Multiple myeloma (MM) is a chronic, malignant disorder of clonal plasma cells characterized by hypercalcemia, anemia, renal insufficiency, and osteolytic bone lesions. The incidence increases with age and the median age of patients at diagnosis is around 65 years.1 In the past two decades, the median survival of the MM patients has greatly increased up to more than 10 years with the development of many novel drugs such as proteasome inhibitors, immunomodulatory agents, and monoclonal antibodies.2

However, MM is a still incurable disease and all patients who show a good response to initial treatment eventually suffer from disease relapse. With the exception of some patients who have short initial response durations, most patients with disease relapse attain prolonged survival with a salvage treatment which includes a combination of agents with different mechanisms of action and/or improved efficacy. For example, lenalidomide, pomalidomide, carfilzomib, and daratumumab can be used in a relapsed/refractory setting.345 However, these treatment options are not always available. Although many novel agents are now reimbursed by the national insurance program in Korea, they still can cause an economic burden. Additionally, many approved regimens require frequent hospital visits and hospitalizations. In this context, a favorable salvage treatment needs several virtues such as acceptable efficacy, oral formulation, low price, and minimal safety issues.

The melphalan, cyclophosphamide and dexamethasone (MCD) regimen consists of conventional anti-myeloma drugs. Melphalan, an oral alkylating agent, had been a main drug in combination with prednisone before the era of novel agents. Furthermore, it is still used in higher doses as a conditioning regimen for autologous stem cell transplantation (ASCT).6 Cyclophosphamide is another alkylator for MM and was used as an induction therapy in combination with thalidomide and dexamethasone in the early 2000s.7 High-dose cyclophosphamide produces a direct toxic effect for cancer cells. In contrast, low-dose cyclophosphamide enhances inhibition of regulatory T cells which interfere with beneficial immune responses.8 Many clinical studies have evaluated its role as an adjunctive treatment to improve response rates and survival.4910 Historically, many triplet regimens for MM were comprised of 1 novel agent such as thalidomide, lenalidomide and bortezomib plus corticosteroid plus alkylating agents. Combinations of two alkylators had never been tried. Cyclophosphamide does not show cross-resistance to melphalan. It has a good oral bioavailability and a good safety profile without cumulative hematologic toxicity.10 So, the purpose of this study is to investigate efficacy and safety of the MCD regimen as a salvage treatment for previously treated myeloma.

We retrospectively analyzed patients who received the MCD regimen from April 2011 and November 2013 for relapsed/refractory MM at a single tertiary center, Chonnam National University Hwasun Hospital, Hwasun, Korea. The patients with AL amyloidosis and/or plasma cell leukemia were excluded. Patients were recruited based on records of chemotherapy prescriptions and their data including characteristics at the diagnosis, previous treatments, treatment responses, toxicities, and survivals were collected using the electronic medical records database. Previous treatments include conventional combination chemotherapies, autologous stem cell transplantation, and novel agents such as bortezomib, thalidomide, lenalidomide.

Almost all patients with MM may ultimately experience disease relapse. In the last several decades, numerous studies were focused on developing the best salvage treatment. As a result, many combination regimens incorporating proteasome inhibitors, immunomodulatory agents, monoclonal antibodies, and histone deacetylase inhibitors were adopted to improve survival and consistency of recommendation by the guidelines.121314 However, a subset of patients with poor prognoses may not have durable responses despite these regimens and need further salvage treatments. Since the choices of salvage treatments for MM are strictly regulated and reimbursed by the national health insurance program in Korea, these heavily pretreated patients eventually have no more options except conventional chemotherapies.

Currently recommended conventional chemotherapeutics used singly or in combination include DCEP (dexamethasone, cyclophosphamide, etoposide and cisplatin), D(T)-PACE (dexamethasone with or without thalidomide, cisplatin, doxorubicin, cyclophosphamide and etoposide) and bendamustine.1516 Table 416171819202122 demonstrates the results of these regimens. Early in the 2000s, Lee et al.17 first reported the results of 4-day continuous infusion of DT-PACE as a salvage treatment for relapsed myeloma. The cohort of that study is different from ours in that no patient experienced ASCT and the majority of patients did not receive any novel agents. The ORR was 32% including 16% CR or near-CR. Of note, the treatment-related mortality (TRM) developed in 4% of patients, and neutropenia of grade 3 or 4 developed in 65% of patients. Prophylactic granulocyte colony-stimulating factor (G-CSF) was routinely administered on day 5 after chemotherapy. In 2007, Gerrie et al.18 also examined D(T)-PACE for patients who relapsed after treatment with agents (median 3) including thalidomide, lenalidomide, bortezomib and carfilzomib. The ORR was 49% with VGPR of 16%. The TRM was in 5% of patients. G-CSF was needed in 65% of cycles for profound neutropenia. The PFS and OS of that population was 5.5 months and 14.0 months, respectively. The DCEP study by Dadacaridou et al.19 and Park et al.20 showed similar efficacy as that of DT-PACE. Although an acceptable response was noted in their studies, the major concern was hematologic toxicities. In this context, the DCEP and DT-PACE regimens have some drawbacks. Since they are 4-day continuous infusional regimens, patients need multiple peripheral venous lines or central venous catheterization as well as hospitalization for several days. Since hematologic toxicities may be increased with each addition of myelosuppressive agent, frequent blood count monitoring and prolonged hospital stays may be needed and supportive treatments such as blood transfusion, G-CSF administration and prophylactic antibiotics result in high medical expenses.

Bendamustine is a chemotherapeutic wildly used in lymphoid malignancy. Since it has a unique feature of structural similarities to both alkylators and purine analogs, it carries incomplete cross-resistance with cyclophosphamide and melphalan.23 Combined with prednisone, bendamustine resulted in an ORR ranging from 30–40%.2124 In 2016, a retrospective study by Kim et al.21 reported a relatively short PFS and OS (3.1 and 5.5 months, respectively), however this results need to be interpreted carefully because enrolled patients were unselected, more frail, and heavily pretreated.

In our study, the MCD regimen delivered to patients with relapsed/refractory MM resulted in an overall response rate of 25.9%. Although this result may be relatively lower than those of other regimens, the majority of patients attained a response of SD or better. In addition, the PFS and OS benefits from MCD were not inferior to those of other conventional salvage regimens. In terms of toxicity, relatively low incidences of myelosuppression were observed. Other advantages of the MCD is that it could be given orally and on an outpatient basis.

Our study has some limitations. First, a relatively small number of patients was analyzed, so the response rate needs to be confirmed in a study of a larger cohort. Second, because our cohorts had exposure to lenalidomide, response in populations refractory to the newest agents such as pomalidomide, carfilzomib and daratumumab could be lower than reported. Third, our cohort had a relatively good performance status at the time of MCD, they are not representative of real-world population with multiple comorbidities.

In conclusion, the efficacy of a combination regimen of melphalan, cyclophosphamide and dexamethasone is comparable with those of multi-agent infusional regimens as a salvage treatment for heavily pretreated patients with myeloma. Additionally, toxicity profiles of MCD are relatively good and can be easily delivered orally. Considering that MM is ultimately a progressive disease and needs multiple salvage treatments, the MCD regimen has a role as a bridge to newer treatment options.