Multiple Myeloma: VMCP/VBAP Alternating ...

Multiple Myeloma: VMCP/VBAP Alternating Combination Chemotherapy Is Not Superior to Melphalan and Prednisone Even in High-Risk Patients By Mario Boccadoro, Filippo Marmont, Maurizio Tribalto, Giuseppe Avvisati, Alessandro Andriani, Tiziano Barbui, Maria Cantonetti, Mario Carotenuto, Benedetto Comotti, Franco Dommacco, Roberto Frieri, Andrea Gallamini, Gabriele Gallone, Piera Giovangrossi, Fausto Grignani, Vito Michele Louta, Marina Liberati, Pellegrino Musto, Giorgio Neretto, Maria Teresa Petrucci, Luigi Resegotti, Alessandro Pileri, and Franco Mandelli The efficacy of alternating vincristine, melphalan (M), cyclophosphamide, prednisone/vincristine, carmustine, doxorubicin, and prednisone (VMCP/VBAP) polychemotherapy was compared with the M and prednisone (MP) regimen as induction treatment in multiple myeloma (MM). Three hundred four MM patients entered this study between March 1983 and July 1986; the analysis was performed in December 1989. The treatment groups did not show significant differences with respect to major prognostic factors. Median overall survival was 33.8 months. In the VMCP/VBAP and MP arms, after 12 induction chemotherapy cycles, 59.0% and 47.3% (P < .068) of the patients achieved an M component reduction greater than 50%. No

significant difference was observed in the two treatment arms in terms of remission duration (21.3 v 19.6 months, P < .66) and survival (31.6 v 37.0 months, P < .28). Patients younger than 65 years did not show any advantage from the alternating polychemotherapy. At diagnosis, the plasma cell labeling index (LI) and serum beta-2 microglobulin (P2-m) were evaluated in 173 and 183 patients, respectively. A significantly reduced survival was observed for patients with LI ; 2% (16.4 months) or p2-m _ 6 mg/L (20.4 months). Even in these poor-risk subgroups, VMCP/ VBAP was not superior to MP. J Clin Oncol 9:444-448. © 1991 by American Society of Clinical Oncology.

THE CHOICE of induction chemotherapy in multiple myeloma (MM) is still controversial. Since the introduction in 1969 of melphalan and prednisone (MP) chemotherapy,' a large number of clinical trials have been carried out in an

(M); Burroughs Wellcome Co, Research Triangle

attempt to increase the percentage of responding

patients and improve survival. Several combination chemotherapy regimens have been compared with standard MP on the assumption that administration of noncrossresistant drugs would lead to greater tumor reduction and prevent or delay the emergence of resistant clones. These trials have provided conflicting 2 results. The high response rate and prolonged survival observed with an association of vincristine and three alkylating agents (Alkeran [melphalan

From the Italian MultipleMyeloma Study Group. Submitted April 17, 1990; acceptedAugust 27, 1990. Supported by grant no. 88.00534.44 from the Italian National Research Council, Special Project "Oncology," and by Associazione ItalianaRicerca Cancro. Address reprint requests to Mario Boccadoro, MD, Dipartimento di Medicina ed Oncologia sperimentale, Cattedra di Ematologia, Via Genova, 3, 10126 Torino, Italy. © 1991 by American Society of Clinical Oncology. 0732-183X/91/0903-0002$3.00/0

444

Park, NC]; Cytoxan [cyciophosphamide; BristolMyers Co, Evansville, IN]; and carmustine) plus

prednisone (M2 protocol)3 were not confirmed by randomized studies comparing a similar regimen with MP.4 Moreover, the Southwest Oncology Group (SWOG), using an alternating combination

chemotherapy regimen containing doxorubicin, reported a higher response rate and better sur-

vival, particularly in stage III patients, in comparison to MP.' These results were not confirmed in a simultaneous study using the same dose regimen at a single institution.6 The Medical Research Council group has recently reported improved survival with the doxorubicin, carmustine, cyclophosphamide, and M regimen compared with M alone, even after correction for serum 32-microglobulin (02-m) values.7 In line with these studies, the Italian Multiple Myeloma Study Group started the M83 protocol in 1983, a randomized multicenter trial comparing

the alternating vincristine, M, cyclophosphamide, prednisone/vincristine, doxorubicin, carmustine, and prednisone (VMCP/VBAP) versus the standard MP. The efficacy of both these regimens was retrospectively evaluated in high-risk subgroups

Journal of Clinical Oncology, Vol 9, No 3 (March), 1991: pp 444-448

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445

VMCP/VBAP VS MP IN MULTIPLE MYELOMA with prognostic factors such as high tumor burden, high serum 12-m level, and high bone marrow

plasma cell labeling index (LI). MATERIALS AND METHODS

At the time of the analysis, 57.6% of the patients were already dead and 104 (34.2%) were at risk. Twenty-five (8.2%) were lost to follow-up with a median time of study of 7.3 months (range, 0.3 to 46.0 months). Median follow-up for censored patients was 42.6 months (range, 0.3 to 75.7 months).

Patients Three hundred four consecutive patients from nine Italian hematologic centers entered the M83 protocol from March 1983 to July 1986. The analysis was performed in December 1989. The SWOG diagnostic criteria were used.8 MM was classified using the Durie and Salmon staging system.' Patients were stratified by stage and randomly allocated to an MP regimen (M 6 mg/m 2 orally on days 1 to 7 and prednisone 60 mg/m2 orally on days 1 to 7) or a VMCP/VBAP regimen (VMCP: vincristine 1 mg intravenously [IV] on day 1, M 6 mg/m2 orally on days 1 to 7, cyclophosphamide 120 mg/m2 orally on days 1 to 7, and prednisone 60 mg/m 2 orally on days 1 to 7; VBAP: vincristine 1 mg IV on day 1, doxorubicin 30 mg/m2 IV on day 1, carmustine 30 mg/m 2 IV on day 1, and prednisone 60 mg/m 2 orally on days 1 to 7). Induction treatment was administered at 28-day intervals for 12 months. Patients who obtained a response or had a stable disease at the end of the induction treatment received no maintenance therapy until a relapse was evident. Response to chemotherapy was defined as an M component decrease greater than 50%. Relapse was defined as an increase greater than 100% from the lowest level of serum M component, or an increase in the size or number of lytic bone lesions. Progression was defined, in nonresponding patients, as an increase greater than 25% of the M component level or increase in size or number of lytic bone lesions during induction treatment. Twenty-six patients were in stage I, 96 in stage II, and 182 in stage III. Forty-three were in substage B. One hundred seventy-six had immunoglobulin G (IgG) MM, 84 IgA MM, and 44 Bence-Jones MM. One hundred fifty-eight patients entered the alternating VMCP/VBAP arm, and 146 the MP arm. The alternating chemotherapy VMCP/VBAP and MP arms were well balanced with respect to the major prognostic factors, including age, sex, stage, renal function, hemoglobin, serum calcium, percentage of plasma cells, and M component isotype. Moreover, even serum 132-m and LI values in 173 and 186 patients, respectively, were equally distributed in the two arms (Table 1).

Kinetic Studies Kinetic characteristics of bone marrow plasma cells were evaluated in vitro at diagnosis in 173 patients. Labeled thymidine incorporation and autoradiography, or bromodeoxyuridine incorporation detected by monoclonal antibodies were used as previously described.1 '1" Thymidine incubation and smear preparations were performed in each center. Slides were then frozen and sent to the nearest reference center (Turin, Rome, or Bari) for LI evaluation. StatisticalAnalysis Survival curves were plotted from the start of therapy. Remission duration was evaluated from the time of remission achievement until relapse. The Kaplan-Meier method was used, 12 and differences between the curves were calculated by the method by Breslow.1 The independence of categoric variables was evaluated by the X2 test.1 4 Student's t-test" and one-way analysis of variance were used to evaluate mean values between groups. All data were processed with selected BMDP programs (1D, 2D, 3D, 7D, 4F, and 1L). 16 RESULTS

One hundred fifty-eight patients entered the VMCP/VBAP arm, and 146 the MP arm. Median overall survival was 33.8 months, and the median remission duration was 21.1 months. The time to response was identical in both study groups at 105 days. During induction treatment, a significant higher response rate was observed in VMCP/VBAP arm in comparison to MP (77.0% v 63.9%, P < .02). However, the percentage of patients in remission phase at the end of 12 months of induction treatment showed a slight trend in favor of the VMCP/VBAP arm (59.0% v 47.3%,

Table 1. Patient Survival According to Chemotherapy and Prognostic Factors MP

VMCP/VBAP

Variable

No.

Survival (months)

No.

Survival (months)

P

Stage < III Stage III Creatinine < 2 mg/dL Creatinine > 2 mg/dL LI < 2% LI Ž 2% P2-m < 6 mg/L 32-m Ž 6 mg/L

60 86 119 27 68 14 46 35

35.5 21.7 33.8 17.9 42.2 20.2 54.2 21.7

62 96 123 35 73 18 46 56

53.0 30.4 39.4 29.2 53.1 14.4 43.9 19.9

.6 .3 .4 .4 .5 .8 .6 .6

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446

BOCCADORO ET AL

P < .068). Eighteen months after diagnosis, this difference completely disappeared (35.4% v 28.7%, P < .2). In conclusion, the high response rate obtained in the VMCP/VBAP arm was not main-

tained. Patients who died early (within 2 months from diagnosis) were excluded from the response rate analysis; their percentage was similar in both groups (2.0% v 3.7%, P < .6). Survival curves of patients treated with VMCP/ VBAP or MP merely overlapped (median, 31.6 v 37.0 months, P < .28) (Fig 1A). Even remission duration was not statistically different (median, 21.3 v 19.6 months, P < .6) (Fig 1B). According to treatments, survival curves were also evaluated in patients younger and older than 65 years, and no statistically significant difference was detected. In 173 patients, the bone marrow plasma cell LI was evaluated at diagnosis. Survival was analyzed according to their bone marrow plasma cell LI. An LI cutoff > 2% identified a patient subgroup with highly reduced survival (42.2 v 16.4 months, P < .0001). Serum 32-m was evaluated at diagnosis in 183 patients. A cutoff of 6 mg/L gave the best patient separation. Patients with high values showed a survival of 20.8 months, those with low values 54.2 months (P < .0001). The efficacy of these two regimens was tested in patient subgroups with unfavorable prognostic factors such as stage III, creatinine greater than 2 mg/dL, LI 2 2%, and P2-m 2 6 mg/L. No significant difference was discovered in these groups in terms of remission duration and survival (Table 1, Fig 2). I U I I v

In 1983, the Italian Multiple Myeloma Study Group began a multicenter trial to compare the alternating VMCP/VBAP versus MP treatments. In a long period of observation, over a series of 304 patients, these two regimens were not statistically different in terms of remission duration and survival. The time to response was almost identical in the two treatment arms at 105 days. At that time the response rate was significantly higher in the VMCP/ VBAP arm. However, this difference progressively decreased, showed just a trend at the end of the 12 months of induction treatment, and completely disappeared 18 months after diagnosis. The bone marrow plasma cell LI was confirmed as a powerful prognostic parameter: an LI > 2% was associated with very short survival (16.4 months).17 High serum 02-m values were also associated with reduced survival, as previously reported." The distribution of these parameters was comparable in the two groups, so bias due to patient selection can be ruled out. The analysis of survival also failed to disclose any advantage for either regimen in unfavorable subgroups, such as patients with stage III disease, bone marrow plasma cell LI > 2%, and high serum 12-m levels. In conclusion, in contrast with previous observations,5 in this study, alternating chemotherapy was not more effective than standard MP, even in high-risk patients. It must be stressed that the previously reported

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Fig 1. (A) Actuarial survival (P < .28) and (B) remission duration (P < .66) of previously untreated MM patients receiving induction chemotherapy with VMCP/VBAP (158 patients) or MP (146 patients); (-) VMCP/VBAP, (---) MP.

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447

VMCP/VBAP VS MP IN MULTIPLE MYELOMA 5 1

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Fig 2. Actuarial survival of previously untreated MM patients with (A) serum 02-M > 6 mg/L (56 and 35 patients, in VMCP/VBAP and MP arm; P < .61) and (B) stage III (96 and 86 patients, in VMCP/VBAP and MP arm; P < .27); (--) VMCP/VBAP, (---) MP.

superiority of VMCP/VBAP over MP has had a limited impact on survival, and a median prolongation of only a few months has been observed. Moreover, no patient has been potentially cured, whereas other newly introduced induction treatments using an "intermediate" cyclophosphamide dose,19 continuous infusion of vincristine and doxorubicin plus dexamethasone (VAD),2 or including interferon (IFN) alfa-2b21 have been followed by about a 30% complete remission. These data suggest that these regimens have to be evaluated in large randomized studies to verify if the reported high percentage of complete remission will correspond to an improved survival. However,

MP, 20 years after its introduction, remains the reference induction treatment for MM, and any new proposed regimen has to be compared with this reference treatment. IFN alfa-2b maintenance treatment can significantly prolong the remission phase of responding patients with a greatly reduced tumor burden. 22 This feature justifies the attempts to increase the complete response rate. These new findings suggest that more intensive induction regimens have to be tested in younger patients, particularly in those with poor prognostic factors, for whom the survival offered by standard treatment is clearly unsatisfactory.

REFERENCES 1. Alexanian R, Haut A, Khan AU, et al: Treatment of multiple myeloma: Combination chemotherapy with different melphalan dose regimens. JAMA 208:1680-1685, 1969 2. Bergsagel DE: Is aggressive chemotherapy more effective in the treatment of plasma cell myeloma? Eur J Cancer Clin Oncol 25:159-161, 1989 3. Lee BJ, Sahakian G, Clarkson BD, et al: Combination chemotherapy of multiple myeloma with alkeran, cytoxan, and BCNU. Cancer 33:533-536, 1974 4. Peest D, Deicher H, Coldeway R, et al: Induction and maintenance therapy in multiple myeloma: A multicenter trial of MP versus VMCP. Eur J Cancer Clin Oncol 24:1061-1067, 1988 5. Salmon SE, Haut A, Bonnet JD, et al: Alternating combination chemotherapy improves survival in multiple myeloma: A Southwest Oncology Group study. J Clin Oncol 1:453-457, 1983 6. Alexanian R, Dreicer R: Chemotherapy for multiple myeloma. Cancer 53:583-588, 1984 7. Mac Lennan CM, Kelly K, Crockson A, et al: Results of the MRC myelomatosis trials for patients entered since 1980. Hematol Oncol 6:145-158, 1988

8. Durie BGM, Salmon SE: Multiple myeloma, macroglobulinemia and monoclonal gammopathies, in Hoffbrand AV, Brown MC, Hirsch J (eds): Recent Advances in Hematology. New York, NY, Churchill Livingstone, 1977, pp 243-261 9. Durie BGM, Salmon SE: A clinical staging system for multiple myeloma. Correlation of measured myeloma cell mass with presenting clinical features, response to treatment and survival. Cancer 36:842-854, 1975 10. Boccadoro M, Gavarotti P, Fossati G, et al: Kinetics of circulating lymphocytes in human myeloma. Blood 61:812814, 1983 11. Boccadoro M, Redoglia V, Gavarotti P, et al: Multiple myeloma plasma cell kinetics: Rapid and reliable evaluation using 5-bromo-2-deoxyuridine (BrdUrd) DNA incorporation detected by an anti-BrdUrd monoclonal antibody. Tumori 72:135-137, 1986 12. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457-481, 1958 13. Breslow N: Statistical methods for censored survival data. Environ Health Perspect 32:181-192, 1979 14. Fleis JL: Statistical methods for rates and proportions. New York, NY, Wiley, 1981, pp 19-24

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448 15. Armitage P: Statistical methods in medical research. New York, NY, Blackwell Scientific, pp 119-126 16. Dixon WJ, Brown MB, Engelman L, et al (eds): BMDP statistical software. Berkeley, CA, University of California, 1985 17. Boccadoro M, Marmont F, Tribalto M, et al: Early responder myeloma: Kinetic studies identify a patient subgroup characterized by very poor prognosis. J Clin Oncol 7:119-125, 1989 18. Bataille R, Grenier J: Serum 3-2 microglobulin in multiple myeloma. A critical review. Eur J Cancer Clin Oncol 23:1829-1832, 1987 19. Pileri A: Complete remission in multiple myeloma: Lancet 1:52, 1990

BOCCADORO ET AL 20. Samson D, Gaminara E, Newland A, et al: Infusion of vincristine and doxorubicin with oral dexamethasone as first line therapy for multiple myeloma. Lancet 2:882-885, 1989 21. Oken MM, Kyle RA, Greipp PR, et al: Complete remission (CR) induction with VBMCP + interferon (rIFNa-2) in multiple myeloma: A 3-year follow-up: Proc Ann Am Soc Clin Onc 8:1062A, 1989 (abstr) 22. Mandelli F, Avvisati G, Amadori S, et al: Maintenance treatment with alpha-2b recombinant interferon significantly improves response and survival duration in multiple myeloma patients responding to conventional induction chemotherapy. Results of an Italian randomized study. New Engl J Med 322:1430-1434, 1990

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