Maintenance treatment with interferon alpha-2b in multiple myeloma: a ...

Leukemia (1998) 12, 1144–1148  1998 Stockton Press All rights reserved 0887-6924/98 $12.00 http://www.stockton-press.co.uk/leu

Maintenance treatment with interferon alpha-2b in multiple myeloma: a prospective randomized study from PETHEMA (Program for the Study and Treatment of Hematological Malignancies, Spanish Society of Hematology) ´ ´ J Blade, JF San Miguel, ML Escudero, M Fontanillas, J Besalduch, S Gardella, J Arias, J Garcıa-Conde, M Carnero, JM Marti, ´ C Rozman, J Estape and E Montserrat PETHEMA, Hematology Department, Hospital Clinic, Villarroel 170, 08036-Barcelona, Spain

The objectives of the present study were to investigate whether interferon alpha (IFN) maintenance could prolong response duration and survival in patients with multiple myeloma (MM) in objective response and to analyze the characteristics of relapse and subsequent survival. From January 1991 to November 1994, 92 patients from the Spanish Cooperative Group PETHEMA with MM in objective response after 12 courses of VCMP/VBAP chemotherapy were randomized to receive IFN maintenance vs no treatment until relapse. Prognostic factors at diagnosis were similar in both groups. IFN was administered at a starting dose of 3 mU/m2 three times per week. The IFN toxicity was moderate with granulocytopenia and fatigue being the most common adverse effects. Median duration of response from randomization until relapse was 13 months in the IFN group vs 7.7 months in the no treatment arm (P = 0.042). Median survival from randomization was 38.8 months for patients given IFN vs 32.7 months for those allocated to the no treatment arm (P = 0.12). Features at relapse were similar in patients who received IFN maintenance and in those assigned to no treatment. Finally, survival from relapse was identical in both groups. In summary, our results show a significant prolongation of response in patients maintained with IFN with no significant influence on survival. In addition, in our series features at relapse and subsequent outcome were similar in both groups. Keywords: multiple myeloma; maintenance treatment; interferon

Introduction In patients with multiple myeloma (MM) conventional chemotherapy produces an objective response rate between 35 and 55% and a median survival ranging from 2 to 3 years.1,2 In patients responding to chemotherapy, the median response duration is less than 2 years.2,3 Maintenance treatment with cytotoxic therapy after a stable response is achieved, has not resulted in a significant survival prolongation.4 Interferon alpha (IFN) was introduced in the treatment of multiple myeloma almost 20 years ago.5 Experimental studies have shown that IFN decreases the in vitro colony formation and the labeling index of myeloma forming cells.6 The most promising role for IFN in MM is as maintenance treatment in patients in whom an objective response has been achieved.7 However, the impact of IFN maintenance on response duration and survival is still controversial.7 On the other hand, it has been suggested that patients maintained with IFN may have more aggressive relapses with a poor subsequent outcome.8 The objectives of the present study have been: (1) to analyze whether IFN maintenance could prolong response duration and survival in patients with MM achieving an objective response to conventional chemotherapy; and (2) to investigate whether IFN maintenance modifies the relapse pattern and compromises subsequent survival. ´ Correspondence: J Blade Received 25 September 1997; accepted 27 January 1998

Patients and methods

Patients and diagnostic criteria From January 1991 to November 1994, 113 patients with MM from PETHEMA (Spanish Cooperative Group for Hematological Malignancies Treatment, Spanish Society of Hematology) in objective response were prospectively randomized to receive IFN maintenance vs no maintenance treatment. These patients were recruited from a PETHEMA study open from January 1990 to May 1994, who had been treated with VCMP/VBAP chemotherapy at standard doses vs VCMP/VBAP with higher doses of cyclophosphamide and adriamycin (see below). Diagnosis of MM was made according to the Chronic Leukemia–Myeloma Task Force criteria.9 All patients had symptomatic MM and were classified according to the Durie and Salmon staging system.10 Twenty-one of the 113 patients were not included in the analysis for the following reasons: failure to achieve the required 50% reduction in the Mcomponent (nine patients), erroneous randomization after the first evaluation (six cycles of VCMP/VBAP) and relapse before the completion of the 12 scheduled cycles of chemotherapy (two patients), randomization after 24 cycles (one patient), no treatment with the scheculed VCMP/VBAP chemotherapy protocol (four patients), monoclonal gammopathy of undetermined significance (one patient), and lack of data (four patients).

Induction treatment and interferon maintenance Within the cohort of 92 patients appropriately randomized for evaluation of IFN efficacy, 41 had received VCMP/VBAP at standard doses: alternating cycles of VCMP (vincristine 1 mg i.v. on day 1, cyclophosphamide 500 mg/m2 i.v. on day 1, melphalan 9 mg/m2 p.o. on days 1–4 and prednisone 60 mg/m2 p.o. or parenteral on days 1–4) and VBAP (vincristine 1 mg i.v.; BCNU and adriamycin i.v., 30 mg/m2 each on day 1; and prednisone 60 mg/m2 p.o. or parenteral on days 1–4). Fifty-one patients had been given the same VCMP/VBAP drug combination, but increasing the doses of cyclophosphamide and adriamycin from 500 to 1200 mg/m2 and from 30 to 50 mg/m2, respectively.11 The planned interval between the VCMP/VBAP cycles was 4 weeks. The median time between initiation of chemotherapy and randomization was 13.9 months. All randomized patients were in objective response after 12 cycles of the above-mentioned chemotherapy. The median time in objective response before randomization was 9.1 months and 87% (84/92) of the patients were in response for more than 4 months. Patients were randomized to receive recombinant interferon alpha-2b (IFN) or to no maintenance treatment. Verbal informed consent was obtained before randomization. IFN was administered at a

Interferon maintenance in multiple myeloma ´ J Blade et al

starting dose of 3 MU/m2 subcutaneously three times per week until relapse. In relapsing patients the initial treatment was re-started.

Criteria for response and relapse Objective response was defined as (1) reduction of ⭓50% in the M-component size in both serum and urine if initially present; (2) a decrease of ⭓50% in the size of plasmacytomas; and (3) improvement in the symptoms of bone pain, anemia and performance status, with no increase in lytic bone lesions and correction of hypercalcemia if initially present.9 Relapse was defined as an increase greater than 50% from the lowest level of serum and/or urine M-protein level achieved with the initial treatment, an increase in the size or number of lytic bone lesions, or development of extraosseous plasmacytomas, anemia or hypercalcemia. In patients in whom the M-component disappeared at serum electrophoresis, its reappearance was considered as criterion of relapse.

Statistical methods The ␹2 test was used to assess the statistical significance of multiple comparisons. Survival and response duration curves were plotted according to the method of Kaplan and Meier12 and statistically compared by means of the log-rank test.13

Table 1

1145

Characteristics of patients at diagnosis

Features

Age (median, years) Sex (M/F) Stage I II III Creatinine (mg/dl) ⭓2 ⬍2 Hemoglobin (g/dl) ⬍9 ⭓9 Calcium (mg/dl) ⭓11.5 ⬍11.5 ␤2-microglobulin (mg/l) ⭓4 ⬍4 not measured LDH (IU/l) ⭓300 ⬍300 not measured M-component type IgG IgA Light-chain others

No therapy (n = 42)

Interferon (n = 50)

65 18/24

62 28/22

2 16 24

1 16 33

5 37

11 39

15 27

20 30

8 34

6 44

14 15 13

20 19 11

15 27 0

16 31 3

18 15 8 1

27 11 10 2

Results

Comparability of treatment groups Of the 92 eligible patients, 50 were assigned to IFN maintenance while the remaining 42 received no treatment. The characteristics of both groups of patients at diagnosis are listed in Table 1. There were no significant differences in prognostic factors between the two groups.

Response duration and survival The median duration of response from the time of randomization until relapse was 13 months in the IFN group vs 7.7 months in the no-treatment arm (Figure 1, P = 0.042). The median duration of response from the date of response to chemotherapy to relapse was 19.8 months in the IFN arm vs 15.3 months in the no-treatment arm (P = 0.09). At the time of this analysis, 12 patients in the IFN arm did not relapse compared with only two in the no-maintenance group. The median duration of interferon maintenance in the 12 nonrelapsing patients was 29.8 months. One patient died of congestive heart failure in continued response after 4 months of IFN maintenance. In five of the non-relapsing patients interferon should be discontinued between 1 and 31 months, while the remaining six patients are still receiving IFN from 28 to 51 months since the initiation of maintenance treatment. Median survival from randomization was 38.8 months for patients given IFN vs 32.7 months for those patients in the notreatment arm (Figure 2, P = 0.12). At the time of this analysis there were 23 patients still alive in the IFN group vs 14 patients in the observation group.

Figure 1 Duration of response from the time of randomization to the date of relapse.

Figure 2

Survival from the time of randomization.


1146

Toxicity

Table 3

In 10 patients (20%) IFN treatment was discontinued before relapse, because of toxicity or poor tolerance (n = 7), associated diseases: polimialgia rheumatica (n = 1), metastatic breast cancer (n = 1), and misinterpretation of the protocol (n = 1). In three of these patients IFN was discontinued within the first month of treatment, while in the remaining seven IFN administration lasted from 4 to 31 months, before it was discontinued. In 15 patients (30%) the dose of IFN had to be reduced mainly because of poor tolerance. In 12 of them the scheduled dose was reduced by 40% or less (ie they received at least 3 MU IFN three times per week), while only three patients required a dose reduction of 50% or more. Toxicity related to IFN, according to the WHO grade,14 is shown in Table 2. As can be seen, 45% of patients had granulocytopenia, usually of moderate degree. Fever and fatigue were observed in 29 and 40% of the patients, respectively; and 24% of the patients had psychological disturbances. Grade 4 toxicity was observed in only one case.

Features

Characteristics of relapse and subsequent outcome Up to now, 78 of the 92 patients (85%) have relapsed. As shown in Table 3, features at relapse in patients who received IFN were similar to those observed in untreated patients. In this sense, no significant differences were found between the two groups regarding the presence of extramedullary plasmacytomas, plasma cell leukemia, amount of M-component in serum and urine, and extent of skeletal involvement. When chemotherapy was restarted in relapsing patients there were no significant differences in the response rate between both groups (44% in the IFN arm vs 36% in the group not receiving maintenance therapy). Moreover, the duration of second responses was not significantly different (median 20.3 vs 35.5 months; P = 0.4). Finally, survival from the time of relapse was identical (Figure 3; median 15.2 months in both groups).

Characteristics of relapse after maintenance

Extramedullary plasmacytomas Plasma cell leukemia Hemoglobin (g/dl) ⬍9 ⭓9 Missing Creatinine (mg/dl) ⬍2 ⭓2 Missing Calcium (mg/dl) ⬍11.5 ⭓11.5 Missing ␤2-microglobulin (ng/ml) ⬍6 ⭓6 Missing LDH (IU/l) ⬍300 ⭓300 Missing Urine protein excretion (g/24 h) ⬍1 ⭓1 Missing M-component size (g/l) ⬍19 20–39 ⭓40 Missing Bone marrow plasma cells ⬍40 ⭓40 Missing Skeletal involvement (Durie and Salmon) 0.1 2.3 Missing

No therapy (n = 42)

Interferon (n = 38)

7 1

7 0

4 30 6

5 30 3

31 3 6

34 1 3

32 2 6

33 2 3

22 4 14

22 5 11

14 16 12

18 15 5

15 11 14

20 7 11

20 15 2 3

19 10 7 2

16 9 15

24 8 6

9 27 4

13 23 2

Discussion An important proportion of patients with MM who respond to the initial chemotherapy enter into a quiescent phase that consists of a period of stability in which tumor progression does not occur despite the persistance of the disease.15 There is no evidence that maintenance chemotherapy is of benefit in Table 2

Toxicity according to the WHO scale in 49 patients

Parameter

Hemoglobin Granulocytes Platelets Fever Fatigue Infection Neurologic Psychological

Toxicity grade 0

1

2

3

4

41 27 42 35 25 44 44 37

7 11 7 6 11 2 2 3

0 8 0 7 7 1 2 6

1 3 0 0 6 2 1 3

0 0 0 1 0 0 0 0

Figure 3

Survival from the time of first relapse.

patients responding to the initial chemotherapy.4 In addition, continued chemotherapy may decrease the response rate in relapsing patients and may lead to the development of myelodysplasia or acute leukemia.16 It has been suggested that in MM, the response state is an immunologically maintained phase rather than simply the effect of the reduction in tumor mass.17 In fact, MM in response is clinically and biologically very similar to the quiescent state observed in patients with


monoclonal gammopathy of undetermined significance (MGUS) or smoldering myeloma.18,19 Nowadays the most promising approach for maintenance treatment in MM is the use of IFN. However, published results of IFN maintenance on response duration and survival are controversial.7 Our results show a significantly longer response duration from randomization in the IFN maintained group. This finding is in agreement with most studies on IFN maintenance in MM.20–23 However, it is worth mentioning that in our study the median response duration was prolonged for only 6 months in the IFN arm compared with the observation group and that the statistical significance is borderline. In this regard, the prolongation of response in studies showing a significant benefit from IFN maintenance has also been modest, with differences in median response duration ranging from 5 to 12 months.20–23 In contrast to these observations, other trials have failed to show a significant advantage in response duration for IFN maintenance.8,24–26 Regarding overall survival, most available data, including our own study, suggest that there are no significant differences in survival from the time of randomization in patients maintained with IFN as compared to the observation group.8,21,24,25 However, two studies have shown a significant survival prolongation in favor of IFN maintenance in patients achieving an objective response to inducation therapy and maintained with IFN.20,22 In addition, a third study showed a survival benefit of borderline significance (P = 0.049) from IFN maintenance when the statistical analysis was done after adjusting for chance imbalances in baseline prognostic factors.23 The reasons for these discrepancies are unclear. It could be speculated, however, that in certain subsets of myeloma patients IFN maintenance might be more beneficial than in others. In this regard, it has been suggested that IFN could be particularly useful in patients with low tumor mass after high-dose therapy followed by autotransplantation.27 A meta-analysis based on all published trials might be helpful to that purpose. Whether results of IFN maintenance therapy can be improved by adding other drugs, such as glucocorticoids, is currently being investigated.28,29 As the goal of our study was to investigate the impact of IFN maintenance in patients with symptomatic MM in objective response at the end of the initial chemotherapy, patients who did not meet the eligibility criteria were not included in the analysis. Thus, results were not analyzed on a pure intentionto-treat basis. It might be speculated, therefore, whether the exclusion of patients erroneously randomized could modify the results of this study. In this trial toxicity due to IFN was similar to that reported in other studies.20–26 In our series, IFN had to be discontinued at some time in 20% of the patients. However, about 75% of our patients were able to receive at least 3 MU of IFN three times per week for all the planned period. The number of patients with grade 3 or 4 WHO toxicity was small. It is worth mentioning that in spite of the fact that IFN maintenance should be discontinued in 20% of the patients, a significant prolongation of at least response duration was noted in the interferon arm. It has recently been suggested that patients relapsing after having received IFN maintenance have a more aggressive disease with a subsequent shorter survival.8 In this regard, we found no significant differences in the features at relapse between patients who received IFN maintenance and those who did not receive IFN. Thus, the clinical and laboratory features (ie presence of extramedullary plasmacytomas or plasma cell leukemia, extent of skeletal involvement, hemo-

globin level, serum calcium, serum creatinine, serum LDH and beta2-microgloublin levels) as well as the serological findings (ie M-component size in serum and urine) were similar in both groups. In addition, the response rate when chemotherapy was restarted was almost identical. Finally, there were no significant differences in survival after relapse between patients treated with IFN and those who received no maintenance treatment. In summary, our results show a significant prolongation of response in patients with MM maintained with IFN, with no significant influence on survival. In addition, in our study the features at relapse and subsequent outcome were similar in both groups. Although IFN might be beneficial in certain subgroups of patients with MM, the role of IFN maintenance in MM treatment should be investigated in larger series and in meta-analyses.

Acknowledgements This work has been supported in part by grants from Fondo de Investigaciones Sanitarias de la Seguridad Social (FIS ´ 95/0828 and 96/0397), Maderas de Llodio, SAL, and Jose Carreras International Leukemia Foundation (FIJC/97/PETH).

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