Phase III Study of Ranimustine, Cyclophosphamide, Vincristine, Melphalan, and Prednisolone (MCNU-COP/MP) versus Modified COP/MP in Multiple Myeloma: A Japan Clinical Oncology Group Study, JCOG 9301

Abstract

To investigate whether combination chemotherapy with vincristine, cyclophosphamide, prednisolone, and melphalan (COP/ MP) with the addition of ranimustine (MCNU) (MCNU-COP/MP) is superior to the slightly modified COP/MP (mCOP/MP) regimen in multiple myeloma (MM), a multicenter randomized study was performed. Two hundred ten patients with newly diagnosed, overt MM not treated with chemotherapy were enrolled from 32 institutions of the Lymphoma Study Group of the Japan Clinical Oncology Group and were randomized to receive either MCNU-COP/MP or mCOP/MP. The response rate (RR) to mCOP/MP was 43.7% (95% confidence interval [CI], 33.9%-53.8%] and to MCNU-COP/MP was 56.1% (95% CI, 46.1%-65.7%) (P = .097). The progression-free survival (PFS) was significantly longer for patients treated with MCNU-COP/MP than for patients treated with mCOP/MP (median, 23.0 months [95% CI, 18.9-25.8] versus 15.8 months [95% CI, 14.1-19.4]) (P = .014). However, no significant difference in overall survival rate (OS) was observed between the groups (median, 49.9 months [95% CI, 40.4-59.1] versus 44.0 months [95%, CI, 32.8-59.8]) (P = .75). Grades 3 and 4 hematological toxicities were more frequently observed with MCNU-COP/MP than with mCOP/MP, but the incidence of grades 3 and 4 nonhematological toxicities was low in both groups. In conclusion, MCNU-COP/MP in comparison with mCOP/MP improved RR and PFS in overt MM; however, this outcome did not contribute to prolonging OS, indicating that addition of MCNU to mCOP/MP has no benefit on survival.

Lymphoma Study Group of JCOG

“…A Phase II study of COP (cyclophosphamide, prednisolone) -MP (melphalan, prednisolone) for untreated overt MM patients (JCOG8906) revealed a similar efficacy to those from the USA and Europe (48). A subsequent randomized Phase III study comparing modified (m)COP-MP with/without ranimustine for untreated overt MM (JCOG9301) revealed that addition of ranimustine to mCOP/ MP has no benefit for survival, despite improving the response rate and PFS, similar to findings of other studies evaluating the addition of new agents to alkylators and steroids in MM (49). Both Phase III and II studies on untreated overt MM patients who were ineligible for HDC/auto-HSCT and eligible, respectively (JCOG0112 and JCOG0005-DI), were terminated early because of poor patient accrual and the results of a planned interim analysis, respectively (50).…”

Proteasome inhibitor, bortezomib, for myeloma and lymphoma

“…13,14 In previously untreated patients with MM, melphalan + prednisolone (MP), MP-like regimens, and vincristine + doxorubicin + dexamethasone (VAD) have been frequently applied. [15][16][17][18] Several but not all randomized controlled trials have shown that high-dose chemotherapy followed by autologous stem cell transplantation (SCT) is superior to conventional-dose chemotherapy in terms of response rate and progression-free and overall survivals, [19][20][21] and highdose chemotherapy is recommended for MM patients 65 years of age or younger as a part of the initial therapy.…”