A modified regimen of pegylated liposomal doxorubicin, bortezomib and dexamethasone (DVD) is effective and well tolerated for previously untreated multiple myeloma patients

The combination of pegylated liposomal doxorubicin (PLD), bortezomib and dexamethasone has shown efficacy in the treatment of multiple myeloma (MM) patients. Our earlier retrospective study suggested that modification of the doses, schedules and route of administration of these drugs appears to reduce toxicity without compromising anti‐MM activity. As a result, we evaluated this modified drug combination in the frontline setting in a prospective multicentre phase II trial. Thirty‐five previously untreated MM patients were enrolled. Dexamethasone IV 40 mg, bortezomib 1 mg/m² and PLD 5 mg/m² were administered on days 1, 4, 8 and 11 of a 4‐week cycle. Patients were treated to their maximum response plus two additional cycles. The treatment regimen was discontinued after a maximum of eight cycles. Our modified schedule and dosing regimen achieved a high overall response rate of 86%, while showing a marked decrease in the incidence and severity of peripheral neuropathy, palmar‐plantar erythrodysesthesia and myelosuppression compared to the standard dosing on a 3‐week cycle using these drugs. This modified regimen of dexamethasone, bortezomib and PLD shows improved tolerability and safety while maintaining a high response rate when compared to standard treatment with these agents in the frontline setting.     

DVd(T)方案治疗多发性骨髓瘤17例临床疗效分析

目的:观察脂质体阿霉素(PLD)联合长春新碱(VCR)、地塞米松(Dex)士沙利度胺(Thal)治疗多发性骨髓瘤(MM)患者的疗效及毒副反应.方法:17例初治或复发难治MM患者接受DVd(PLD 40 mg·m-2d1、VCR 2 mg d1、Dex 40 mg d1～4)或DVdT(PLD及VCR用法用量同上,Dex:40 mg,d1～4、d9～12;Thal:100 mg,d1～21)治疗,按照EBMT标准评价疗效、WHO标准判断毒副反应.结果:①17例患者共完成了34个周期的治疗,总有效率(ORR=CR+nCR+VGPR+PR)为58.8%,与国外文献报道接近,与历史上我院采用的VAD及其类似方案相比疗效也接近.②采用DVd方案治疗的11例患者的ORR为4/11(36.4%).其中6例初治患者的ORR为2/6(33.3%).采用DVdT方案化疗的6例患者均为初治病例,其ORR为6/6(100%).对于初治患者.DVdT方案的ORR显著好于DVd方案.③多数治疗相关毒副反应为1～2级且可耐受.17例患者中有13例在接受DVd(T)化疗前心电图或心脏B超示不同程度的心律失常或左室舒张功能降低,但均未因化疗增加心脏毒性.DVd组与DVdT组的毒副反应接近.结论:DVd方案具有较好的耐受性,适当延长Dex用量并加入Thal可以在不增加化疗相关毒性的同时显著提高DVd方案疗效.     

Thalidomide-dexamethasone plus pegylated liposomal doxorubicin vs. thalidomide-dexamethasone: a case-matched study in advanced multiple myeloma

OBJECTIVES: Nearly all patients with multiple myeloma (MM) relapse or become refractory to front-line therapy. Several salvage therapies have been explored, but the optimal combination regimen has not been defined. We performed a case-matched study comparing patients with relapsed/refractory MM receiving thalidomide-dexamethasone alone or the combination thalidomide-dexamethasone-liposomal pegylated doxorubicin. METHODS: Forty-seven patients received thalidomide (100 mg/d), dexamethasone (40 mg p.o. on days 1-4 and 9-12), and pegylated liposomal doxorubicin (40 mg/m(2) on day 1 every 28 d) (ThaDD). Their clinical outcome was compared with that of 47 pair mates selected from patients treated at relapse with thalidomide (100 mg/d) and dexamethasone (40 mg p.o. on days 1-4) (Thal-Dex) and matched for age, beta2-microglobulin and previous therapy. RESULTS AND CONCLUSIONS: Overall response rate was significantly higher in ThaDD group (92% vs. 63.5%; P < 0.0001) as partial response rate (> or =PR) (75.5% vs. 59.5%; P = 0.077), very good partial response rate (> or =VGPR) (36% vs. 15%; P = 0.018) and near complete remission rate (> or =nCR) (30% vs. 10.5%; P = 0.002). Non-hematologic toxicity was similar in the two groups of patients whereas hematologic toxicity and infections were significantly higher in ThaDD patients. Median progression-free survival, event-free survival, and overall survival were significantly longer in patients receiving ThaDD than in those treated with Thal-Dex. ThaDD regimen significantly improved response rate and overall survival in comparison with Thal-Dex. Although the frequency of hematologic toxicity and infections resulted higher in ThaDD group compared with control group, they were not particularly frequent after adequate prophylaxis was added and were easily managed when occurred.     

PAD combination therapy (PS-341/bortezomib, doxorubicin and dexamethasone) for previously untreated patients with multiple myeloma

Bortezomib (formerly PS-341) has significant activity in patients with relapsed multiple myeloma (MM), its efficacy is increased with the addition of dexamethasone and it demonstrates synergy with doxorubicin, thus providing the rationale for combination therapy with bortezomib, doxorubicin and dexamethasone (PAD). Patients with untreated MM received four 21-d cycles of PAD, comprising bortezomib 1.3 mg/m(2) on days 1, 4, 8 and 11, along with dexamethasone 40 mg on days 1-4, 8-11 and 15-18 during cycle 1 and days 1-4 during cycles 2-4. During days 1-4, patients also received 0, 4.5 or 9 mg/m(2) of doxorubicin at dose levels 1, 2, and 3 respectively. Following peripheral blood stem cell (PBSC) collection, patients received high-dose melphalan (MEL200) with PBSC transplantation (PBSCT). After PAD induction alone, 20 of 21 patients (95%) achieved at least a partial response (PR), including complete response (CR) in five patients (24%). Twenty of 21 had PBSC mobilized, and 18 of 20 received MEL200/PBSCT. In an intention-to-treat analysis, response rates were: CR 43%, near CR 14%, very good PR 24%, PR 14% and stable disease 5%. PAD was effective, did not prejudice subsequent PBSC collection, and should be further evaluated in prospective randomized trials.     

An open‐label phase I/II study of cyclophosphamide,bortezomib, pegylated liposomal doxorubicin,and dexamethasone in newly diagnosed myeloma

We conducted a phase 1/2 trial evaluating the combination of cyclophosphamide, bortezomib, pegylated liposomal doxorubicin, and dexamethasone (CVDD) for newly diagnosed multiple myeloma (MM). The primary objective of the phase 1 was to evaluate the safety and tolerability of maximum planned dose (MPD) and the phase 2 was to assess the overall response rate. Patients received 6–8 cycles of CVDD at four dose levels. There were no dose‐limiting toxicities. The MPD was cyclophosphamide 750 mg/m² IV on day 1, bortezomib 1.3 mg/m² IV on days 1, 4, 8, 11, pegylated liposomal doxorubicin 30 mg/m² IV on day 4, and dexamethasone 20 mg orally on the day of and after bortezomib (21‐d cycle). Forty‐nine patients were treated at the MPD of which 22% had high‐risk myeloma. The most common grade ≥3 toxicities included myelosuppression, infection, and fatigue. Overall response and complete response rates were 91% and 26% in standard‐risk, and 100% and 58% in high‐risk cohort, respectively. After a median follow‐up of 34 months, the median progression‐free survival was 31.3 months. The 2‐yr overall survival was 91.1% in the standard‐risk and 88.9% in the high‐risk cohort, respectively. CVDD regimen was well tolerated and was highly active in newly diagnosed MM.     

PAD方案治疗初治多发性骨髓瘤的疗效研究

目的:观察硼替佐米联合脂质体多柔比星及地塞米松(PAD)方案治疗初治多发性骨髓瘤(MM)的疗效和不良反应。方法:初治MM患者19例,其中男11例,女8例,中位年龄66(43～77)岁。均给予PAD方案为一线治疗:硼替佐米1.3mg/m2,静脉注射,第1、4、8、11天;脂质体多柔比星20mg,静脉滴注,第1、4、8天;地塞米松20mg/d,静脉滴注,第1、4、8、11天,每4周为一个周期。采用国际骨髓瘤工作组(IMWG)标准观察疗效,并按国际肿瘤组织毒副作用统一命名法的标准(NCICTCAE)(第3版)判断不良反应。结果:平均(3.9±1.1)(2～6)个疗程后的疗效观察,总有效率为89%,其中完全缓解(CR)8例(42%),非常好的部分缓解(VGPR)2例(11%),部分缓解(PR)6例(31%),轻微反应(MR)1例(5%),疾病稳定(SD)2例(11%)。可见初始疗效的中位时间为2.8(1～5)周,最佳疗效的中位时间为2.7(1～4)个月。骨髓瘤细胞、血清单克隆蛋白量、红细胞沉降率均较治疗前下降。中位随访期19(6～35)个月,所有患者目前均生存。最常见的不良反应为胃肠道症状,其中便秘7例(37%),腹泻1例(5%),恶心2例(11%),黏膜炎1例(5%)。其次为血液学改变,中性粒细胞减少6例(32%),贫血3例(16%),血小板减少5例(26%)。另外,周围神经病变(PN)较为多见,1～2级4例(21%),3级1例(5%)。3例(16%)患者出现手足综合征,3例(16%)患者出现乏力。结论:PAD方案治疗初治MM疗效明确,不良反应较少。     

Administration of a modified chemotherapeutic regimen containing vincristine, liposomal doxorubicin and dexamethasone to multiple myeloma patients: preliminary data

For elderly patients with multiple myeloma (MM), conventional melphalan and prednisone (MP) therapy has been the treatment of choice; the vincristine, doxorubicin and dexamethasone (VAD) regimen is preferred for younger patients who also receive high-dose melphalan in combination with autologous or allogeneic bone marrow transplantation (BMT). Although survival time is similar in both the MP and VAD regimens, the continuous infusion of doxorubicin which the latter treatment entails constitutes a disadvantage along with the 4-day hospitalization required. Doxorubicin also induces cardiotoxicity, particularly in the elderly. A modified form of VAD therapy includes liposomal doxorubicin (Caelyx) (40 mg/m2 for 1 d) [corrected], oncovin (2 mg for 1 d) and dexamethasone 40 mg for 4 d per os. Doxorubicin encapsulated with liposomes has less cardiotoxicity, is more efficient and has fewer side effects than conventional doxorubicin, and it can be administered on an outpatient basis: dexamethasone can be given orally and vincristine in bolus infusion. In order to estimate its efficacy and tolerability, we administered this regimen to 12 patients (first-line treatment in 6 patients, salvage therapy in 6 patients). All patients exhibited good tolerance to liposomal doxorubicin with no severe side effects. Eight patients achieved complete hematological remission and three partial response. One patient died before completing the treatment. In conclusion, compared to other therapies, this modified VAD regimen containing liposomal doxorubicin can be more easily administered to MM patients, without severe side effects and with increased full remission rates, almost similar to those with the conventional VAD treatment.     

Doxorubicin and dexamethasone followed by thalidomide and dexamethasone is an effective well tolerated initial therapy for multiple myeloma

Among the drug combinations designed for the initial treatment of multiple myeloma, none has been unequivocally shown to be superior. However, a regimen leading to a high response rate and a low incidence of adverse events is highly desirable. We report the results of a phase II clinical trial involving 45 patients with Durie-Salmon stage II and III multiple myeloma. Doxorubicin and dexamethasone were given for 2 or 3 months followed by thalidomide and dexamethasone for 2 months (AD-TD regimen) with prophylactic antibiotics and daily aspirin (81 mg/d). Among the 42 patients whose response could be assessed, 38 responded to therapy (90.5%). The intent-to-treat response rate was 84.4% with seven complete responses (CR 15.5%), nine near complete responses (nCR 20.0%), and 22 partial responses (PR 48.9%). Two patients had stable disease (4.4%), and two progression of disease (4.4%). Normalization of the free light chain ratio after one or two cycles of treatment was highly predictive of achievement of CR or nCR. Patients tolerated the treatment well although five patients developed thromboembolic complications (11%). AD-TD administered with low dose aspirin for deep vein thrombosis prophylaxis was well tolerated and yielded a high response rate with minimal treatment-related morbidity.     

Bortezomib, doxorubicin and dexamethasone (PAD) front-line treatment of multiple myeloma: updated results after long-term follow-up

Bortezomib, doxorubicin and dexamethasone (PAD) was evaluated as induction before stem cell transplantation in newly diagnosed multiple myeloma (MM) patients, using bortezomib 1.3 mg/m(2) (PAD1, N = 21) or 1.0 mg/m(2) (PAD2, N = 20). Complete/very good partial response rates with PAD1/PAD2 were 62%/42% postinduction and 81%/53% post-transplant. Progression-free survival (29 vs. 24 months), time to re-treatment (36 vs. 29 months) and overall survival (1 year: 100% vs. 95%; 2 years: 95% vs. 73%) were statistically similar but favoured PAD1 versus PAD2. Toxicity was lower in PAD2; bortezomib dose reduction may help manage toxicities while retaining efficacy. PAD is highly active as front-line induction in MM.     

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...     

Phase 2 study of two sequential three‐drug combinations containing bortezomib,cyclophosphamide and dexamethasone,followed by bortezomib,thalidomide and dexamethasone as frontline therapy for multiple myeloma

Novel sequential combination therapy for induction may improve the quality of response and therefore prolong survival in newly diagnosed multiple myeloma (MM) patients. We report results from a phase 2 study of two sequential three‐drug combinations. Forty‐four previously untreated, symptomatic MM patients received: bortezomib 1·3 mg/m² (days 1, 4, 8, 11), cyclophosphamide 300 mg/m² (days 1, 8), plus dexamethasone 40 mg (day of and day after bortezomib) for three 21‐day cycles, followed by bortezomib 1·0 mg/m², dexamethasone 40 mg and thalidomide 100 mg daily for three cycles. Overall response rate for 42 evaluable patients was 95%, including 19% stringent complete response (sCR), 26% CR, and 57%≥ very good partial response. Twenty‐two patients have undergone stem‐cell transplantation. After a median follow‐up of 20·9 months, five patients have died; none was induction therapy‐related. Median event‐free survival (EFS) and overall survival (OS) have not been reached; estimated 1‐year EFS and OS rates were 81% and 91% respectively. Both three‐drug combinations were well tolerated; 82% of patients completed all six cycles. Toxicities were predictable and manageable; the most‐commonly reported grade 3/4 toxicity was neuropathy (11%). This novel sequential three‐drug combination therapy is effective and well‐tolerated in previously untreated MM patients.     

A steroid-independent regimen of bortezomib, liposomal doxorubicin and thalidomide demonstrate high response rates in newly diagnosed multiple myeloma patients

Novel agents have provided a new foundation for multiple myeloma therapies. When combined with other anti-myeloma agents, these compounds significantly enhance clinical efficacy. High-dose steroids are frequently used in anti-myeloma combination regimens; however, the doses employed are often poorly tolerated, especially in patients with concurrent comorbid conditions. We hypothesized that a steroid-independent combination regimen could be developed without significant compromise of efficacy. The availability of such a regimen will be important for patients whose concurrent ailments make them poor candidates for steroid containing anti-myeloma regimens. A phase II single institute, non-randomized clinical trial was conducted to investigate a novel steroid-free three-drug combination of bortezomib (V), pegylated liposomal doxorubicin (D), and thalidomide (T), the VDT regimen. Forty-three newly diagnosed multiple myeloma patients requiring treatment were enrolled on this study. The overall response rate and complete response (CR) + near complete response (nCR) rate was 78% and 35%, respectively. Median time to progression was 29·5 months. Fatigue, rash, neuropathy, constipation and infections were the most common side effects. We concluded that VDT is a tolerable and an effective regimen capable of inducing high response rates and can be employed in patients considered to be poor candidates for steroid-based treatment regimens.     

Low-dose thalidomide plus low-dose dexamethasone therapy in patients with refractory multiple myeloma

We report the results of a non-randomized phase II study of low-dose thalidomide plus low-dose dexamethasone therapy in 66 patients with refractory multiple myeloma. The overall response rate (near complete, partial and minimal response) was 63.6%, and progression-free and overall survival periods were 6.2 and 25.4 months. In adverse events, the incidence of peripheral neuropathy and deep vein thrombosis was lower than the data reported in USA and Europe. On the other hand, leukopenia was observed in 41% of patients, including 11% of those with Grade 3. Leukopenia was closely related to pretreatment pancytopenia, especially thrombocytopenia. The incidence of adverse events related to dexamethasone was low. In conclusion, low-dose thalidomide plus low-dose dexamethasone therapy was as effective as high-dose thalidomide plus high-dose dexamethasone therapy in patients with refractory multiple myeloma. Leukopenia is one of the most serious adverse events in Japanese patients, especially in patients with pretreatment pancytopenia.     

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.     

Safety and efficacy of pomalidomide,dexamethasone and pegylated liposomal doxorubicin for patients with relapsed or refractory multiple myeloma

Immunomodulatory drugs including thalidomide, lenalidomide (LEN) and pomalidomide (POM), are effective for treating multiple myeloma (MM). POM has shown enhanced efficacy with dexamethasone (DEX). Pegylated liposomal doxorubicin (PLD) with bortezomib is US Food and Drug Administration‐approved for treating MM. PLD with LEN or thalidomide has shown efficacy for MM patients. LEN with DEX, PLD and bortezomib achieves high response rates. We evaluated the combination of POM with DEX 40 mg and PLD 5 mg/m² with the latter two drugs administered on days 1, 4, 8 and 11 on a 28‐day cycle for the treatment of relapsed/refractory MM patients. During Phase 1, the maximum tolerated dose of POM was 4 mg, and was used in Phase 2, which also required patients to be refractory to LEN. However, neutropenia ≥ grade 3 was observed in 10/17 (59%) patients, and the dose was lowered to 3 mg. Median PFS was 5·4 months (range, 0·3–29·0 +  months). Overall response rates for patients in Phase 2 were 39% and 31% among subjects receiving POM at 3 mg and 4 mg, respectively, and clinical benefit rates were 51% and 44%, respectively. POM, PLD and DEX is a treatment option for relapsed/refractory MM patients including those who are refractory to LEN.     

硼替佐米联合环磷酰胺和地塞米松治疗多发性骨髓瘤28例临床观察

目的:观察硼替佐米联合环磷酰胺和地塞米松治疗多发性骨髓瘤的临床疗效和药物不良反应。方法:对28例初发和复发难治性多发性骨髓瘤用硼替佐米1.0～1.3mg/m2,每疗程的第1、4、8、11天静脉注射;环磷酰胺0.3g/m2,每疗程的第1、4、8、11天静脉注射;地塞米松40mg/d,每疗程的第1～2天、第4～5天、第8～9天及第11～12天静脉滴注,每28d为1个疗程,接受4个疗程的治疗,同时在每个疗程的开始进行骨髓细胞学、血M蛋白、β2-微球蛋白(β2-MG)进行检测,并观察药物的不良反应。结果:①28例患者都有效,有效率为100%,其中完全缓解(CR)8例,CR率为28%,接近完全缓解(nCR)2例,部分缓解(PR)13例,轻微反应(MR)5例。②骨髓瘤细胞百分比、M蛋白含量、β2-MG含量在化疗前后均差异有统计学意义(均P<0.05)。③不良反应以胃肠道反应最为常见,同时也可出现血小板减少,带状疱疹,周围神经病变等。结论:硼替佐米联合环磷酰胺和地塞米松对初发和复发难治性多发性骨髓瘤有明显的临床疗效,且药物不良反应较轻,耐受性良好。