Melphalan is a chemotherapeutic agent for the palliative treatment of myeloma. It also is used as a conditioning agent before autologous stem cell transplantation (ASCT).

Melphalan exists in different formulations and is marketed under several brand names.

Alkeran, manufactured by GlaxoSmithKline (GSK), is available as oral tablets or as an injection. Alkeran tablets are used as a palliative treatment. They are typically combined with prednisone and treatment also may include a proteasome inhibitor, such as Velcade (bortezomib) or an immunomodulatory agent such as Thalomid (thalidomide). Alkeran for injection is administered intravenously at a high dose prior to ASCT. It also can be used at a lower dose for the palliative treatment of patients with myeloma for whom oral therapy is not appropriate.

Evomela, marketed by Acrotech Biopharma, is an injectable formulation of melphalan without propylene glycol, a chemical compound with significant side effects. It is used as a conditioning treatment before ASCT and as palliative treatment in patients with myeloma for whom oral therapy is not suitable.

Melflufen (Ygalo), marketed by Oncopeptides, is an investigational melphalan formulation for the treatment of relapsed refractory multiple myeloma (RRMM). In melflufen, melphalan is bound to flufenamide, increasing its effectiveness. Oncopeptides submitted a new drug application for melflufen in combination with dexamethasone to the U. S. Food and Drug Administration (FDA) in July of 2020. The FDA granted the application priority review and a decision is expected in February 2021. Oncopeptides also announced that they would soon seek conditional approval in Europe.

Before an approval decision is reached, melflufen is available through an expanded access program called sEAPort (NCT04534322) to multiple myeloma patients who did not respond to a proteasome inhibitor, an immunomodulatory agent, or an anti-CD38 monoclonal antibody.

How does melphalan work?

Melphalan is an alkylating agent that attaches chemical molecules known as alkyl groups to DNA. The alkyl groups interfere with DNA replication, which is essential for cell division. Melphalan primarily affects rapidly dividing cells, such as myeloma cells.

As a palliative treatment, it helps control myeloma cell propagation. Melphalan also is used at higher doses as myeloablative chemotherapy prior to ASCT. At these doses, melphalan is more potent against myeloma cells, but also drastically reduces the number of healthy blood-forming cells in the bone marrow.

Melphalan in clinical trials

The effectiveness of melphalan together with other medications has been tested in many clinical trials.

A meta-analysis of six randomized controlled trials compared the effect of oral melphalan plus prednisone (MP) versus MP in combination with Thalomid (MPT) on overall survival (OS), progression-free survival (PFS), and one-year response rates in previously untreated elderly patients with multiple myeloma. The median OS for MPT was 39.3 months compared to 32.7 months for MP. The median PFS was 20.3 months for MPT, and 14.9 months for MP. The one-year response rates were 59% with MPT and 37% with MP.

A Phase 3 clinical trial (NCT00111319) called VISTA assessed whether the addition of Velcade to melphalan plus prednisone therapy decreases the time to disease progression in patients with previously untreated multiple myeloma. During the trial, 682 patients were assigned randomly to receive nine six-week cycles of melphalan (at a dose of 9 mg/m2) and prednisone (at a dose of 60 mg/m2) either alone or in combination with Velcade (at a dose of 1.3 mg/m2). The response rate was 71% in the group receiving melphalan, prednisone, and Velcade, compared to 35% in the group receiving melphalan and prednisone only. The median time to disease progression was 24 months in the group including Velcade, and 16.6 months in the group without Velcade.

Another clinical trial randomized 200 newly diagnosed multiple myeloma patients below age 65 to receive either high-dose intravenous melphalan to conventional-dose chemotherapy as conditioning therapy prior to ASCT. The conventional-dose group received a combination of chemotherapeutic agents known as VMCP and BVAP. The VMCP regimen included 1 mg intravenous vincristine, 5 mg/m2 oral melphalan, 110 mg/m2 oral cyclophosphamide, and 60 mg/m2 oral prednisone. The BVAP regimen included 1 mg intravenous vincristine, 30 mg/m2 intravenous carmustine, 30 mg/m2 intravenous doxorubicin, and 60 mg/m2 oral prednisone. VMCP and BVAP were administered at alternating cycles of three-week intervals for 12 months, for a total of 18 cycles.

The high-dose group first received four to six alternating cycles of VMCP and BVAP, before receiving 140 mg/m2 intravenous melphalan and undergoing total body irradiation prior to stem cell transplant. The response rate of patients receiving high-dose therapy was 81%, compared to 57% on standard-dose therapy. The probability of event-free survival for five years was 28% in the high-dose group and 10% in the conventional-dose group. The overall estimated five-year survival rate was 52% in the high-dose group and 12% in the conventional-dose group. Treatment-related mortality did not differ significantly between the two groups.

An open-label Phase 2b clinical trial (NCT01660633) assessed the safety and effectiveness of high-dose Evomela as a conditioning regimen prior to ASCT. During the trial, 61 patients received two doses of Evomela at 100 mg/m2 each, three days and two days before ASCT. The ORR was 100%, of which 21% was a complete response.

A Phase 1/2 trial, called O-12-M1 (NCT01897714), tested the effectiveness of escalating doses of melflufen in combination with dexamethasone to find the maximum tolerated dose of melflufen in patients with RRMM. Results of the trial published in the journal Lancet Haematology indicated that 15, 25 and 40 mg doses were well-tolerated in patients but at 55 mg patients experienced too many adverse events. In phase 2 of the trial, 45 patients were given 40 mg doses of melflufen plus dexamethasone and 31% experienced an overall response and 49% showed a clinical benefit.

HORIZON, a Phase 2 clinical trial (NCT02963493) is investigating the use of melflufen in combination with dexamethasone. Patients received 40 mg intravenous (IV) injections of melflufen with 40mg of oral dexamethasone once a week. Full data of the study were published in the Journal of Clinical Oncology in December 2020. The trial recruited 157 patients with multiple myeloma who had not responded to at least two other previous forms of treatment. Results showed that 29% of the 157 patients had an overall response. The subgroup of 119 patients who were resistant to three different types of treatment (a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 monoclonal antibody) had an overall response rate of 26%. Oncopeptides used the data from this trial to form a new drug application (NDA) for the FDA in July 2020. The study is still active and it is expected to conclude in September 2022.

A Phase 3 trial, called OCEAN (NCT03151811), seeks to compare the effects of melflufen plus dexamethasone with Pomalyst plus dexamethasone. The trial has enrolled 495 participants with multiple myeloma that have not responded to other therapies, especially lenalidomide. Patients were randomized to receive one of the two drug combinations and will be monitored for effects for up to 24 months. The study is still active but is no longer recruiting with study completion expected by July 2022.

Melflufen in combination with dexamethasone and either bortezomib or daratumumab will be tested in an open-label Phase 1/2a trial, called ANCHOR (OP-104, NCT03481556). The study has a targeted enrollment of 80 patients with multiple myeloma who have tried one to four previous treatments. Interim results of the study were presented in December 2020 for 33 patients who received the treatment arm with daratumumab and 13 who received the treatment combination with bortezomib. Both treatments showed encouraging results with good tolerability. The daratumumab arm showed that 30 mg should be recommended for future studies compared to the higher 40 mg dose. The bortezomib arm of the trial is still recruiting patients in the U.S., Czech Republic, and Spain.

Another Phase 2 trial, BRIDGE (NCT03639610), will investigate the pharmacokinetics (how the drug moves through the body) of melflufen plus dexamethasone in multiple myeloma patients with impaired renal function. The study aims to recruit 25 participants at locations in the Czech Republic, Greece, and Poland to receive once-a-week IV infusions of melflufen in combination with oral dexamethasone. The study is expected to conclude in December 2021.

The pharmacokinetics, safety, and tolerability will be compared between central and peripheral IV infusions of melflufen in a Phase 2 trial called PORT (NCT04412707). Treatment will be given in combination with dexamethasone to an estimated 20 participants with multiple myeloma. The study is currently recruiting at locations in Europe and the U.S. The study is expected to conclude in March 2022.

Other information

Melphalan treatment leads to bone marrow suppression, which is characterized by a low count of white blood cells, platelets, and hemoglobin. This consequently increases the risk of infection, bleeding, and anemia. When used as a palliative treatment, blood counts have to be regularly monitored to find the optimal dosage of treatment and to avoid toxicity. High doses as part of a conditioning regimen for ASCT can be applied only when stem cells are available for rescue.

Common side effects of melphalan include nausea, vomiting, mucositis (inflammation and ulceration of mucous membranes), and diarrhea.

Because melphalan damages the genetic material, it may cause secondary malignancies, such as acute nonlymphocytic leukemia and myeloproliferative syndrome.


Last updated: Jan. 8, 2021


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