Multiple myeloma: Intensified maintenance therapy with recombinant interferon-a -2b plus glucocorticoids

Palumbo A, Boccadoro M, Garino LA, Gallone G, Frieri R, Pileri A. Multiple myeloma: Intensified maintenance therapy with recombinant interferon-a-2b plus glucocorticoids. Eur J Haematol 1992: 49: 93-97.

Abstract: Interferon-a-2b has been demonstrated to prolong remission duration and survival in responding multiple myeloma patients. The aim of this study was to evaluate intensification of this maintenance therapy through the addition of glucocorticoids. Eighteen myeloma patients at diagnosis received six-12 courses of conventional chemotherapy and then interferon + glucocorticoids. This treatment included 3 megaunits of interferon three times a week, plus 4 days of pulsed high-dose dexamethasone (40 mg/d for 4 d every 28 d for 6 months/year) in patients <70 yr old, or oral prednisone (50 mg three times a wk) in patients > 70 yr old. Conventional chemotherapy induced an objective response in 13/18 patients and a further reduction of the M component (> 50%) was achieved during interferon + glucocorticoids treatment in 7/13. 4/18 patients relapsed with a median follow-up of 22 months (range 13-40). These findings indicate that interferon + glucocorticoids, after inductional chemotherapy, further reduces tumor burden and may prolong remission.

In multiple myeloma (MM) conventional chemother- apy reduces the tumor burden in about 50-60% of patients (l), and no drug combinations have as yet shown clear advantage over the melphalan and pred- nisone (MP) protocol (1,2). Tumor burden is re- duced over a period of 3-6 months, then no further reduction takes place and a “plateau phase” is reached (3). Chemotherapy prolonged until relapse does not improve survival, but increases the risk of chemoresistance and the potential leukemogenesis of alkylating agents (4, 5) . Recombinant interferon-a-2b (IFN) has been ini- tially tested in relapsing patients, of whom 22% re- sponded, while a response rate of 25 % was observed in previously untreated patients (6). Several preclin- ical studies have suggested a synergy between IFN and chemotherapeutic agents: IFN increased the an- titumor activity of MP against the RPMI 8226 human myeloma cell line (7). Several groups have combined IFN with standard induction therapy. Randomized studies have compared MP versus MP- IFN (8, 9) and combination chemotherapy (VMCP, VAD) versus VMCP-IFN (10-12) and VAD-IFN (13). An increased objective response has been dem-

* This work was partially supported by the Associazione Italiana Ricerca Cancro, Milano, Italy.

Antonio Palumbo, Mario Boccadoro, Lucia A. Garino, Gabriele Gallone, Roberto Frieri and Alessandro Pileri Dipartimento di Medicina e Oncologia Sperimentale, Sezione di Ematologia, Universita’ di Torino, Torino 10126, Italy*

Key words: multiple myeloma - maintenance chemotherapy - a-interferon - glucocorticoids

Correspondence: Antonio Palumbo, Cattedra di Ematologia, Via Genova 3, 10126 Torino, Italy

Accepted for publication 20 May 1992

onstrated. Addition of IFN, however, induced a my- elosuppression that required reduction of the che- motherapy, and no survival benefit was found. IFN has proved advantageous in maintenance therapy: patients responding to the induction therapy showed a longer response duration and survival in compari- son to the untreated control arm (14). These results have been recently confirmed by the Swedish group (15). There is also evidence that maintenance with IFN prolongs complete remissions achieved with autologous bone marrow transplantation (16, 17).

Glucocorticoids (GLU) have a major role in the treatment of MM. In patients treated at diagnosis with the MP regimen, comparison of survival and dose intensity showed a positive correlation with prednisone (PDN), but none with melphalan (18). Moreover, when the dexamethasone (DEX) dose was varied in the VAD regimen, a significantly longer survival was observed in the high-dose arm (19). GLU show a remarkable effect in resistant patients: high-dose DEX gives a 27% response rate and is considered the best treatment (20). Alternate-day oral PDN has also proved a suitable strategy for refractory MM (21).

Synergy between IFN and PDN has been dem- onstrated in a lymphoblastic cell line, MOLT-4 (22). Furthermore, in a clinical trial 29 MM patients, with

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low tumor mass at diagnosis, were treated with in- termittent courses of IFN + DEX. The response rate was 59%, significantly higher than the 24% found in a control group treated with IFN alone (23).

This paper describes the use of IFN + GLU main- tenance therapy to prolong remission in 18 MM pa- tients after conventional chemotherapy. Our prelim- inary results indicate that this schedule further decreases the tumor burden during the plateau phase, and may prolong the duration of tumor control.

Material and methods Patients

Eighteen MM patients at diagnosis entered the pro- tocol from June 1988 to September 1990. The anal- ysis was performed in October 1991. The SWOG diagnostic criteria were used (24). MM was classi- fied using the Durie and Salmon staging system (25). Patient characteristics are summarized in Table 1. The induction treatment was MP (melphalan 6 mg/ m2 and prednisone 60mg/m' orally on d 1 to 7) every 28 d for 6 months. Four MMs required pro- longed chemotherapy, beyond the original six courses, to obtain a plateau phase that was sus- tained for at least 3 months before I F N + G L U : hence any further decrease would not be due to pre- vious chemotherapy. Patients who obtained a com- plete, objective, partial response or stable disease after chemotherapy received IFN + GLU. Patients who progressed received further chemotherapy only.

For the 9 patients < 70 yr, maintenance consisted of 3 megaunits of IFN-a-2b S.C. three times a week plus 40 mg of DEX i.m. each morning for 4 d, every 28 d for 6 months (IFN + DEX), thereafter 6 months IFN was alternated with 6 months IFN + DEX. The 9 patients > 70 yr received oral PDN 50 mg three times a week in association with IFN (IFN + PDN) until the first evidence of relapse. Prophylactic treat- ment with ofloxacin, ranitidine and allopurinol was administered. All subjects were treated on an out-

Table 1, Clinical characteristics of patients treated with interferon t glucocorticoids as maintenance therapy

at diagnosis

No. of patients Median age (range] Male/Female I9G I9A BJP Clinical stage

I II Ill A/B

18

919 70 (38-871

12 4 2

2 6

10 1612

patient basis. The M-component was evaluated monthly, and a bone marrow aspiration was per- formed every 3 months.

Complete remission was defined as absence of the M-component on serum electrophoresis and bone marrow plasma cells < 5 %; objective response as M-component reduction > 50% ; partial response as M-component decrease > 25 % but < 50 %, stable disease as M-component decline > 0 % but < 25 % . Progression was defined as an increase > 25% of the M-component level or increase in the size or number of lytic bone lesions during induction treat- ment. Relapse was defined as an increase > 100% from the lowest level of serum M-component, or an increase in the size or number of lytic bone lesions.

Results

Patients treated with DEX and those treated with PDN are combined. The well-known side-effects of DEX imposed a different protocol for patients aged > 70 yr. The M-component reduction was evaluated after 6 months of GLU treatment. All patients were in plateau phase for at least 3 months prior to main- tenance.

A further reduction (> 50%) of the M-component, obtained during IFN + GLU therapy, was ob- tained in 4 patients treated with DEX (Fig. 1) and 3 with PDN (Fig. 2). This M-component decrement was only observed among the 13 MMs with an ob- jective response after induction therapy. Moreover IFN + GLU elicited a slight M-component reduc- tion (> 25 %, < 50%) in the 6 subjects with objec- tive or partial response after chemotherapy (Table 2).

Remission duration was evaluated from remission

n B a4 v CI

$ 3

$ 2

0 P

1

0 -12-10 -8 -6 -4 -2 0 2 4 6 8 10 12 Months

.?-"- MP D X

Fig. 1. Reduction of M component in 4 MM patients responding to 6-12 courses of melphalan and prednisone (MP), treated with interferon (IFN) + dexamethasone (DEX) and then with IFN. Month 0 indicates the beginning of IFN + DEX administration.

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Glucocorticoid and interferon-a-2b MM maintenance therapy

0.9-

0.7- g 0.6- a 0.5- ;ii 0.4-

!= 0.8-

P

* & 0.3,

-12-10 -8 -6 -4 -2 0 2 4 6 8 10 12 Months

' IP MP- PDN

Fig. 2. Reduction of myeloma protein in 3 MM patients respond- ing to chemotherapy (MP) and then treated with interferon (IFN) + prednisone (PDN). Month 0 indicates the beginning of IFN + PDN administration.

I l l

I l l I I I 1

to relapse (Fig. 3). Fourteen patients are still in re- mission after a median follow-up of 22 months (range 13-40, median not reached). Four MMs relapsed at 10, 11, 12, 18 months. Of interest, one of them showed stable disease and progressed after 10 months of maintenance therapy. Another one re- quired suspension of PDN for diabetes after 12 months of maintenance therapy, and a month later he relapsed. Seventeen patients are still alive.

IFN toxicity was confined to a mild flu-like syn- drome during the first 2 or 3 wk and was controlled by paracetamol. PDN administration abrogated this IFN side-effect while DEX did so only during a few days a month. No increases in serum creatinine, AST or ALT concentrations were noted. No patient required hospitalization for treatment of fever or in- fection. No psychosis or severe gastrointestinal com- plications were observed. A slight weight increase and moderate hypertension were noticed and they were not exclusive of the elderly group, while os- teoporosis was mainly worsened in the PDN group that never required treatment discontinuation. No

0.d I I I I I I

5 10 15 20 25 30 Months

Fig. 3. Actuarial remission duration of previously untreated MM patients receiving induction chemotherapy and then inter- feron + glucocorticoids (total 18, fail 4).

patient developed diabetes; however, a preexisting diabetes was clearly exacerbated by PDN treatment.

Table 2. Response evaluation of interferon plus glucocorticoids maintenance therapy in 18 MM patients

Discussion

Several pilot studies have recently demonstrated that new chemotherapeutic protocols greatly reduce the tumor burden: about 30% of complete remission was observed using the VAD protocol (26), inter- mediate cyclophosphamide dose (27), standard che- motherapy associated with IFN (12), and up to 50% with high-dose chemotherapy followed by autolo- gous bone marrow transplantation (28). However, no significant survival benefit has been described for patients in complete remission, and their remission duration is quite similar to that of partial remission after conventional chemotherapy (29), while their survival curves never tend to a plateau, suggesting that tumor eradication is never achieved. Myeloma could actually be a neoplastic alteration of a he- mopoietic stem cell that is impossible to eliminate, suggesting the need for an effective maintenance therapy to prolong survival.

Maintenance chemotherapy, or prolonged con-

Disease status after chemotherapy

No. of patients Total (DEX:PDN)*

Further M-component reduction

Tot (DEX:PDN) Tot (DEX:PDN) Relapse

Tot (DEX:PDN)

Complete remission Objective response Partial response Stable disease

2 ( 2 : O ) 13 ( 6 : 7 ) 2 ( 1 : l ) 1 (0:l)

4(1:3) 2(1:1)

1 (1:O) 2(1:1)

1 (0:l)

Total 18 (9:9) 7 (4:3) 6 (2:4) 4 (2:21

* Total number of patients treated with IFNtDEX, or with IFNSPDN.

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Palumbo et al.

ventional chemotherapy, has been virtually aban- doned by all cooperative groups: it has been clearly demonstrated by large randomized studies that che- motherapy during remission cannot prolong survival ( 3 ) . Alternative maintenance therapy, with IFN, seems to be more effective, and an Italian random- ized study has reported a significant prolongation of remission and survival (14). Significant advantages, however, have only been observed in patients with a substantial tumor burden reduction: an effective induction chemotherapy is still the first step in pro- longing survival.

Improved survival through IFN maintenance ther- apy is of importance because it has opened up a new therapeutic strategy: “biological response modifiers” may be of little effect during induction, but have a major impact during remission.

In this study, IFN was combined with GLU to enhance tumor control after induction chemother- apy. Our pilot study shows that this type of main- tenance treatment achieves a further marked tumor reduction. All patients had a stable M-component before IFN + GLU treatment and the reduction can- not be referred to previous chemotherapy. Two con- clusions can be drawn: 1. IFN + GLU accomplish a further tumor reduction that is virtually absent when IFN is used alone (14); 2. the antitumor effect of IFN + GLU, like IFN alone, is primarily exerted on a low tumor mass, thus a high tumor burden reduc- tion is still the first step for a prolonged tumor con- trol.

The effect of such a further reduction on the length of remission and survival remains to be determined. In our series, 14/18 MMs are still in remission with a median follow-up of 22 months.

In conclusion, these data suggest the usefulness of an intensified maintenance program. They form the basis of a new ongoing randomized study by the Italian Multiple Myeloma Study Group.

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