2 HOVON trial was designed to evaluate escalated dosages of Bortezomib (B) given once weekly and daily Lenalidomide (L) combined with weekly Dexamethasone (D) (eVRD) followed by Lenalidomide maintenance in an homogenous group of patients with symptomatic MM in first relapse. The goal was to explore the maximum tolerated dose of this combination in order to achieve a durable second remission. Methods: Dose levels were B 1.3 mg/m2, L 10 mg, (level 1); B 1.6 mg/m2, L 10 mg (level 2); B 1.6 mg/m2, L 15 mg (level 3); B 1.6 mg/m2, L 20 mg (level 4). D dose was 20 mg days 1–2, 8–9, 15–16 in all dose levels. Inclusion criteria were symptomatic MM ISS stage 1–3, aged 18–80 in first relapse after initial treatment. The primary endpoint was response (complete response (CR) according to IMWG criteria, very good partial response (VGPR), partial response (PR), together overall response (ORR)) with Progression-free Survival (PFS), overall survival (OS) and toxicity as secondary endpoints. Results: Eighty-one patients were included, i.e. 15 patients in dose levels 1, 2 and 3, followed by 66 in the phase 2 part. This report is based on 12 patients in the dose escalation phase and the first 42 patients in the phase 2 part. Median age was 67 yrs, with ISS stages 1 (56%), 2 (40%) and 3 (5%). 37/54 patients had received HDM followed by stem cell transplant as part of first-line treatment. The MTD was reached at dose level 3 when the maximum of 3 SAEs in 5 patients was observed. After establishment of the MTD, the phase 2 part of the trial was performed with B 1.6 mg/m2 once weekly for 3 weeks, L 20 mg days 1–21 and D 20 mg days 1–2, 8–9, 15–16, for 8 cycles of 28 days followed by L maintenance 10 mg days 1–21 of a 28 days cycle. The median number of cycles was 6 in the dose-escalation phase and 7 cycles in phase 2. 7/12 (58%) patients in the dose-escalation phase and 23/42 (55%) patients in phase 2 started lenalidomide maintenance. Reasons for premature discontinuation of the protocol treatment were toxicity (14%), progression (24%), no response (5%) or other (14%). Polyneuropathy grade 3–4 occurred in 19% with a median time to maximum PNP of 123 days. Hematological toxicity grade 3 and 4 was observed in 29 % of patients In the phase 2 part including 42 patients the ORR was 92 %, ≥VGPR 64% and CR/nCR 30%. Median time to response was 1.1 cycles. At a median follow-up of 13.6 months PFS at 18 months was 52% and OS 76%. Among predetermined risk factors ISS stage, prior HDM/ASCT and achieved response on protocol, depth of response was the only significant factor which was associated with PFS (p<0.001) and OS (p<0.001), Eight patients died from progressive MM (n=4) or other causes (n=4). One second primary malignancy was observed in dose level 3. Conclusions: Escalated VRD followed by Lenalidomide maintenance is effective and feasible in patients with first relapse MM. We will present an updated follow-up at ASH This trial was registered as Eudract nr 2007–002533–37. Unrestricted grants and study drug were provided by Janssen and Celgene. Disclosures: Sonneveld: Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Onyx: Honoraria, Research Funding.

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