Cell death escape is one of the most prominent features of tumor cells and closely linked to the dysregulation of members of the Bcl-2 family of proteins. Among those, the anti-apoptotic family ...member myeloid cell leukemia-1 (MCL-1) acts as a master regulator of apoptosis in various human malignancies. Irrespective of its unfavorable structure profile, independent research efforts recently led to the generation of highly potent MCL-1 inhibitors that are currently evaluated in clinical trials. This offers new perspectives to target a so far undruggable cancer cell dependency. However, a detailed understanding about the tumor and tissue type specific implications of MCL-1 are a prerequisite for the optimal (i.e., precision medicine guided) use of this novel drug class. In this review, we summarize the major functions of MCL-1 with a special focus on cancer, provide insights into its different roles in solid vs. hematological tumors and give an update about the (pre)clinical development program of state-of-the-art MCL-1 targeting compounds. We aim to raise the awareness about the heterogeneous role of MCL-1 as drug target between, but also within tumor entities and to highlight the importance of rationale treatment decisions on a case by case basis.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
We conducted a pooled analysis of 869 individual newly diagnosed elderly patient data from 3 prospective trials. At diagnosis, a geriatric assessment had been performed. An additive scoring system ...(range 0-5), based on age, comorbidities, and cognitive and physical conditions, was developed to identify 3 groups: fit (score = 0, 39%), intermediate fitness (score = 1, 31%), and frail (score ≥2, 30%). The 3-year overall survival was 84% in fit, 76% in intermediate-fitness (hazard ratio HR, 1.61; P = .042), and 57% in frail (HR, 3.57; P < .001) patients. The cumulative incidence of grade ≥3 nonhematologic adverse events at 12 months was 22.2% in fit, 26.4% in intermediate-fitness (HR, 1.23; P = .217), and 34.0% in frail (HR, 1.74; P < .001) patients. The cumulative incidence of treatment discontinuation at 12 months was 16.5% in fit, 20.8% in intermediate-fitness (HR, 1.41; P = .052), and 31.2% in frail (HR, 2.21; P < .001) patients. Our frailty score predicts mortality and the risk of toxicity in elderly myeloma patients. The International Myeloma Working group proposes this score for the measurement of frailty in designing future clinical trials. These trials are registered at www.clinicaltrials.gov as #NCT01093196 (EMN01), #NCT01190787 (26866138MMY2069), and #NCT01346787 (IST-CAR-506).
•Elderly patients with myeloma are heterogeneous and assessment strategies are needed to define the frailty profile.•The proposed frailty score aims to better assess patients and provide them with more suitable therapies.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The term monoclonal gammopathy of renal significance (MGRS) was introduced by the International Kidney and Monoclonal Gammopathy Research Group (IKMG) in 2012. The IKMG met in April 2017 to refine ...the definition of MGRS and to update the diagnostic criteria for MGRS-related diseases. Accordingly, in this Expert Consensus Document, the IKMG redefines MGRS as a clonal proliferative disorder that produces a nephrotoxic monoclonal immunoglobulin and does not meet previously defined haematological criteria for treatment of a specific malignancy. The diagnosis of MGRS-related disease is established by kidney biopsy and immunofluorescence studies to identify the monotypic immunoglobulin deposits (although these deposits are minimal in patients with either C3 glomerulopathy or thrombotic microangiopathy). Accordingly, the IKMG recommends a kidney biopsy in patients suspected of having MGRS to maximize the chance of correct diagnosis. Serum and urine protein electrophoresis and immunofixation, as well as analyses of serum free light chains, should also be performed to identify the monoclonal immunoglobulin, which helps to establish the diagnosis of MGRS and might also be useful for assessing responses to treatment. Finally, bone marrow aspiration and biopsy should be conducted to identify the lymphoproliferative clone. Flow cytometry can be helpful in identifying small clones. Additional genetic tests and fluorescent in situ hybridization studies are helpful for clonal identification and for generating treatment recommendations. Treatment of MGRS was not addressed at the 2017 IKMG meeting; consequently, this Expert Consensus Document does not include any recommendations for the treatment of patients with MGRS.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
This randomized study assessed whether the best overall response rate (ORR) of cetuximab combined with oxaliplatin, leucovorin, and fluorouracil (FOLFOX-4) was superior to that of FOLFOX-4 alone as ...first-line treatment for metastatic colorectal cancer. The influence of KRAS mutation status was investigated.
Patients received cetuximab (400 mg/m(2) initial dose followed by 250 mg/m(2)/wk thereafter) plus FOLFOX-4 (oxaliplatin 85 mg/m(2) on day 1, plus leucovorin 200 mg/m(2) and fluorouracil as a 400 mg/m(2) bolus followed by a 600 mg/m(2) infusion during 22 hours on days 1 and 2; n = 169) or FOLFOX-4 alone (n = 168). Treatment was continued until disease progression or unacceptable toxicity. KRAS mutation status was assessed in the subset of patients with assessable tumor samples (n = 233).
The confirmed ORR for cetuximab plus FOLFOX-4 was higher than with FOLFOX-4 alone (46% v 36%). A statistically significant increase in the odds for a response with the addition of cetuximab to FOLFOX-4 could not be established (odds ratio = 1.52; P = .064). In patients with KRAS wild-type tumors, the addition of cetuximab to FOLFOX-4 was associated with a clinically significant increased chance of response (ORR = 61% v 37%; odds ratio = 2.54; P = .011) and a lower risk of disease progression (hazard ratio = 0.57; P = .0163) compared with FOLFOX-4 alone. Cetuximab plus FOLFOX-4 was generally well tolerated.
KRAS mutational status was shown to be a highly predictive selection criterion in relation to the treatment decision regarding the addition of cetuximab to FOLFOX-4 for previously untreated patients with metastatic colorectal cancer.
Summary Introduction of the proteasome inhibitor bortezomib and the immunomodulatory drugs thalidomide and lenalidomide has substantially improved outcomes for patients with multiple myeloma. As a ...result, these drugs have become cornerstones of current antimyeloma treatment regimens. However, after several years of clinical experience it has become apparent that peripheral neuropathy is the most common and potentially disabling non-haematological side-effect associated with thalidomide and bortezomib. Maximising treatment benefit while preserving quality of life therefore requires a careful balance between achieving optimum activity and minimising toxicity, including neuropathy, to further enhance efficacy. In this review, we discuss all aspects of drug-induced peripheral neuropathy in myeloma, with a particular focus on thalidomide and bortezomib.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
It is essential that there be consistency in the conduct, analysis, and reporting of clinical trial results in myeloma. The goal of the International Myeloma Workshop Consensus Panel 1 was to develop ...a set of guidelines for the uniform reporting of clinical trial results in myeloma. This paper provides a summary of the current response criteria in myeloma, detailed definitions for patient populations, lines of therapy, and specific endpoints. We propose that future clinical trials in myeloma follow the guidelines for reporting results proposed in this manuscript.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Multiple myeloma is a disease typical of the elderly, and, because of the increase in life expectancy of the general population, its incidence is expected to grow in the future. Elderly patients ...represent a particular challenge due to their marked heterogeneity. Many new and highly effective drugs have been introduced in the last few years and results from clinical trials are promising. Besides the availability of novel agents, a careful evaluation of elderly patients showed to be a key factor for the success of therapy. A geriatric assessment is a valid strategy to better stratify patients. In particular, different scores are available today to appropriately assess elderly patients and define their fitness/frailty status. The choice of treatment-transplantation, triplets, doublets, or reduced-dose therapies including novel agents-should depend on the patient's fitness status (fit, intermediate-fit or frail). Second-generation novel agents have also been evaluated as salvage therapy in the elderly, and these new agents certainly represent a further step forward in the treatment armamentarium for elderly patients with multiple myeloma.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Survival of myeloma patients has greatly improved with the use of autologous stem cell transplantation and novel agents, such as proteasome inhibitors, immunomodulatory drugs and monoclonal ...antibodies. Compared to bortezomib- and lenalidomide-based regimens alone, the addition of high-dose melphalan followed by autologous transplantation significantly improves progression-free survival, although an overall survival benefit was not observed in all trials. Moreover, follow up of recent trials is still too short to show any difference in survival. In the light of these findings, novel agent-based induction followed by autologous transplantation is considered the standard upfront treatment for eligible patients (level of evidence: 1A). Post-transplant consolidation and maintenance treatment can further improve patient outcome (1A). The availability of several novel agents has led to the development of multiple combination regimens such as salvage treatment options. In this context, the role of salvage autologous transplantation and allotransplant has not been extensively evaluated. In the case of prolonged remission after upfront autologous transplantation, another autologous transplantation at relapse can be considered (2B). Patients who experience early relapse and/or have high-risk features have a poor prognosis and may be considered as candidates for clinical trials that, in young and fit patients, may also include an allograft in combination with novel agents (2B). Ongoing studies are evaluating the role of novel cellular therapies, such as inclusion of antibody-based triplets and quadruplets, and chimeric antigen receptor-T cells. Despite encouraging preliminary results, longer follow up and larger patient numbers are needed before the clinical use of these novel therapies can be widely recommended.
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