A Phase II trial of pegylated liposomal doxorubicin, vincristine, and reduced-dose dexamethasone combination therapy in newly diagnosed multiple myeloma patients

Authors


Abstract

BACKGROUND

Patients with multiple myeloma (MM) have increased bone marrow angiogenesis, a low plasma cell labeling index, and multidrug resistance (the primary cause of chemotherapy failure). MM patients receiving the vincristine, doxorubicin, and dexamethasone (VAD) regimen develop resistance and cardiac and steroid toxicity. Pegylated liposomal doxorubicin (Doxil®/CAELYX™) could potentially extend the duration of malignant plasma cell exposure to therapeutic levels of doxorubicin. This Phase II study evaluates combination pegylated liposomal doxorubicin, vincristine, and reduced-dose dexamethasone in MM patients.

METHODS

Thirty-three newly diagnosed patients with MM received intravenous pegylated liposomal doxorubicin (40 mg/m2), vincristine (2.0 mg, Day 1), and oral or intravenous dexamethasone (40 mg per day for 4 days) every 4 weeks for six or more cycles and/or for two cycles after the best response.

RESULTS

The overall response rate was 88%: 4 (12%) patients achieved a complete response, 18 (55%) a major response, and 7 (21%) a minor response. Three patients (9%) had stable and one (3%) had progressive disease. The median time to progression was 23.1 months, with 2-year and 3-year progression-free survival rates of 42% and 23%, respectively. The patient survival rate at 3 years was 67%. No patients discontinued treatment due to adverse events. Myelosuppression was manageable. The most common toxicities were Grade 3 palmar–plantar erythrodysesthesia, mucositis, and neutropenia. Only one patient experienced cardiotoxicity.

CONCLUSIONS

Substituting pegylated liposomal doxorubicin for doxorubicin in the VAD regimen and reducing the dose of dexamethasone in patients with MM improve the safety profile and convenience of the treatment regimen without compromising efficacy. Cancer 2002;95:2160–8. © 2002 American Cancer Society.

DOI 10.1002/cncr.10946

Patients with multiple myeloma (MM) typically respond to initial chemotherapy, but many have disease recurrence. Multidrug resistance remains an obstacle to the successful treatment of patients with this disease.1–3 Younger patients with MM often receive intensive therapy, including myeloablative chemotherapy with stem cell support. However, because of the advanced age of the typical patient at presentation (> 65 years), the majority are reluctant to proceed with transplantation. The mainstay of MM therapy is treatment with melphalan and prednisone,4, 5 which results in response rates of 50–70%. The median survival of older MM patients with standard therapy is approximately 3 years.6

Favorable results also have been obtained with doxorubicin-based combination regimens. An intensive regimen of vincristine and doxorubicin infused over 4 days in combination with oral dexamethasone (VAD)7 has achieved response rates of 50–80% in newly diagnosed patients and approximately 50% in patients with disease recurrence.8–10 The progression-free survival (PFS) period for newly diagnosed patients treated with VAD is 9–12 months.7 However, the efficacy of VAD may be compromised because treatment is often suspended after four cycles due to toxicity.11–13

Pegylated liposomal doxorubicin (Doxil® [marketed and distributed in the United States by Ortho Biotech Products, L.P., Raritan, NJ]/CAELYX™ [marketed and distributed in Europe by Schering Plough, Kenilworth, NJ]) is doxorubicin encapsulated within STEALTH® (STEALTH is a registered trademark of ALZA Corporation, Mountain View, CA) liposomes. STEALTH liposomes, methoxypolyethylene glycol (MPEG) coatings, escape detection and phagocytosis by the immune system.14–16 Therefore, pegylated liposomal doxorubicin has an extended circulation time compared with unencapsulated or conventional doxorubicin.17–19 Pharmacokinetic analysis of pegylated liposomal doxorubicin demonstrated that the initial half-life (t1/2) in plasma is 2–5 hours, followed by a prolonged secondary t1/2 of 20–54 hours.20 For standard doxorubicin, the initial t1/2 is 5–10 minutes and the secondary t1/2 is approximately 30 hours.21 The MPEG coating also reduces protein binding to the surface of the liposomes, thereby increasing their stability. In addition, the STEALTH liposomes are small (average diameter of approximately 85–100 nm), which allows extravasation through the highly permeable vessels characteristic of tumors and accumulation within the tumor tissue.20, 22 The extended circulation time of pegylated liposomal doxorubicin allows the drug to be administered at a lower dose than conventional doxorubicin, potentially reducing the incidence of anthracycline toxicities. Pegylated liposomal doxorubicin has less cardiotoxicity than conventional doxorubicin23 and results in less nausea and vomiting, alopecia, and severe granulocytopenia. However, it is associated with dose-limiting palmar–plantar erythrodysesthesia (PPE) because of the tendency of the liposomes to diffuse out of the capillaries of the hands and feet.

Patients with MM have increased angiogenesis in the bone marrow.23–25 Myeloma cells also have a low mitotic rate.26–28 Therefore, increased exposure of MM patients to doxorubicin could improve response rates. Conventional doxorubicin and vincristine therapy is administered as a continuous intravenous infusion via a permanent venous port. This mode of infusion is inconvenient and can lead to infectious and thrombotic complications. The improved pharmacokinetics of pegylated liposomal doxorubicin allow for rapid administration, thereby eliminating the need for hospitalization for prolonged chemotherapy administration. Finally, the improved pharmacokinetics of pegylated liposomal doxorubicin should also increase the time of exposure of malignant plasma cells to high concentrations of anthracycline, resulting in higher antitumor activity.26, 27

Given the demonstrated efficacy of VAD in MM patients and the potential for pegylated liposomal doxorubicin to extend the duration of bone marrow exposure to therapeutic levels of doxorubicin, a combination regimen of pegylated liposomal doxorubicin, vincristine, and dexamethasone (DVD) has been actively investigated in patients with MM. Phase I studies of DVD in patients with MM suggested that the regimen was safe, active, better tolerated, and more convenient than VAD at a dose of 40 mg/m2 pegylated liposomal doxorubicin.29, 30 However, DVD is associated with steroid toxicity due to the 8–12-day course of dexamethasone. We initiated a Phase II study to evaluate the efficacy and tolerability of the DVD regimen with dexamethasone administered only during the first 4 days of each therapeutic cycle (DVd) to reduce steroid toxicity in the treatment of patients with newly diagnosed, progressive MM. This dose modification was reported previously31 for the VAD regimen, however; reduced efficacy was suggested. The current study was designed to assess the toxicity of DVd and the preliminary efficacy of pegylated liposomal doxorubicin in the management of MM patients, with less reliance on steroids.

MATERIALS AND METHODS

Patient Eligibility

Patients with newly diagnosed, symptomatic MM were eligible for the study. Patients were required to have an Eastern Cooperative Oncology Group performance status of 0–3, a life expectancy of 3 months or more, and acceptable hematologic, renal, and liver functions. Acceptable laboratory values included an absolute neutrophil count of 1000 or more cells per microliter (or white blood cell count ≥ 2500 cells per microliter) and more than 75,000 platelets per microliter, unless patients presented with cytopenias related to MM (≥ 50% plasma cells in the bone marrow), splenomegaly, or plasma cell leukemia, a total serum bilirubin level less than or equal the institutional upper limits of normal, and liver enzyme levels (aspartate aminotransferase or alanine aminotransferase) less than or equal to two times the upper limit of normal liver involvement. Patients with renal failure were also eligible. Another criterion for study entry was a left ventricular ejection fraction (LVEF) of greater than or equal to 50% as demonstrated by multiple gated acquisition scan or echocardiogram (ECG). The study was approved by the Institutional Review Board and all patients provided written informed consent.

Exclusion criteria included Class II or higher cardiac disease according to the New York Heart Association and a history of hypersensitivity to doxorubicin hydrochloride or to liposomal or pegylated drug formulations. Patients were excluded if they had previous malignancies at other sites, with the exception of adequately treated cervical carcinoma in situ, basal or squamous cell carcinoma of the skin, or other cancer from which the patient had been disease free for 5 or more years. Also excluded were patients with solitary bone or extramedullary plasmacytoma or active infections requiring intravenous antibiotics. Pregnant or lactating women were not eligible and both men and women with reproductive potential were required to use an approved method of contraception. Patients were not allowed to receive any other chemotherapy during the study.

Study Design

The primary end points in this single-arm, open-label, Phase II study were response rate, safety, and tolerability. Secondary efficacy end points were PFS and overall survival. This was a two-stage, Phase II study in which 14 patients were initially enrolled. Enrollment was extended to a total of 33 patients if one or more objective responses were observed in the first 14 patients. Responses were assessed after one cycle of therapy (1 month) and then after each subsequent therapy cycle until the maximum response was achieved. After the maximum response was achieved, patients were followed until their disease progressed.

Baseline assessments were performed within 14 days before study entry and included a complete medical history, physical examination, determination of performance status, hematology evaluation, and clinical chemistry assessments.32 All patients underwent a complete bone survey if one had not been performed within 3 months or if new symptoms had developed. Baseline disease was assessed by measurements of β-2-microglobulin (β-2M) and serum and urine protein content by electrophoresis and myeloma typing. Determinations of serum B12, red blood cell folate, methylmalonic acid, and serum homocysteine were also used as part of the initial disease assessment. In addition, the extent of bone marrow involvement was assessed with an aspirate and a core marrow biopsy and subsequent cytogenetics and labeling index measurements. Bone marrow sampling was performed after six cycles of therapy or as soon as there was no peripheral evidence of disease and was repeated every other cycle thereafter until the maximum response was achieved. Baseline assessments, β-2M measurements, and 24-hour urine protein quantitation were repeated before each subsequent cycle and at the completion of chemotherapy. A complete bone survey was performed every 6 months. After a total cumulative dose of 500 mg/m2 pegylated liposomal doxorubicin, LVEF was reevaluated by multiple gated acquisition scan or ECG. Subsequently, LVEF was determined before every other cycle of pegylated liposomal doxorubicin. Pegylated liposomal doxorubicin therapy was discontinued if the LVEF decreased by either greater than 15% from baseline or to a value of less than 45%.

Treatment

Patients received intravenous pegylated liposomal doxorubicin (40 mg/m2) and vincristine (2.0 mg) on Day 1 and oral or intravenous dexamethasone (40 mg per day) for 4 days. This regimen was repeated every 4 weeks for a minimum of six cycles and for two cycles after the maximum response was achieved. Dose modifications due to myelosuppression were determined for each patient using the criteria in Table 1. Prophylactic use of growth factors was prohibited. However, granulocyte-macrophage–colony-stimulating factor or granulocyte–colony-stimulating factor was permitted in patients with prolonged neutropenia or with febrile neutropenia that occurred in a previous cycle of treatment. If neutropenia recurred despite the use of growth factors, treatment was resumed with a 25% reduction in the pegylated liposomal doxorubicin dose. For acute infusion-related reactions, pegylated liposomal doxorubicin infusion was interrupted and diphenhydramine (25–50 mg) and hydrocortisone (100 mg) were administered intravenously. Pegylated liposomal doxorubicin treatment was resumed at a 50% reduced rate of infusion. Due to the high incidence of PPE in the first nine patients treated, vitamin B6 was added to the treatment protocol to reduce the development of PPE.33 Patients who developed PPE were treated with vitamin B6 (200 mg per day). The full DVd treatment regimen was then continued without dose delays or reductions. If patients developed Grade 3 or 4 PPE despite the addition of vitamin B6, dose modifications and/or treatment delays were applied as outlined in Table 2.34

Table 1. Guidelines for Pegylated Liposomal Doxorubicin Dose Modifications for Patients Experiencing Hematologic Toxicity on Day 1 of Therapy
GradeANC (cells/μL)Platelets/μLModification
  1. ANC: absolute neutrophil count; GM-CSF: granulocyte-macrophage–colony-stimulating factor; WBC: white blood cell.

11000–150075,000–150,000Resume treatment with no dose reduction
2500–< 99950,000–< 75,000Wait until ANC ≥ 1000 cells/μL and platelets ≥ 75,000/μL, or 75% of the level at the start of the cycle.
   Redose with no dose reduction.
3< 500< 25,000Wait until ANC ≥ 1500 cells/μL and platelets ≥ 75,000/μL.
   Redose at a 25% dose reduction or continue full dose with cytokine support.
4Use of GM-CSF Prolonged neutropenia, failure of WBC count to recover by Day 22, or the occurrence of febrile neutropenia in the previous cycle of treatment.
Table 2. Guidelines for Pegylated Liposomal Doxorubicin Dose Modification for Patients Experiencing Palmar–Plantar Erythrodysesthesia
Toxicity gradeTime after dose (weeks)
456
  1. From Data on File.34

1: Mild erythema, swelling, or desquamation not interfering with daily activitiesRedose unless patient has experienced previous Grade 3 or 4 skin toxicity. If so, delay an additional week.Redose unless patient has experienced previous Grade 3 or 4 skin toxicity. If so, delay an additional week.Redose at 25% dose reduction; return to 4-week interval or withdraw patient per investigator's assessment.
2: Erythema, desquamation, or swelling interfering with, but not precluding, normal physical activities; small blisters or ulcerations < 2 cm in diameterDelay treatment 1 week.Delay treatment 1 weekRedose at 25% dose reduction; return to 4-week interval or withdraw patient per investigator's assessment.
3: Blistering, ulceration, or swelling interfering with walking or normal daily activities; cannot wear regular clothingDelay treatment 1 week.Delay treatment 1 week.Withdraw patient.
4: Diffuse or local process causing infectious complications, or a bed-ridden state, or hospitalizationDelay treatment 1 week.Delay treatment 1 week.Withdraw patient.

Response Criteria

A complete remission (CR) was defined as the complete disappearance of myeloma protein from the serum and urine by immune fixation, a bone marrow biopsy demonstrating less than 3% plasma cells, the absence of monoclonal plasma cells by immune staining of the bone marrow on two occasions 4 weeks apart, and no evidence of progressive disease by any other parameters. A major response was defined as a 50% or greater decrease of myeloma protein from the serum and urine. A minor response was defined as a decrease in bone pain, an improvement of performance status by one grade, and a reduction in serum myeloma protein of 25% or greater. Stable disease was defined as a less than 25% decrease in M-protein. Disease progression was defined as a greater than 50% increase in serum or urine myeloma protein above the lowest remission level, a greater than 50% increase in soft tissue plasmacytoma, the appearance of new lytic bone lesions or an increase of greater than 50% in the size of existing lesions, or unequivocal new bone lysis requiring palliative radiation. Disease was also considered to have progressed if there were a 25% to less than 50% increase in myeloma protein, a calcium level higher than 12 mg/dL, or a decrease of 2 g/dL in hemoglobin level (due to progressive bone marrow replacement with plasma cells, not to bleeding or chemotherapy-induced bone marrow suppression). Patients with stable disease did not meet any of the criteria for response or progression. Patients who required stem cell harvesting and/or autologous bone marrow transplantation were considered to be treatment failures. The safety and tolerability of treatment were monitored and graded according to National Cancer Institute Common Toxicity Criteria version 2.0.

Angiogenesis Measurements of Bone Marrow Biopsies

Adequate bone marrow samples at pretreatment and at the plateau phase were evaluated to determine the effect of DVd on the angiogenic process in the bone marrow. Bone marrow biopsy specimens were prepared from paraffin-embedded blocks. Two bone marrow samples were acquired: one before DVd and one at the time of the patient's maximum response. Immunohistochemical staining for CD34 was performed to visualize vascular spaces. Microvessel density (MVD) counts were performed on the CD34-stained slides at × 100 magnification. Ten fields in two focal planes were counted for each biopsy.

Statistics

Categorical data were summarized as percentages. Continuous data were summarized as the mean ± standard deviation, median, and range. MVD counts were analyzed by first calculating the average MVD for each focal plane and the overall average MVD for the entire sample. The Wilcoxon signed-rank test was used to compare data from the two focal planes and from the pretreatment versus posttreatment samples. The Wilcoxon rank-sum test was used to compare pretreatment MVD between patients achieving a CR or major response and those achieving less than a major response.

Time to progression was measured from the date on-study to the first date of documented disease progression or recurrence. Patients not known to have disease progression/recurrence were censored as their last clinical evaluation. Survival was measured from the date on-study to the date of death or the date the patient was last known to be alive. Time to progression and survival was summarized using the Kaplan–Meier method. The Cox proportional hazards model was used to assess the impact on time to progression of pretreatment MVD and MVD change. All P values presented are two sided.

RESULTS

Patient Demographics

Thirty-three patients (19 males, 14 females), with a mean age of 57 years, were enrolled in the study (Table 3). The majority of the patients had a performance status of 0 or 1 and one patient had a performance status of 2. More than one-half of the patients exhibited an immunoglobulin Gκ-type myeloma. One patient exhibited a nonsecretory myeloma. The mean β-2M level was 3.2 μg/mL (± 2.2 μg/mL). Twenty patients were Stage III (Stage IIIa = 15, Stage IIIb = 5), seven patients were Stage IIa, and six patients were Stage Ia.35 Two of the six Stage Ia patients had a greater than 80% plasma cell bone marrow involvement. Three of these patients had infiltrating plasma cells with plasmablastic morphology and one patient had deteriorating performance status attributed to her disease. All patients had newly diagnosed MM, had not received previous chemotherapy, and had progressive disease.

Table 3. Patient Demographics and Disease Characteristics (n = 33)
CharacteristicNo. (%)
  • SD: standard deviation; Ig: immunoglobulin.

  • a

    Standard deviation shown in parentheses.

Gender 
 Male19 (58)
 Female14 (42)
Age (yrs) 
 Mean (SD)56.9 (12.1)
 Median54
 Range32–82
Performance status 
 013 (39)
 119 (58)
 21 (3)
Myeloma type 
 IgGκ17 (52)
 IgGλ7 (21)
 IgAλ2 (6)
 κ light chain4 (12)
 λ light chain2 (6)
 Nonsecretory1 (3)
β-2-microglobulin (n = 32) 
 Mean (μg/L)3.2 (2.2)a
 Median (μg/L)2.5
 Range (μg/mL)0.2–9.0

Response Rates

Patients received a mean of 9.1 ± 2.7 cycles of DVd (range, 3–14 cycles). Responses occurred in 29 of 33 (88%) patients, including 4 (12%) CRs, 18 (55%) major responses, and 7 (21%) minor responses. Three (9%) patients had stable disease and one (3%) patient had progressive disease. The median time to first response was 1.1 months (range, 0.7–6.7 months) and the median time to maximum response was 4.6 months (range, 0.7–13.5 months). Thirteen of 20 patients who achieved a minor response after a single cycle of DVd achieved a major response after 4.1 months (range, 1.0–7.4 months) of continued therapy. Although it was not included in the overall response rate, stable disease (< 25% decrease in monoclonal [M-protein]) is an important response in patients with MM. In a large Canadian study, Browman et al.36 demonstrated that patients with stable disease survived longer than responders who were randomized to the control arm of the study. In the current study to date, 26 patients have experienced progression or recurrence of disease and 11 patients have died. The median time to progression was 23.1 months, with a 2-year and 3-year PFS of 42% and 23%, respectively (Fig. 1). The 3-year survival rate was 67% (Fig. 2). Consequently, the median survival has not yet been reached. For three patients, bone marrow was harvested for future transplantation. These patients were considered treatment failures as of the date of chemotherapy for the harvest procedure. One of these three patients received autologous bone marrow transplantation for cardiac amyloidosis that was detected during a routine follow-up ECG after the completion of therapy.

Figure 1.

Kaplan–Meier estimate of progression-free survival.

Figure 2.

Kaplan–Meier estimate of overall survival.

Angiogenesis Data

As angiogenesis may be involved in tumor growth and has been of prognostic value in several malignancies,24, 26, 37 we measured the effect of DVd therapy on MVD in the bone marrow of 20 patients who had adequate pretreatment and posttreatment bone marrow samples.38 No statistically significant difference in MVD counts was seen between the two focal planes either pretreatment (P = 0.95) or posttreatment (P = 0.91). Among 17 patients with both pretreatment and posttreatment evaluations, posttreatment MVD (mean, 1.6 ± 2.3; median, 0.7; range, 0.2–9.7) was significantly decreased compared with pretreatment levels (mean, 3.8 ± 3.3; median, 3.2; range, 0.5–12.3; P < 0.001). We also evaluated the prognostic implications of MVD pretreatment and posttreatment. Using Cox proportional hazards models, increased pretreatment MVD was associated with poorer PFS (P = 0.02), but the change in MVD was not (P = 0.88). Pretreatment MVD also correlated with response. Among patients achieving a CR or major response, the mean pretreatment MVD was significantly lower (2.7 ± 2.4; median, 2.0; range, 0.4–9.4) than that of patients achieving less than a major response (7.5 ± 3.6; median, 7.4; range, 2.4–12.3; P = 0.01; Table 4).

Table 4. MVD for 20 Multiple Myeloma Patients Treated with DVd
Patient populationnPretreatment MVD
Mean (SD)MedianRange
  1. MVD: microvessel density; DVd: pegylated liposomal doxorubicin, vincristine, and dexamethasone, with dexamethasone 40 mg per day administered only on Days 1–4 of each therapeutic cycle; SD: standard deviation; CR: complete remission.

CR or major response152.7 (2.39)2.00.4–9.4
Less than major response57.5 (3.61)7.42.4–12.3
All patients203.8 (3.34)2.80.4–12.3

Safety

The DVd regimen was well tolerated and none of the patients discontinued therapy due to adverse events. The most common Grade 3 or 4 adverse events were PPE, neutropenia, and mucositis (Table 5). Dose reductions were required in six patients and treatment was delayed due to adverse events in one patient. In four patients, the dose of pegylated liposomal doxorubicin was reduced to 30 mg/m2 for one or more cycles. Three patients required vincristine dose reduction to 1.5 mg for two or more cycles. Dexamethasone was tapered in two patients over 6 days. Six patients required packed red blood cell transfusions and one patient required a platelet transfusion. No growth factors were necessary and no patients were hospitalized for neutropenic fevers or for intravenous antibiotics.

Table 5. Grade 3 and 4 Adverse Events Related to Therapy (n = 33)
EventPatients (%)
Grade 3Grade 4
Palmar–plantar erythrodysesthesia6 (18)1 (3)
Mucositis4 (12)0
Deep vein thrombosis1 (3)0
Dehydration1 (3)0
Anemia4 (12)3 (9)
Neutropenia7 (21)3 (9)
Thrombocytopenia3 (9)0

The incidence of nonhematologic Grade 3 or 4 toxicities was less than 10% for each category and nonhematologic toxicity did not result in dose reductions or treatment discontinuation. During the early stages of this protoco,l prophylactic vitamin B6 was not administered and five of nine patients developed Grade 3 PPE. Of the remaining 24 patients receiving vitamin B6 as outlined in the Materials and Methods, only 2 patients developed Grade 3 or 4 PPE. One patient experienced delayed cardiotoxicity. This 82-year-old patient had received 13 cycles of DVd (cumulative pegylated liposomal doxorubicin dose of 520 mg/m2). Nine months into the plateau phase, the patient developed congestive heart failure. The endocardial biopsy indicated that the cardiotoxicity was treatment related and there was no evidence of amyloidosis. No other form of cardiotoxicity was noted.

DISCUSSION

The results of this Phase II study suggest that DVd is an effective and well tolerated treatment regimen for patients with newly diagnosed MM. The overall response rate in this study for patients treated with DVd was 88% and 67% of patients achieved a CR or major response. This response rate is similar to the rate previously reported for VAD8 and was not adversely affected by the dose reduction of the steroids as had been previously reported with the modified VAD regimen.31 In the current study, the PFS was not positively affected by chemotherapy in preparation for bone marrow harvesting because only three patients were involved in this process. These patients were considered treatment failures as of the date of preparatory chemotherapy. Only one of the three patients, who developed cardiac amyloidosis, received a bone marrow transplant. The bone marrow transplant was performed 7 months before our data analysis and does not affect the survival outcome for the group as a whole. Six patients with Stage IA disease were included in this study. These six patients were biologically advanced because they had a greater than 40% bone marrow involvement, three of them having a greater than 70% bone marrow involvement. Heavy general proteinuria in one patient and thrombocytopenia in two patients suggested advanced disease and bone marrow compromise.

The DVd regimen was well tolerated compared with published reports of VAD therapy for MM patients. None of the patients in this study experienced an infection requiring intravenous antibiotics. In a study of the VAD regimen for MM patients, 23% of patients developed bacteremia and 19% developed pulmonary infections.39 Because the current study was performed at a single institution, selection bias could partly account for the mild toxicity profile. However, the patients enrolled in this study were taken from a pool of 34 consecutive patients requiring therapy for MM. Only one patient declined the study. Therefore, selection bias seems unlikely. Finally, the somewhat young age of these patients and their good overall health status could account for part of the improved safety results, but these demographic features are not sufficient to account for these remarkable results.

A cumulative doxorubicin dose of greater than 500 mg/m2 is associated with acute cardiac toxicity, and late cardiac toxicity can appear as much as 4–20 years after therapy.11, 12, 40, 41 In the current study, only one case of cardiac toxicity occurred. However, the cumulative dose of doxorubicin in this 82-year-old patient was 520 mg/m2. The VAD regimen is also associated with substantial myelosuppression.5 Because of its slower release and longer half-life, pegylated liposomal doxorubicin results in less severe myelosuppression. None of the DVd-treated patients experienced Grade 4 thrombocytopenia and the incidence of Grade 4 neutropenia was only 9%. Although patient withdrawals and dose reductions are common during VAD administration, no patients withdrew from the current study due to adverse events and only four pegylated liposomal doxorubicin dose reductions were necessary.

In a Phase I/II study, Gautier et al.29 reported their preliminary experience of a DVD regimen in 19 patients with MM using a dexamethasone dose (40 mg on Days 1–4 and Days 15–18) similar to standard VAD therapy. The overall response rate was 89% in previously untreated patients and 56% in patients with disease recurrence. Three patients experienced Grade 3 or 4 neutropenia and two patients experienced Grade 3 or 4 thrombocytopenia. The authors concluded that the DVD regimen, with pegylated liposomal doxorubicin at a dose of 40 mg/m2, was well tolerated.

Increased angiogenesis, evidenced by increased MVD, is an adverse prognostic finding for MM patients because angiogenesis aids in the proliferation and metastasis of hematologic malignancies as well as in solid tumors.24, 26, 37 The antiangiogenic activity of pegylated liposomal doxorubicin-containing regimens reported in this study and others,17, 42 coupled with the high response rates achieved with DVd therapy, suggest that it may have clinical benefit before bone marrow transplantation or in combination with other immunomodulatory therapy such as thalidomide.43, 44

Although STEALTH-liposome MPEG encapsulation of doxorubicin prolongs the circulation time and improves tolerability of doxorubicin, the liposomes leak from the capillaries of the hands and feet, causing PPE. Therefore, PPE is typically the dose-limiting toxicity associated with DVd. In this study, the dose of pegylated liposomal doxorubicin was reduced temporarily in patients experiencing PPE to allow the PPE to resolve, and all patients tolerated further treatment. No patients withdrew from the study due to PPE. In the current study, the addition of vitamin B6 to the regimen in patients developing Grade 1 or 2 PPE decreased the rate of Grade 3 or 4 PPE. However, this result should be interpreted with caution because the decrease in PPE may also be attributed to the increase in the medical team's expertise in administering the DVd regimen, specifically, the rigorous instructions and education given to patients to avoid increased activity resulting in hand and foot pressure, to wear comfortable clothing, and to avoid rinsing with hot water.

In conclusion, DVd appears to an efficacy similar to that of VAD for the treatment of newly diagnosed MM patients. Because of the reduction in toxicity, DVd represents a potential alternative for front-line therapy. Although the current study is a single-institution trial, the CR rates (using strict criteria) are higher than those previously reported for VAD. In addition, DVd reduced MVD in the bone marrow of patients with MM. The results of this Phase II study suggest that DVd administered in an outpatient setting is active and generally well tolerated in patients with MM. A randomized, Phase III study is now in progress to directly compare VAD (with reduced-dose dexamethasone) with DVd therapy in patients with newly diagnosed MM.

Ancillary