Phase II MMRC trial of extended treatment with carfilzomib (CFZ), lenalidomide (LEN), and dexamethasone (DEX) plus autologous stem cell transplantation (ASCT) in newly diagnosed multiple myeloma (NDMM).

Zimmerman, Todd; Griffith, Kent A.; Jasielec, Jagoda; Rosenbaum, Cara A.; McDonnell, Kathryn; Waite-Marin, Jessica; Berdeja, Jesús G.; Raje, Noopur; Reece, Donna; Vij, Ravi; Alonge, Mattina M.; Rosebeck, Shaun; Gurbuxani, Sandeep; Faham, Malek; Kong, Katherine A.; Levy, Joan; Jakubowiak, Andrzej

doi:10.1200/jco.2015.33.15_suppl.8510

Cited by 11 publications

(6 citation statements)

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“…A phase II study of extended treatment with carfilzomib, lenalidomide, and dexamethasone (KRd) plus AHSCT in newly diagnosed MM patients showed that this regimen resulted in higher stringent CR rates than KRd without AHSCT. There was also a higher rate of minimal residual disease negativity in the transplantation group [ 20 ]. The improvement in response rate after induction was observed in our analysis where the CR plus VGPR after BUMELVEL followed by AHSCT increased from 42% pre-transplantation to 70% post-AHSCT.…”

Section: Discussionmentioning

confidence: 99%

Busulfan, Melphalan, and Bortezomib versus High-Dose Melphalan as a Conditioning Regimen for Autologous Hematopoietic Stem Cell Transplantation in Multiple Myeloma

Rodriguez

Hari

Stiff

et al. 2016

Biology of Blood and Marrow Transplantation

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High-dose melphalan 200 mg/m2 (MEL 200) is the standard of care as a conditioning regimen for autologous hematopoietic stem cell transplantation (AHSCT) for multiple myeloma (MM). We compared a novel conditioning combination incorporating busulfan, melphalan, and bortezomib (BUMELVEL) versus standard MEL 200 in newly diagnosed patients undergoing AHSCT for MM. Between July 2009 and May 2012, 43 eligible patients received BUMELVEL conditioning followed by AHSCT. BU was administered i.v. daily for 4 days to achieve a target area under the concentration-time curve total of 20,000 mM·min based on pharmacokinetic analysis after the first dose. MEL 140 mg/m2 (MEL 140) and VEL 1.6 mg/m2 were administered i.v. on days −2 and −1, respectively. Outcomes were compared with a contemporaneous North American cohort (n = 162) receiving MEL 200 matched for age, sex, performance status, stage, interval from diagnosis to AHSCT, and disease status before AHSCT. Multivariate analysis of relapse, progression-free survival (PFS), and overall survival (OS) was performed. The median follow-up was 25 months. No transplant-related mortality was observed in the study cohort at 1 year. PFS at 1 year was superior in the BUMELVEL cohort (90%) in comparison with 77% in MEL 200 historical control subjects (P = .02). Cumulative incidence of relapse was lower in the BUMELVEL group versus the MEL 200 group (10% at 1 year versus 21%; P = .047). OS at 1 year was similar between cohorts (93% versus 93%; P =.89). BU can be safely combined with MEL 140 and VEL without an increase in toxicities or transplant-related mortality. We observed a superior PFS in the BUMELVEL cohort without maintenance therapy, warranting further trials.

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Section: Discussionmentioning

confidence: 99%

Busulfan, Melphalan, and Bortezomib versus High-Dose Melphalan as a Conditioning Regimen for Autologous Hematopoietic Stem Cell Transplantation in Multiple Myeloma

Rodriguez

Hari

Stiff

et al. 2016

Biology of Blood and Marrow Transplantation

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“…Upfront combination therapies with novel combination regimens without autologous HCT demonstrated near CR/CR rates approximating 31 % after eight cycles of carfilzomib/lenalidomide/dexamethasone [ 17 ]. Integrating autologous HCT into carfilzomib/lenalidomide/dexamethasone treatment resulted in near CR/CR rates of 91 % [ 56 ]. Although limited in a number of patients and follow-up, Zimmerman et al demonstrated that 15/17 evaluable patients (88 %) achieved MRD-negative status [ 56 ].…”

Section: Discussionmentioning

confidence: 99%

“…Integrating autologous HCT into carfilzomib/lenalidomide/dexamethasone treatment resulted in near CR/CR rates of 91 % [ 56 ]. Although limited in a number of patients and follow-up, Zimmerman et al demonstrated that 15/17 evaluable patients (88 %) achieved MRD-negative status [ 56 ]. Collectively, these results highlight the improving depth of response attainable with future management strategies.…”

Section: Discussionmentioning

confidence: 99%

“…These data suggest that CR at minimum should be the goal of therapy for all myeloma patients. Recent studies evaluating the contemporary combination therapy using carfilzomib/lenalidomide/dexamethasone induction, followed by high-dose therapy and autologous HCT, and subsequently carfilzomib/lenalidomide/dexamethasone consolidation have the potential to further improve the treatment outcomes in the frontline setting [ 17 , 56 ]. Although the long-term outcomes of the newer regimens remain to be seen, these data illustrate the enormous potential for providing consistently much deeper responses in newly diagnosed multiple myeloma patients; thus, our current serological (and nephelometric) methods of measuring myeloma responses will soon be outdated and defining new response criteria deeper than the conventional CR will be urgently needed.…”

Section: Mrd Testing As a New Standard Of Carementioning

confidence: 99%

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Minimal Residual Disease Assessment in the Context of Multiple Myeloma Treatment

Nishihori

Song

Shain

2016

Curr Hematol Malig Rep

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With contemporary therapeutic strategies in multiple myeloma, heretofore unseen depth and rate of responses are being achieved. These strategies have paralleled improvements in outcome of multiple myeloma patients. The integration of the next generation of proteasome inhibitors and antibody therapeutics promise continued improvements in therapy with the expectation of consistent depth of response not quantifiable by current clinical methods. As such, there is a growing need to develop adequate tools to evaluate deeper disease response after therapy and to refine the response criteria including the minimal residual disease. Several emerging techniques are being evaluated for these purposes including multi-parameter flow cytometry, allele-specific oligonucleotide polymerase chain reaction, next-generation sequencing, and imaging modalities. In this review, we highlight the recent developments and evaluate advantages and limitations of the current technologies to assess minimal residual disease. We also discuss future applications of these methodologies in potentially guiding multiple myeloma treatment decisions.

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“…Traditional and modern therapies exhibit different characteristics with respect to availability, efficacy and safety, and response monitoring (Table ). Compared with traditional therapies, modern treatment is more effective and less toxic, and up to 80% of patients with newly diagnosed multiple myeloma achieve a CR . Moreover, an association between the depth of response and outcomes has been observed for combination regimens incorporating modern agents across the myeloma disease continuum (Fig.…”

Section: Deeper Treatment Response and Longer Survivalmentioning

confidence: 99%

Modern multiple myeloma therapy: deep, sustained treatment response and good clinical outcomes

2017

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Abstract. Landgren O, Iskander K (Memorial SloanKettering Cancer Center, New York, NY, USA; Amgen, Thousand Oaks, CA, USA). Modern multiple myeloma therapy: deep, sustained treatment response and good clinical outcomes. J Intern Med 2017; 281: 365-382.In the USA at the beginning of this century, the average overall survival in patients with multiple myeloma was about 3 years. Around that time, three drugs (bortezomib, lenalidomide and thalidomide) were introduced for the treatment of multiple myeloma and, in 2012, carfilzomib received accelerated approval by the US Food and Drug Administration (FDA). Driven by access to better drugs, median overall survival in younger patients (aged <50 years) was >10 years by 2014. The FDA approved 14 new drugs for the treatment of cancer in 2015; four of these were approved for the treatment of myeloma (panobinostat, daratumumab, elotuzumab and ixazomib). In 2015 and 2016, expanded label indications were approved by the FDA for lenalidomide and carfilzomib, respectively. The recent increase in approved, highly effective combination therapies for patients with multiple myeloma has led the way to redefining the goals of therapy. Here, we review and provide a clinical perspective on the treatment goals and management of multiple myeloma in the era of modern therapy. Recent meta-analyses show that minimal residual disease (MRD) negativity is associated with longer progression-free and overall survival in patients with multiple myeloma. With the use of modern combination therapy, large proportions (>60-70%) of newly diagnosed multiple myeloma patients achieve complete responses and MRD negativity. Modern combination therapies induce rapid, deep and sustainable responses (including MRD negativity), supporting a treatment paradigm shift away from palliative two-drug combinations towards the use of modern, potent, three-or four-drug combination regimens in early lines of therapy. Data support the use of modern therapy upfront rather than reserving it for later stages of the disease. As survival time increases with modern combination therapies, development of early reliable surrogate end-points for survival, such as MRD negativity, are needed for expedited read-out of future randomized clinical trials.

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Phase II MMRC trial of extended treatment with carfilzomib (CFZ), lenalidomide (LEN), and dexamethasone (DEX) plus autologous stem cell transplantation (ASCT) in newly diagnosed multiple myeloma (NDMM).

Cited by 11 publications

References 0 publications

Busulfan, Melphalan, and Bortezomib versus High-Dose Melphalan as a Conditioning Regimen for Autologous Hematopoietic Stem Cell Transplantation in Multiple Myeloma

Busulfan, Melphalan, and Bortezomib versus High-Dose Melphalan as a Conditioning Regimen for Autologous Hematopoietic Stem Cell Transplantation in Multiple Myeloma

Minimal Residual Disease Assessment in the Context of Multiple Myeloma Treatment

Modern multiple myeloma therapy: deep, sustained treatment response and good clinical outcomes

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