Melphalan: old and new uses of a still master drug for multiple myeloma

The treatment of multiple myeloma has seen significant changes from the initial use of melphalan to the introduction of stem cell transplantation and, most recently, to the era of novel targeted agents. Melphalan still remains as a reference drug for combination regimens, including emerging newer therapeutic options, either used at a standard dose for initial or salvage treatments in patients who are not eligible for more intensive therapies, or in conjunction with new molecules within high-dose chemotherapy programs. In this review, the authors analyze old and novel regimens, including melphalan for the treatment of newly diagnosed or relapsed/resistant patients with multiple myeloma in the clinical settings of standard chemotherapy, as well as autologous or allogeneic stem cell transplantation.     

An old drug with a new future: bendamustine in multiple myeloma

Although levodopa remains the gold standard treatment for Parkinson’s disease, many patients develop motor complications with chronic levodopa exposure. Tolcapone is a catechol-O-methyltransferase inhibitor that extends the action of levodopa. When used in conjunction with levodopa, tolcapone has been shown to be effective in improving motor fluctuations and reducing levodopa requirements in Parkinson’s disease patients. However, rare reports of severe hepatotoxicity have limited its use. A recent review of the data on tolcapone-treated patients suggests that, with proper monitoring of liver function, the potential for hepatotoxicity with tolcapone use is negligibly small.     

Melphalan hydrochloride for the treatment of multiple myeloma

Introduction: Multiple myeloma (MM) is an incurable disease characterized by clonal plasma cell proliferation and overproduction of monoclonal paraprotein, hypercalcemia, renal failure, anemia, osteolytic bone lesions, and infections.

Melphalan, a nitrogen mustard, is an alkylating agent synthesized in 1953, and it has been used in multiple myeloma therapy for fifty years. Although novel agents have been introduced in the past few decades improving prognosis of the disease, melphalan still maintains a crucial role in the treatment of MM acting both as cytotoxic agent through damage to DNA, and as immunostimulatory drug by inhibiting Interleukin-6, as well as interaction with dendritic cells, and immunogenic effects in tumor microenvironment.

Areas covered: This review focuses on available data about melphalan pharmacology and its role in clinical practice.

Expert opinion: Melphalan remains crucial in therapy of multiple myeloma because of its good manageability, safety profile, efficacy, and economic sustainability. These characteristics make it pivotal also for new regimens in combination with novel agents.     

治疗多发性骨髓瘤的新药-Daratumumab

Daratumumab是FDA新批准的用于治疗多发性骨髓瘤的CD38单克隆抗体,主要用于患有严重多发性骨髓瘤,且之前接受过两行或两行以上疗法治疗,或者对蛋白酶体抑制剂和免疫调节药物耐受的患者,其治疗结果安全有效,并且无严重不良事件报道。本文对其临床前研究、临床试验、药代动力学和不良反应进行了综述。     

治疗多发性骨髓瘤的新药:埃罗妥珠单抗

多发性骨髓瘤(MM)的治疗在不断进步,但复发/难治性MM仍是临床上的难题。埃罗妥珠单抗是美国食品和药物管理局批准的第一个针对靶向信号淋巴细胞激活分子家族成员7(SLAMF7)的单克隆抗体,与来那度胺和地塞米松联合(E-Ld)用于已接受一种或多种治疗方案的复发/难治性MM的治疗。与来那度胺+地塞米松联合疗法相比,E-Ld方案可显著延长复发/难治性MM患者的无进展生存期,降低疾病进展或死亡风险。埃罗妥珠单抗治疗期间常见不良反应包括淋巴细胞减少、输液反应、感染、二次原发性恶性肿瘤及肝毒性,与来那度胺和地塞米松联用患者耐受性好。     

Minocycline: old and new therapeutic uses

Since the introduction of minocycline HCl in the late 1960's, it has been used for disease states that have ranged from typical community-acquired infectious diseases to others that are non-infectious, such as resistant rheumatoid arthritis. Owing to its high penetration characteristics throughout the body, minocycline can be used in the treatment of a wide variety of extracellular and intracellular pathogens. This review examines the known and potential therapeutic uses of minocycline in a clinical setting.     

Tissue protective and anti-fibrotic actions of suramin: new uses of an old drug

Suramin is a polysulfonated naphthylurea, which was originally synthesized and designed as a treatment for trypanosomiasis and selected malignancies and metastatic diseases. Increasing evidence indicates that suramin is also effective in interfering with many other pathophysiological processes in animal models. For example, suramin can enhance renal regeneration after ischemia/reperfusion injury, attenuate liver damage following CD95 stimulation and endotoxic shock, reduce brain injury induced by ischemia, and suppress myocardial inflammation. Further, suramin has an anti-fibrotic effect in liver and muscle. Mechanistic studies show that suramin inhibits apoptosis, suppresses expression of proinflammatory cytokines, inactivates myofibroblasts and stimulates proliferation of renal epithelial cells. This review highlights the novel actions of suramin in a variety of tissues and organs.     

Current drug therapy for multiple myeloma

Recent years have witnessed tremendous advances in the molecular pathogenesis and management of multiple myeloma. Standard chemotherapy (melphalan and prednisone; MP) has been the mainstay of treatment of multiple myeloma for about 3 decades. However, it is no longer considered the 'gold standard', particularly for those patients who will subsequently undergo intensive chemotherapy with autologous or allogeneic peripheral blood stem cell (PBSC) or bone marrow transplantation (BMT), or for patients with refractory myeloma. A variety of induction combination chemotherapy regimens have been developed, some of which have demonstrated an improved response rate and duration and a superior 5-year survival rate when compared with standard chemotherapy. The early use of high dose chemotherapy with autologous PBSC support or BMT has significantly increased the complete remission rate, and has prolonged event-free sur vival and overall survival. Allogeneic bone marrow or PBSC transplantation may be a good option for selected patients with poor prognostic features. The role of interferon-alpha in multiple myeloma is still inconclusive despite many years of clinical evaluation. The clinical application of chemosensitising agents that can inhibit P-glycoprotein (P-gp) expression and function, and particularly the development of more potent P-gp modulators such as valspodar (PSC 833) and elacridar (GF120918) has made it possible to reverse multidrug resistance in some refractory patients and to enhance the efficacy of chemotherapeutic agents. Immunotherapeutic approaches to purging of autologous bone marrow or PBSC, or as adjuvant therapy for minimal residual disease, show great promise. Finally, a number of new therapies specifically designed to treat many of the complications of multiple myeloma are improving clinical outcomes and quality of life for these patients.     

Current therapeutic uses of lenalidomide in multiple myeloma

Thalidomide has demonstrated a broad spectrum of pharmacological and immunological effects, with potential therapeutic applications that span a wide spectrum of diseases: cancer and related conditions; infectious diseases; autoimmune diseases; dermatological diseases; and other disorders such as sarcoidosis, macular degeneration and diabetic retinopathy. Immunomodulatory derivative lenalidomide has more potent antitumour and anti-inflammatory effects. The molecular mechanisms of antitumour activity of lenalidomide have been extensively studied in multiple myeloma (MM). It directly induces growth arrest and/or apoptosis of even drug-resistant MM cells; inhibits binding of MM cells to bone marrow extracellular matrix proteins and stromal cells; modulates cytokine secretion and inhibits angiogenesis in the bone marrow milieu; and augments host antitumour immunity. Importantly, lenalidomide induces significant clinical responses even in patients with relapsed/refractory MM. Therefore, lenalidomide represents a new class of antitumour agents that is useful in the treatment of MM. Lenalidomide has received fast track designation from the FDA for the treatment of MM and myelodysplastic syndromes.     

Current therapeutic uses of lenalidomide in multiple myeloma

Thalidomide has demonstrated a broad spectrum of pharmacological and immunological effects, with potential therapeutic applications that span a wide spectrum of diseases: cancer and related conditions; infectious diseases; autoimmune diseases; dermatological diseases; and other disorders such as sarcoidosis, macular degeneration and diabetic retinopathy. Immunomodulatory derivative lenalidomide has more potent antitumour and anti-inflammatory effects. The molecular mechanisms of antitumour activity of lenalidomide have been extensively studied in multiple myeloma (MM). It directly induces growth arrest and/or apoptosis of even drug-resistant MM cells; inhibits binding of MM cells to bone marrow extracellular matrix proteins and stromal cells; modulates cytokine secretion and inhibits angiogenesis in the bone marrow milieu; and augments host antitumour immunity. Importantly, lenalidomide induces significant clinical responses even in patients with relapsed/refractory MM. Therefore, lenalidomide represents a new class of antitumour agents that is useful in the treatment of MM. Lenalidomide has received fast track designation from the FDA for the treatment of MM and myelodysplastic syndromes.     

Thalidomide as a novel therapeutic agent: new uses for an old product

Thalidomide and its immunomodulatory analogues have numerous effects on the body's immune system, including potential anti-cancer and anti-inflammatory activities. Thalidomide is currently used experimentally to treat various cancers, dermatological, neurological and inflammatory diseases. This drug is approved in the USA for cutaneous manifestations of lepromatous leprosy and is in Phase III trials for multiple myeloma. Thalidomide and its analogues modulate the immune system in various ways. Some of these immunomodulatory activities, together with the anti-angiogenic, anti-proliferative and pro-apoptotic properties, are believed to mediate anti-tumor responses as observed in multiple myeloma and some solid tumors. The analogue lenalidomide has shown potential in treating the bone marrow disorders multiple myeloma and myelodysplastic syndrome, and is presently in Phase II and III trials, respectively.     

治疗多发性骨髓瘤新药：抗CD38单克隆抗体isatuximab

isatuximab(Isa)是由赛诺菲公司开发的IgG1单克隆抗体,可与造血细胞和肿瘤细胞[包括多发性骨髓瘤(MM)细胞]表面表达的CD38结合,通过多种生物学机制发挥抗肿瘤作用,如抗体依赖细胞介导的细胞毒作用和补体依赖的细胞毒作用等。2020年3月2日,美国食品和药物管理局(FDA)批准Isa联合泊马度胺和地塞米松(Isa-Pom-Dex)用于治疗既往至少接受过2种药物(包括来那度胺和1种蛋白酶体抑制剂)治疗的MM成人患者。最新研究表明,接受Isa-Pom-Dex治疗的MM患者中位无进展生存期为11.5个月,客观缓解率为60.4%(93/154),常见不良反应有中性粒细胞减少、血小板减少和贫血等。     

Ketamine: new indications for an old drug

Ketamine is a non-competitive antagonist to the phencyclidine site of N-methyl-d-aspartate (NMDA) receptor for glutamate, though its effects are mediated by interaction with many others receptors. It has been introduced in clinical use since 1960's but today it is not largely employed as a general anaesthetic for its undesired psychic effects (emergence reactions) occurring in approximately 12% of patients. In the last decade, there has been a renewed interest in the use of subanaesthetic doses of ketamine for the treatment of acute and chronic pain. In the late 1990's, multiple prospective, randomised, controlled study has shown the efficacy of low dose of ketamine for postoperative pain relief, for analgesia during regional or local anaesthesia, and for opioid-sparing effect. At present, non-definitive conclusion can be drawn. More data are needed to define the possible long term effects and the clinical goal of ketamine use.     

Amphotericin B: new life for an old drug

Interest in amphotericin B has undergone a renaissance of sorts over the past few years despite the advent of the newer less-toxic azole antifungal drugs. This is, in part, owing to the unfortunate increase in fungal diseases worldwide. It is also, however, owing to the reduction of toxicity via innovative liposomal delivery systems, better understanding of drug mechanism and distribution and a surprising expansion of the antibiotic spectrum of amphotericin B to include select virus, parasite and possibly prion infections. In this article, Scott Hartsel and Jacques Bolard summarize the recent leaps in pharmaceutics, spectrum and molecular mechanistic knowledge of this surprising molecule.     

Cutaneous adverse reactions linked to targeted anticancer therapies bortezomib and lenalidomide for multiple myeloma: new drugs,old side effects

Context: Cutaneous toxicity is a frequent side effect of new anticancer targeted therapies. Skin reactions can severely impact the patient’s physical, psychological and social well-being and may sometimes lead to discontinuations either treatment dose reductions.

Objective: This study evaluates the impact of cutaneous adverse drug reactions (cADR) of the new therapies bortezomib and lenalidomide and presents a review of their skin side effects.

Materials and method: Type, frequency, severity, time of onset and management of cADR were collected and the medical records of all multiple myeloma patients receiving bortezomib or lenalidomide in the Hematology and Medical Oncology Institute of the University of Bologna, were analyzed.

Results: A total of 17 cADR occurred in 10 patients of 17 (58.8% of patients) treated with bortezomib: 5 rashes, 3 events of pruriginous rash, 1 purpuric rash, 2 records of mouth swelling, 1 stomatitis-mucositis, 3 cases of edema in the lower limbs, 1 patient referred pruritus and another telogen effluvium. Eight skin manifestations were due to lenalidomide in 7 patients of 25 treated (28%): 2 pruriginous rashes, 3 cases of edema, 2 records of pruritus, 1 case of stomatitis-mucositis. Three adverse events linked to bortezomib and 4 to lenalidomide forced to a complete withdrawal of the drug, while 3 reactions due to bortezomib mandated a dose reduction. Dermatological evaluation was performed only in 2 patients treated with bortezomib and 1 with lenalidomide.

Discussion: Evaluations of cADR due to bortezomib and lenalidomide were performed. There are no other reports focused on skin events in patients treated with the triple regimen velcade (bortezomib)-thalidomide-dexamethasone (VTD) up to date. Our study suggests that cutaneous toxicities, when researched by Dermatologists, are a side effect even more frequent than the reported data.

Limitations: As it is a single institute and retrospective study, ongoing cADR were rarely evaluated by dermatologists; thus, it is possible that cutaneous reactions (especially mild) may have been under reported by Hematologists and Oncologists in clinical records.

Conclusions: Even with the development of new drugs for cancer treatment, “old” cutaneous side effects may still be present, compromising patients’ quality of life. Physicians prescribing bortezomib and lenalidomide should monitor their patients for the spectrum of cADR, and they should involve dermatologists in consultations and management of these events. A multidisciplinar approach is necessary to oncologic patient in order to provide a tailored supportive clinical care.     

多发性骨髓瘤治疗策略及治疗新药

多发性骨髓瘤是一种起病隐匿、治疗难度较大的浆细胞恶性增殖性疾病,如何更准确地判断治疗时机以及选择适宜的治疗策略和治疗药物一直是临床上亟待解决的重大课题。近20年来,随着造血干细胞移植术和治疗新药的应用,多发性骨髓瘤治疗已取得重大进展,治疗疗效和患者的预后都得到了明显改善。     

Paracetamol: new vistas of an old drug

Paracetamol (acetaminophen) is one of the most popular and widely used drugs for the treatment of pain and fever. It occupies a unique position among analgesic drugs. Unlike NSAIDs it is almost unanimously considered to have no antiinflammatory activity and does not produce gastrointestinal damage or untoward cardiorenal effects. Unlike opiates it is almost ineffective in intense pain and has no depressant effect on respiration. Although paracetamol has been used clinically for more than a century, its mode of action has been a mystery until about one year ago, when two independent groups (Zygmunt and colleagues and Bertolini and colleagues) produced experimental data unequivocally demonstrating that the analgesic effect of paracetamol is due to the indirect activation of cannabinoid CB(1) receptors. In brain and spinal cord, paracetamol, following deacetylation to its primary amine (p-aminophenol), is conjugated with arachidonic acid to form N-arachidonoylphenolamine, a compound already known (AM404) as an endogenous cannabinoid. The involved enzyme is fatty acid amide hydrolase. N-arachidonoylphenolamine is an agonist at TRPV1 receptors and an inhibitor of cellular anandamide uptake, which leads to increased levels of endogenous cannabinoids; moreover, it inhibits cyclooxygenases in the brain, albeit at concentrations that are probably not attainable with analgesic doses of paracetamol. CB(1) receptor antagonist, at a dose level that completely prevents the analgesic activity of a selective CB(1) receptor agonist, completely prevents the analgesic activity of paracetamol. Thus, paracetamol acts as a pro-drug, the active one being a cannabinoid. These findings finally explain the mechanism of action of paracetamol and the peculiarity of its effects, including the behavioral ones. Curiously, just when the first CB(1) agonists are being introduced for pain treatment, it comes out that an indirect cannabino-mimetic had been extensively used (and sometimes overused) for more than a century.