Natl Med J India 2007;20:121–24

INTRODUCTION

Multiple myeloma accounts for about 1% of all cancer deaths.1 For decades, the regimen of oral melphalan and prednisolone has remained the cornerstone of therapy for patients with multiple myeloma. With this regimen, the complete response (CR) rate is <10%, the overall response rate is 50%–60%, the median survival about 3 years, and the 5-year survival rate 25%.2 Attempts have been made to improve upon these results by using combination chemotherapy with multiple drugs resulting in overall response rates of 60%–70% and CR rates of 10%–15%, but no survival benefits. 3-6 High dose chemotherapy followed by autologous stem cell transplantation (SCT) has a CR of 20%–40% with an overall response rate of 75%–90%.7-9 However, this is also not curative. Moreover, this treatment modality is associated with major side-effects and toxicity, is expensive and not feasible for all patients. The combination of melphalan and prednisolone thus remains the standard therapy for patients who are not candidates for autologous SCT owing to advanced age, poor performance status, pronounced renal failure, economic constraints or co-morbid conditions. The alternatives to melphalan and prednisolone are useful when a rapid reduction of tumour burden is required in case of renal failure or when the combination of melphalan and prednisolone is ineffective.
   A combination of vincristine and doxorubicin administered as a continuous infusion along with intermittent high dose dexamethasone (VAD) provides a rapid response in newly diagnosed patients with multiple myeloma.11-14 Although it does not cause alkylating agent-mediated stem cell damage, its disadvantage is a 24% incidence of sepsis and thrombosis due to administration of drugs using a central venous catheter.11-12Therefore, there is a need for treatment regimens that produce faster and better responses and are feasible for outpatient administration.
   In the absence of a curative treatment for patients with multiple myeloma, strategies that enhance tumour reduction and survival duration are likely to be of clinical benefit. The activity of melphalan and dexamethasone as single agents for patients with multiple myeloma and in vitro evidence of their synergy provided the rationale for investigating this combination in newly diagnosed patients with multiple myeloma who were not candidates for SCT.

METHODS

Patient eligibility

This was a non-randomized, prospective, phase II, pilot study to evaluate the efficacy and toxicity of oral melphalan and dexamethasone in untreated patients with multiple myeloma who were not candidates for autologous SCT.
   The diagnosis and staging for multiple myeloma were done according to the criteria defined by Durie and Salmon.15 Eligible patients were treatment-naïve, symptomatic (having a measurable monoclonal component), and not willing or not eligible to receive high dose chemotherapy and autologous SCT (age, medical contraindication or financial constraints). Only patients who gave informed consent for participation in the study and had a ECOG performance status <4 and a life expectancy >3 months were included.
   Patients who were asymptomatic, had non-secretory multiple myeloma, were eligible/willing to undergo autologous SCT, had uncontrolled diabetes mellitus or serum creatinine >3 mg/dl after adequate hydration were excluded. Patients with concurrent severe hepatic, cardiac or pulmonary disease were also excluded.

Patient evaluation prior to treatment and at commencement of each cycle included haemoglobin, total and differential leukocyte counts, platelet counts, urea, creatinine, liver function tests, calcium, total proteins and serum albumin levels. In addition, serum and urine electrophoresis, immunofixation, bone marrow trephine biopsy and touch smear tests were done at baseline and after every 2 cycles.

Chemotherapy consisted of oral melphalan (8 mg/m2) on days 1–4 and oral dexamethasone (40 mg/day) on days 1–4 and days 9–12. The cycles were repeated every 28 days for a total of 12 cycles or until intolerance or disease progression was observed. In addition, all patients received trimethoprim–sulphamethoxazole 960 mg b.i.d. for prophylaxis against infections. Allopurinol was also given at a dose of 300 mg/day during the first 2 cycles.

Patients were assessed clinically prior to each course of chemotherapy. The following definitions were used:
   Complete response (CR): Complete disappearance of myeloma paraprotein in the serum or urine with <5% plasma cells in a representative bone marrow sample.
   Near CR (nCR): Absence of serum or urine M band which was not confirmed with immunofixation studies.
   Partial response (PR): Reduction by >50% in serum paraprotein, (>90% reduction in urine M band) and bone marrow plasmacytosis with normalization of renal function and disappearance of symptoms.
   Stable disease (SD): Stabilization of paraprotein with <25% deviation on a minimum of 2 occasions observed 4 weeks apart.
   Disease progression (PD): >25% increase in paraprotein and/or bone marrow plasmacytosis.
   Relapse: Reappearance of abnormality on serum or urine electrophoresis, bone marrow examination or skeletal survey.
   Toxicity was evaluated according to the National Cancer Institute Common Toxicity Criteria (NCI-CTC) Version 2 (www.fda.gov/cder/cancer/toxicityframe.htm).

Descriptive and comparative analysis of the results was done using non-parametric methods. Survival data were calculated using the Kaplan–Meier method.

Results
Patient characteristics

Thirty-four patients with multiple myeloma (21 men; 61.8%) were included in the study from November 2000 to February 2004; 30 of these were evaluated for response. Their median age was 57 years (range 27–75 years). Two patients had stage IIA disease, 20 had stage IIIa disease (55.8%) and 12 had stage IIIB disease (35.3%) at the time of enrolment. Nineteen patients had IgG paraprotein, 2 had IgA paraprotein, while 12 had pure light chain disease (10 in the urine and 2 in the serum). In one patient M band was absent.

Response and survival
Analysis was done on an intent-to-treat basis. The median follow up of surviving patients was 40 months. Nine of 34 patients (26.1%) were in CR/nCR (5 had negative immunofixation and in the rest immunofixation could not be done) at a median of 4 cycles, 15 patients (44%) showed PR and 4 patients had SD (Table I). Two patients had PD, 1 died after the first cycle and 4 were lost to follow up without response assessment. At present, 3 patients are alive without any evidence of disease, 12 still have disease and 16 have died due to PD. The 3-year actuarial overall survival rate was 53% and the progression-free survival rate was 38%. The median overall and progression-free survival was 58 and 28 months, respectively (Figs 1 and 2).

Toxicity
There were no episodes of febrile neutropenia, opportunistic infections or peptic ulcers. None of the patients required hospitalization and treatment was completed in the outpatient setting. Dexamethasone was discontinued in 3 patients due to proximal myopathy after a median of 8 cycles. There were no treatment-related deaths.

Discussion

High dose chemotherapy followed by autologous SCT significantly improves the response rate and survival of patients with multiple myeloma. 7 -9 However, a fair number of patients with multiple myeloma do not undergo SCT due to various reasons including the lack of adequate facilities and financial constraints. The regimen of melphalan and prednisolone has been the cornerstone of therapy for multiple myeloma for many years. It provides a 5-year survival rate of about 25% and an overall response rate of 50%–60%.2 Combination chemotherapy such as the VAD regimen may be more effective than melphalan and prednisolone in inducing an objective and rapid response because of its activity against the bulk of plasma cells that proliferate slowly and are differentiated. On the other hand, alkylating agent-based therapy such as the combination of melphalan and prednisolone may be more active against rapidly dividing clonogenic cells, explaining the slower and perhaps more durable decline of myeloma paraprotein in patients who respond to melphalan. Although VAD therapy has a superior objective response, it has not been shown to prolong overall survival.3 -6 In addition, VAD therapy has a higher rate of complications and it may not be the best option for patients who are not candidates for SCT. These patients are usually treated with melphalan and prednisolone.
   The rationale for the combination of melphalan and dexamethasone to generate better and quicker responses has evolved through their use as single agents, in vivo and in vitro synergies20 -23 and valid activity in combinational regimens such as VAD.16-17

 Table I. Response rates with a combination of melphalan and dexamethasone (n=34)

*Lost to follow up before response assessment; however, survival data available Values in parentheses are percentages

Table II. Reported response rates with a combination of melphalan–dexamethasone/prednisone

combination of melphalan and dexamethasone compared with melphalan and prednisolone. Further, the delivery of this regimen on an outpatient basis and the acceptable side-effect profile makes it a viable alternative for patients who are not candidates for high dose chemotherapy and SCT.

Our study has shown response rates comparable to those observed with the VAD infusion regimen but better than those with melphalan and prednisolone. The safety of this combination in all the patients including those with renal failure has been documented. Hence, we feel that this combination is effective for patients who are not eligible/willing for high dose chemotherapy and autologous SCT, and should be evaluated further in randomized trials.

REFERENCES