| Japanese Journal of Clinical Oncology | Pages |
Alternating Combination Chemotherapy COP (Cyclophosphamide, Vincristine, Prednisone) and MP (Melphalan, Prednisone) in Multiple Myeloma: a Multicenter Phase II Study (JCOG8906)
Introduction
Patients And Methods
Patient Eligibility
Chemotherapy
Evaluation of Response, Progression-free Survival (PFS), Overall Survival (OS) and Toxicity
Statistical Analysis
Results
Patient Population
Treatment Response and Survival
Toxicity
Discussion
Acknowledgments
Affiliation of the Authors
References
Alternating Combination Chemotherapy COP (Cyclophosphamide, Vincristine, Prednisone) and MP (Melphalan, Prednisone) in Multiple Myeloma: a Multicenter Phase II Study (JCOG8906)
Method: Between November 1989 and December 1991, a multicenter phase II study of alternating conventional dose combination chemotherapy (CCT) with COP (cyclophosphamide, vincristine, prednisone) and MP (melphalan and prednisone) to evaluate its clinical usefulness for overt MM patients was conducted by the Lymphoma Study Group of the Japan Clinical Oncology Group (JCOG).
Results: Eighty-one previously untreated patients were enrolled in the study. For 69 eligible patients, the response rate was 50.7% [95% confidence interval (CI) 38.4-63.0%]. The median survival time was 38.5 (95% CI 32.0-44.4) months. The survival rate at 3 and 5 years was 50.7 and 27.3%, respectively. Grade 4 toxicity by the criteria of the World Health Organization consisted of anemia in eight patients, leucocytopenia in three, cardiac in one and hepatic in two, but there was no treatment-related death.
Conclusion: The COP-MP regimen for overt MM is thought to be one of the effective CCTs according to the results of the present phase II study.
INTRODUCTION
Before the introduction of alkylating agents, the median survival of multiple myeloma (MM) was less than 1 year (1,2). Treatment with melphalan and prednisone (MP) has constituted the standard regimen for MM for more than two decades, with a response rate of 40-50% and median survival ranging from 2 to 3 years (3-5).
Cyclophosphamide has been reported to have therapeutic activity in MM similar to that of melphalan (6). Also, vincristine was reported to be an effective agent for MM (7) and multiagent chemotherapy including vincristine has been applied to improve the response (8,9). Furthermore, no cross-resistance has been shown between melphalan and cyclophosphamide in both experimental (10) and clinical studies (11).
Based on these observations, the Lymphoma Study Group (LSG) of the Japan Clinical Oncology Group (JCOG) began a multicenter phase II study (JCOG8906) of alternating combination chemotherapy (CCT) with COP (cyclophosphamide, vincristine, prednisone) and MP for symptomatic MM patients in November 1989. We report here the results of the final analysis for survival and toxicity with a median follow-up of 6 years for surviving patients.
PATIENTS AND METHODS
Patient entry began in November 1989 and continued through December 1991. Verbal or written informed consent in keeping with the guidelines of the JCOG and the Institutional Review Board of all participating institutions was obtained before entry to the study.
Patient Eligibility
MM was diagnosed according to the Southwest Oncology Group criteria (12). Patients were classified as to clinical stage using the method of Salmon et al. (13). Studies conducted for initial evaluation included skeletal roentgenograms, bone marrow aspiration or biopsy, serum and/or urine protein electrophoresis and immunoelectrophoresis, in addition to peripheral blood counts and serum chemistries.
Patients were determined to be eligible if they had symptoms (bone pain, malaise, etc.) of MM, performance status (PS) (14) 0-3 or PS 4 with bone pain only, under 75 years old, no prior systemic therapy and no severe organodysfunction (pulmonary, PaO2 [ge]70 mmHg; cardiac, ejection fraction [ge]50%; hematopoietic, granulocytes [ge]1500/µl and platelets [ge]10 × 104/µl; hepatic, GOT/GPT[le]2 times normal upper limit; renal, serum creatinine [le]4.0 mg/dl and/or BUN [le]50 mg/dl). Patients were ineligible when they had complications such as severe infection, diabetes mellitus requiring insulin therapy, active gastroduodenal ulcer or other active malignancies.
Chemotherapy
The alternating chemotherapy consisted of a COP regimen and MP regimen with dose schedules as shown in Table 1. The cycle was repeated every 7 weeks depending on the hematological parameters. If the pretreatment granulocyte count was <1500/µl or platelet count <10 × 104/µl, treatment was postponed for at least 1 week. In cases needing more than 2 weeks for hematological recovery, the doses of drugs except prednisone were reduced to 90% in subsequent treatment cycles. The vincristine dose was reduced or temporarily discontinued if signs of neurotoxicity (severe motor weakness, severe paresthesia or severe constipation) appeared.
Patients who responded were treated until maximum response or the plateau phase of M-protein concentration was achieved and followed without further therapy until relapse or progression. Nonresponders with progressive disease were taken off treatment immediately and those with stable disease were continued for at least three cycles as a rule.
Table 1.
| Regimen | Drug | Dose (mg/m2) | Route | Days |
| COP | Cyclophosphamide | 350 | Drip i.v. | 1, 8, 15 |
| Vincristine (Oncovin) | 1 | Push i.v. | 1, 8, 15 | |
| Prednisone | 40 | p.o. | 1-3, 8-10, 15-17 | |
| MP | Melphalan | 6 | p.o. | 29-31 |
| Prednisone | 40 | p.o. | 29-31 |
Evaluation of Response, Progression-free Survival (PFS), Overall Survival (OS) and Toxicity
Objective response was evaluated by the following four factors: plasmacytoma, serum M-protein, urinary Bence-Jones protein and bone lesions.
Complete response (CR) and partial response (PR) were defined as disappearance and reduction by more than 50% of the abnormalities continuing for more than 4 weeks, respectively. No response (NR) was defined as definite clinical improvement, but with less than 50% reduction of the abnormalities. Progressive disease (PD) was defined as a progression from the baseline level of each factor and/or development of new lesions.
PFS and OS were dated from initiation of the first cycle of COP. Events included disease progression, relapse or death from any cause. Relapse was defined as recurrence of monoclonal protein or bone marrow plasmacytosis in case of CR and a 25% increase from minimal tumor mass in case of PR.
Patients were closely monitored for adverse drug reactions with dose adjustment if necessary. Toxic grade was evaluated according to the toxicity criteria of World Health Organization (WHO) (15).
Statistical Analysis
Data were analyzed as of December 1997. PFS and OS distributions were estimated by the product-limit method (16).
RESULTS
Patient Population
Eighty-one patients were registered at 19 participating institutions between November 1989 and December 1991. Twelve of 81 patients were declared ineligible after registration for various reasons (violation of SWOG criteria in one patient, granulocytopenia in five, thrombocytopenia in two, high GOT/GPT level in three and high creatinine level in one).
The characteristics of the 69 eligible and evaluable patients (33 males and 36 females) are summarized in Table 2. Patient ages ranged from 36 to 75 (median 64) years. Forty-three patients (62.3%) had PS 0-1, 34 (49.3%) had M-protein of IgG class and 51 (73.9%) had Stage III. Thirty-nine patients (56.5%) had more than 30% plasma cells in the bone marrow at study entry. Hypercalcemia ([ge]5.5 mEq/l) was present in six (8.7%) patients, 35 (50.7%) had a hemoglobin level <10 g/dl, four (5.8%) had a serum creatinine level [ge]2.0 mg/dl and 35 (50.7%) had extensive bone involvements.
Treatment Response and Survival
Fifty-one (74%) of 69 eligible patients were treated with at least three courses of COP-MP, seven (10%) received two courses and 11 (16%) received one course or less. The reasons for early discontinuation of treatment in 18 patients were PD in five, adverse drug reactions in six (four infections, one arrhythmia, one interstitial pneumonia), patient refusal in five and other reasons in two (physician's misjudgment, change of address). The number of COP-MP courses administered ranged from one to eight (median four). The total dose was 500-14 400 (median 6300) mg for cyclophosphamide, 1.5-40.8 (median 18.0) mg for vincristine, 0-270 (median 100) mg for melphalan and 60-6720 (median 2340) mg for prednisone.
All 81 patients and 69 eligible patients were analyzed for response. Among the eligible patients, there were 35 responders [50.7%, 95% confidence interval (CI) 38.4-63.0%] with two CRs and 33 PRs as shown in Table 3. In all 81 patients, the overall response rate was 54.3% (95% CI 42.9-65.4%).
Table 2.
| Characteristic | No. | % |
| Age (years) | ||
| <60 | 24 | 34.8 |
| >60 | 45 | 65.2 |
| Gender | ||
| Male | 33 | 47.8 |
| Female | 36 | 52.2 |
| Performance status (ECOG) | ||
| 0-1 | 43 | 62.3 |
| 2-4 | 26 | 37.7 |
| M-protein | ||
| IgG | 34 | 49.3 |
| IgA | 18 | 26.1 |
| IgD | 1 | 1.4 |
| Light chain only | 14 | 20.3 |
| Non-secretory | 2 | 2.9 |
| Stage (Salmon et al.) | ||
| I | 2 | 2.9 |
| II | 16 | 23.2 |
| III | 51 | 73.9 |
| Bone marrow plasma cells (%) | ||
| <10 | 5 | 7.3 |
| 10-30 | 25 | 36.2 |
| >30 | 39 | 56.5 |
| Hemaglobin (g/dl) | ||
| <10 | 35 | 50.7 |
| [ge]10 | 34 | 49.3 |
| Calcium (mEq/l) | ||
| <5.5 | 63 | 91.3 |
| [ge]5.5 | 6 | 9.7 |
| Creatinine (mg/dl) | ||
| <2 | 65 | 94.2 |
| [ge]2 | 4 | 5.8 |
| Bone disease | ||
| Osteoporosis alone | 13 | 18.9 |
| 1-2 lytic lesions | 21 | 30.4 |
| [ge]3 lytic lesions/bone fracture | 35 | 50.7 |
Table 3.
| Response | No. of patients |
| CR | 2 (2.9%) |
| PR | 33 (47.8%) |
| NC | 27 (39.1%) |
| PD | 7 (10.2%) |
At the time of analysis (December 1, 1997) there had been 59 deaths, of which 41 were attributed to progressive disease. The main causes of death in the remaining 18 patients were pneumonia (four), secondary amyloidosis (three), bacteremia (two), cerebrovascular accident (two) and acute cardiac disease, rectal cancer, acute leukemia and bladder cancer in one patient each.
Figure 1. (A) Overall survival curve and (B) progression-free survival curve in 69 eligible patients treated with COP-MP regimen. Tick marks indicate the date on which the patient was last examined (alive). The OS and PFS of eligible patients are shown in Fig. 1A and B, respectively. The median survival time (MST) for 69 eligible patients was 38.5 (95% CI 32.0-44.4) months. The survival rate at 3 and 5 years was 50.7 and 27.3%, respectively. The median PFS was 13.1 (95% CI 10.6-17.2) months.
Table 4.
| Toxicity | Toxic grade (WHO) | ||||
| 1 | 2 | 3 | 4 | NA* | |
| Hemoglobin | 7 | 16 | 27 | 8 | 4 |
| Platelets | 5 | 6 | 4 | ||
| Leucocytes | 12 | 21 | 21 | 3 | 4 |
| T. bilirubin | 6 | 1 | 1 | ||
| GOT/GPT | 17 | 11 | 1 | 2 | 1 |
| Cardiac | 1 | 2 | 1 | 2 | |
| Pulmonary | 2 | ||||
| Fever | 16 | 12 | 2 | 1 | |
| Infection | 10 | 7 | 1 | ||
| Nausea/vomiting | 11 | 6 | |||
| Stomatitis | 7 | 3 | |||
| Alopecia | 19 | 7 | 3 | ||
| Paresthesia | 29 | 12 | 3 | ||
| Constipation | 16 | 8 | 1 | ||
| Diarrhea | 4 | 2 | |||
| Insomnia | 1 | ||||
| Hiccup | 1 | ||||
| Vasalgia | 1 | 2 | |||
| Gastric ulcer | 1 | 1 | |||
| Hyperglycemia | 1 | ||||
Toxicity
Adverse drug reactions and their grade observed during a total of 289 treatment courses in 69 patients are summarized in Table 4. There were no deaths considered as treatment-related death (TRD). As for grade 4 hematological toxicity, eight patients in anemia and three in leucocytopenia were observed during the treatment courses. However, thrombocytopenia more than grade 3 was not seen in any patient. Three patients had localized herpes zoster. Bacterial infection ([ge]grade 2) was documented in eight patients (four pneumonias, one pulmonary tuberculosis, one bacteremia, one osteomyelitis, one perirenal abscess). There were no patients diagnosed with systemic fungal infection. In two patients, treatment was stopped owing to cardiotoxicity manifesting II° A-V block or ventricular tachycardia. Two patients had interstitial pneumonia treated with high-dose corticosteroid hormone therapy. Prednisone was discontinued for gastric ulcer in two patients and hyperglycemia in one patient. Nausea and vomiting accounted for most of the gastrointestinal toxicity and were mostly of mild ([le]grade 2). One of two patients had grade 4 liver transaminases (GOT and GPT) elevation, resulting in discontinuation of further treatment. Two patients had grade 3 alopecia. In three of 43 patients with paresthesia due to peripheral neuropathy, vincristine was discontinued or changed to vindesine.
DISCUSSION
Chemotherapy is the preferred initial treatment for overt and symptomatic MM. No treatment, however, has been associated with the survival of more than a handful of patients for more than 10 years. There is no indication that treatments introduced within the last decade are curative.
Although allogeneic or autologous bone marrow transplantation combined with high-dose chemotherapy might achieve cure occasionally, the incidence of relapse after this approach is high (17-22).
The main form of cytotoxic treatment is conventional dose chemotherapy at present. The standard treatment of MM has been intermittent courses of MP for many years (3). Because of the shortcomings of MP, various combinations of other chemotherapeutic drugs have been used since the 1970s. Many CCT regimens other than melphalan and/or cyclophosphamide with prednisone such as carmustine, semustine, ranimustine, vincristine and adriamycin have been compared with MP in randomized studies (13,22-32). According to those studies, the survival rate at 2 years and the MSTs for the MP ranged between 87 and 45% and between 50 and 19 months, respectively. However, those for the CCT regimen ranged between 71 and 52% and between 43 and 25 months, respectively. Three of 11 randomized studies demonstrated a significant improvement in response rate for the CCT regimen when compared with MP (23,31,32). However, a significant prolongation of MST after the CCT regimen compared with that after MP was observed in only one trial (29).
In a meta-analysis of 18 randomized studies, there was no significant difference in efficacy between CCT and MP (33). However, there was an implication that MP was superior for patients with a good prognosis, whereas CCT was superior for patients with a poor prognosis.
In the present study of overt MM patients, the overall response (CR + PR) rate in 69 evaluable patients was 50.7% and MST was 38.5 months. This result is compatible with other CCT regimens (13,23-31). However, some problems have been noted about the quality of study. For example, patients who deviated from the eligibility criteria accounted for 15% (12/81) of the registered patients. The main reason was considered to be that eligibility checks were not strictly performed before registration because a central registration system was not adopted in the present trial. Furthermore, 19% of eligible patients were treated with less than three courses for various reasons other than PD.
Myelosuppression was the main toxic effect presenting exclusively as leucocytopenia and anemia, whereas treatment-related thrombocytopenia was infrequent and mild. Consequently, bacterial and viral infections were the main adverse events, but there was no TRD due to infection in this study. Grade 4 cardiotoxicity with ventricular tachycardia possibly induced by cyclophosphamide was observed in a 54-year-old man on the sixth day after its administration. Although such toxicity due to a conventional dose of this drug is rare (34), attention is needed during the COP regimen. Grade 3 peripheral neuropathy due to vincristine interrupted COP-MP treatment in three patients and two of these patients were treated with vindesine instead of vincristine. However, the neurotoxicity of the COP-MP regimen was thought to be acceptable generally.
In summary, from the results of the present phase II study, our alternating COP and MP regimen for overt MM was thought to be an effective chemotherapeutic regimen similar to conventional CCTs including anthracycline and/or nitrosourea.
Acknowledgments
This work was supported in part by Grants-in-Aid for Cancer Research (2S-1, 5S-1, 1-1 and 4-5) and for a New 10-year Strategy for Cancer Control from the Ministry of Health and Welfare. The authors are grateful to Drs K. Deura, I. Aoki, S. Konda, M. Nagai and T. Suzuki and other participating doctors from the 19 institutions in the Lymphoma Study Group of the Japan Clinical Oncology Group for their cooperation.
Affiliation of the Authors
1Department of Internal Medicine, National Cancer Center Hospital, Tokyo, 2Second Department of Internal Medicine, Mie University Faculty of Medicine, Tsu, 3Department of Internal Medicine, Sapporo National Hospital, Sapporo, 4Department of Internal Medicine, Iwaki-Kyoritsu Hospital, Iwaki, 5Department of Internal Medicine, Saga Medical School, Saga, 6Second Department of Internal Medicine, Ryukyu University School of Medicine, Nakagusuku, 7Department of Internal Medicine, Fujita Health University School of Medicine, Toyoake, 8Third Department of Internal Medicine, Akita University School of Medicine, Akita, 9Department of Hematology, Tenri Yorozu-Sodan-Sho Hospital, Tenri, 10Department of Internal Medicine, Atomic Disease Institute, Nagasaki University School of Medicine, Nagasaki, 11Second Department of Internal Medicine, Kagoshima University Faculty of Medicine, Kagoshima, 12Department of Internal Medicine, Aoto Hospital, Jikei University School of Medicine, Tokyo, 13Department of Internal Medicine, Kurashiki Central Hospital, Kurashiki, 14Department of Internal Medicine, National Shikoku Cancer Center Hospital, Matsuyama, 15Department of Medical Oncology, National Cancer Center Hospital, Tokyo, 16Cancer Information and Epidemiology Division, National Cancer Center Research Institute, Tokyo and 17Department of Internal Medicine, Nagoya National Hospital, Nagoya, Japan
References
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