Multiple myeloma is the second most common hematologic malignancy. It accounts for 20,580 new cancer cases in the USA in 2009, including 11,680 cases in men, 8,900 cases in women, and 10,580 deaths overall. Although the disease remains still incurable, outcomes have improved substantially over recent years thanks to the use of high-dose therapy and the availability of novel agents, such as the immunomodulatory drugs thalidomide and lenalidomide, and the proteasome inhibitor bortezomib. Various trials have shown the advantages linked to the use of novel agents in the transplant and not-transplant settings. In particular, this paper will present an overview of the results achieved with lenalidomide-containing combinations in patients eligible for high-dose therapies, namely, young patients. The advantages obtained should always be outweighed with the toxicity profile associated with the regimen used. Therefore, here, we will also provide a description of the main adverse events associated with lenalidomide and its combination.
For many years, the combination vincristine-doxorubicin-dexamethasone (VAD) was the standard induction treatment for young patients with multiple myeloma (MM) eligible for autologous stem cell transplantation (ASCT). Ten years ago patients candidate for transplant used to receive VAD for 4–6 cycles before undergoing transplantation, leading to a partial response (PR) rate ranging from 52% to 63%, with 3% to 13% of complete response (CR) rate. The availability of new drugs, such as thalidomide, lenalidomide, and bortezomib, has dramatically changed the treatment paradigm of this disease and significantly increased the therapeutic options [
Lenalidomide is an immunomodulatory drug with higher potency than its analogue thalidomide and without sedative or neurotoxic adverse effects. Differences between lenalidomide and thalidomide activity have been shown in preclinical studies. In comparison with thalidomide, lenalidomide has more antiproliferative activity against hematopoietic tumors, including myeloma cell lines and patients’ cells [
On the basis of two phase 3 clinical trials, lenalidomide has already shown additive and/or synergistic effects when used in association with dexamethasone [
Lenalidomide has been tested in various clinical trials as induction regimen before ASCT. In one randomized trial, lenalidomide in combination with high-dose dexamethasone (RD) showed to be superior to dexamethasone alone [
The efficacy of this combination was further improved by reducing the dose of dexamethasone. A phase 3 trial also demonstrated superior survival and lower toxicity with lenalidomide plus low-dose dexamethasone (Rd) [
The role of Rd induction was also assessed in an Italian study [
Based on the promising results obtained with lenalidomide in combination with dexamethasone, new combinations including lenalidomide have been tested to further improve outcomes and to achieve maximal tumour reduction.
A case-matched study compared clarithromycin-lenalidomide plus low-dose dexamethasone (BiRd) with Rd as initial therapy for newly diagnosed MM patients [
Richardson and colleagues evaluated the role of bortezomib-lenalidomide-dexamethasone (VRD) in a phase 1-2 study including 66 patients with MM [
The role of VRD was also confirmed in a French phase 2 trial [
Lenalidomide associated with adriamycin and dexamethasone (RAD; lenalidomide 25 mg days 1–21; infusional adriamycin 9 mg/m2 per day on days 1–4; dexamethasone 40 mg days 1–4 and 17–20) was assessed in another phase 2 study [
A more intense combination including four drugs has been recently tested. Promising results were achieved in a phase 2 multicenter study comparing bortezomib-dexamethasone-cyclophosphamide plus lenalidomide (VDCR) with VDR, bortezomib-cyclophosphamide-dexamethasone (VDC), and VDC modified (VDC-mod) [
A phase 1-2 study evaluated the combination VRD plus pegylated liposomal doxorubicin (VRDD) [
The incidence of both venous and arterial thrombosis in newly diagnosed patients increases when lenalidomide is combined with dexamethasone or chemotherapy: thus, thromboprophylaxis is recommended for the first 6 months of therapy. For patients with standard thromboembolic risk, low-dose aspirin is indicated; for patients with high thromboembolic risk, low-molecular-weight heparin is recommended [
Recent reports have focused on hypothetical negative impact of new drugs on stem cell mobilization. Particularly, hematologic toxicity related to treatment with lenalidomide has raised concerns about lenalidomide use in early phase of treatment and on its possible negative effect on peripheral blood stem cell (PBSC) collection in young patients undergoing ASCT.
In fact, patients mobilized with granulocyte colony-stimulating factor (G-CSF) alone after RD induction have collected a median yield of stem cell ranging from 3.1 to
By contrast, the use of cyclophosphamide in addition to G-CSF may overcome this problem and significantly increases the yield of stem cells collected. Different retrospective published trials on lenalidomide induction have in fact shown a median yield of PBSC ranging from 6.3 to
Consolidation and maintenance therapies have the potential to improve the results achieved after induction treatment and transplantation [
Consolidation treatment with MPR has been tested in the Italian study, comparing MPR (six 28-day cycles of melphalan (0.18 mg/Kg days 1–4), prednisone (2 mg/Kg days 1–4), and lenalidomide (10 mg days 1–21)) versus tandem MEL200 (melphalan 200 mg/m2) with stem cell support [
In a phase 3 randomized double-blind, placebo-controlled study (CALGB 100104), patients with non-progressive disease after a first line ASCT were randomized to receive placebo or lenalidomide at starting dose of 10 mg daily, escalated to 15 mg daily after 3 months [
In the IFM2005-02 study, MM patients younger than 65 years of age, with at least standard disease after a first line ASCT, were randomly assigned to receive consolidation with lenalidomide (25 mg daily, 21 days/month, for 2 months) followed by maintenance with placebo or lenalidomide (10 to 15 mg daily) until relapse [
Of note, both the CALGB and IFM2005-02 studies detected an improvement in PFS with lenalidomide maintenance, but only the CALGB study reported also an OS benefit with this approach [
Recently, the higher incidence of second cancer in patients treated with lenalidomide for long time led to reconsidering the benefit and the duration of lenalidomide maintenance. In both the CALGB 100104 and IFM2005-02, the rate of second primary malignancy was 8%. An analysis of pooled data from 2459 patients enrolled in different studies including maintenance with lenalidomide was performed. Not all the studies showed an increased second cancer risk, whereas different studies confirmed that the benefits achieved with lenalidomide maintenance outweigh the risk to develop a second primary malignancy [
Considering its dual mechanism of action of lenalidomide, comprising tumoricidal effects which rapidly reduce the MM tumor burden, and its immunomodulatory effects which enhance the immune function and maintain disease suppression, this novel agent showed to be effective and safe in patients with newly diagnosed MM. In particular, the combination Rd proved to be a good induction treatment in this setting of patients.
Based on the promising results achieved with Rd, ongoing trials are now testing this regimen in combination with other agents upfront with the aim to increase the tumoricidal effect. Preliminary results showed the positive role of Rd in association with clarithromycin, bortezomib, adriamycin or cyclophosphamide.
In addition, studies are under way to assess the role of long-term treatment with lenalidomide as consolidation/maintenance treatment after ASCT, but longer followup is necessary to draw any definitive conclusion.
B. Lupo and A. Palumbo wrote the paper.
A. Palumbo has received honoraria from Celgene, Janssen-Cilag, Merck, Amgen, and advisory committee from Celgene, Janssen-Cilag.
The authors would like to thank the Editorial Assistant Giorgio Schirripa.