Role of thalidomide in previously untreated patients with multiple myeloma

Thalidomide represents one of the most relevant therapeutic advances for patients with multiple myeloma over the last 10 years. Despite some toxicities, it has demonstrated significant efficacy in elderly patients, as well as in the setting of younger subjects receiving autologous stem cell transplantation. Here, we report and discuss the clinical results achieved with thalidomide alone or in combination with dexamethasone or other drugs, such as melphalan, cyclophosphamide, doxorubicin and bortezomib, in previously untreated myeloma patients.     

Role of thalidomide in previously untreated patients with multiple myeloma

Thalidomide represents one of the most relevant therapeutic advances for patients with multiple myeloma over the last 10 years. Despite some toxicities, it has demonstrated significant efficacy in elderly patients, as well as in the setting of younger subjects receiving autologous stem cell transplantation. Here, we report and discuss the clinical results achieved with thalidomide alone or in combination with dexamethasone or other drugs, such as melphalan, cyclophosphamide, doxorubicin and bortezomib, in previously untreated myeloma patients.     

91例初诊多发性骨髓瘤临床及实验室检查分析

目的 总结初诊多发性骨髓瘤（MM）的临床和有关实验室检查的特点。方法 对91例初诊MM患者的临床和实验摩资料作回顾性分析。结果 ①MM起病以骨痛和贫血最多见，IRG和IgA是最常见的免疫分型，占全部MM的83．5％。②本病起病隐匿．临床表现多样化。容易误诊。③大多异常的实验室检查结果无明显特异性。结论临床表现结合实验室相关指标检查，能够提高多发性骨髓瘤诊断的准确性．为临床诊断提供可靠依据。     

Antitumor effect of zoledronic acid in previously untreated patients with multiple myeloma

Bisphophonates are the treatment of choice to prevent skeletal events in patients with multiple myeloma. Some preclinical studies suggested that bisphophonates can be useful as antitumor drugs in some malignancies. We conducted a controlled clinical trial to assess if zoledronic acid can have this clinical activity. Ninety four patients with previously untreated multiple myeloma were treated with a conventional chemotherapy program: cyclophosphamide, vincristine, melphalan, and prednisone (CVMP) and were randomized to received either zoledronic acid (4 mg, iv, every 28 d) or not (control group). The end-point of the present study was to assess improvement in outcome, measured by event-free survival (EFS) and overall survival (OS), and the second-end point was to confirm the efficacy in preventing skeletal events. In an intent-to-treat analysis, all patients were available for efficacy and toxicity. Median follow up was 49.6 mo (range: 34-72 mo). Five year actuarial curves showed that EFS was 80% in the zoledronic acid group, which was statistically different from 52% in the control group (p < 0.01). Actuarial 5 yr OS was 80% in the zoledronic acid arm, and 46% in the control group (p < 0.01). Sketeletal events were more frequent in the control group when compared to zoledronic acid. Toxicity was mild. We confirm the efficacy of zoledronic acid to prevent skeletal events, but we felt that we can demonstrate that zoledronic acid has a clinical antitumor effect measured from a increase in complete response rate and EFS and OS that were better when compared with the control group. We began a controlled clinical trial with modern treatment (including transplant procedures) in combination with zoledronic acid to define the role of zoledonic acid in this setting of patients.     

A meta-analysis and systematic review of thalidomide for patients with previously untreated multiple myeloma

A systematic review and meta-analysis was performed to determine the efficacy and toxicity of thalidomide in previously untreated patients with myeloma. Medline, Embase, Cochrane Controlled Trials Register, and abstracts from the American Society of Hematology and the American Society of Clinical Oncology were searched for randomized controlled trials (RCTs) of either induction or maintenance thalidomide in adults with previously untreated myeloma. Nine RCTs of induction thalidomide, three RCTs of maintenance thalidomide, and one RCT of induction and maintenance thalidomide were identified, involving a total of 4144 subjects. When thalidomide was added to standard, non-transplantation myeloma therapy, overall survival (OS) improved (HR 0.67; 95% CI 0.56-0.81). When thalidomide was given as maintenance following autologous transplantation (ASCT), there was a trend to improved OS (HR 0.61, 95% CI 0.37-1.01); when the only trial which combined induction and maintenance thalidomide was excluded from this analysis, a significant survival advantage emerged (HR 0.49, 95% CI 0.32-0.74). The relative risk of venous thromboembolism (VTE) with induction thalidomide was 2.56 (95% CI 1.88-3.49). A meta-analysis of trials/sub-groups administering low molecular weight heparin (LMWH) as VTE prophylaxis, suggested a persistently increased relative risk of VTE with induction thalidomide (RR 1.54, 95% CI 1.07-2.22). The relative risk of VTE was substantially lower, but still elevated, when thalidomide was given as maintenance therapy following ASCT (RR 1.95, 95% CI 1.15-3.30). In summary, thalidomide appears to improve the overall survival of patients with newly diagnosed myeloma both when it is added to standard, non-transplantation therapy, and when it is given as maintenance therapy following ASCT. However, thalidomide is associated with toxicity, particularly a significantly increased risk of VTE.     

Therapy‐related peripheral neuropathy in multiple myeloma patients

This review discusses the most common issues concerning multiple myeloma (MM)‐related peripheral neuropathy (PN). This is an important MM complication, observed in up to 54% of newly diagnosed patients, caused by the disease itself or its treatment. Although its aetiology is largely unknown, a number of mechanisms are suspected. It is important to know the neurological status of a patient, as many new antimyeloma medicines can trigger or exacerbate any pre‐existing neuropathy. Examples include thalidomide‐induced and bortezomib‐induced PN (TiPN and BiTN, respectively), which are key MM treatment options. TiPN is usually sensory and sensorimotor, whereas BiPN is typically sensory. The mechanisms of chemotherapy‐induced neurotoxicity in MM are well known; thalidomide seems to induce PN through its antiangiogenic properties, whereas bortezomib neurotoxicity is connected with disrupted calcium homeostasis. TiPN incidence ranges from 25% to 75%, and its prevalence and severity appears to be dose‐dependent. BiPN incidence is almost 40% and is dose‐related as well. Poor (25%) reversibility of TiPN prompted the recommendations for dose and exposure reduction, whereas BiPN cases are mostly reversible (64%). Peripheral sensory neuropathy is very rare in patients receiving bendamustine monotherapy. Because of this favourable toxicity profile, bendamustine may be considered a promising option for combination therapies in pre‐existing PN in myeloma patients. Considering the lack of curative therapy for treatment‐emergent PN, prevention is a key management strategy in MM patients. All patients should be evaluated for PN before the administration of a neurotoxic drug, and those under treatment should be closely monitored by a neurologist. Copyright © 2014 John Wiley & Sons, Ltd.     

Bortezomib-induced tumor lysis syndrome in multiple myeloma

Tumor lysis syndrome (TLS) is exceedingly rare in multiple myeloma because of the relatively slow proliferation and response of the malignant cells. Bortezomib is a novel agent that inhibits proteasome and has shown activity against multiple myeloma. We report 8 episodes of TLS seen in 7 patients with bortezomib therapy, with or without dexamethasone, among 496 patients treated on 3 phase II multicenter studies. Biochemical abnormalities resolved with supportive therapy in 6 patients (including hemodialysis in 2) but proved fatal in 1. Clinicians should be alert for TLS in patients with myeloma with significant disease burden treated with bortezomib because of the potential for rapid onset of cell lysis with this agent.     

Thalidomide for previously untreated indolent or smoldering multiple myeloma.

We conducted a clinical trial of thalidomide as initial therapy for asymptomatic smoldering (SMM) or indolent multiple myeloma (IMM). Sixteen patients were studied. Thalidomide was given orally at a dose of 200 mg/day for 2 weeks, and then increased as tolerated by 200 mg/day every 2 weeks to a maximum dose of 800 mg/day. Bone marrow microvessel density (MVD) and angiogenesis grading were estimated using CD34 immunostaining. Six patients had a confirmed response to therapy with at least 50% or greater reduction in serum and urine monoclonal (M) protein. When minor responses (25-49%) decrease in M protein concentration) were included, 11 of 16 patients (69%) responded to therapy. Major grade 3-4 toxicities included two patients with somnolence, and one patient each with syncope and neutropenia. Pre-treatment MVD was not a significant predictor of response to therapy, median MVD 4 and 12 in responders and non-responders respectively, P = 0.09. We conclude that thalidomide has significant activity in the treatment of newly diagnosed SMM/IMM. However, we do not recommend treatment with thalidomide at this stage since some patients with SMM/IMM can be stable for several months or years without any therapy. Additional randomized trials are needed to determine if thalidomide will delay progression to active multiple myeloma.     

Management of treatment-emergent peripheral neuropathy in multiple myeloma

Peripheral neuropathy (PN) is one of the most important complications of multiple myeloma (MM) treatment. PN can be caused by MM itself, either by the effects of the monoclonal protein or in the form of radiculopathy from direct compression, and particularly by certain therapies, including bortezomib, thalidomide, vinca alkaloids and cisplatin. Clinical evaluation has shown that up to 20% of MM patients have PN at diagnosis and as many as 75% may experience treatment-emergent PN during therapy. The incidence, symptoms, reversibility, predisposing factors and etiology of treatment-emergent PN vary among MM therapies, with PN incidence also affected by the dose, schedule and combinations of potentially neurotoxic agents. Effective management of treatment-emergent PN is critical to minimize the incidence and severity of this complication, while maintaining therapeutic efficacy. Herein, the state of knowledge regarding treatment-emergent PN in MM patients and current management practices are outlined, and recommendations regarding optimal strategies for PN management during MM treatment are provided. These strategies include early and regular monitoring with neurological evaluation, with dose modification and treatment discontinuation as indicated. Areas requiring further research include the development of MM-specific, patient-focused assessment tools, pharmacogenomic analysis of patient DNA, and trials to assess the efficacy of pharmacological interventions.     

Treatment-related peripheral neuropathy in multiple myeloma: the challenge continues

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.     

Thalidomide alone or with dexamethasone for previously untreated multiple myeloma.

PURPOSE: To evaluate the activity of thalidomide in patients with asymptomatic multiple myeloma and of thalidomide-dexamethasone in patients with previously untreated symptomatic myeloma. PATIENTS AND METHODS: Twenty-eight patients with previously untreated asymptomatic myeloma were treated with thalidomide 100 to 200 mg orally (PO) at bedtime (qhs) with serial increments of 50 to 100 mg at weekly intervals, as tolerated to a maximum of 600 mg PO qhs. Forty consecutive previously untreated patients with symptomatic myeloma were also treated as above (maximum dose 400 mg) and received dexamethasone 20 mg/m(2) for 4 days beginning on days 1, 9, and 17; the second and third cycles of repeated dexamethasone were begun on day 30. Both groups of patients were treated for at least 3 months. RESULTS: The response rate was 36% for patients treated with thalidomide alone and 72% for patients treated with thalidomide-dexamethasone, the latter including complete remission in 16% of patients. The median time to remission was 4.2 months with thalidomide alone and 0.7 months with thalidomide-dexamethasone. Grade 3 toxicity included infections (nine patients) and thrombotic/embolic events (seven patients). Five deaths have occurred as a result of multiple myeloma (two patients), infection (one patient), unknown cause (one patient), and a possible thromboembolic event (one patient). CONCLUSION: Thalidomide alone was effective in patients with newly diagnosed myeloma. The combination with dexamethasone induced a high frequency of response, rapid onset of remission, and low incidence of serious irreversible toxicity. These observations support further studies of this promising combination for patients with newly diagnosed multiple myeloma.     

Bortezomib-induced pneumonitis during bortezomib retreatment in multiple myeloma

Bortezomib is a proteasome inhibitor and is active against multiple myeloma. Most toxicities associated with bortezomib are mild to moderate and manageable; however, bortezomib-induced pneumonitis has been reported in some multiple myeloma cases. Bortezomib-induced pneumonitis was reported to occur relatively soon after the first administration of bortezomib. A 64-year-old Japanese man with multiple myeloma received low-dose dexamethasone followed by bortezomib monotherapy as the initial therapy. He had no pulmonary complications during bortezomib treatment. Thereafter, he was treated with high-dose chemotherapy, followed by autologous peripheral blood stem cell transplantation. Ten months after autologous peripheral blood stem cell transplantation, his disease relapsed and he received bortezomib retreatment. On the fifth day after the second dose of weekly bortezomib, he complained of mild dyspnea, dry cough and fever. High-resolution computed tomography of the chest showed bilateral infiltrates with partial ground glass appearance in the lower lobes. The diagnosis of bortezomib-induced pneumonitis was made. His bortezomib-induced pneumonitis responded to steroid therapy and his respiratory symptoms disappeared. This is the first report in which bortezomib-induced pneumonitis occurred during bortezomib retreatment for relapsed multiple myeloma. Careful management is needed during bortezomib retreatment, even after the previous course of bortezomib was administered safely.     

多发性骨髓瘤周围神经病变临床特征分析

目的探讨多发性骨髓瘤周围神经病变(MMPN)患者的临床和神经电生理异常表现。方法回顾性分析2010年3月至2018年6月山西省人民医院诊断的35例MMPN患者的临床资料。所有患者均进行神经电生理检测,包括神经传导速度(NCV)及皮肤交感反应(SSR)。结果 MMPN患者最常见周围神经受累的表现为感觉异常(25例,71%),包括根性疼痛(3例,9%)、双下肢或上肢痛觉减弱(18例,51%)、运动障碍(15例,43%)、双下肢膝反射或踝反射减低或消失(13例,37%)以及自主神经障碍症状(20例,57%)。感觉神经传导速度(SCV)异常和(或)运动神经传导速度(MCV)异常共29例(83%)。上肢NCV异常13例,上肢潜伏期延长5例,波幅降低10例;下肢NCV异常8例,下肢潜伏期延长6例,波幅降低4例。SSR检查发现17例(49%)异常。仅上肢SSR异常8例,上肢潜伏期延长2例,波幅降低7例,波形消失1例;仅下肢SSR异常6例,下肢潜伏期延长1例,波幅降低4例,波形消失2例;上下肢SSR均异常3例。结论 MM最常见的周围神经系统损害表现为"袜子和手套样"分布的感觉减退,自主神经也可累及;NCV检查是诊断MMPN的一种基本方法,SSR对于检测MMPN自主神经障碍有重要作用。     

Prognostic significance of magnetic resonance imaging of bone marrow in previously untreated patients with multiple myeloma.

BACKGROUND: Magnetic resonance imaging (MRI) has been a useful technique for the assessment of patients with multiple myeloma (MM). We evaluated the prognostic significance of different MRI patterns in symptomatic patients with MM. PATIENTS AND METHODS: A total of 142 symptomatic MM patients underwent MRI before treatment. MRI patterns of involvement were correlated with known prognostic variables, including the International Staging System (ISS), response to treatment and survival. RESULTS: Focal marrow lesions were identified in 50% of patients, diffuse marrow replacement in 28%, a variegated pattern in 14% and normal pattern in 8%. When patients with the diffuse pattern were compared with patients with the other MRI patterns, they had features of more advanced disease such as higher ISS, anemia, hypercalcemia, elevated lactate dehydrogenase and extensive marrow plasmacytosis. Response rate was similar among patients with different MRI patterns. Median survival was 24 months for patients with the diffuse pattern, 51 months for those with the focal pattern, 52 months for those with the variegated pattern and 56 months for patients with the normal pattern (P = 0.001). The presence or absence of a diffuse MRI pattern separated patients with ISS stages I and II into two subgroups with significantly different survival times of 28 months and 61 months, respectively (P = 0.01). Furthermore, a diffuse MRI pattern predicted inferior outcome regardless of whether or not patients had received high-dose therapy with autologous stem cell transplantation. CONCLUSION: Diffuse marrow replacement on MRI adds to the evaluation of patients with multiple myeloma and their management.     

Biological modifiers as cytoreductive therapy before stem cell transplant in previously untreated patients with multiple myeloma.

BACKGROUND: High dose chemotherapy with supporting autologous stem cell transplantation is now considered the treatment of choice in patients with multiple myeloma <65 years old. The best regimen appears to be VAD (vincristine, doxorubicin and dexamethasone), but acute and late toxicity can limit the use of this combination. The use of biological modifiers has not been considered in this situation. We developed a new cytoreductive regimen, in an attempt to retain clinical efficacy but reduce toxicity. PATIENTS AND METHODS: Thirty-six patients, previously untreated with diagnosis of multiple myeloma were enrolled to received the DAI regimen (dexamethasone 30 mg/m(2), i.v., days 1-4, all-trans-retinoic acid 45 mg/m(2), p.o., days 5-14 and interferon alpha 2a, 4.5 MU s.c., days 5-14) administered every 28 days for six cycles before high-dose chemotherapy (melphalan 200 g/m(2)) and autologous stem cell transplantation. RESULTS: Overall response was observed in 29 cases (80%), complete response in 19 and partial response in 10 patients. Five patients were >65 years old and were treated with dexamethasone/thalidomide. Twenty-four patients underwent transplants. At a median follow-up of 31.6 months, no relapse or disease progression was observed, thus actuarial curves at 3-years showed that event-free survival was 86% and overall survival was 94%. Toxicity was mild. CONCLUSIONS: This regimen appears to be an excellent alternative as cytoreductive treatment before high-dose chemotherapy and autologous stem cell transplantation with excellent overall response and minimal toxicity. Controlled clinical trials are warranted to define the role of this new therapeutic approach.     

多发性骨髓瘤相关周围神经病变的研究进展

 周围神经病变（PN）是多发性骨髓瘤（MM）的一个主要的并发症,它不仅可由疾病本身引起,也可以由治疗MM的药物引起。因为PN诊断和鉴别的复杂性以及自主感觉的差异,所以给其诊断和治疗带来一定困难。     

Residual serum monoclonal protein predicts progression‐free survival in patients with previously untreated multiple myeloma

BACKGROUND:

Currently used treatment response criteria in multiple myeloma (MM) are based in part on serum monoclonal protein (M‐protein) measurements. A drawback of these criteria is that response is determined solely by the best level of M‐protein reduction, without considering the serial trend. The authors hypothesized that metrics incorporating the serial trend of M‐protein would be better predictors of progression‐free survival (PFS).

METHODS:

Fifty‐five patients with measurable disease at baseline (M‐protein ≥1 g/dL) who received ≥4 cycles of treatment from 2 clinical trials in previously untreated MM were included. Three metrics based on the percentage of M‐protein remaining relative to baseline (residual M‐protein) were considered: metrics based on the number of times residual M‐protein fell within prespecified thresholds, metrics based on area under the residual M‐protein curve, and metrics based on the average residual M‐protein reduction between Cycles 1 and 4. The predictive value of these metrics was assessed in Cox models using landmark analysis.

RESULTS:

The average residual M‐protein reduction was found to be significantly predictive of PFS (P = .02; hazard ratio, 0.37), in which a patient with a 10% lower average residual M‐protein reduction from Cycle 1 to 4 was estimated to be at least 2.7× more likely to develop disease progression or die early. None of the other metrics was predictive of PFS. The concordance index for the average residual M‐protein reduction was 0.63, compared with 0.56 for best response.

CONCLUSIONS:

The average residual M‐protein reduction metric is promising and needs further validation. This exploratory analysis is the first step in the search for treatment‐based trend metrics predictive of outcomes in MM. Cancer 2010. © 2009 American Cancer Society.     

Bortezomib‐induced peripheral neuropathy: A genome‐wide association study on multiple myeloma patients

The proteasome‐inhibitor bortezomib was introduced into the treatment of multiple myeloma more than a decade ago. It is clinically beneficial, but peripheral neuropathy (PNP) is a side effect that may limit its use in some patients. To examine the possible genetic predisposing factors to PNP, we performed a genome‐wide association study on 646 bortezomib‐treated German multiple myeloma patients. Our aim was to identify genetic risk variants associated with the development of PNP as a serious side effect of the treatment. We identified 4 new promising loci for bortezomib‐induced PNP at 4q34.3 (rs6552496), 5q14.1 (rs12521798), 16q23.3 (rs8060632), and 18q21.2 (rs17748074). Even though the results did not reach genome‐wide significance level, they support the idea of previous studies, suggesting a genetic basis for neurotoxicity. The identified single nucleotide polymorphisms map to genes or next to genes involved in the development and function of the nervous system (CDH13, DCC, and TENM3). As possible functional clues, 2 of the variants, rs12521798 and rs17748074, affect enhancer histone marks in the brain. The rs12521798 may also impact expression of THBS4, which affects specific signal trasduction pathways in the nervous system. Further research is needed to clarify the mechanism of action of the identified single nucleotide polymorphisms in the development of drug‐induced PNP and to functionally validate our in silico predictions.