Prospective Study of Cardiac Events During Proteasome Inhibitor Therapy for Relapsed Multiple Myeloma

PURPOSE Cardiovascular adverse events (CVAEs) can occur during proteasome inhibitor (PI) therapy. We conducted a prospective, observational, multi-institutional study to define risk factors and outcomes in patients with multiple myeloma (MM) receiving PIs. PATIENTS AND METHODS Patients with relapsed MM initiating carfilzomib- or bortezomib-based therapy underwent baseline assessments and repeated assessments at regular intervals over 6 months, including cardiac biomarkers (troponin I or T, brain natriuretic peptide [BNP], and N-terminal proBNP), ECG, and echocardiography. Monitoring occurred over 18 months for development of CVAEs. RESULTS Of 95 patients enrolled, 65 received carfilzomib and 30 received bortezomib, with median 25 months of follow-up. Sixty-four CVAEs occurred, with 55% grade 3 or greater in severity. CVAEs occurred in 51% of patients treated with carfilzomib and 17% of those treated with bortezomib ( P = .002). Median time to first CVAE from treatment start was 31 days, and 86% occurred within the first 3 months. Patients receiving carfilzomib-based therapy with a baseline elevated BNP level higher than 100 pg/mL or N-terminal proBNP level higher than 125 pg/mL had increased risk for CVAE (odds ratio, 10.8; P < .001). Elevated natriuretic peptides occurring mid–first cycle of treatment with carfilzomib were associated with a substantially higher risk of CVAEs (odds ratio, 36.0; P < .001). Patients who experienced a CVAE had inferior progression-free survival (log-rank P = .01) and overall survival (log-rank P < .001). PI therapy was safely resumed in 89% of patients, although 41% required chemotherapy modifications. CONCLUSION CVAEs are common during PI therapy for relapsed MM, especially with carfilzomib, particularly within the first 3 months of therapy. CVAEs were associated with worse overall outcomes, but usually, discontinuation of therapy was not required. Natriuretic peptides were highly predictive of CVAEs; however, validation of this finding is necessary before uniform incorporation into the routine management of patients receiving carfilzomib.

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A Phase I Study of Ixazomib in Combination with Panobinostat and Dexamethasone in Patients with Relapsed or Refractory Multiple Myeloma

Blood ◽

10.1182/blood.v126.23.4221.4221 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4221-4221 ◽

Cited By ~ 15

Author(s):

Frederic J. Reu ◽

Jason Valent ◽

Ehsan Malek ◽

Ronald M. Sobecks ◽

Beth M Faiman ◽

...

Keyword(s):

Multiple Myeloma ◽

Adverse Events ◽

Proteasome Inhibitor ◽

Research Funding ◽

Response Criteria ◽

Additional Patient ◽

Cardiac Events ◽

Minor Response ◽

Refractory Multiple Myeloma ◽

Grade 3

Abstract Background: In a pivotal trial addition of panobinostat at 20mg three times a week, two weeks on, one week off, to bortezomib and dexamethasone increased progression-free survival of relapsed or relapsed and refractory multiple myeloma (MM) but clinically significant adverse events, including severe diarrhea and unexpected cardiac events limited enthusiasm. Here we describe safety and preliminary efficacy data for an all-oral regimen that uses ixazomib as proteasome inhibitor and every other week dosing of panobinostat. Methods: Two dose levels (DL) of ixazomib (3mg, 4mg) given on day 1, 8, 15 every 28 days were evaluated in combination with panobinostat 20mg on day 1, 3, 5, 15, 17, 19 and dexamethasone 20mg day 1, 2, 8, 9, 15, 16 using a classical 3 x 3 design. Inclusion criteria included at least two prior regimens, previous therapy with a proteasome inhibitor and IMiD, measurable disease according to uniform response criteria, and adequate organ function with QTcF < 450msec and estimated creatinine clearance of at least 30ml/min. Results: Eleven patients (pts) of median age 65 (range 50-73), all with MM refractory to their last regimen, were enrolled after a median of 5 prior regimens (range 2-10). Their disease was refractory to lennalidomide (n=11), bortezomib (n=10), proteasome inhibititor with IMiD (n=9), carfilzomib (n=7), and alkylating chemotherapy (n=7). The target dose level 2 was reached without dose limiting toxicity (DLT). Median time on therapy as of July 21, 2015 is 54 days (range 21-183) including three pts who remain on study. No serious adverse event was observed and no dose reductions of panobinostat or ixazomib were required. No non-hematologic CTCAE v. 4.03 grade 3/4 toxicities were seen but 3 pts developed grade 3 hematologic toxicities (2 neutropenia, 1 thrombocytopenia). Worst diarrhea was grade 1 (n=6), worst nausea grade 2 (n=1) and 4 additional pts developed transient grade 1 nausea. Other possibly panobinostat or ixazomib related grade 1/2 adverse events included thrombocytopenia (n=5), neutropenia (n=3), fatigue (n=2), anemia (n=2), anorexia (n=1) and arthralgia (n=1). Median QTcF before treatment start was 405 msec (range 378-430) and increased on average by 4.3% (maximally by 13%). One patient developed transient grade 1 QTcF prolongation to 552 msec. No other cardiac adverse events were observed. Best response according to uniform response criteria with adapted EBMT criteria for minor response (MR) was MR in 3 pts, of whom two had disease progressive on proteasome/IMiD combinations at study entry. One MR is ongoing; the other two each lasted 6 months. One additional patient had stable disease for 6 months. Conclusions: Addition of panobinostat at 20mg three times a week every other week to ixazomib at target 4mg weekly, three weeks on, one week off, with dexamethasone 20mg on the day of and after ixazomib was very well tolerated and demonstrated activity in extensively pretreated multiple myeloma patients with progressive disease on proteasome/IMiD combinations. We therefore propose this regimen for phase 2 evaluation. Disclosures Reu: Celgene: Research Funding; Takeda/Millennium: Research Funding; Novartis: Research Funding. Off Label Use: Panobinostat and Ixazomib combined in myeloma. Valent:Takeda/Millennium: Speakers Bureau; Celgene: Speakers Bureau. Faiman:Celgene: Consultancy, Speakers Bureau; Amgen/Onyx: Consultancy; Takeda/Millennium: Consultancy. Hamilton:Takeda/Millennium: Speakers Bureau. Smith:celegene, spectrum, genentech: Honoraria.

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Carfilzomib, lenalidomide, and dexamethasone plus transplant in newly diagnosed multiple myeloma

Blood ◽

10.1182/blood.2020007522 ◽

2020 ◽

Vol 136 (22) ◽

pp. 2513-2523 ◽

Cited By ~ 1

Author(s):

Jagoda K. Jasielec ◽

Tadeusz Kubicki ◽

Noopur Raje ◽

Ravi Vij ◽

Donna Reece ◽

...

Keyword(s):

Multiple Myeloma ◽

High Risk ◽

Residual Disease ◽

Progression Free Survival ◽

Complete Response ◽

Newly Diagnosed ◽

Cardiac Events ◽

End Point ◽

Depth Of Response ◽

Grade 3

Abstract In this phase 2 multicenter study, we evaluated the incorporation of autologous stem cell transplantation (ASCT) into a carfilzomib-lenalidomide-dexamethasone (KRd) regimen for patients with newly diagnosed multiple myeloma (NDMM). Transplant-eligible patients with NDMM received 4 cycles of KRd induction, ASCT, 4 cycles of KRd consolidation, and 10 cycles of KRd maintenance. The primary end point was rate of stringent complete response (sCR) after 8 cycles of KRd with a predefined threshold of ≥50% to support further study. Seventy-six patients were enrolled with a median age of 59 years (range, 40-76 years), and 35.5% had high-risk cytogenetics. The primary end point was met, with an sCR rate of 60% after 8 cycles. Depth of response improved over time. On intent-to-treat (ITT), the sCR rate reached 76%. The rate of minimal residual disease (MRD) negativity using modified ITT was 70% according to next-generation sequencing (<10−5 sensitivity). After median follow-up of 56 months, 5-year progression-free survival (PFS) and overall survival (OS) rates were 72% and 84% for ITT, 85% and 91% for MRD-negative patients, and 57% and 72% for patients with high-risk cytogenetics. For high-risk patients who were MRD negative, 5-year rates were 77% and 81%. Grade 3 to 4 adverse events included neutropenia (34%), lymphopenia (32%), infection (22%), and cardiac events (3%). There was no grade 3 to 4 peripheral neuropathy. Patients with NDMM treated with KRd with ASCT achieved high rates of sCR and MRD-negative disease at the end of KRd consolidation. Extended KRd maintenance after consolidation contributed to deepening of responses and likely to prolonged PFS and OS. Safety and tolerability were manageable. This trial was registered at www.clinicaltrials.gov as #NCT01816971.

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Safety and efficacy of single-agent lenalidomide in patients with relapsed and refractory multiple myeloma

Blood ◽

10.1182/blood-2008-12-196238 ◽

2009 ◽

Vol 114 (4) ◽

pp. 772-778 ◽

Cited By ~ 110

Author(s):

Paul Richardson ◽

Sundar Jagannath ◽

Mohamad Hussein ◽

James Berenson ◽

Seema Singhal ◽

...

Keyword(s):

Multiple Myeloma ◽

Single Agent ◽

Progression Free Survival ◽

Prior Treatment ◽

Once Daily ◽

Free Survival ◽

Refractory Multiple Myeloma ◽

Treatment Regimens ◽

Common Grade ◽

Grade 3

Abstract Lenalidomide plus dexamethasone is effective for the treatment of relapsed and refractory multiple myeloma (MM); however, toxicities from dexamethasone can be dose limiting. We evaluated the efficacy and safety of lenalidomide monotherapy in patients with relapsed and refractory MM. Patients (N = 222) received lenalidomide 30 mg/day once daily (days 1-21 every 28 days) until disease progression or intolerance. Response, progression-free survival (PFS), overall survival (OS), time to progression (TTP), and safety were assessed. Overall, 67% of patients had received 3 or more prior treatment regimens. Partial response or better was reported in 26% of patients, with minimal response 18%. There was no difference between patients who had received 2 or fewer versus 3 or more prior treatment regimens (45% vs 44%, respectively). Median values for TTP, PFS, and OS were 5.2, 4.9, and 23.2 months, respectively. The most common grade 3 or 4 adverse events were neutropenia (60%), thrombocytopenia (39%), and anemia (20%), which proved manageable with dose reduction. Grade 3 or 4 febrile neutropenia occurred in 4% of patients. Lenalidomide monotherapy is active in relapsed and refractory MM with acceptable toxicities. These data support treatment with single-agent lenalidomide, as well as its use in steroid-sparing combination approaches. The study is registered at http://www.clinicaltrials.gov as NCT00065351.

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Bortezomib administration is a risk factor associated with the development of tumor lysis syndrome in male patients with multiple myeloma: A retrospective study

10.21203/rs.3.rs-22557/v4 ◽

2020 ◽

Author(s):

Masahiro Kondo ◽

Yuji Hotta ◽

Karen Yamauchi ◽

Akimasa Sanagawa ◽

Hirokazu Komatsu ◽

...

Keyword(s):

Risk Factors ◽

Multiple Myeloma ◽

Odds Ratio ◽

Tumor Lysis Syndrome ◽

Low Risk ◽

Novel Therapies ◽

Tumor Lysis ◽

Factors Associated ◽

Increased Risk ◽

Male Patients

Abstract Background: Novel agents such as proteasome inhibitors have been developed for several years to treat multiple myeloma. Although multiple myeloma is a low-risk disease for developing tumor lysis syndrome (TLS), treatment with these novel therapies might increase TLS risk. Previous studies, mostly case reports or case series, have reported bortezomib-induced TLS in patients with multiple myeloma. This study aimed to investigate risk factors associated with TLS development in multiple myeloma patients.Methods: We retrospectively investigated incidences of laboratory and clinical TLS (LTLS and CTLS, respectively) in patients who received primary therapy for treatment-naive, symptomatic multiple myeloma between May 2007 and January 2018. We used multivariate logistic regression analyses to evaluate the associations between TLS and several parameters previously reported to be associated with increased risk.Results: This study included 210 patients with multiple myeloma, of which ten (4.8%) had LTLS and seven (3.3%) had CTLS. The characteristics of the administered anticancer or prophylactic antihyperuricemic agents were similar between patients with and without TLS. Multivariate analyses revealed that TLS was most strongly associated with bortezomib-containing therapy (odds ratio = 3.40, P = 0.069), followed by male sex (odds ratio = 2.29, P = 0.153). In a subgroup analysis focused on men, treatment with bortezomib-containing therapy was significantly associated with increased risk of TLS (odds ratio = 8.51, P = 0.046).Conclusion: In the present study, we investigated the risk factors associated with TLS development in 210 multiple myeloma patients, which, to the best of our knowledge, is the largest number of patients reported to date. Furthermore, this study is the first to evaluate TLS risk factors in MM by adjusting for the effects of potential confounding factors in patients’ backgrounds. Consequently, we found that bortezomib-containing therapy increases the risk of TLS in male patients with multiple myeloma. TLS risk should be evaluated further in low-risk diseases such as multiple myeloma, since a significant number of novel therapies can achieve high antitumor responses.

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Cardiovascular complications of novel multiple myeloma treatments

ESC CardioMed ◽

10.1093/med/9780198784906.003.0293 ◽

2018 ◽

pp. 1176-1178

Author(s):

Daniel J. Lenihan

Keyword(s):

Heart Failure ◽

Multiple Myeloma ◽

Heart Disease ◽

Early Detection ◽

Antithrombotic Therapy ◽

Cardiovascular Events ◽

Cardiovascular Complications ◽

Novel Therapies ◽

Cardiac Events ◽

Increased Risk

The treatment of multiple myeloma has dramatically changed in the last decade. Novel therapies have had an important impact on the overall outcome for patients but are associated with important cardiovascular events. There is certainly concern about the development of heart failure but also treatment-induced hypertension and a known increased risk of thrombotic events, including ischaemic heart disease. The management of these cardiac events includes prevention, early detection, and optimal treatment with antithrombotic therapy as well as medical therapy for heart failure.

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Redefining Cardiac Biomarkers in Predicting Mortality of Inpatients With COVID-19

Hypertension ◽

10.1161/hypertensionaha.120.15528 ◽

2020 ◽

Vol 76 (4) ◽

pp. 1104-1112 ◽

Cited By ~ 7

Author(s):

Juan-Juan Qin ◽

Xu Cheng ◽

Feng Zhou ◽

Fang Lei ◽

Gauri Akolkar ◽

...

Keyword(s):

Natriuretic Peptide ◽

Troponin I ◽

Cox Model ◽

Cardiac Injury ◽

High Sensitivity ◽

Cardiac Biomarkers ◽

Cardiac Biomarker ◽

Increased Risk ◽

Poor Outcomes ◽

Prognostic Power

The prognostic power of circulating cardiac biomarkers, their utility, and pattern of release in coronavirus disease 2019 (COVID-19) patients have not been clearly defined. In this multicentered retrospective study, we enrolled 3219 patients with diagnosed COVID-19 admitted to 9 hospitals from December 31, 2019 to March 4, 2020, to estimate the associations and prognostic power of circulating cardiac injury markers with the poor outcomes of COVID-19. In the mixed-effects Cox model, after adjusting for age, sex, and comorbidities, the adjusted hazard ratio of 28-day mortality for hs-cTnI (high-sensitivity cardiac troponin I) was 7.12 ([95% CI, 4.60–11.03] P <0.001), (NT-pro)BNP (N-terminal pro-B-type natriuretic peptide or brain natriuretic peptide) was 5.11 ([95% CI, 3.50–7.47] P <0.001), CK (creatine phosphokinase)-MB was 4.86 ([95% CI, 3.33–7.09] P <0.001), MYO (myoglobin) was 4.50 ([95% CI, 3.18–6.36] P <0.001), and CK was 3.56 ([95% CI, 2.53–5.02] P <0.001). The cutoffs of those cardiac biomarkers for effective prognosis of 28-day mortality of COVID-19 were found to be much lower than for regular heart disease at about 19%–50% of the currently recommended thresholds. Patients with elevated cardiac injury markers above the newly established cutoffs were associated with significantly increased risk of COVID-19 death. In conclusion, cardiac biomarker elevations are significantly associated with 28-day death in patients with COVID-19. The prognostic cutoff values of these biomarkers might be much lower than the current reference standards. These findings can assist in better management of COVID-19 patients to improve outcomes. Importantly, the newly established cutoff levels of COVID-19–associated cardiac biomarkers may serve as useful criteria for the future prospective studies and clinical trials.

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Melflufen and Dexamethasone in Heavily Pretreated Relapsed and Refractory Multiple Myeloma

Journal of Clinical Oncology ◽

10.1200/jco.20.02259 ◽

2020 ◽

pp. JCO.20.02259

Author(s):

Paul G. Richardson ◽

Albert Oriol ◽

Alessandra Larocca ◽

Joan Bladé ◽

Michele Cavo ◽

...

Keyword(s):

Multiple Myeloma ◽

Overall Survival ◽

Overall Response Rate ◽

Response Rate ◽

Progression Free Survival ◽

Free Survival ◽

Duration Of Response ◽

Heavily Pretreated ◽

Grade 3

PURPOSE Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and rapidly and selectively releases alkylating agents into tumor cells. The phase II HORIZON trial evaluated the efficacy of melflufen plus dexamethasone in relapsed and refractory multiple myeloma (RRMM), a population with an important unmet medical need. PATIENTS AND METHODS Patients with RRMM refractory to pomalidomide and/or an anti-CD38 monoclonal antibody received melflufen 40 mg intravenously on day 1 of each 28-day cycle plus once weekly oral dexamethasone at a dose of 40 mg (20 mg in patients older than 75 years). The primary end point was overall response rate (partial response or better) assessed by the investigator and confirmed by independent review. Secondary end points included duration of response, progression-free survival, overall survival, and safety. The primary analysis is complete with long-term follow-up ongoing. RESULTS Of 157 patients (median age 65 years; median five prior lines of therapy) enrolled and treated, 119 patients (76%) had triple-class–refractory disease, 55 (35%) had extramedullary disease, and 92 (59%) were refractory to previous alkylator therapy. The overall response rate was 29% in the all-treated population, with 26% in the triple-class–refractory population. In the all-treated population, median duration of response was 5.5 months, median progression-free survival was 4.2 months, and median overall survival was 11.6 months at a median follow-up of 14 months. Grade ≥ 3 treatment-emergent adverse events occurred in 96% of patients, most commonly neutropenia (79%), thrombocytopenia (76%), and anemia (43%). Pneumonia (10%) was the most common grade 3/4 nonhematologic event. Thrombocytopenia and bleeding (both grade 3/4 but fully reversible) occurred concomitantly in four patients. GI events, reported in 97 patients (62%), were predominantly grade 1/2 (93%); none were grade 4. CONCLUSION Melflufen plus dexamethasone showed clinically meaningful efficacy and a manageable safety profile in patients with heavily pretreated RRMM, including those with triple-class–refractory and extramedullary disease.

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Efficacy of Melphalan and Prednisone Plus Thalidomide in Patients Older Than 75 Years With Newly Diagnosed Multiple Myeloma: IFM 01/01 Trial

Journal of Clinical Oncology ◽

10.1200/jco.2008.21.0948 ◽

2009 ◽

Vol 27 (22) ◽

pp. 3664-3670 ◽

Cited By ~ 284

Author(s):

Cyrille Hulin ◽

Thierry Facon ◽

Philippe Rodon ◽

Brigitte Pegourie ◽

Lotfi Benboubker ◽

...

Keyword(s):

Multiple Myeloma ◽

Overall Survival ◽

Elderly Patients ◽

Progression Free Survival ◽

Phase Iii ◽

Standards Of Care ◽

Newly Diagnosed ◽

Grade 3 ◽

To Receive

Purpose Until recently, melphalan and prednisone were the standards of care in elderly patients with multiple myeloma. The addition of thalidomide to this combination demonstrated a survival benefit for patients age 65 to 75 years. This randomized, placebo-controlled, phase III trial investigated the efficacy of melphalan and prednisone plus thalidomide in patients older than 75 years with newly diagnosed myeloma. Patients and Methods Between April 2002 and December 2006, 232 previously untreated patients with myeloma, age 75 years or older, were enrolled and 229 were randomly assigned to treatment. All patients received melphalan (0.2 mg/kg/d) plus prednisone (2 mg/kg/d) for 12 courses (day 1 to 4) every 6 weeks. Patients were randomly assigned to receive 100 mg/d of oral thalidomide (n = 113) or placebo (n = 116), continuously for 72 weeks. The primary end point was overall survival. Results After a median follow-up of 47.5 months, overall survival was significantly longer in patients who received melphalan and prednisone plus thalidomide compared with those who received melphalan and prednisone plus placebo (median, 44.0 v 29.1 months; P = .028). Progression-free survival was significantly prolonged in the melphalan and prednisone plus thalidomide group (median, 24.1 v 18.5 months; P = .001). Two adverse events were significantly increased in the melphalan and prednisone plus thalidomide group: grade 2 to 4 peripheral neuropathy (20% v 5% in the melphalan and prednisone plus placebo group; P < .001) and grade 3 to 4 neutropenia (23% v 9%; P = .003). Conclusion This trial confirms the superiority of the combination melphalan and prednisone plus thalidomide over melphalan and prednisone alone for prolonging survival in very elderly patients with newly diagnosed myeloma. Toxicity was acceptable.

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Subcutaneous Administration of Bortezomib in Combination with Thalidomide and Dexamethasone for Treatment of Newly Diagnosed Multiple Myeloma Patients

BioMed Research International ◽

10.1155/2015/927105 ◽

2015 ◽

Vol 2015 ◽

pp. 1-6 ◽

Cited By ~ 8

Author(s):

Shenghao Wu ◽

Cuiping Zheng ◽

Songyan Chen ◽

Xiaoping Cai ◽

Yuejian Shi ◽

...

Keyword(s):

Multiple Myeloma ◽

Overall Survival ◽

Adverse Events ◽

Subcutaneous Administration ◽

Progression Free Survival ◽

The Other ◽

Newly Diagnosed ◽

Efficacy And Safety ◽

Free Survival ◽

Grade 3

Objective. To investigate the efficacy and safety of the treatment of the newly diagnosed multiple myeloma (MM) patients with the therapy of subcutaneous (subQ) administration of bortezomib and dexamethasone plus thalidomide (VTD) regimen.Methods. A total of 60 newly diagnosed MM patients were analyzed. 30 patients received improved VTD regimen (improved VTD group) with the subQ injection of bortezomib and the other 30 patients received conventional VTD regimen (VTD group).The efficacy and safety of two groups were analyzed retrospectively.Results. The overall remission (OR) after eight cycles of treatment was 73.3% in the VTD group and 76.7% in the improved VTD group (P>0.05). No significant differences in time to 1-year estimate of overall survival (72% versus 75%,P=0.848) and progression-free survival (median 22 months versus 25 months;P=0.725) between two groups. The main toxicities related to therapy were leukopenia, neutropenia, thrombocytopenia, asthenia, fatigue, and renal and urinary disorders. Grade 3 and higher adverse events were significantly less common in the improved VTD group (50%) than VTD group (80%,P=0.015).Conclusions. The improved VTD regimen by changing bortezomib from intravenous administration to subcutaneous injection has noninferior efficacy to standard VTD regimen, with an improved safety profile and reduced adverse events.

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Pharmacogenetic Assessment of Toxicity and Outcome in Patients With Metastatic Colorectal Cancer Treated With LV5FU2, FOLFOX, and FOLFIRI: FFCD 2000-05

Journal of Clinical Oncology ◽

10.1200/jco.2009.25.2106 ◽

2010 ◽

Vol 28 (15) ◽

pp. 2556-2564 ◽

Cited By ~ 108

Author(s):

Valérie Boige ◽

Jean Mendiboure ◽

Jean-Pierre Pignon ◽

Marie-Anne Loriot ◽

Marine Castaing ◽

...

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Tumor Response ◽

Progression Free Survival ◽

Hematologic Toxicity ◽

First Line ◽

Free Survival ◽

Increased Risk ◽

Grade 3 ◽

Cancérologie Digestive

Purpose The aim was to investigate whether germline polymorphisms within candidate genes known or suspected to be involved in fluorouracil (FU), oxaliplatin, and irinotecan pathways were associated with toxicity and clinical outcome in patients with metastatic colorectal cancer (mCRC). Patients and Methods Blood samples from 349 patients included in the Fédération Francophone de Cancérologie Digestive 2000-05 randomized trial, which compared FU plus leucovorin (LV5FU2) followed by FU, leucovorin, and oxaliplatin (FOLFOX) followed by FU, leucovorin, and irinotecan (FOLFIRI; sequential arm) with FOLFOX followed by FOLFIRI (combination arm) in terms of progression-free survival (PFS) and overall survival, were collected. Twenty polymorphisms within the DPD, TS, MTHFR, ERCC1, ERCC2, GSTP1, GSTM1, GSTT1, and UGT1A1 genes were genotyped. Results The ERCC2-K751QC allele was independently associated with an increased risk of FOLFOX-induced grade 3 or 4 hematologic toxicity (P = .01). In the sequential arm, TS-5′UTR3RG and GSTT1 alleles were independently associated with response to LV5FU2 (P = .009) and FOLFOX (P = .01), respectively. The effect of oxaliplatin on tumor response increased with the number of MTHFR-1298C alleles (test for trend, P = .008). The PFS benefit from first-line FOLFOX was restricted to patients with 2R/2R (hazard ratio [HR] = 0.39; 95% CI, 0.23 to 0.68) or 2R/3R (HR = 0.59; 95% CI, 0.42 to 0.82) TS-5′UTR genotypes, respectively. Conversely, patients with the TS-5′UTR 3R/3R genotype did not seem to benefit from the adjunction of oxaliplatin (HR = 0.96; 95% CI, 0.66 to 1.40; trend between the three HRs, P = .006). Conclusion A pharmacogenetic approach may be a useful strategy for personalizing and optimizing chemotherapy in mCRC patients and deserves confirmation in additional prospective studies.

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