Therapeutic approaches for newly diagnosed multiple myeloma patients in the era of novel drugs

The treatment of newly diagnosed multiple myeloma (MM) has evolved rapidly over recent years. The availability of new effective drugs with novel mechanisms of action, such as thalidomide, lenalidomide and bortezomib in the last decade, has resulted in a new scenario expected to impact favorably on the outcome of patients with MM. The introduction of new drugs in the treatment of patients eligible for autologous stem cell transplantation (ASCT) has allowed for a significant increase of complete response rate with a positive impact on progression‐free survival. In patients not eligible for ASCT, randomized trials have shown that both thalidomide and bortezomib when combined with melphalan and prednisone (MP) are superior to MP and are now considered the standard of care. Ongoing trials are assessing whether MP plus lenalidomide or the combination of lenalidomide plus dexamethasone should be considered an attractive treatment option, while additional studies are needed to determine the role of routine maintenance or consolidation therapy with these new drugs. This new therapeutic armamentarium in light of adequate prophylaxis and supportive care allows clinicians to greatly improve the survival perspectives for both young and elderly patients. In this review, we report updated data for the front‐line therapy of MM, examining the role of new drugs either when administered as induction therapy before ASCT in younger patients or when combined with alkylating agents for the treatment of older patients. The most relevant articles on therapy of MM published from November 1982 to January 2010 (selected through PubMed), and recent meeting abstracts were used as sources for this review.     

Bortezomib and thalidomide, a steroid free regimen in newly diagnosed patients with multiple myeloma

Despite their efficacy in myeloma, corticosteroids have acute and chronic toxicities. Newer agents with significant anti-myeloma activity permit the development of steroid-free regimens. We designed a Phase II clinical trial to study the toxicity and efficacy of a steroid-free combination of bortezomib and thalidomide as a first-line treatment in patients with symptomatic myeloma. Patients received bortezomib 1·3 mg/m(2) on days 1, 4, 8 and 11 every 21 d and thalidomide 150 mg/d for a maximum of eight cycles. Amongst 27 evaluable patients, the overall response was 81·5% with 25·8% near complete response or greater. The response rate was comparable to most other two drug combinations for upfront therapy but lower than that obtained with the use of three drugs. The most common grade 3 toxicities were peripheral neuropathy (22%), pneumonia (15%), fatigue (7%) and anaemia (7%). Peripheral neuropathy completely resolved in 80% of the patients upon completion of therapy, but not in the remaining 20% of patients. No venous thromboembolic events were observed even in the absence of prophylactic anticoagulation. The median progression-free survival was 16·8 months (95% confidence interval 8·7-21·6 months). Median overall survival has not yet been reached at a median follow up of 39 months. The 3-year overall survival was 74%. This study demonstrates: (i) the efficacy of a steroid-free regimen; (ii) mostly reversible treatment-related peripheral neuropathy; and (iii) the absence of venous thrombotic events.     

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多发性骨髓瘤仍是一种不可治愈的血液肿瘤,近10年的治疗突破很大程度上依赖新药的研发,主要包括蛋白酶体抑制剂硼替佐米、免疫调节剂如来那度胺和沙利度胺等。力求达到完全缓解(CR)是目前的治疗目标,因为CR意味着无进展生存期(PFS)甚至总生存期(OS)的延长。以新药为基础的不同诱导方案显著提高一线治疗缓解率。缓解后或移植后进行巩固和维持治疗显著延长PFS。文章主要对包含新药的诱导方案进行总结,并简要讨论难治复发骨髓瘤患者的治疗。     

Current status of new drugs for the treatment of patients with multiple myeloma

Multiple myeloma, a malignant disorder of plasma cells, is the second most common haematological malignancy. Although treatable, multiple myeloma remains incurable in virtually all cases, with a median survival of 3-4 years. Fortunately for patients with this disease, traditional treatment paradigms have been challenged with the emergence of a number of new therapies entering clinical practice over the last 6 years. In this review, we focus on the use of thalidomide (Thalidomide Pharmion; Boulder, CO, USA), lenalidomide (Revlimid; Celgene Corporation, Summit, NJ, USA) and bortezomib (Velcade; Janssen Pharmaceutica N.V., Belgium) in the treatment of myeloma. We present the current clinical experience with respect to efficacy and toxicity of these promising new agents and how the incorporation of these drugs with traditional therapies may improve the outcome for patients with multiple myeloma.     

A comparison of lenalidomide/dexamethasone versus cyclophosphamide/lenalidomide/dexamethasone versus cyclophosphamide/bortezomib/dexamethasone in newly diagnosed multiple myeloma

Novel agents are considered standard components of induction therapy for newly diagnosed patients with multiple myeloma. We retrospectively compared the results of three consecutive phase 2 clinical trials; RD (lenalidomide/dexamethasone, n = 34), CRD (cyclophosphamide/lenalidomide/dexamethasone, n = 53) and CyBorD (cyclophosphamide/bortezomib/dexamethasone, n = 63) (N = 150). Response rates after four cycles of treatment were: ≥near complete response (nCR), 12% vs. 2% vs. 41%, P < 0·0001 and very good partial response or better, 35% vs. 30% vs. 65%, P = 0·0003, respectively. With all cycles of therapy considered, ≥nCR was 35%, 15% and 41%, P = 0·006. However, there is no evidence that one regimen produced superior progression‐free survival (PFS) (median: 3·2 vs. 2·3 vs. 2·7 years, P = 0·11) or overall survival (3‐year: 88% vs. 79% vs. 88%, P = 0·23). Transplantation did not impact PFS (median: 2·7 vs. 2·3 years, P = 0·41) but was associated with improved OS (3‐year: 93% vs. 75%, P ≤ 0·001). High genetic risk patients (n = 40) had earlier relapse despite lenalidomide or bortezomib (median: 2·1 vs. 2·7 years, P = 0·45). Grade 3/4 toxicities were least with CyBorD while CRD had most toxicity. In conclusion, CyBorD demonstrated superior responses and less frequent serious toxicity but more neuropathy when compared to RD and CRD. Importantly, 80% of patients treated with modern therapeutic approaches are alive at 4 years.     

Clinical impact of chromosomal aberrations in multiple myeloma

Chromosomal aberrations are frequently found in multiple myeloma cells and play a major role in patient outcome and management of the disease. The most important chromosomal aberrations associated with poor outcome are del(17p), t(4;14), t(14;16) and t(14;20). Others that may be associated with adverse prognosis include amp(1)(q21), del(1p32), del(13), del(8p21) and hypodiploidy. Many chromosomal aberrations have no or uncertain impact; for example, t(11;14), t(8;14) and hyperdiploidy. Attempts have been made to overcome the negative prognostic impact of chromosomal aberrations using autologous or allogeneic transplantation or new immunomodulatory drugs such as thalidomide, lenalidomide and the proteasome inhibitor bortezomib, but the results are controversial. Data suggest that allogeneic transplantation and treatment with bortezomib or lenalidomide may help to overcome the negative effect of del(13) on prognosis, whereas bortezomib may have some influence on reducing the impact of del(17p), t(4;14) and t(14;16). Chromosome analysis should always be performed at diagnosis of multiple myeloma to improve the prediction of outcome and to aid treatment decision-making.     

不同剂量硼替佐米治疗多发性骨髓瘤的临床研究

目的:观察1.6mg/m2和1.3mg/m2两种剂量硼替佐米联合沙利度胺、地塞米松治疗多发性骨髓瘤患者的疗效和毒副反应。方法:快速静脉给予1.6mg/m2或1.3mg/m2 2种不同剂量的硼替佐米,同期应用沙利度胺和地塞米松。采用2006年国际骨髓瘤工作组制定的标准判定疗效,并按NCI CTCAE标准判断不良反应。结果:①剂量为1.6mg/m2的9例患者中,3例达到完全缓解(CR),CR率为33%;1.3mg/m2组25例患者中,8例达到CR,CR率为32%,2组差异无统计学意义(P>0.05);②2个疗程后早期评价疗效,1.6mg/m2组的总有效率(ORR)为87.5%,1.3mg/m2组ORR为43.5%,两组差异具有统计学意义(P<0.05);③2组主要不良反应多为胃肠道症状、周围神经病变、血小板减少,1.6mg/m2组发生率依次为66.7%、55%和33%,1.3mg/m2组发生率依次64%、56%和28%,两组差异无统计学意义(P>0.05)。结论:硼替佐米联合沙利度胺、地塞米松治疗多发性骨髓瘤临床疗效明显,不良反应轻微,1.6mg/m2硼替佐米组患者的症状改善明显,且起效快于1.3mg/m2组,患...     

Light chain deposition disease: novel biological insights and treatment advances

Light chain deposition disease (LCDD) is a monoclonal gammopathy characterized by nonamyloid deposition of immunoglobulin light chains in various organs. Most cases present with renal dysfunction, a ubiquitous feature of this disease, and in some instances, it may progress to end-stage renal disease. Unfortunately, until now, no standard treatment has been established. The use of alkylating agents and steroids has been extensively reported. However, conventional chemotherapy response is generally limited with minor effects on kidney function. The use of novel agents such as bortezomib has shown a more rapid response with a dramatically important reduction of light chains in serum and/or urine in small series of cases. Furthermore, autologous stem cell transplantation has been reported as a feasible strategy in LCDD, able to prolong the dialysis-free survival. Nonetheless, toxicity from these therapies should be considered carefully because most of patients might present with kidney dysfunction that could limit the use of some agents.     

From the bench to the bedside: emerging new treatments in multiple myeloma

Within the last decade, several novel classes of anti-myeloma therapeutics have become available. The clinical successes achieved by thalidomide, lenalidomide, and the proteasome inhibitor bortezomib, and in particular the ability of these agents to lead to major clinical responses in patients resistant to conventional or high-dose chemotherapy, have highlighted the importance of expanding further the spectrum of classes of agents utilized for the treatment of myeloma. Herein, we review the current status for the development of novel anti-myeloma agents, with emphasis on classes of therapeutics which have already translated into clinical trials or those in advanced stages of preclinical development. These include second-generation proteasome inhibitors (NPI-0052 and PR-171), heat shock protein 90 (hsp90) inhibitors, 2-methoxyestradiol, histone deacetylase (HDAC) inhibitors (e.g. SAHA and LBH589), fibroblast growth factor receptor 3 (FGF-R3) inhibitors, insulin-like growth factor 1 receptor (IGF-1R) inhibitors, mTOR inhibitors, monoclonal antibodies, and agents specifically targeting the tumor microenvironment, such as defibrotide.     

Short progression-free survival predicts for poor overall survival in older patients with multiple myeloma treated upfront with novel agent-based therapy

Objectives: To assess the importance of the quality of response and of early relapse in unselected elderly patients with myeloma treated upfront with novel agents. Methods: We analyzed 135 unselected transplant‐ineligible patients older than 65 yr who were treated upfront with novel agent‐based regimens in a single center. Results: On intent to treat, 81% of patients achieved a response (28% sCR/CR, 23% VGPR, and 30% PR). Median progression‐free survival (PFS) for patients who achieved sCR/CR was 31 vs. 20 months for VGPR and 23 months for PR (P = 0.048). Median overall survival (OS) for patients with sCR/CR was 62 months, 53 months for VGPR and 38 months for patients with PR (P = 0.028). Early relapse (PFS < 12 months) was more common in patients with PR (39% vs. 21% for VGPR vs. 3% for sCR/CR). Patients who relapsed or progressed <12 months from initiation of treatment had a median OS of 15.4 months compared with 53 months (P < 0.001) for patients who had a PFS > 12 months despite the fact that after relapse or progression most patients were treated again with novel agents. In multivariate analysis, short PFS was the most significant adverse prognostic factor affecting OS, associated with a 7.25‐fold (P < 0.0001) increase in the risk of death. Conclusion: In newly diagnosed patients over 65 yr, treated upfront with novel agents achievement of CR and a PFS ≥12 months is associated with improved outcome. Patients who fail to respond or experience early relapse after primary therapy with novel agent‐based regimens should be encouraged to participate in clinical trials of novel agents and combinations.     

Proteomic profiling of naïve multiple myeloma patient plasma cells identifies pathways associated with favourable response to bortezomib‐based treatment regimens

Toward our goal of personalized medicine, we comprehensively profiled pre‐treatment malignant plasma cells from multiple myeloma patients and prospectively identified pathways predictive of favourable response to bortezomib‐based treatment regimens. We utilized two complementary quantitative proteomics platforms to identify differentially‐regulated proteins indicative of at least a very good partial response (VGPR) or complete response/near complete response (CR/nCR) to two treatment regimens containing either bortezomib, liposomal doxorubicin and dexamethasone (VDD), or lenalidomide, bortezomib and dexamethasone (RVD). Our results suggest enrichment of ‘universal response’ pathways that are common to both treatment regimens and are probable predictors of favourable response to bortezomib, including a subset of endoplasmic reticulum stress pathways. The data also implicate pathways unique to each regimen that may predict sensitivity to DNA‐damaging agents, such as mitochondrial dysfunction, and immunomodulatory drugs, which was associated with acute phase response signalling. Overall, we identified patterns of tumour characteristics that may predict response to bortezomib‐based regimens and their components. These results provide a rationale for further evaluation of the protein profiles identified herein for targeted selection of anti‐myeloma therapy to increase the likelihood of improved treatment outcome of patients with newly‐diagnosed myeloma.     

The roles of consolidation and maintenance therapy with novel agents after autologous stem cell transplantation in patients with multiple myeloma

Novel agents including immunomodulatory drugs and proteasome inhibitors incorporated into induction regimens and subsequently followed by autologous stem cell transplantation in cases of multiple myeloma have resulted in enhancement of response rate and its depth. Maintaining or even improving the response is an important treatment goal. Most clinical trials have revealed increased progression‐free survival after consolidation and maintenance therapy. Some of them have also shown prolongation of overall survival. However, continuous therapy may be associated with significant side effects and costs, and therefore remains controversial. Treatment decisions should be individualized and based upon projected benefits and risks.     

Role of autologous stem-cell transplantation in multiple myeloma

Multiple myeloma (MM) is one of the diseases in which the impact of dose intensity has been demonstrated. Consequently, in 2005 MM was the first disease for which autologous stem-cell transplantation (ASCT) was indicated in Europe and the US. However, ASCT is not curative, and most patients relapse in a median of 3 years. The introduction of novel agents such as thalidomide, bortezomib (Velcade) or lenalidomide (Revlimid) was logical to try to improve the high-dose strategy, and promising results have been reported. This article will focus on the current results of ASCT and will discuss the main research area to try to improve this strategy.     

硼替佐米为主化疗方案治疗初治与复发难治多发性骨髓瘤近期疗效分析

目的:分析硼替佐米为主化疗方案治疗初治与复发难治多发性骨髓瘤(MM)患者的临床疗效和不良反应.方法:初治MM患者11例,复发、难治MM患者7例均采用VD方案化疗:硼替佐米1.0～1.3 mg/m2第1、4、8和11天快速静脉注射,地塞米松20 mg第1～4天(7例复发难治予地塞米松40 mg)静脉滴注,3周为1疗程,所...     

Bortezomib in multiple myeloma

Multiple myeloma (MM) remains an incurable disease, and novel agents are therefore needed to improve outcome. Bortezomib is the first proteasome inhibitor to be approved by the US Food and Drug Administration and the European Agency for the Evaluation of Medicinal Products for the treatment of refractory/relapsed MM. Bortezomib has demonstrated significant anti-myeloma activity as a single agent in refractory/relapsed MM. When used in combination with other agents, responses have suggested the possibility of chemosensitization and synergy. All these facts have been the rationale for the use of bortezomib-based regimens as upfront treatment in young and elderly newly diagnosed MM patients. Furthermore, bortezomib does not appear to have an adverse effect on subsequent stem-cell collection. Bortezomib is well tolerated; most side-effects are only mild to moderate and manageable. Practical management of these side-effects is given so that they can be recognized and minimized by dose modification or concomitant therapy.