Carfilzomib therapy for relapsed myeloma: results of a UK multicentre experience

The prognosis of multiple myeloma has considerably improved due to the introduction of novel agents in the upfront setting. However, the great majority of patients ultimately relapse, and choosing a salvage treatment at first relapse remains challenging. The natural history of first relapsed disease in the current era is also not well described. We retrospectively studied 300 patients with first relapsed myeloma seen between 2004 and 2019 from two institutes in Singapore. The median duration from diagnosis to first relapse was 22.7 months (1.1–97.0 months). Most patients received novel agent-based induction therapy, and 41.3% underwent autologous stem cell transplant. A very good partial response (VGPR) or better was achieved in 48.6%. Regarding first relapse, 50.5% were symptomatic and 19.0% received newer agent-containing regimens. Nearly a third of patients (31.7%) had a VGPR or better response. The median progression free and overall survival from first relapse was 12.0 and 44.8 months, respectively. Based on a randomized sample splitting, we first identified non-hyperdiploid karyotype at diagnosis, clinical relapse, and treatment sequence as impacting survival independently from a testing cohort, and we then further demonstrated their significance in a validation cohort. This study provides a real-world picture of first relapsed myeloma and highlights the prognostic importance of the treatment sequence.

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Persistent Hypercalcemia Leading to Acute Pancreatitis in a Patient with Relapsed Myeloma and Renal Failure

Nephron ◽

10.1159/000045004 ◽

1998 ◽

Vol 79 (1) ◽

pp. 109-110 ◽

Cited By ~ 3

Author(s):

İsmail Çelik ◽

Şule Apraş ◽

Ayşe Kars ◽

İbrahim Barışta ◽

İbrahim Güllü ◽

...

Keyword(s):

Renal Failure ◽

Acute Pancreatitis ◽

Relapsed Myeloma

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Phase I Trial of Flavopiridol In Relapsed Myeloma: Brief Response In t(4;14) with Significant Neutropenia

Blood ◽

10.1182/blood.v116.21.1933.1933 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1933-1933

Author(s):

Craig C. Hofmeister ◽

Mindy A Bowers ◽

Seungsoo Lee ◽

Mitch A. Phelps ◽

Don M Benson ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Phase I ◽

Human Serum ◽

Intravenous Infusion ◽

Median Number ◽

Lymphocytic Leukemia ◽

Intravenous Bolus ◽

Continuous Intravenous Infusion ◽

Relapsed Myeloma ◽

Final Cohort

Abstract Abstract 1933 Introduction: A pharmacokinetically derived schedule of flavopiridol administered as a 30 min intravenous bolus followed by 4-hour continuous intravenous infusion is active in fludarabine-refractory chronic lymphocytic leukemia, but no studies examining the feasibility and maximum tolerated dose of this schedule have been reported in relapsed multiple myeloma. Flavopiridol is a novel anti-cancer agent that targets cyclin dependent kinases (CDK) including the CDK9/cyclin T complex (preventing activation of RNA polymerase II), downregulates Mcl-1 and other anti-apoptotic proteins, and induces mitochondrial permeability changes. Flavopiridol is highly protein bound when in human serum, compared to protein binding seen in fetal bovine serum. This difference helps to explain the previous lack of clinical activity of flavopiridol (Dispenzieri et al, Haematologica, 2006) that targeted plasma concentrations based on in vitro cytotoxicity. A novel schedule of administration was designed to achieve and maintain target plasma levels predicted to be active in chronic lymphocytic leukemia from preclinical studies performed in human serum: 30-minute intravenous bolus (IVB) followed by 4-hour intravenous infusion (IVB/CIVI). This schedule, given for four of six weeks, is highly active in fludarabine refractory chronic lymphocytic leukemia. Methods: This was a phase I 3×3 single arm (standard method) study for relapsed myeloma patients having received at least two prior therapies. Adequate organ function was required with creatinine < 1.5 mg/dL and total bilirubin < 2x IULN. Adequate hematologic parameters were required with Hb > 9 g/dL, ANC>1500, and platelets > 50K during screening unless attributable to the patient's underlying myeloma. Results: 15 patients (ages 49–81 y.o.) with relapsed myeloma were consented. Median number of prior therapies was 7 (3-12). At the time of study entry, 8 patients displayed a complex karyotype, 2 patients with 17p deletion by CD138-selected FISH, and one patient with t(4;14); 3 patients with karyotypic chr 13 deletion and 9 patients by FISH. At study entry, 7 patients had ISS stage 3 disease, 4 with stage 2, and 4 with stage 1. 5 patients were treated in cohort 1 (30 mg/m2 bolus/30 mg/m2 CIV), 3 patients in cohort 2 (30 mg/m2 bolus/50 mg/m2 CIV), and 7 patients in cohort 3 (50 mg/m2 bolus/50 mg/m2 CIV). Median number of cycles received was 1. No patients achieved a confirmed PR – two patients achieved a minor response by IMWG criteria (see figure). The one patient with near 50% response in his IgA myeloma was the only patient with a t(4;14), 13-, and tetraploid cytogenetics by FISH. Grade 3/4 toxicities were significant with grade 4 neutropenia (10 patients), diarrhea (6 patients), transaminitis (4 patients), thrombocytopenia (3 patients), and anemia (5 patients). The most common toxicities included neutropenia, diarrhea, and AST elevation. Two patients in the first cohort and 1 patient in the final cohort were replaced due to inability to complete the first cycle. Pharmacokinetic results and immunohistochemical staining results for cyclin-D1 and pRb will be presented at the meeting; cyclin-D1 overexpression has been linked to CDK-inhibitor response (Dai Y et al, Cell Cycle 2006). One patient is undergoing screening to complete the final cohort and complete response and toxicity data will be reported. Discussion: Flavopiridol as a single agent given by intravenous bolus/continuous intravenous infusion causes significant neutropenia and diarrhea but objective clinical responses were uncommon. (ClinicalTrials.gov Identifier: NCT00112723). Disclosures: Jones: Glaxo Smith-Kline: Consultancy; Abbott: Research Funding.

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Velcade, Vorinostat and Dexamethasone (V2 D) in Relapsed Myeloma: Results of the Phase 2 Muk Four Trial

Blood ◽

10.1182/blood.v126.23.1852.1852 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1852-1852

Author(s):

Matthew W Jenner ◽

Avie-Lee Tillotson ◽

Sarah R Brown ◽

Louise M Flanagan ◽

Debbie Sherratt ◽

...

Keyword(s):

Peripheral Neuropathy ◽

Disease Progression ◽

Board Of Directors ◽

Dose Reduction ◽

Response Rate ◽

Prior Treatment ◽

Phase 2 ◽

Advisory Committees ◽

Grade 3 ◽

Relapsed Myeloma

Abstract Introduction: Bortezomib (Velcade) and dexamethasone is a standard combination for relapsed myeloma. Both in vitro data and initial clinical trials signalled the efficacy of the combination of intravenous bortezomib and the oral histone deacetylase inhibitor vorinostat. Although the randomised phase 3 VANTAGE 088 trial identified an improvement in progression free survival with the combination of bortezomib and vorinostat compared to bortezomib monotherapy in relapsed myeloma, 50% of patients in the vorinostat group had at least one dose reduction compared with 25% in the placebo group, with potential impact on clinical outcomes. Subcutaneous bortezomib has now become the standard route of administration because of lower rates of peripheral neuropathy. MUK four is a single arm phase 2 multi-centre UK trial to evaluate the toxicity profile and efficacy of an alternative dosing schedule of vorinostat in combination with subcutaneous bortezomib and oral dexamethasone. We report the final analysis of toxicity and response data. Methods: Patients with relapsed myeloma treated with 1-3 prior lines of therapy received up to 8 cycles of V2 D (bortezomib 1.3 mg/m2 subcutaneously days 1, 4, 8 and 11, vorinostat 400 mg orally days 1-4, 8-11 and 15-18 and dexamethasone 20 mg orally days 1, 2, 4, 5, 8, 9, 11 and 12 of a 21 day cycle). Following completion of a minimum of 3 cycles of V2 D, participants received maintenance vorinostat (400 mg days 1-4 and 15-18 of a 28 day cycle) until disease progression, intolerance or participant withdrawal. Responses were assessed using the modified IMWG response criteria and toxicities graded using CTCAE v4.0. Results: Between August 2013 and November 2014, 16 participants were recruited to MUK four. Median age was 69.5 years (range 50.0-78.0) and median lines of prior treatment was 1 (1-3). Prior treatment included thalidomide-based combinations in 13/16 (81.3%), bortezomib-based in 7/16 (43.8%) and lenalidomide-based in 2/16 (12.5%). 9/16 (56.3%) participants had received prior high dose melphalan ASCT. Median time from diagnosis was 38.6 months (9.3-120.4). At analysis in June 2015 8/16 (50%) participants continued on maintenance vorinostat. All 16 patients were evaluable for response within the first 8 cycles of V2 D. Overall response rate was 81.3% (13/16, 95% CI [55.4-96.0]) consisting of CR in 4/16 (25.0%), VGPR 2/16 (12.5%) and PR in 7/16 (43.8%). The remaining 3/16 (18.8%) achieved MR giving a clinical benefit response rate of 16/16 (100%). Participants received a median of 6 cycles of initial treatment with 6/16 (37.5%) receiving all 8 cycles. Treatment was discontinued in 4/8 (50%) because of disease progression, in 2/8 (25%) because of toxicity and in 2/8 (25%) for clinician discretion. Overall 12/16 (75%) participants experienced a dose reduction of either vorinostat or bortezomib or terminated treatment early as a result of toxicity. 11/16 (68.8%) reduced vorinostat and 10/16 (62.5%) reduced bortezomib. The most frequent grade 2 toxicities during the first 8 cycles were fatigue in 8/16 (50%), anaemia in 7/16 (43.8%), diarrhoea in 5/16 (31.3%), nausea in 4/16 (25.0%) and peripheral neuropathy in 4/16 (25.0%). The most frequent grade 3-4 toxicities encountered during the first 8 cycles were thrombocytopenia in 8/16 (50%), anaemia in 1/16 (6.3%), diarrhoea in 1/16 (6.3%) and fatigue in 1/16 (6.3%). During maintenance vorinostat only 1 participant experienced an adverse reaction above grade 2 (grade 3 neutropenia). Conclusion: Bortezomib, vorinostat and dexamethasone is a highly effective combination in relapsed myeloma with good response rates. Maintenance vorinostat is well tolerated. Although toxicity and dose reductions are observed with combination therapy, this study demonstrates that the combination of proteasome inhibitor, HDAC inhibitor and dexamethasone offers promise. Further data on PFS will be presented. Disclosures Jenner: Amgen: Honoraria; Takeda: Honoraria. Off Label Use: Vorinostat for treatment of myeloma. Pawlyn:Celgene: Honoraria, Other: Travel support; The Institute of Cancer Research: Employment. Williams:Celgene: Consultancy, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau. Davies:Array-Biopharma: Membership on an entity's Board of Directors or advisory committees; Takeda-Millennium: Membership on an entity's Board of Directors or advisory committees; University of Arkansas for Medical Sciences: Employment; Onyx-Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees.

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Efficacy and Safety of Triplet Versus Doublet Salvage Therapies Among Patients with Multiple Myeloma (MM) Experiencing Early Relapse: Meta-Analysis of Phase III Randomized Controlled Trials (RCTs)

Blood ◽

10.1182/blood.v126.23.5344.5344 ◽

2015 ◽

Vol 126 (23) ◽

pp. 5344-5344 ◽

Cited By ~ 1

Author(s):

Ajay K. Nooka ◽

Jonathan L. Kaufman ◽

Madhusmita Behera ◽

Charise Gleason ◽

Hannah Collins ◽

...

Keyword(s):

Multiple Myeloma ◽

Research Funding ◽

Mixed Model ◽

Meta Analysis ◽

Phase Iii ◽

P Value ◽

Serious Adverse Events ◽

Early Relapse ◽

The Impact ◽

Relapsed Myeloma

Abstract Introduction: Controversy exists regarding the choice of triplet versus doublet salvage therapy among patients with multiple myeloma (MM) experiencing early relapse. Triplet therapies produce deeper responses (CR, ≥VGPR, ORR) and result in prolonged progression free survival (PFS) while doublet therapies demonstrate an improved toxicity profile. We performed a meta-analysis of the RCTs comparing triplet to doublet salvage regimens in early relapsed myeloma patients (1-3 prior lines of therapy). The objective is to test the hypothesis that triplet regimens are tolerable, improve CR, ≥VGPR, ORR rates and would translate to an improved PFS. Methods: We searched Pubmed, Cochrane databases and ASH, ASCO conference proceedings from 01/2000 through 07/2015 for publications and abstracts to identify the phase III RCTs comparing triplet vs. doublet salvage therapies among patients with relapsed myeloma. A meta-analysis of 4 RCTs (PANORAMA1, MMVAR/IFM 2005-04, ASPIRE, ELOQUENT2 consisting of 2475 patients) was performed using the fixed (Mantel-Haenszel) and random (DerSimonain and Laird) models to calculate the impact of triplets versus doublets (table 1) by evaluating the CR, ≥VGPR, ORR, PFS and toxicities. Mature OS data was not available for the RCTs, hence not included in meta-analysis. The consistency of results (effect sizes) among studies was investigated by means of 2 heterogeneity tests: the χ 2-based Cochran's Q test, and the I2 Statistic. We considered that heterogeneity was present when the P-value of the Cochran's Q test was <.1 and the I2 statistic was > 50%. Results: The pooled odds ratios of ORR, ≥VGPR and CR with triplets vs. doublets were 1.935 (P <0.000; 95% CI: 1.614-2.321); 2.185 (P <0.000; 95% CI: 1.832-2.606); 2.461 (P <0.000; 95% CI: 1.888-3.207) respectively, indicating that the odds of achieving higher quality responses are improved with triplet regimens compared to the use of a doublet regimens. The pooled hazard ratio (HR) for PFS was 0.661 (95% CI 0.596-0.734; P =0.000) in favor of triplet regimens (Figure 1). The Q-statistic for PFS (P =0.725; df =3; I2 = 0.00) suggests homogeneity across studies. Though the relative risk of selected ≥grade 3 serious adverse events (G3 SAE) was higher with triplet regimens (diarrhea, fatigue, thrombocytopenia 2.288 (95% CI 1.637-3.197; P =0.000), 1.654 (95% CI 1.263-2.166; P =0.000), 2.434 (95% CI 1.934-3.063; P =0.000), respectively), the overall G3 SAE were comparable with RR 1.498 (95% CI 1.176-1.908; P =0.001) favoring doublets. Conclusion: Our mixed model meta-analysis demonstrates that triplet regimens in early relapsed myeloma patients result in improved ORR, ≥VGPR, CR and PFS compared to doublets. G3 SAEs are higher with triplet regimens, however this appears to be influenced by the regimen-related toxicity from the PANORAMA1 trial. Appropriate dose modifications or use of selective HDAC inhibitors in future may mitigate the toxicities of the regimen. The pooled estimates ofresponse and survival strongly favor triplets in the early relapsed setting. Table 1. Triplet vs. doublet regimens in RCTs Trial Triplet regimen Doublet regimen PANORAMA1 Panobinostat, bortezomib, dexamethasone Placebo, bortezomib, dexamethasone MMVAR/IFM 2005-04 Bortezomib, thalidomide, Dexamethasone Thalidomide, Dexamethasone ASPIRE Carfilzomib, lenalidomide, Dexamethasone Lenalidomide, Dexamethasone ELOQUENT 2 Elotuzumab, lenalidomide, Dexamethasone Lenalidomide, Dexamethasone Figure 1. VGPR rates and PFS with triplet vs. doublet regimens Figure 1. VGPR rates and PFS with triplet vs. doublet regimens Disclosures Nooka: Spectrum Pharmaceuticals: Consultancy; Onyx Pharmaceuticals: Consultancy. Kaufman:Onyx: Consultancy; Celgene: Consultancy; Novartis: Research Funding; Onyx: Research Funding; Merck: Research Funding; Janssen: Consultancy; Spectrum: Consultancy; Novartis: Consultancy. Gleason:Onyx: Consultancy; Novartis: Consultancy; Celgene: Consultancy. Lonial:Janssen: Consultancy, Research Funding; Onyx: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Celgene: Consultancy, Research Funding.

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Infusion of lymphocytes obtained from a donor immunised with the paraprotein idiotype as a treatment in a relapsed myeloma

Bone Marrow Transplantation ◽

10.1038/sj.bmt.1702399 ◽

2000 ◽

Vol 25 (10) ◽

pp. 1105-1108 ◽

Cited By ~ 22

Author(s):

R Cabrera ◽

F Díaz-Espada ◽

Y Barrios ◽

M Briz ◽

R Forés ◽

...

Keyword(s):

Relapsed Myeloma

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