Ilaria Avonto

Oral melphalan and prednisone chemotherapy plus thalidomide compared with melphalan and prednisone alone in elderly patients with multiple myeloma: randomised controlled trial

BACKGROUND Since 1960, oral melphalan and prednisone (MP) has been regarded as the standard of care in elderly multiple myeloma patients. This multicentre randomised trial compared oral MP plus thalidomide (MPT) with MP alone in patients aged 60-85 years. METHODS Patients with newly diagnosed multiple myeloma were randomly assigned to receive oral MP for six 4-week cycles plus thalidomide (n=129; 100 mg per day continuously until any sign of relapse or progressive disease) or MP alone (n=126). Analysis was intention-to-treat. This study is registered at , number NCT00232934. RESULTS Patients treated with thalidomide had higher response rates and longer event-free survival (primary endpoints) than patients who were not. Combined complete or partial response rates were 76.0% for MPT and 47.6% for MP alone (absolute difference 28.3%, 95% CI 16.5-39.1), and the near-complete or complete response rates were 27.9% and 7.2%, respectively. 2-year event-free survival rates were 54% for MPT and 27% for MP (hazard ratio [HR] for MPT 0.51, 95% CI 0.35-0.75, p=0.0006). 3-year survival rates were 80% for MPT and 64% for MP (HR for MPT 0.68, 95% CI 0.38-1.22, p=0.19). Rates of grade 3 or 4 adverse events were 48% in MPT patients and 25% in MP patients (p=0.0002). Introduction of enoxaparin prophylaxis reduced rate of thromboembolism from 20% to 3% (p=0.005). CONCLUSION Oral MPT is an effective first-line treatment for elderly patients with multiple myeloma. Anticoagulant prophylaxis reduces frequency of thrombosis. Longer follow-up is needed to assess effect on overall survival.

Bortezomib, doxorubicin and dexamethasone in advanced multiple myeloma

BACKGROUND Bortezomib has shown significant activity in myeloma. In this multicenter trial, we assessed for the first time the combination of bortezomib, doxorubicin and low-dose dexamethasone (PAd) in the treatment of relapsed/refractory myeloma. PATIENTS AND METHODS Sixty-four patients were treated for a median of four 28-day cycles (1-6). Bortezomib was given at 1.3 mg/m(2) (days 1, 4, 8, 11) and dexamethasone at 40 mg (days 1-4); 34 patients receive doxorubicin at 20 mg/m(2) (days 1, 4) while 30 patients pegylated liposomal doxorubicin at 30 mg/m(2) (day 1). RESULTS Fifty-eight percent of patients had undergone prior autologous transplantation, 70% prior anthracycline and 27% prior bortezomib-based regimens. Forty-three patients (67%) achieved at least a partial response including 16 (25%) with at least a very good partial response. One-year event-free survival was 34% after PAd and 31% after the previous line of therapy (hazard ratio 1.20, 95% confidence interval 0.76-1.90, P = 0.43). One-year overall survival from the start of PAd was 66%. Grade 3-4 toxic effects included thrombocytopenia (48%), neutropenia (36%), infections (15%), anemia (13%), gastrointestinal disturbances (11%) and peripheral neuropathy (10%). Two patients had grade 3-4 cardiac heart failure. CONCLUSIONS PAd is an active salvage therapy with manageable toxicity in patients with relapsed/refractory myeloma.

Intravenous melphalan, thalidomide and prednisone in refractory and relapsed multiple myeloma.

Objectives: Thalidomide combined with conventional chemotherapies including oral melphalan shows significant anti‐myeloma activity. To address this issue, feasibility and efficacy of a three drug combination consisting of intravenous (i.v.) melphalan, thalidomide and prednisone [M(i.v.)PT] was evaluated in advanced myeloma patients. Patients and methods: Twenty‐four advanced myeloma patients were treated with multiple cycles of a regimen consisting of low dose i.v. melphalan (20 mg/m2) at d 1, thalidomide at the dose of 50–100 mg/d given continuously and oral prednisone at the planned dose of 50 mg/d every other day. Intravenous melphalan was administered every fourth month. Median time from diagnosis was 40 months (range: 8–144 months). Fifteen patients (66%) had previously been treated with a combination of thalidomide and dexamethasone or with thalidomide alone. Results: Overall, on an intent‐to treat basis, 14 patients responded: three achieved near complete remission (nCR), seven achieved partial response (PR), four minimal response (MR). Six patients showed stable disease (SD) and four‐disease progression. Interestingly, of five patients who had previously progressed while on thalidomide and prednisone, one reached nCR, two PR and one MR. After a median follow up of 14 months, median progression free survival was 9 months. Response duration was longer than that induced by the previous line of treatment in eight patients (33%). Thalidomide‐associated toxicity mainly consisted of constipation, tingling and sedation. Conclusions: M(i.v.)PT is an effective regimen, which can overcome resistance to thalidomide plus prednisone in advanced myeloma with acceptable toxicity.

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.

Melphalan and its role in the management of patients with multiple myeloma

Melphalan is an alkylating agent approved for the treatment of multiple myeloma and ovarian cancer. The combination of oral melphalan and prednisone was first introduced in the 1960s and remains the standard therapy for elderly multiple myeloma patients. High-dose melphalan followed by autologous stem cell support became the standard treatment for younger patients since the 1990s. The occurrence of drug resistance is the major limiting factor for the long-term success of this therapy, and relapse always occurs. In recent years, advances in the understanding of the pathogenesis of myeloma and the mechanism of drug resistance have led to the development of novel targeted therapies that are able to overcome resistance and show additive or synergistic effects with melphalan. Thalidomide, its immunomodulatory derivative lenalidomide and the proteasome inhibitor bortezomib, in combination with oral melphalan in the elderly and with intravenous melphalan in younger patients, are changing the traditional treatment paradigm of multiple myeloma.

Time to first disease progression, but not β2‐microglobulin, predicts outcome in myeloma patients who receive thalidomide as salvage therapy

Baseline parameters that may be predictive of outcome after thalidomide treatment have been investigated to identify which myeloma patient subgroups will most benefit from this drug.

Investigational treatments for multiple myeloma.

Multiple myeloma remains a fatal neoplasm and new treatments are urgently needed. In recent years, advances in understanding the molecular pathophysiology of myeloma and the mechanisms of drug resistance led to the development of several novel agents. The drugs with the most available clinical data are thalidomide, bortezomib and lenalidomide. Impressive results obtained with these agents – both in relapsed disease and in newly diagnosed patients – have significantly improved the outcome of myeloma patients. Several other new targeted agents are presently under investigation. These include monoclonal antibodies, agents that target mammalian target of rapamycin, histone acetylation, heat-shock proteins, growth factor signalling cascades, oncogenes, signal transducer and activators of the transcription pathway, Akt pathway and MAPK pathway. Their mechanisms of action, the available knowledge on their efficacy, safety and possible future clinical application are reviewed.