Liposomal daunorubicin and dexamethasone as a treatment for multiple myeloma – the DD Protocol

ABSTRACT CONTEXT AND OBJECTIVE: Liposomal daunorubicin has been used to treat hematological malignancies, including multiple myeloma (MM). The goal was to evaluate efficacy, side-effects and toxicity of liposomal daunorubicin and dexamethasone (“DD Protocol”). DESIGN AND SETTING: Prospective study at Sírio-Libanês, São Camilo, Brasil and Alemão Oswaldo Cruz hospitals. METHODS: Twenty consecutive patients with active MM received four cycles of liposomal daunorubicin intravenously for two hours (25-30 mg/m2/day) on three consecutive days per month, with oral dexamethasone (10 mg every six hours) on four consecutive days three times a month. RESULTS: The male/female ratio was 1:1 and median age 60. Nine patients were stage IIA, ten IIIA and one IIIB. The median from diagnosis to starting DD was 13 months. All patients received four cycles, except one. Fifteen had already received chemotherapy before DD. Responses of > 50% reduction in serum monoclonal para-protein were observed in six patients after first cycle (30%), six after second (30%) and four after third (20%), while four (20%) did not obtain this. Initially, 17 patients (85%) had anemia: 12 (70%) achieved correction. Progressive disease was observed in three patients (15%), while one had minimal response, four (20%) partial and 12 (60%) complete. Hematological toxicity was acceptable: three patients (15%) had neutrophils < 1,000/mm3; none had thrombocytopenia. Gastrointestinal toxicity was mild: nausea (10%), anorexia (15%) and no vomiting. CONCLUSIONS: This treatment has mild toxicity and good response rate. It may therefore be feasible before autologous bone marrow transplantation.


INTRODUCTION
2][3] The major mechanisms for resistance to daunorubicin in the treatment of MM include amplification or overexpression of the multidrug resistance 1 (MDR-1) gene, which codes for transmembrane P-glycoprotein (PGP).This latter is thought to pump several cytotoxic drugs out of cells, thus giving rise to the so-called classic MDR. 4,5MM is incurable by conventional chemotherapy regimens because of the rapid development of MDR. 6 Liposomal encapsulation of anthracyclines is a potential method of drug targeting, thereby altering both the antitumor activity and side-effects profile.Liposomal daunorubicin (DaunoXome  ) was developed in an attempt to increase the delivery of the drug to tumors and protect normal tissue from its toxicity. 7In addition, liposomal daunorubicin presents different pharmacokinetics, with a potential for reducing dose-limiting cardiotoxicity in comparison with conventional daunorubicin.Moreover, the pharmacokinetic profile of liposomal daunorubicin provides sustained plasma levels following short periods of infusion and thus offers a practical alternative to continuous infusion.Liposomal daunorubicin has been shown to cause mild toxicity to patients.
Dexamethasone has been included in several chemotherapy schedules for treating MM.][10] On the basis of this background, we decided to study the effectiveness of a combination of liposomal daunorubicin and dexamethasone ("DD protocol") on our MM patients.

OBJECTIVE
The goal of this phase II prospective study was to evaluate the efficacy, side effects and toxicity of liposomal daunorubicin and dexamethasone in 20 consecutive patients with MM.

METHODS
Twenty consecutive patients with active MM were enrolled in the DD protocol.The male/female ratio was 1:1 and the median age was 60 years (range: 40-73 years).The Durie and Salmon staging system 11 was utilized for all the patients.Nine of the 20 patients (45%) presented MM in stage IIA, ten (50%) was in stage IIIA and one (5%) was in stage IIIB.Fourteen of the 20 patients (70%) patients had the immunoglobulin G myeloma type (IgG), three (15%) had the immunoglobulin A myeloma type (IgA) and three (15%) had lightchain MM, of whom two (10%) were kappa and one (5%) lambda.The median length of time from diagnosis to starting the DD protocol was 13 months (range: 1-76 months).Fifteen patients (75%) had already received a median of 11 courses of some chemotherapy before DD (range: 5-43 courses).Of these, 10 patients (50%) had continued with progressive disease and five (25%) patients presented partial response to the previous chemotherapy.For five patients (25%), the DD protocol was their first-line therapy.Table 1 shows the patients' characteristics.
The protocol proposed (the "DD protocol") consisted of the administering of Dau-noXome  at a dose of 25 to 30 mg/m 2 /day, intravenously over a two-hour period, for three consecutive days every 30 days, for four months (four cycles).This was given in association with oral dexamethasone, 10 mg every six hours for four consecutive days three times a month (days 1 to 4, 9 to 12 and 17 to 20), every month.Table 2 shows the DD protocol.
An echocardiogram was performed before the first and after the last cycle.In order to monitor the response to the treatment, a complete evaluation of the disease was carried out before each cycle.The criteria utilized for defining the disease response are summarized in Table 3. 12 Table 2. "DD Protocol": treatment scheme for multiple myeloma with liposomal daunorubicin and dexamethasone      Tables 4 and 5 describe the chemotherapy that each patient had previously undergone, according to disease stage, paraprotein type and disease response to the DD protocol.

Statistical analysis
The statistical analysis was based on the data for the MM group in day/month/year format (D/M/Y).All data were analyzed using descriptive statistical methods, making use of the proportions of patients with each characteristic and outcome, including shortterm side effects.

RESULTS
A reduction of more than 50% in serum monoclonal paraprotein was observed in six of the 20 patients (30%) after the first DD cycle, six patients (30%) after the second cycle and four patients (20%) after the third cycle, while four patients (20%) did not obtain such a reduction.Initially, 17 patients (85%) presented anemia, and 12 of these patients (70%) achieved correction by the end of the treatment protocol.All three light-chain MM patients are still alive and still presenting a complete response after time periods ranging from 10 to 31 months subsequent to undergoing the protocol.Of the three IgA patients, two had a partial response and one had a complete response, but all they relapsed and died of progression of the disease.Of the 14 IgG patients, eight (57%) had a complete response, two (14%) had a partial response, one (7%) had a minimal response and three (21%) had progressive disease.Five patients received the treatment as first-line therapy, of whom three achieved a complete response (two IgG and one kappa) and two a partial response (one IgG and one IgA).Overall, there was progressive disease in three patients (15%), a minimal response in one patient, a partial response in four patients (20%) and a complete response in 12 patients (60%), as shown in Figure 1.Eleven out of the twenty patients (55%) treated are still presenting a complete response after a median time period of 9 months (range: 3-31 months) subsequent to the treatment.

Side-effects and toxicity
The hematological toxicity was very acceptable.Only three patients (15%) presented neutrophils < 1,000/mm 3 , and no patients had thrombocytopenia (defined as platelet count of less than 50,000/mm 3 ).One patient presented a urinary tract infection and two others pneumonia.

REFERENCES
testinal toxicity was mild, and it consisted of nausea (10%) and anorexia (15%), but without vomiting.Three patients (15%) had asthenia, and no cardiac abnormalities were observed and no lethal complication.No alopecia as a consequence of the DD protocol was observed.

DISCUSSION
Anthracyclines are frequently utilized in the treatment of MM.Liposomal daunorubicin shows a potential for reducing doselimiting cardiotoxicity, in comparison with conventional daunorubicin.Such cardiotoxicity is generally irreversible and refractory to medical therapy. 4,5his phase II study seems to confirm the efficacy of liposomal daunorubicin plus dexamethasone in patients with MM who have previously been treated or are receiving it as front-line therapy.Several of the most popular chemotherapy regi-mens utilized for treating MM 1,13 involve continuous infusion of anthracyclines over several days.Liposomal daunorubicin provides sustained plasma levels following a short infusion and thus offers a practical alternative to continuous infusion. 14,15n the present study, by using liposomal daunorubicin we achieved an overall response rate of 80%, of which 60% was a complete response and 20% was a partial response.Most of our patients obtained a stable response after two cycles of treatment.All of the previously untreated patients presented some response: three out of these five patients achieved a complete and the other two obtained a partial response.These results are slightly better than in data published by other authors [8][9][10] and suggest that the DD Protocol could be used as first-line therapy for this type of MM patients.However, few controlled studies have used liposomal daunorubicin in the treatment of MM. [8][9][10] Mohrbacher et al., 9 using liposomal daunorubicin plus dexamethasone, demonstrated activity in bad prognosis MM patients that was comparable to the activity of standard regimens.In our study, the side-effects and toxicity related to liposomal daunorubicin were mild and easily controlled.Only three of the 20 patients (15%) presented neutropenia (counts of less than 1,000/mm 3 ), and there were two cases of pneumonia that were treated with antibiotics.No cardiac abnormality was observed.No lethal complication has been observed so far.

1 .
Complete response (CR) a) Absence of the original monoclonal paraprotein b) Less than 5% of plasma cells in bone marrow, confirmed with bone marrow biopsy 2. Partial response (PR) a) More than 50% reduction of the monoclonal paraprotein b) More than 50% reduction in plasma cells in bone marrow 3. Minimal response (MR) a) Less than 50% reduction of the monoclonal paraprotein and plasma cells in the bone marrow 4. Progressive disease (PD) a) No response to treatment Sao Paulo Med J. 2005;123(6):266-70.

Figure 1 .
Figure 1.Responsiveness of 20 patients with multiple myeloma to a new protocol including dexamethasone and liposomal daunorubicin.

Table 3 .
12iteria for defining the response to the "DD Protocol" in patients with multiple myeloma, in accordance with definitions from the European Bone Marrow Transplant group12

Table 5 .
Previous chemotherapy (paraprotein type and response to "DD Protocol") of 11 patients with stage III multiple myeloma