Multidisciplinary tumor board analysis: validation study of a central tool in tumor centers.

The established standard to ensure state-of-the-art cancer treatment is through multidisciplinary tumor boards (TBs), although resource- and time-intensive. In this validation study, the multiple myeloma (MM)-TB was reexamined, aiming to validate our previous (2012-2014) results, now using the TB data from March 2020 to February 2021. We assessed MM-TB protocols, physicians' documentation, patient, disease, remission status, progression-free survival (PFS), and overall survival (OS) as left-truncated survival times. Moreover, TB-adherence, level of evidence according to grade criteria, time requirements, study inclusion rates, and referral satisfaction were determined. Within a 1-year period, 312 discussed patients were documented in 439 TB protocols. Patient and disease characteristics were typical for comprehensive cancer centers. The percentages of patients discussed at initial diagnosis (ID), with disease recurrence or in need of interdisciplinary advice, were 39%, 28%, and 33%, respectively. Reasons for the MM-TB presentation were therapeutic challenges in 80% or staging/ID-defining questions in 20%. The numbers of presentations were mostly one in 73%, two in 20%, and three or more in 7%. The TB adherence rate was 93%. Reasons for non-adherence were related to patients' decisions or challenging inclusion criteria for clinical trials. Additionally, we demonstrate that with the initiation of TBs, that the number of interdisciplinarily discussed patients increased, that TB-questions involve advice on the best treatment, and that levels of compliance and evidence can be as high as ≥ 90%. Advantages of TBs are that they may also improve patients', referrers', and physicians' satisfaction, inclusion into clinical trials, and advance interdisciplinary projects, thereby encouraging cancer specialists to engage in them.

Choosing the Right Therapy for Patients with Relapsed/Refractory Multiple Myeloma (RRMM) in Consideration of Patient-, Disease- and Treatment-Related Factors.

Treatment of relapsed/refractory multiple myeloma (RRMM) is more complex today due to the availability of novel therapeutic options, mostly applied as combination regimens. immunotherapy options have especially increased substantially, likewise the understanding that patient-, disease- and treatment-related factors should be considered at all stages of the disease. RRMM is based on definitions of the international myeloma working group (IMWG) and includes biochemical progression, such as paraprotein increase, or symptomatic relapse with CRAB criteria (hypercalcemia, renal impairment, anemia, bone lesions). When choosing RRMM-treatment, the biochemical markers for progression and severity of the disease, dynamic of disease relapse, type and number of prior therapy lines, including toxicity and underlying health status, need to be considered, and shared decision making should be pursued. Objectively characterizing health status via geriatric assessment (GA) at each multiple myeloma (MM) treatment decision point has been shown to be a better estimate than via age and comorbidities alone. The well-established national comprehensive cancer network, IMWG, European myeloma network and other national treatment algorithms consider these issues. Ideally, GA-based clinical trials should be supported in the future to choose wisely and efficaciously from available intervention and treatment options in often-older MM adults in order to further improve morbidity and mortality.

Multidisciplinary tumor boards and their analyses: the yin and yang of outcome measures.

BACKGROUND: The standard to ensure utmost cancer treatment is a prerequisite in national cancer plans for comprehensive cancer centers (CCCs) and ensured through multidisciplinary tumor boards (MTBs). Despite these being compulsory for CCCs, various analyses on MTBs have been performed, since MTBs are resource-intensive. Outcome measures in these prior analyses had been survival (OS), MTB-adherence and -satisfaction, inclusion of patients into clinical trials and better cancer care. MAIN BODY: A publication from Freytag et al. performed an analysis in multiple tumor entities and assessed the effect of number of MTBs. By matched-pair analysis, they compared response and OS of patients, whose cases were discussed in MTBs vs. those that were not. The analysis included 454 patients and 66 different tumor types. Only patients with > 3 MTBs showed a significantly better OS than patients with no MTB meeting. Response to treatment, relapse free survival and time to progression were not found to be better, nor was there any difference for a specific tumor entity with vs. without MTB discussions. An in-depth discussion of these results, with respect to the literature (PubMed search: "MTBs AND cancer") and within the author group, including statisticians specialized in data analysis of cancer patients and questions addressed in MTBs, was performed to interpret these findings. We conclude that the results by Freytag et al. are deceiving due to an "immortal time bias" that requires more careful data interpretation. CONCLUSIONS: The result of Freytag et al. of a seemingly positive impact of higher number of MTBs needs to be interpreted cautiously: their presumed better OS in patients with > 3 MTB discussions is misleading, due to an immortal time bias. Here patients need to survive long enough to be discussed more often. Therefore, these results should not lead to the conclusion that more MTBs will "automatically" increase cancer patients' OS, rather than that the insightful discussion, at best in MTBs and with statisticians, will generate meaningful advice, that is important for cancer patients.

Sorafenib Maintenance After Allogeneic Hematopoietic Stem Cell Transplantation for Acute Myeloid Leukemia With FLT3-Internal Tandem Duplication Mutation (SORMAIN).

PURPOSE: Despite undergoing allogeneic hematopoietic stem cell transplantation (HCT), patients with acute myeloid leukemia (AML) with internal tandem duplication mutation in the FMS-like tyrosine kinase 3 gene (FLT3-ITD) have a poor prognosis, frequently relapse, and die as a result of AML. It is currently unknown whether a maintenance therapy using FLT3 inhibitors, such as the multitargeted tyrosine kinase inhibitor sorafenib, improves outcome after HCT. PATIENTS AND METHODS: In a randomized, placebo-controlled, double-blind phase II trial (SORMAIN; German Clinical Trials Register: DRKS00000591), 83 adult patients with FLT3-ITD-positive AML in complete hematologic remission after HCT were randomly assigned to receive for 24 months either the multitargeted and FLT3-kinase inhibitor sorafenib (n = 43) or placebo (n = 40 placebo). Relapse-free survival (RFS) was the primary endpoint of this trial. Relapse was defined as relapse or death, whatever occurred first. RESULTS: With a median follow-up of 41.8 months, the hazard ratio (HR) for relapse or death in the sorafenib group versus placebo group was 0.39 (95% CI, 0.18 to 0.85; log-rank P = .013). The 24-month RFS probability was 53.3% (95% CI, 0.36 to 0.68) with placebo versus 85.0% (95% CI, 0.70 to 0.93) with sorafenib (HR, 0.256; 95% CI, 0.10 to 0.65; log-rank P = .002). Exploratory data show that patients with undetectable minimal residual disease (MRD) before HCT and those with detectable MRD after HCT derive the strongest benefit from sorafenib. CONCLUSION: Sorafenib maintenance therapy reduces the risk of relapse and death after HCT for FLT3-ITD-positive AML.

[Multidisciplinary Tumor Boards: Facts and Satisfaction Analysis of an Indispensable Comprehensive Cancer Center Instrument]. / Multidisziplinäre Tumorboards: Fakten und Zufriedenheitsanalyse eines unverzichtbaren Instruments von Tumorzentren.

Background The established standard to ensure State-of-the-art cancer treatment - as a prerequisite in the national cancer plan and for comprehensive cancer centers (CCCs) today - is through interdisciplinary tumor boards (TBs). Methods This analysis assessed a newly founded CCC-TB for multiple myeloma (MM) patients, namely a) questions solved therein, b) level of compliance and c) evidence, d) frequency of clinical trial (CT) inclusion, d) progression free (PFS) and overall survival (OS) and e) satisfaction of TB-participants, referring physicians and MM patients. Results With initiation of the MM-TB, patients discussed therein substantially increased. TB-questions mostly involved symptomatic patients and recommendations on best treatment. The level of compliance and evidence were 94 % and 96.5 %, respectively; all noncompliance being coherently justified. CT inclusion was improved through the TB, leading to 18.8 % of patients being treated therein. Median PFS and OS were 2.9 and 4.7 years, respectively; also those of substantially pretreated, relapsed/refractory patients were favorable. The satisfaction of 58 participants, 33 referring physicians and 100 MM patients with the MM-TB was rewarding. Conclusion The detailed assessment of this CCC-TB on TB-questions, compliance and evidence levels, survival and satisfaction responses could serve as a valuable example for other TBs and CCCs and excite subsequent analyses on TBs.

Prevalence of iron overload vs iron deficiency in multiple myeloma: resembling or different from MDS--and stem cell transplant (SCT)--patients?

BACKGROUND: Most MM patients develop anemia with progression to symptomatic disease. Usually, this is normocytic/normochromic, with normal or low iron and elevated ferritin levels. Because ferritin levels alone do not correctly reflect iron stores, we performed a comprehensive analysis of iron parameters (iron, ferritin, transferrin, transferrin saturation [TRFS]) to more precisely assess patients' iron metabolism. PATIENTS AND METHODS: We analyzed: (1) the frequency of IO vs. ID in 136 consecutive MM patients; (2) the prognostic effect on progression-free (PFS) and overall survival (OS); and (3) specific risk groups according to patients' iron metabolism. RESULTS: Most patients had normal iron metabolism or ID: median iron, ferritin, transferrin, and TRFS values were 75 µg/dL, 446 µg/L, 195 mg/dL, and 26%, respectively. Ferritin levels of < 400 µg/L, 400 to 1000 µg/L, and > 1000 µg/L were observed in 46%, 30%, and 24%, and TRFS levels < 20%, 20% to 45%, and > 45% in 32%, 46%, and 22% of patients, respectively. When patients with modified (ID or IO) vs. normal iron metabolism were compared, laboratory parameters (prohormone of brain natriuretic peptide, estimated glomerular filtration rate, c-reactive protein, reflecting cardiac, renal, or infectious impairment), and PFS and OS appeared impaired with modified metabolism, albeit age- and disease-specific differences were insignificant. CONCLUSION: Normal iron metabolism and ID is more frequent in MM patients than IO. ID and IO correlate with organ impairment and impaired survival in MM. This knowledge should be incorporated into the design of future studies that will determine the benefit of iron supplementation with ID, and iron chelators with IO in MM.

Preclinical models of multiple myeloma: a critical appraisal.

INTRODUCTION: Preclinical models, by definition, are an approximation of reality, and their use in developing anticancer drugs is eagerly explored. Positive clinical correlations have been identified with different test systems, in addition to limitations and a need to improve preclinical model systems. Predicting whether a potential new anticancer agent will have a positive therapeutic index in patients remains a challenge. AREAS COVERED: We here review the fundamental requirements and remarkable progress of preclinical in vitro and in vivo assays used to assess the therapeutic potential of experimental anticancer drugs in multiple myeloma (MM). In MM, the interaction with the bone marrow microenvironment (BMM) plays a crucial role in disease progression, including resistance to antimyeloma agents. In vitro and in vivo approaches are, therefore, discussed with respect to their ability to mimic the important characteristics of MM and its BMM. In general, MM models should parallel the biological, genetic, etiological, immunological and therapeutic properties of the human disease. EXPERT OPINION: All models discussed here have their defined strengths, but also limitations with respect to their predictive features. Understanding the preclinical models in a more profound way should lead to optimized clinical trials, thereby expanding the therapeutic arsenal and improving patient outcome further.

Potent in vitro and in vivo activity of sorafenib in multiple myeloma: induction of cell death, CD138-downregulation and inhibition of migration through actin depolymerization.

Despite considerable advances, multiple myeloma (MM) remains incurable and the development of novel therapies targeting the interplay between plasma cells (PCs) and their bone marrow (BM) microenvironment remains essential. We investigated the effect of various agents in vitro on the proliferation, phenotype, morphology, actin polymerization and migration of MM cells and, in vivo, the tumour growth of L363-bearing non-obese diabetic severe combined immunodeficient mice with a deficient interleukin-2 receptor gamma chain (NSG). In vitro, we observed a dose-dependent cytotoxicity with bortezomib and sorafenib. Using RPMI8226 cells co-expressing histone 2B-mCherry and cytochrome c-GFP, bortezomib- and sorafenib-induced apoptosis was confirmed, and both agents combined showed synergism. Sorafenib induced CD138-downregulation and abolished CXCL12-induced actin polymerization. L363 cells expressed CCR4 and CCR5 and migrated to their common ligand CCL5. Chemotaxis to BM stroma cells was notable and significantly reduced by sorafenib. Downregulation of phospho-ERK appeared relevant for the inhibition of actin polymerization and chemotaxis. Sorafenib alone, and combined with bortezomib, showed substantial antitumour activity in L363-bearing NSG. Correspondingly, sorafenib induced clinical responses in MM-/AL-amyloidosis patients. We conclude that, in addition to the cytotoxic and anti-angiogenic effects of sorafenib, blocking of MM cell migration and homing represent promising mechanisms to interrupt the interplay between PCs and their supportive microenvironment.

State of the art therapy in multiple myeloma and future perspectives.

Treatment for multiple myeloma (MM) has changed beyond recognition in the past decades. While until the early 1980s, MM caused a slow progressive decline in quality of life until death after about two years, today's patients can expect a 50% chance of achieving a complete remission, a median survival time of five years and a 20% chance of surviving longer than ten years. State of the art therapy comprises: evidence-based supportive care; highly effective and well tolerated chemotherapeutic regimens; and for patients qualifying for intensive high-dose conditioning, autologous haematopoietic stem cell transplantation (HSCT) is an option. Maintenance therapy has become increasingly important since a majority of patients is able to achieve a good remission after front-line therapy which is aimed to be preserved as long as possible. In addition, improved understanding of the disease biology has led to the development of novel biological treatment agents, such as thalidomide, bortezomib and others, targeted at cellular mechanisms and interactions, e.g. with the bone marrow microenvironment. These strategies are incrementally integrated into modern MM care. This review considers recent clinical advancements in anti-myeloma strategies and provides an overview of the state of the art management of MM patients.