Panobinostat: a novel pan-deacetylase inhibitor for the treatment of relapsed or relapsed and refractory multiple myeloma

Outcomes for patients with multiple myeloma (MM) have improved significantly over the past decade. Despite these advances, MM remains incurable and an unmet medical need remains for patients who are relapsed and/or refractory. Panobinostat is a potent, oral pan-deacetylase inhibitor that elicits anti-myeloma activity through epigenetic modulation of gene expression and disruption of protein metabolism. Preclinical data demonstrated that panobinostat has synergistic effects on myeloma cells when combined with bortezomib and dexamethasone. In a Phase III clinical trial evaluating bortezomib and dexamethasone in combination with panobinostat or placebo in patients with relapsed or relapsed and refractory MM (PANORAMA 1), panobinostat led to a significant increase in median progression-free survival. Panobinostat is currently under regulatory review with a recent accelerated approval granted for the treatment of relapsed disease, in which both bortezomib and immunomodulatory drugs have failed. Here, we summarize the preclinical, pharmacokinetic and clinical data for panobinostat in MM.     

A phase II trial with gemcitabine and paclitaxel for the treatment of refractory and relapsed multiple myeloma patients

Multiple myeloma (MM) is an incurable disease with a 10-year survival of <20%. We have previously shown that the combination of gemcitabine and paclitaxel acts synergistically to induce apoptosis of myeloma cells in vitro. Based on these preclinical studies and phase I-II clinical trials in patients with solid tumors, we initiated a phase II clinical trial of paclitaxel 150 mg/m(2) IV over 3 h followed by gemcitabine 3000 mg/m(2) IV over 30-60 min in patients with relapsed or refractory MM. This regimen was administered every two weeks for a total of six cycles. Twelve patients enrolled, 3 discontinued treatment after 1 or 2 cycles because of severe neutropenia. As a result the protocol was modified to reduce the starting dose of gemcitabine to 2,000 mg/m(2). This resulted in tolerable hematological and mild non-hematological toxicities in the rest of the patients. One patient died before the onset of treatment. Of the 8 remaining patients treated with a reduced dose of gemcitabine, 1 achieved a durable CR, 3 had PR, 1 had minor response (MR), 1 had stable disease and 2 had progressive disease. The CR patient had a 98% reduction in the M-protein, beta2-microglobulin and plasma cells. His CR continued for more than 6 months. The 3 PR patients had a >50% reduction in the M-protein and >40% reduction in beta2-microglobulin. Bone marrow plasma cells were reduced by >50% in these patients. Treatment with the combination of paclitaxel and gemcitabine is an active and well-tolerated regimen in patients with relapsed or refractory multiple myeloma.     

Survivin在多发性骨髓瘤患者骨髓细胞中的表达及其临床意义

背景与目的:Survivin是凋亡抑制蛋白家族成员之一,在多种恶性肿瘤中高表达,但在正常成人分化组织无表达。其表达与多种肿瘤的预后及肿瘤对放、化疗的耐受有关。本研究旨在通过检测Survivin在正常人、初治及复发/难治多发性骨髓瘤(multiplemyeloma,MM)患者骨髓细胞及骨髓瘤细胞系KM3中的表达,以揭示Survivin在骨髓瘤中的表达与耐药及疗效的关系。方法:RT-PCR和Westernblot法检测29例MM患者(其中初治17例,复发/难治12例)、9例正常人骨髓标本及KM3细胞系中SurvivinmRNA和蛋白质水平表达。结果:骨髓瘤细胞系KM3高表达Survivin。SurvivinmRNA在正常人、初治和难治/复发MM患者骨髓细胞中阳性率分别为22.2%、70.5%和83.3%,表达水平(Survivin/β-actin比值)分别为0.06±0.04、0.31±0.14和0.69±0.24,骨髓瘤患者表达率和表达水平显著高于正常人(P<0.01),而难治/复发MM组表达水平高于初治组(P<0.05)。所有的正常人标本中均未检测到Survivin蛋白,在初治和难治/复发MM组Survivin蛋白阳性率分别为41.1%和58.3%(P>0.05),表达水平(Survivin/α-tubulin半定量比值)分别为0.11±0.07和0.21±0.12,难治/复发MM组明显为高(P<0.05)。17例初治患者中,7例Survivin阳性者4例部分缓解(partialresponse,PR),1例微小反应(minorresponse,MR),2例无变化(nochange,NC),有效率[完全缓解(completeresponse,CR) PR MR]71.4%;10例Survivin阴性者中2例CR,4例PR,2例MR,2例NC,有效率80%,略高于阳性组。但统计学分析未发现两组有效率存在显著性差异。结论:Survivin在骨髓瘤患者中的高表达可能是部分患者对化疗不敏感的原因之一,由于Survivin仅特异性表达于骨髓瘤细胞,Survivin可作为逆转骨髓瘤细胞耐药治疗中的潜在靶点。     

Immunohistochemical identification of HER-2/neu overexpression and CD117 (c-kit) expression in multiple myeloma

Multiple myeloma (MM) is the most common plasma cell dyscrasia. Conventional therapy results in a median survival of 3-5 years. Patients with B-cell disorders and coexistent HER-2/neu overexpression in solid tumors have a poorer prognosis than those without an underlying B-cell disorder. This, and the recent success of the tyrosine kinase inhibitor, imatinib mesylate in chronic myelogenous leukemia, led us to evaluate the incidence and role of c-kit (CD117) and HER-2/neu overexpression in MM. We conducted a retrospective study to determine the incidence of HER-2/neu and c-kit overexpression in MM. HER-2/neu overexpression was evaluated using the DAKO Hercep test and c-kit overexpression was assessed using conventional immunohistochemistry (IHC); 69 patients with a diagnosis of MM were identified, of whom, 31 patients (19 males and 12 females) had an adequate pathological specimen available for IHC testing; 4 out of 31 patients (12.9%) showed HER-2/neu overexpression, while 5/31 (16.13%) showed CD117 expression. Two patients (6.45%) showed both HER-2/neu and c-kit overexpression. Although both HER-2/neu and c-kit are not expressed very frequently in patients with MM, there appears to be a subgroup of patients in whom, either one or both these oncogenes is overexpressed. Given our small sample size, it is difficult to comment on the effect of CD117 and/or HER-2/neu overexpression on survival. Future larger studies are needed to define the association in MM and to determine if the presence of one (CD117 or HER-2/neu) has an effect on overexpression of the other oncoprotein. Furthermore, it would be beneficial to identify the molecular nature of the interplay between HER-2/neu and c-kit, if any. Target-directed signal transduction inhibition therapy using tyrosine kinase inhibitors, may be a distinct possibility in a select group of patients with MM.     

Feasibility and correlates of arsenic trioxide combined with ascorbic acid-mediated depletion of intracellular glutathione for the treatment of relapsed/refractory multiple myeloma.

Patients with multiple myeloma (MM) invariably relapse with chemotherapy-resistant disease, underscoring the need for new agents that bypass these resistance mechanisms. We have reported that ascorbic acid (AA) enhances the activity of arsenic trioxide (As(2)0(3)) against drug-resistant MM in vitro by depleting intracellular glutathione (GSH). These data led us to open a National Cancer Institute/Cancer Therapy Evaluation Program-sponsored Phase I/II trial of As(2)0(3) + AA for relapsed/refractory MM. We now present the completed Phase I component of this trial. The primary objective of the trial's Phase I component was to assess whether the addition of AA affected the well-described toxicity profile of As(2)0(3) alone. Correlative studies were undertaken of As(2)0(3) and AA pharmacokinetics, the ability of AA to deplete intracellular GSH in vivo, and the development of arsenic resistance. Six patients with stage IIIA relapsed/refractory myeloma were studied. We found that 0.25 mg/kg/day As(2)O(3) + 1,000 mg/day AA could be given for 25 days (over a 35-day period) without dose-limiting toxicity. One episode of grade 3 hematological toxicity (leukopenia) and no grade 3 nonhematological toxicities (in particular, cardiac) were observed. The coadministration of AA did not alter the pharmacokinetics of As(2)0(3), and elevated AA levels were associated with decreased intracellular GSH. Serial in vitro studies demonstrated continued sensitivity of patient myeloma cells to As(2)0(3) + AA. Two patients (both with thalidomide-refractory disease) had partial responses; four patients had stable disease. In conclusion, we have found that As(2)0(3) + AA has acceptable toxicity and that there is promising evidence of activity in refractory/relapsed myeloma.     

Panobinostat: A Review in Relapsed or Refractory Multiple Myeloma

Oral panobinostat (Farydak®), a potent nonselective histone deacetylase inhibitor, is approved in several countries for use in combination with bortezomib and dexamethasone in patients with multiple myeloma (MM) [USA] or relapsed and/or refractory MM (EU) who have received at least two prior treatment regimens, including bortezomib and an immunomodulatory drug (IMiD). In a pivotal phase III trial (PANORAMA 1) in patients with relapsed or relapsed and refractory MM who had received one to three previous lines of therapy, progression-free survival (PFS) was significantly prolonged with panobinostat plus bortezomib and dexamethasone compared with placebo plus bortezomib and dexamethasone. The significantly favourable effect of panobinostat- versus placebo-based treatment on PFS was also observed in a subgroup analysis of patients who had previously received an IMiD, bortezomib plus an IMiD, or at least two lines of treatment including bortezomib and an IMiD. Panobinostat plus bortezomib and dexamethasone had a generally manageable tolerability profile, with the most frequent grade 3–4 adverse events being myelosuppression, diarrhoea, asthenia or fatigue, peripheral neuropathy and pneumonia. Thus, panobinostat, in combination with bortezomib and dexamethasone, is a useful addition to the available treatment options for patients with relapsed or refractory MM.     

靶向B细胞成熟抗原在多发性骨髓瘤中的治疗进展

过去20年,多发性骨髓瘤（multiple myeloma,MM）的治疗取得了较大的进展,患者的生存时间获得显著延长,但多数患者最终仍会复发或变为难治性,MM仍然无法治愈。B细胞成熟抗原（B cell maturation antigen,BCMA）的表达仅限于一些B细胞谱系,在MM细胞上广泛表达,是MM的一个理想靶抗原。多种靶向BCMA的治疗,包括嵌合抗原受体（chimeric antigen receptor,CAR）T 细胞、双特异性抗体（bispecific antibodies,BsAbs）和抗体-药物偶联物（antibod-drug conjugate,ADC）,在复发/难治性MM患者中取得显著的临床反应。本文综述了近年来MM靶向BCMA治疗的研究进展。      

基于维奈托克的方案治疗(t11;14)复发难治多发性骨髓瘤一例并文献复习

目的探讨基于维奈托克的治疗方案对t(11;14)复发难治多发性骨髓瘤(RRMM)患者的治疗效果。方法回顾性分析海军军医大学长征医院2019年6月收治的1例接受基于维奈托克治疗方案的t(11;14)RRMM患者资料,并进行相关文献复习。结果该t(11;14)RRMM患者经三线治疗进展后,予以选择性bcl-2抑制剂维奈托克联合达雷妥尤单抗、地塞米松治疗,疾病达到部分缓解,且一度血象恢复,美国东部肿瘤协作组(ECOG)体能状态评分由3分下降至1分,生命质量明显改善。结论(t 11;14)RRMM患者可从基于维奈托克的治疗中获益,未来尚需对维奈托克治疗多发性骨髓瘤的安全性、敏感性等进行深入探索。     

KD-PACE Salvage Therapy for Aggressive Relapsed Refractory Multiple Myeloma,Plasma Cell Leukemia and Extramedullary Myeloma

BackgroundPatients with advanced/aggressive multiple myeloma have limited treatment options to achieve rapid disease control. In eligible patients, bortezomib, dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, and etoposide is often used. However, many patients are refractory to or have toxicities from bortezomib and there is a need for bridging therapy. We have used a modified regimen incorporating the second-generation proteasome inhibitor carfilzomib (carfilzomib, dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide and etoposide [KD-PACE]) instead of bortezomib for relapsed/refractory multiple myeloma.Patients and MethodsThis 2-center retrospective study included consecutive patients receiving KD-PACE for relapsed or refractory multiple myeloma, plasma cell leukemia, or extramedullary myeloma. The primary outcome was the feasibility of KD-PACE as a bridging therapy to a more definitive treatment option.ResultsFifty-two patients were included. The median age was 57 years, and 67% were male. Thirty-one patients were bridged with KD-PACE to autologous hematopoietic stem cell transplant (29%), allogenic hematopoietic stem cell transplant (27%), or a clinical trial (12%). Patients bridged to autologous hematopoietic stem cell transplant, allogenic hematopoietic stem cell transplant, or a clinical trial had a superior progression-free survival (8.3 months vs 2.3 months in the nonbridged group; P < .001) and overall survival (median, 16.7 months vs 4.3 months in the nonbridged group; P < .001). No unexpected toxicities occurred from the treatment regimen.ConclusionKD-PACE is a promising treatment option for select patients with advanced/aggressive forms of myeloma requiring rapid disease control before a more definitive salvage therapy such as auto/allotransplantation or a clinical trial.     

Clinical Updates Regarding Multiple Myeloma From the 2019 American Society of Hematology Annual Meeting

In this review, we summarize novel clinical data on multiple myeloma (MM) that were presented at the 2019 annual meeting of the American Society of Hematology. The Master trial showed that a response-adapted approach may effectively guide therapeutic decisions in terms of treatment intensification after autologous transplantation among patients with newly diagnosed MM. The Alcyone study confirmed the superiority of adding daratumumab to the backbone combination of bortezomib, melphalan, and dexamethasone among diagnosed MM patients unfit for transplantation, which resulted in a significant overall survival benefit. The Candor trial showed that the addition of daratumumab to carfilzomib and dexamethasone is associated with a significant benefit in progression-free survival among patients with relapsed/refractory MM after 1 to 3 prior lines of therapy. Novel agents including selinexor- and venetoclax-based combinations offer new therapeutic choices for relapsed/refractory MM. Furthermore, the trispecific CC-93269 represents the new generation of highly active T-cell engagers. Chimeric antigen receptor T-cell constructs show significant efficacy among patients with heavily pretreated relapsed/refractory MM; however, the sustainability of responses remains a challenge.     

CD45 expression by bone marrow plasma cells in multiple myeloma: clinical and biological correlations.

Multiple myeloma (MM) is characterized by accumulation of clonal plasma cells (PCs). CD45, a key regulator of antigen-mediated signaling and activation in lymphocytes, is present in early stages of PCs development. We studied CD45 expression on MM PCs by flow cytometry, correlating it to important biological disease characteristics. Additionally, we examined the expression of various adhesion molecules on PCs. A total of 75 patients with untreated MM (29), relapsed MM (17), smoldering MM (12), and monoclonal gammopathy of undetermined significance (MGUS) (17) were studied. The proportion of PCs expressing CD45 was higher among those with early disease (MGUS or smoldering MM) compared to those with advanced disease (new or relapsed MM) (43 vs 22%; P=0.005). Among those with advanced disease, patients with bone lesions had a lower percentage of CD45-positive (CD45+) PCs; 14 vs 34% (P=0.02). Patients with high-grade angiogenesis had a lower percentage of CD45+ PCs; 13 vs 31% (P=0.03). The median overall survival for the CD45+ group (>20% PCs positive) was 39 vs 18 months for the CD45-negative (CD45-) group (P=0.07). The expression of CD138, CD56 and CD54 were higher among the CD45- PCs. This study demonstrates important biological correlates of CD45 expression on myeloma cells.     

A Phase I Study to Assess the Safety and Pharmacokinetics of Single-agent Lorvotuzumab Mertansine (IMGN901) in Patients with Relapsed and/or Refractory CD–56-positive Multiple Myeloma

Background

Despite therapeutic advancements that have significantly improved outcomes in multiple myeloma (MM), it remains an incurable disease. Patients with relapsed and/or refractory MM have an aggressive disease course, with inferior outcomes, necessitating the need for agents with novel therapeutic mechanisms. We present the results of a completed phase I trial of single-agent lorvotuzumab mertansine, a unique antibody-drug conjugate targeting CD56, which is frequently expressed in MM.

Efficacy and safety results with the combination therapy of arsenic trioxide, dexamethasone, and ascorbic acid in multiple myeloma patients

BACKGROUND: Single-agent arsenic trioxide has shown promising results in patients with relapsed or refractory multiple myeloma (MM). Because preclinical data suggested greater activity with dexamethasone and ascorbic acid, a phase 2 trial of the combination of arsenic trioxide, dexamethasone, and ascorbic acid in patients with relapsed or refractory MM was conducted. METHODS: Twenty patients in whom no more than two previous therapies had failed were enrolled. The mean age was 62 yr, and 55% of the patients had refractory disease. The regimen consisted of 14- or 15-wk cycles, with the first cycle considered induction, followed by one or two consolidation cycles with a reduced steroid schedule and then a maintenance cycle in responding patients. RESULTS: The overall response rate was 30%, with at least stable disease in 80% of patients. Median progression- free survival was 316 d in all patients and 584 d in those with a response. The regimen was well tolerated, with most adverse events being mild or moderate. CONCLUSIONS: This study showed the clinical efficacy and tolerability of the combination of arsenic trioxide, dexamethasone, and ascorbic acid. Further study is warranted.     

Pharmacokinetic and clinical phase II trial of imatinib in patients with impaired liver function and advanced hepatocellular carcinoma

OBJECTIVES: No effective chemotherapy for advanced hepatocellular carcinoma (HCC) exists. Expression of the platelet-derived growth factor receptor (PDGFR) has been demonstrated in HCC, which may derive from hepatic stem cells that express c-kit. The aim of this trial was to evaluate imatinib, a tyrosine kinase inhibitor of PDGFR and c-kit, in patients with advanced HCC and impaired liver function. PATIENTS AND METHODS: Patients were treated with 400-600 mg imatinib daily. Immunohistochemical staining was performed for PDGFR and c-kit. Response was assessed by CT scans every 8 weeks. For pharmacokinetics studies, 74 plasma samples were assessed. RESULTS: Of the 17 patients enrolled in the study, 15 were evaluable for response. Only 1 tumor was positive for PDGFR and none was positive for c-kit. Grade 3/4 neutropenia occurred in 2 patients (1 had neutropenic fever). There was no objective response, and 5 (33%) patients had stable disease. Median time to treatment failure was 1.8 months in the whole study cohort and 3.7 months in the patients with stable disease. Patients treated with 400 mg imatinib did not significantly differ in pharmacokinetics from patients with chronic myelogenous leukemia (CML). CONCLUSION: In this small group of patients with advanced, mostly PDGFR- and c-kit-negative HCC, imatinib showed no therapeutic effect. In contrast to CML patients, the pharmacokinetics of imatinib were not significantly affected by impaired liver function.     

Emerging Targets and Cellular Therapy for Relapsed Refractory Multiple Myeloma: A Systematic Review

Multiple myeloma is the second most common hematologic malignancy and remains incurable. Patients who fail multiple lines of therapy typically have a poor prognosis despite recent advances in myeloma treatment. Chimeric antigen receptor T (CAR T) cell treatment has emerged as a promising therapy for many hematologic malignancies, including recently approved and emerging applications for myeloma treatment. A systematic review of the available clinical trial data for CAR T therapies in multiple myeloma was undertaken. All multiple myeloma trials registered at ClinicalTrials.gov were reviewed and studies mentioning CAR T and studying relapsed/refractory multiple myeloma (R/R MM) were included. PubMed, Google Scholar, and conference proceedings were also reviewed to determine which trials had reported data. Twenty-seven registered clinical trials in humans with published data were identified as of March 10, 2021. The majority of these trials were CAR T cells targeting B-cell maturation antigen (BCMA), and many were Phase I studies. Data demonstrated promising short-term (<12 months) efficacy with low incidence of grade 3 or higher toxicities. CAR T cell therapy in R/R MM remains a promising treatment modality. While one biologic has recently received FDA-approval, the majority of products remain investigational and in early-phase trials. More investigation is needed to determine which CAR T constructs and combination therapies optimize patient outcomes.     

Meta-Analysis of the Efficacy and Safety of Bortezomib Re-Treatment in Patients With Multiple Myeloma

IntroductionBortezomib is administered for a finite course; thus, patients might remain sensitive to bortezomib-based therapy at relapse. We report a meta-analysis of bortezomib-based retreatment in relapsed/refractory myeloma.Patients and MethodsA systematic literature review identified studies of bortezomib-based retreatment in relapsed/refractory myeloma. Proportions of bortezomib-refractory patients and additional prognostic factors were extracted and used in weighted stratified analyses of TTP and OS. Random-effect pooled estimates were calculated for overall response rate (ORR) and rates of common AEs.ResultsTwenty-three studies (n = 1051 patients) were identified. Bortezomib was administered intravenously in all studies. Across studies in which data were available, pooled, weighted average ORR was 39.1% (95% confidence interval, 30.8%-47.4%), and pooled, weighted average median TTP and OS were 7.5 and 16.6 months, respectively. Patients with fewer previous therapies (≤ 4) and relapsed (not refractory) patients achieved higher ORRs, of 43.4% and 57.2%, respectively. Random-effects meta-regression analysis confirmed that relapsed patients were associated with a higher ORR by 28 to 41 percentage points versus refractory patients. In relapsed patients, median TTP and OS were 8.5 and 19.7 months, respectively. Common Grade 3/4 AEs included thrombocytopenia (35%), neutropenia (15%), anemia (14%), pneumonia (10%), and peripheral neuropathy (3%).ConclusionBased on these findings, bortezomib retreatment is well tolerated and appears efficacious in relapsed patients. In an era of new and emerging treatment options for relapsed and/or refractory myeloma, these data indicate that bortezomib retreatment might be a highly effective option in previously treated patients.     

Junctional adhesion molecule-A is overexpressed in advanced multiple myeloma and determines response to oncolytic reovirus

Despite the development of several new agents for multiple myeloma (MM) therapy over the last decade, drug resistance continues to be a significant problem. Patients with relapsed/refractory disease have high mortality rates and desperately need new precision approaches that directly target specific molecular features that are prevalent in the refractory setting. Reolysin is a proprietary formulation of reovirus for cancer therapy that has demonstrated efficacy in multiple clinical trials. Its selective effects against solid tumors have been largely attributed to RAS-mediated control of reovirus replication. However, the mechanisms regulating its preferential anti-neoplastic effects in MM and other hematological malignancies have not been rigorously studied. Here we report that the reovirus receptor, junctional adhesion molecule-A (JAM-A) is highly expressed in primary cells from patients with MM and the majority of MM cell lines compared to normal controls. A series of experiments demonstrated that JAM-A expression, rather than RAS, was required for Reolysin-induced cell death in MM models. Notably, analysis of paired primary MM specimens revealed that JAM-A expression was significantly increased at relapse compared to diagnosis. Two different models of acquired resistance to bortezomib also displayed both higher JAM-A expression and elevated sensitivity to Reolysin compared to parental cells, suggesting that Reolysin may be an effective agent for patients with relapsed/refractory disease due to their high JAM-A levels. Taken together, these findings support further investigation of Reolysin for the treatment of patients with relapsed/refractory MM and of JAM-A as a predictive biomarker for sensitivity to Reolysin-induced cell death.     

MPV方案治疗难治性复发性多发性骨髓瘤18例临床观察

目的评估MPV方案治疗难治性复发性多发性骨髓瘤（MM）的疗效。方法18例难治性复发性MM患者,均给予MPV方案化疗,治疗4个周期观察疗效。观察项目包括血清M蛋白、肝肾功能、尿蛋白、骨髓像、血像等。结果经4个周期治疗,7例完全缓解,8例部分缓解,总有效率为83．33％。结论MPV方案是治疗难治性复发性MM较好的选择。     

雷利度胺为主方案治疗多发性骨髓瘤25例疗效分析

 目的　观察雷利度胺为主方案治疗多发性骨髓瘤（MM）患者的疗效及不良反应。方法　MM患者25例,其中5例为初治患者,13例为含沙利度胺方案治疗后难治、复发患者,7例为治疗后达平台期维持治疗患者。初治MM患者均采用R-PAD方案,难治、复发患者选用R-MD方案,维持治疗MM患者由于出现Ⅱ级伴疼痛以上的周围神经炎（PN）,采用雷利度胺单药治疗。结果　初治组5例,经过2个疗程的治疗均达到完全缓解（CR）（100 %）;难治、复发组13例,CR率为23.08 %（3／13）,非常好的部分缓解（VGPR）率为15.38 %（2／13）,部分缓解（PR）率为38.46 %（5／13）,总反应率（ORR）为76.92 %（10／13）;其余3例无反应患者中,2例疾病稳定（SD）,1例疾病进展（PD）。维持治疗组7例在平均38周的随访期内均维持缓解;改用雷利度胺后,PN获得不同程度的缓解。结论　对于初治MM患者,R-PAD方案缓解率高,起效快;对于难治、复发患者,特别是伴严重PN的MM患者,R-MD是值得选择的方案;雷利度胺还可用于伴PN的MM患者的维持治疗。