Risk Stratification Before and During Treatment in Newly Diagnosed Multiple Myeloma: From Clinical Trials to the Real-World Setting

Multiple Myeloma (MM) is a hematologic malignancy characterized by a wide clinical and biological heterogeneity leading to different patient outcomes. Various prognostic tools to stratify newly diagnosed (ND)MM patients into different risk groups have been proposed. At baseline, the standard-of-care prognostic score is the Revised International Staging System (R-ISS), which stratifies patients according to widely available serum markers (i.e., albumin, β 2-microglobulin, lactate dehydrogenase) and high-risk cytogenetic abnormalities detected by fluorescence in situ hybridization. Though this score clearly identifies a low-risk and a high-risk population, the majority of patients are categorized as at “intermediate risk”. Although new prognostic factors identified through molecular assays (e.g., gene expression profiling, next-generation sequencing) are now available and may improve risk stratification, the majority of them need specialized centers and bioinformatic expertise that may preclude their broad application in the real-world setting. In the last years, new tools to monitor response and measurable residual disease (MRD) with very high sensitivity after the start of treatment have been developed. MRD analyses both inside and outside the bone marrow have a strong prognostic impact, and the achievement of MRD negativity may counterbalance the high-risk behavior identified at baseline. All these techniques have been developed in clinical trials. However, their efficient application in real-world clinical practice and their potential role to guide treatment-decision making are still open issues. This mini review will cover currently known prognostic factors identified before and during first-line treatment, with a particular focus on their potential applications in real-world clinical practice

Diagnostic and therapeutic challenges in the management of intermediate and frail elderly multiple myeloma patients

Multiple myeloma (MM) mostly affects elderly patients, which represent a highly heterogeneous population. Indeed, comorbidities, frailty status and functional reserve may vary considerably among patients with similar chronological age. For this reason, the choice of treatment goals and intensity is particularly challenging in elderly patients, and it requires a multidimensional evaluation of the patients and the disease. In recent years, different tools to detect patient frailty have been developed, and the International Myeloma Working Group frailty score currently represents the gold standard. It identifies intermediate-fit and frail patients requiring gentler treatment approaches compared to fit patients, aiming to preserve quality of life and prevent toxicities. This subset of patients is underrepresented in clinical trials, and studies exploring frailty-adapted approaches are scarce, making the choice of therapy extremely challenging. Treatment options for intermediate-fit and frail patients might include dose-adapted combinations, doublets, and less toxic combinations based on novel agents. This review analyzes the available tools for the assessment of frailty and possible strategies to improve the discriminative power of the scores and expand their use in real-life and clinical trial settings. Moreover, it addresses the main therapeutic challenges in the management of intermediate-fit and frail MM patients at diagnosis and at relapse

Therapeutic monoclonal antibodies and antibody products: Current practices and development in multiple myeloma

Immunotherapy is the latest innovation for the treatment of multiple myeloma (MM). Monoclonal antibodies (mAbs) entered the clinical practice and are under evaluation in clinical trials. MAbs can target highly selective and specific antigens on the cell surface of MM cells causing cell death (CD38 and CS1), convey specific cytotoxic drugs (antibody-drug conjugates), remove the breaks of the immune system (programmed death 1 (PD-1) and PD-ligand 1/2 (L1/L2) axis), or boost it against myeloma cells (bi-specific mAbs and T cell engagers). Two mAbs have been approved for the treatment of MM: the anti-CD38 daratumumab for newly-diagnosed and relapsed/refractory patients and the anti-CS1 elotuzumab in the relapse setting. These compounds are under investigation in clinical trials to explore their synergy with other anti-MM regimens, both in the front-line and relapse settings. Other antibodies targeting various antigens are under evaluation. B cell maturation antigens (BCMAs), selectively expressed on plasma cells, emerged as a promising target and several compounds targeting it have been developed. Encouraging results have been reported with antibody drug conjugates (e.g., GSK2857916) and bispecific T cell engagers (BiTEs®), including AMG420, which re-directs T cell-mediated cytotoxicity against MM cells. Here, we present an overview on mAbs currently approved for the treatment of MM and promising compounds under investigation

An investigation into the use of CALNN capped gold nanoparticles for improving microwave heating

The use of microwaves for both therapeutic and diagnostic applications has become an accepted alternative in the clinics. For diagnostics, gold (Au) nanoparticles have been used for imaging tumour vasculature and also served as potential diagnostic markers for cancer. [1] In high-frequency therapeutic applications, two different treatments exist; hyperthermia and ablation. [2] In hyperthermia, the tumour tissue is heated to supra-physiological temperatures, making it more susceptible to traditional treatment methods such as chemotherapy and radiotherapy. This type of treatment could be administered externally. However, there still remains a challenge to focus the heating to particular areas which need to be treated, while avoiding unwanted hotspots. To date, numerous methods have been used to focus the heat from different antennas. A novel technique which is being investigated is the use of nanoparticles to improve focusing and thus achieve better localised heating effect. A previous study by Cardinal et al. [3] showed that at RF-frequencies, remarkable improvements resulted from using Au nanoparticles. In this work, the use of CALNN peptide capped Au nanoparticles for the focusing of microwaves at 2.45 GHz is investigated. The CALNN capped Au nanoparticles were prepared as described elsewhere. [4] Au nanoparticles were added to tissue mimicking solutions (such as muscle, liver or fat) to compare their dielectric properties with the those of the control (without Au nanoparticles). The frequency range investigated was from 400 MHz to 20 GHz. During this study, various concentrations, particle sizes and shapes of Au nanoparticles were considered. The study also investigated the heating rates of the pseudo-biological tissue samples and how these varied with the addition of the nanoparticles. The outcome of this study will determine the viability of using CALNN capped Au nanoparticles to assist in the focusing of microwave radiation during microwave hyperthermia

Mental and behavioral disorders due to substance abuse and perinatal outcomes: A study based on linked population data in New South Wales, Australia

Background: The effects of mental and behavioral disorders (MBD) due to substance use during peri-conception and pregnancy on perinatal outcomes are unclear. The adverse perinatal outcomes of primiparous mothers admitted to hospital with MBD due to substance use before and/or during pregnancy were investigated. Method: This study linked birth and hospital records in NSW, Australia. Subjects included primiparous mothers admitted to hospital for MBD due to use of alcohol, opioids or cannabinoids during peri-conception and pregnancy. Results: There were 304 primiparous mothers admitted to hospital for MBD due to alcohol use (MBDA), 306 for MBD due to opioids use (MBDO) and 497 for MBD due to cannabinoids (MBDC) between the 12 months peri-conception and the end of pregnancy. Primiparous mothers admitted to hospital for MBDA during pregnancy or during both peri-conception and pregnancy were significantly more likely to give birth to a baby of low birthweight (AOR = 4.03, 95%CI: 1.97-8.24 for pregnancy; AOR = 9.21, 95%CI: 3.76-22.57 both periods); preterm birth (AOR = 3.26, 95% CI: 1.52-6.97 for pregnancy; AOR = 4.06, 95%CI: 1.50-11.01 both periods) and admission to SCN or NICU (AOR = 2.42, 95%CI: 1.31-4.49 for pregnancy; AOR = 4.03, 95%CI: 1.72-9.44 both periods). Primiparous mothers admitted to hospital for MBDO, MBDC or a combined diagnosis were almost three times as likely to give birth to preterm babies compared to mothers without hospital admissions for psychiatric or substance use disorders. Babies whose mothers were admitted to hospital with MBDO before and/or during pregnancy were six times more likely to be admitted to SCN or NICU (AOR = 6.29, 95%CI: 4.62-8.57). Conclusion: Consumption of alcohol, opioids or cannabinoids during peri-conception or pregnancy significantly increased the risk of adverse perinatal outcomes. © 2014 by the authors; licensee MDPI, Basel, Switzerland