Role of alpha interferon in multiple myeloma

Blood Reviews (1997) 11, 191-200 0 1997 Harcourt Brace & Co. Ltd

Haematological oncology

Role of alpha interferon in multiple myeloma

D. E. Joshua,S. MacCallum, J. Gibson Interferons are soluble proteins produced by cells in response to viruses. Although they were first introduced as therapeutic agents for myeloma in 1979 their exact role in the management of myeloma remains to be precisely defined. Interferons have both anti-proliferative and immune regulation effects, but the predominant mode of action of interferons in myeloma is still unclear. Recombinant alpha interferon has been used in clinical trials as a single induction agent, co-induction agents with combination chemotherapy, as salvage therapy, and as therapy to maintain plateau phase after conventional chemotherapy or complete remission after auto or allogeneic transplantation. Interferon as a single induction or co-induction agent with other forms of chemotherapy appears to be of only minimal benefit in myeloma. However, its role as maintenance agent has received a great deal of interest and investigation. Its most beneficial role would appear to be in those patients who have had good responses to either conventional therapy or to bone marrow transplantation and the beneficial role of interferon in the maintenance of plateau phase is gaining credence. Its maximum advantage appears to be in patients with initial good response who have obtained plateau phase, or in patients who have developed complete remission after auto transplantation. It also has a role as salvage treatment in refractory patients with myeloma where the combination of interferon and dexamethazone may be a useful therapeutic modality. This review will examine the biological role of interferon in myeloma, and then review the clinical evidence for the efficacy of interferon therapy in a variety of clinical settings, viz: 1) as a single agent; 2) in conjunction with conventional induction chemotherapy; 3) as maintenance therapy following conventional chemotherapy induction; 4) as maintenance therapy following autologous and allogeneic transplantation; and 5) as salvage therapy.

INTRODUCTION The interferons (alpha, beta and gamma) were originally described in 1957’ as soluble proteins produced by cells in response to viruses. Subsequently, however, the antitumour activity of alpha interferon (hereafter referred to as interferon) has been documented in a variety of haematological and non-haematological malignancies. Interferon was first introduced as a therapeutic agent for myeloma in 1979? but despite a considerable number of in vivo and in vitro studies its exact place in the management of myeloma still remains to be precisely determined. D. E. Joshua, Royal Prince

S. MacCallum, Alfred Hospital,

Correspondence

to: Professor

PHARMACOLOGY The most widely available alpha interferons are those produced by recombinant DNA technology, although ‘natural’ interferon derived from leucocytes or lymphoblasts has also been used therapeutically. Interferon protein variants are designated by a number and further qualified by a letter to indicate the amino acid

J. Gibson, Institute of Haematology, Camperdown, NSW 2050, Australia. D. E. Joshua

191

192

Blood

Reviews

sequences at positions 23 and 34. Interferon-alpha2a has lysine at 23 and histidine at 34, interferon-alpha2b has arginine at 23 and histidine at 34, and interferonalpha 2c has arginine at both positions.’ Although human tumour clonogenic assays (not involving myeloma cells) suggest some variation in tumour response to different interferon subtypes, it appears that there is little difference in the spectrum of clinical activity of the various interferon-alpha variants.4

BIOLOGICAL MYELOMA

ROLE OF INTERFERON

IN

Interferons potentially exert antitumour activity via their antiproliferative and immunomodulatory properties. A variety of effects including down-regulation of oncogenes, inhibition of protein translation, and enhancement of natural killer cells and macrophage activity have been demonstrated.5 The initial use of interferon therapy in myeloma came from clinical observation, and laboratory studies are ongoing to determine the precise antitumour mechanisms and to aid in refining its use. It is currently unclear whether the main effects of interferon are cytotoxicity or cytostasis of myeloma cells in vivo, and whether it acts directly on the tumour cells or modulates the host response. Antiproliferative

effect

Interferon is a potent inhibitor of the cell cycle, leading to an accumulation of cells in G,, with a decrease in the transition to G, and the arrest of some cells in G,.6 Although the exact mechanism of this is not clear, an important component is the induction of a 2’,5’ oligoadenylate synthetase, which in turn activates an endoribonuclease, thereby interrupting transcription and translation by degrading mRNA.’ Other potential antiproliferative mechanisms are down-regulation of c-myc and the induction of a protein kinase which inhibits translation.8 Immune regulation A variety of effects of interferon on cells of the immune system have been reported. These include enhancement of the cytotoxic effect of natural killer cells and macrophages, induction of the secretion of other cytokines, induction of the expression of cell surface antigens for major histocompatibility complex (MHC) and increase in the expression of Fc receptors on the surface of lymphocytes and macrophages.9

EVIDENCE MYELOMA

FOR INTERFERON

ACTIVITY

IN

Clonogenic assays have been used to examine the cytotoxic effects of interferon on myeloma cells, both as a single agent and in combination with chemotherapy. Using concentrations of interferon which were known to be achievable in vivo, Salmon observed a reduction in colony formation of myeloma cells4 and Brenning et al documented a decrease in labelling index.’ The mechanism of this antiproliferative effect is still unclear. Interferon has been shown to downregulate the interleukin-6 (IL-6) receptor in the myeloma cell line U266” thus depriving these cells of a potentially important autocrine loop. In addition, it has been shown that monoclonal immunoglobulin (M-protein) production by myeloma cells in culture is exquisitely sensitive to interferon, with significant suppression of M-protein secretion occurring at lower concentrations of interferon than were responsible for the cytotoxic effect.‘* Interestingly, one of the well-described antiproliferative actions of interferon may not operate in myeloma, as 2’,5’ oligoadenylate synthetase levels in patients receiving interferon therapy did not correlate with response.13 Similarly, definitive evidence for an immune modulatory effect has not been demonstrated, as in one study the maintenance of response after intensive therapy did not correlate with the appearance of specific lymphocyte subsets, particularly natural killer cells.14 A major area of interest in interferon therapy and the rationale of several randomized trials has been the in vitro synergism observed between interferon and chemotherapeutic agents. In a clonogenic assay using RPMI-8226 myeloma cells, synergism between interferon and commonly used chemotherapeutic agents was demonstrated, with the greatest cytotoxic effect seen with the three-drug combination of interferon, melphalan and prednisone. The effect of interferon was dose-dependent.14 Another study demonstrated in vitro synergism between interferon and dexamethasone.16 A summary of the evidence for an in vitro antimyeloma effect of interferon is given in Table 1.

Table I

Evidence

for an in vitro

antimyeloma

effect

Decreased myeloma cell colony formation Decreased plasma cell labelling index Decreased M-protein production Down-regulation of IL-6 receptor expression In vitro synergism with melphalan and corticosteroids

of interferon

Alpha interferon in multiple myeloma

ANTIBODIES

TO INTERFERON

IN MYELOMA

Exposure to natural or recombinant protein such as interferon may produce neutralizing antibodies. In some B cell disorders such as hairy cell leukaemia neutralizing antibodies to interferon have been associated with a transient decrease in response, but not alteration of clinical outcomes.” ‘Naturally occurring’ auto-antibodies to interferon have been descibed in cancer patients prior to treatment.‘* The clinical significance of anti-interferon antibodies remains unclear. A study of 29 myeloma patients receiving interferon for maintenance therapy demonstrated interferon antibodies, as measured by ELISA, in 58% but only in 16% when measured in a virus growth inhibition assay; none were associated with relapse.19 Furthermore, two patients with antibodies who remained in remission subsequently lost their neutralizing titre, despite continuing to receive interferon. Unresponsiveness to interferon BCL-2 oncoprotein is a known inhibitor of apoptosis. It is expressed in plasma cells but its expression in myeloma has not been shown to have prognostic significance.‘” In a study of 63 myeloma patients, overexpression of BCL-2 was associated with resistance to interferon.”

Haematological side-effects These side-effects are dose-related, and are most common at doses above 10 MU daily.‘5 They include anaemia, leucopenia, thrombocytopenia, and may be of critical importance in myeloma therapy when interferon is administered to patients with substantial marrow disease, combined with chemotherapy or given after autologous transplantation.

CLINICAL

TRIALS WITH INTERFERON

Assessing the impact of new therapeutic modalities in myeloma is difficult due to the need for long follow-up periods and the use of a variety of criteria for response. Studies vary greatly with respect to both inclusion and exclusion criteria, thus leading to disparate patient cohorts. Most investigators define complete remission (CR) as < 5% plasma cells in the bone marrow, an absence of serum and urine paraprotein by immunofixation, and normal haemoglobin, creatinine and calcium. The definition of a partial remission (PR) varies considerably. Many groups accept a > 50% reduction in paraproteinZh whilst others require > 75% reduction.” These variations are potentially significant when analysing the impact of maintenance therapy.

INTERFERON THERAPY SIDE-EFFECTS

AS A SINGLE INDUCTION

OF INTERFERON

Interferon therapy is associated with a number of haematological and non-haematological side-effects.” Non-haematological

193

side-effects

The transient ‘flu-like’ syndrome of malaise, fever, headache and myalgia occurs at the initiation of therapy in up to 90% of patients.24 It usually responds to simple analgesia and tachyphylaxis is frequent, allowing many patients to achieve the desired dose. Prolonged interferon administration is associated with a variety of significant side-effects, and may require dose reduction or cessation. These include depression, malaise, asthenia, impaired consciousness, neuropathy and, although rare, encephalopathy and coma. Cardiovascular effects include arrhythmias and cardiomyopathy. Most cardiac events are more common in those patients with pre-existing heart disease. In addition, abnormalities in liver function tests are common and severe hepatotoxicity and renal toxicity have been described.

In the seminal report on the therapeutic effect of interferon in myeloma, four chemoresistant patients achieved at least a partial response.’ In previously untreated patients, the first randomized trial of the use of interferon as a single agent versus melphalan and prednisone reported a 14% response rate for interferon, compared with a 44% response rate for melphalan and prednisone.” Further studies using higher doses of interferon (10 MU daily for 1 week in every 3) produced a higher response rate of 36%, particularly in immunoglobulin A (IgA) and light chain myeloma, but at the cost of considerable toxicity.” Refractory patients were studied in an ECOG trial in which they were scheduled to receive interferon 10 MU/m? thrice-weekly. Twenty-five per cent achieved a PR; however, 75% required dose reduction, and a maximum tolerated dose of only 5 MU/m’ thriceweekly was attained.‘” An interesting observation by one investigator in only small numbers of patients has been the return to chemosensitivity following interferon therapy in previously chemo-resistant patients3’ These results are summarized in Table 2.

194

Blood

Reviews

Table

2

Interferon

Single

agent activity

as single

induction

of interferon

therapy

Table 4

is 14-36%

Response responses

is dose related; the highest doses produced and the most severe side-effects

Interferon refractory

as a single agent may be active patients

Interferon

combined

with induction

therapy

Randomized trials with a variety of chemotherapy interferon doses have yielded conflicting results

the highest

WITH INDUCTION

Interferon reduction

The single agent activity of interferon and its in vitro synergism with steroids and melphalan led to expectations of efficacy in combination with ‘standard’ induction chemotherapy for newly diagnosed patients with myeloma. There have been over ten randomized trials designed to evaluate the contribution of interferon in this context, with conflicting results. In addition, comparison of the different trials has also been hampered by varying induction regimes and varying dosing schedules of interferon. It has been suggested, for example, that sequential use of interferon is more effective than administering it concomitantly with cytotoxics.‘* These trials are summarized in Tables 3 and 4.

Table

3

Interferon

as a co-induction

Author Group Year

Patient no

Cooper CALGB 1993

212

Osterborg MGCS 1993

335

Cassasus KIF 1994 Ludwig 1995 Oken ECOG 1996 NMSG 1996

201

M 9 mg/m* P 40 mg/m* Day l-4 28-day cycle M 0.25 mg/kg/day P 2 mgikglday Day14 6-week cycle VMCPNBAP

256

Joshua ALSG 1997

113

Chemotherapy

and

Meta-analysis of 1518 patients has shown statistically significant, but slight, improvement in response rate, progression-free survival and overall survival with interferon

in chemotherapy

A selective advantage for interferon therapy and light chain disease has been reported

INTERFERON COMBINED CHEMOTHERAPY

regimes

is generally was reported

in patients

well tolerated, but chemotherapy in several studies

with dose

CALGB study33 In this study, interferon was used as a co-induction agent for 2 weeks of a 28-day cycle, with melphalan and prednisone for the first 4 days, There was no improvement in response rate, progression-free survival and overall survival in the interferon arm. The constitutional side-effects of interferon were tolerable, and the haematological toxicity did not result in an overall statistically significant dose reduction for melphalan, although by cycle 12, only 48% on the interferon arm were receiving full dose melphalan on time, compared with 71% of the conventionally treated group.

agent Interferon dose

Response

IFN + chemo

IgA

rate %

Chemotherapy alone

Progression-free survival (months) IFN + chemo

Chemotherapy alone

Overall survival (months) IFN + chemo

Chemotherapy alone

2 MU/m* thrice-weekly 214 weeks

38

44

18

20

36

37

7 MU/m* Day l-5 & Day 22-26

68

42

18

17

29

27

54

39

22

15

39

30

VMCP

3 MU/m* thrice-weekly between cycles 2 MU 5 x week

67

60

23

16

39

30

628

VBMCP 6-week cycle

5MU thrice-weekly

69

69

30

26

N/A

N/A

583

M 0.25 mg/kg/day P 100 mg/day Day l-4 6-week cycle PCAB 28-day cycle

5MU thrice-weekly

45

44

21

15

29

32

3 MU/m*

41

48

17

13

45

39

Key: M: melphalan; P: prednisone; VBMCP: vincristine, carmustine (BCNU), melphalan, cyclophosphamide, prednisone; VMCPNBAP: vincristine, melphalan, cyclophosphamide, prednisone, alternating with vincristine, carmustine (BCNU), doxorubicin (Adriamycin), prednisone; PCAB: prednisone, cyclophosphamide, doxorubicin (Adriamycin), carmustine (BCNU).

Alpha interferon in multiple myeloma

ECOG Following their successful pilot study of interferon and cytotoxic chemotherapy co-induction,34 Oken et al performed a large study in which newly diagnosed patients were randomized to receive VBMCP alone, VBMCP and high dose cyclophosphamide, or VBMCP alternating with IFN-a 5 MU/m’ thriceweekly.3’ Overall survival was similar in the three arms, but there was a significant increase in those achieving CR in the interferon arm (170/o), and this group also showed a trend towards improved failurefree survival. MGCP The Swedish investigators compared melphalan and prednisone alone with melphalan, prednisone and interferon, but in contrast with the CALGB study, the interval between the cycles was longer (6 weeks), the doses of interferon were higher, and the dosing schedule for interferon was different. They were able to demonstrate an improved response rate with the addition of interferon (68% vs 42%) which was particularly striking in the subgroups of patients with IgA (85% vs 48%) and light chain disease (71% vs 27%). Response rates were least enhanced by interferon in patients with stage III disease (62% vs 46%). Progression-free and overall survival was not improved by interferon except in those with IgA and light chain disease, who recorded a median survival of 32 months compared with 17 months (P < 0.05). Despite a high incidence of ‘flu-like side-effects in patients on interferon (68%) only 7/164 withdrew from treatment for this reason. Haematological toxicity was greater in the interferon arm, but did not result in significant reductions in melphalan dosing. KIF trial” Patients were randomized to receive VBAP-VMCP alone or with 3 MU/m2 interferon for 2 weeks between cycles. At 36 months follow-up, there was no significant difference in relapse rate or overall survival between the two groups, but the interferon group showed a trend in favour of event-free survival at 3 years (57% vs 43%). Multicentre international triaP* Two hundred and fifty-six patients were randomized to receive VMCP with or without interferon 2 MU five times weekly. Response rates and overall survival times were similar for the two groups, but patients receiving interferon showed prolonged progression-free survival

195

(23 vs 16 months). Quality of life and performance state did not differ between the two groups. Nordic myeloma study group3y This group enrolled patients to receive 6-weekly cycles of melphalan and prednisone with or without interferon, which was administered at a lower dose than in the Swedish study. The interferon was continued throughout plateau phase and into relapse. They failed to show that interferon improved response rates or overall survival, but did demonstrate a significant 5-month improvement in progression-free survival in those who achieved a partial response. Again, greater grade III-IV haematological toxicity was reported in the interferon arm, resulting in significant decreases in melphalan dose. ALSG myeloma IP In the Australian study, all patients received 12 cycles of PCAB induction chemotherapy at 4-weekly intervals. After two cycles, half were randomized to interferon 3 MU/m’ five times a week, which was continued until progressive disease occurred. There was no demonstrable difference between the groups in response rate, percentage of patients achieving plateau, time to treatment failure and overall survival. Though not statistically significant, there was a trend towards prolongation of plateau in the interferon arm (25 vs 17 months), which was reflected in a trend to longer survival in those who achieved plateau while receiving interferon (48 vs 36 months). Haematological toxicity was increased in patients receiving interferon and this resulted in a lower dose intensity of the cytotoxic drugs. Quality of life assessments, completed by patients, did not demonstrate a statistically significant difference between the two groups, although there was a trend towards a lower ECOG status in the interferon arm. Summary A meta-analysis of 1518 patients has been previously reported.38 This demonstrated a small but statistically significant advantage for interferon in response rates (58.8% vs 49.3%), progression-free survival (22 vs 18 months), and overall survival (37 vs 31 months). The usual cautions relating to meta-analyses apply, as a variety of cytotoxic regimes were employed, and a range of interferon dosing was used. Several studies required dose reduction of cytotoxics, and it is tempting to speculate that with improved cytokine support and full dosing, better results may be obtained. The improved survival times reported for induction trials

196 Table

Blood

Reviews

5 Interferon as maintenance therapy

Author Group Year

Total number

Mandelli 1990

101

Salmon SWOG 1994 Westin 1995 Ludwig 1995

193

Induction regime

M&Por VMCPIVBAP

125

VMCPNBAP or VAD or VMCPPNBAP M&P

100

VMCP or IFN-a 2 bNMCP

Interferon dose

Progression-free survival (months)

10 MU/m2 then 3 MU/m’ twice-weekly 3MU thrice-weekly

Overall survival (months)

IFN

Control

IFN

Control

26

14

52

39

12

11

31

38

16

6

36

35

21

8

46

34

5 MU twice-weekly 2 MU twice-weekly

Key: M: melphalan; P: prednisone; VBMCP: vincristine, carmustine (BCNU), melphalan, cyclophosphamide, prednisone; VMCPNBAP: vincristine, melphalan, cyclophosphamide, prednisone, alternating with vincristine, carmustine (BCNU), doxorubicin (Adriamycin), prednisone; PCAB: prednisone, cyclophosphamide, doxorubicin (Adriamycin), carmustine (BCNU); VAD: vincristine, doxorubicin (Adriamycin), dexamethasone.

may have been influenced by the use of interferon as maintenance. The meta-analysis suggests a c 10% improvement in response rate, a 4-month prolongation of plateau, and a 6-month increase in survival. Whether the gains outweigh the expense, toxicity and inconvenience of interferon therapy as co-induction remains debatable.

INTERFERON AS MAINTENANCE IN PLATEAU PHASE

THERAPY

The smaller post-treatment tumour burden of myeloma and its low proliferative activity (plateau phase) led to attempts to maximize the effects of interferon by using it as maintenance therapy, It has been previously shown that cytotoxic chemotherapy does not prolong the plateau phase,4’ so there has been great interest in the use of interferon in this setting. The trials evaluating interferon in this setting are shown in Tables 5 and 6. Mandelli” The first randomized trial of interferon as maintenance was conducted by the Italian group in 1993 who enrolled patients with at least a partial response to induction chemotherapy (melphalan and prednisone, or VCMPNBAP). It is worth noting that the first 12 patients in the interferon arm initially received 10 MU/m’ thrice-weekly, but this dose was reduced to 3 MU/m2 due to severe toxicity. Interferon prolonged the duration of the response (26 vs 14 months) but did not improve overall survival. A subgroup of patients

Table

6 Interferon for maintenance of plateau phase

Interferon maintenance therapy is associated with a more durable plateau phase, and a modest longer overall survival In some studies, the best results of interferon were seen in patients who responded optimally to induction therapy, although the SWOG trial is an exception Good results are repeated with interferon doses 2-5 MU thrice-weekly The haematological and non-haematological usually tolerable at the doses described

side-effects are

In studies where it has been assessed,interferon therapy has not led to impaired quality of life parameters

who had achieved a decrease of > 75% from baseline M-protein showed a statistically significant improvement in overall survival in the interferon arm. SWOG” This large study began in 1994 with 522 patients who received a variety of induction regimes. Only 193 who achieved a > 75% reduction in baseline M-protein were randomized to receive interferon 3 MU thriceweekly. No difference in progression-free or overall survival was seen between the two arms. Westin” In 1995 Swedish investigators randomized 125 patients with at least a partial response after melphalan and prednisone induction therapy to receive interferon or no maintenance. The duration of plateau was prolonged in those receiving interferon (16 vs 6 months),

Alpha interferon in multiple myeloma

and this was true for all immunoglobulin subtypes, particularly light chain disease, but there was no perceived advantage for complete responders as compared with partial responders. Unfortunately, the prolonged plateau did not translate into a survival advantage for the interferon arm. The major cause of death in both groups was progressive disease. Interferon was well tolerated, with 15% ceasing the drug largely because of ‘flu-like side-effects, and 22% developing grade III neutropenia, without significant infection. It is unclear why the prolongation of the plateau in patients treated with interferon did not lead to improved survival; the authors postulate a late clonal evolution from plasma cells sensitive to cytostatic agents to resistant disease, but this remains speculative. ALSG myeloma IP”

The experience of the Australian study with interferon as a co-induction agent has been discussed previously. Although interferon did not significantly increase the proportion of patients entering plateau (73 vs 72%) there was a trend to improved survival in those patients entering plateau (median 48 vs 36 months, P = 0.1) and a trend to prolongation of plateau. Patients who achieved plateau showed a longer survival than patients who did not and achievement of plateau was associated with a 44% decrease in the rate of death (hazard ratio 0.56 (95% CI (0.29-1.07)). As with duration of plateau, patients who attained plateau on the interferon arm showed a trend for longer survival following the recommencement of plateau than patients on the chemotherapy alone arm. Adjusting for the initial beta 2 microglobulin level, interferon in this study was associated with a 33% decrease in the rate of death (hazard ratio 0.67 (95% CI(O.41-1 .ll)). Multicentre

international

trial”’

This international trial randomized 100 patients who had previously participated in the trial of interferon as a co-induction agent with VMCP to receive interferon 2 MU thrice-weekly or no maintenance for a year. Interferon was found to delay disease progression, prolong plateau, and increase overall survival. The greatest gain was in progression-free survival, which was 8 months in the group receiving no maintenance therapy, and 21 months in the group receiving interferon. The main adverse effects of interferon were mild haematological toxicity (WHO grade I-II) and fatigue, but this did not result in treatment discontinuation.

197

Summary

Meta-analysis of 924 patients in these and other trials has been performed by Ludwig et a1.38The results show an advantage for interferon in the prolongation of plateau phase (19 vs 12 months) and overall survival (40 vs 37 months). The authors point out that some studies may have introduced bias by interferon priming as it was used as a co-induction agent as well as a maintenance agent.

INTERFERON

AFTER HIGH DOSE THERAPIES

Dose-intensification of chemotherapy with autologous bone marrow, and more recently, peripheral blood stem cell rescue has been shown to be feasible in patients with myeloma, with high response rates and tolerable toxicity.44 More significantly, patients who received this modality experienced prolonged remissions when compared with those receiving standard dose combination chemotherapy. The major cause of death, however, remains relapse and there has been great interest in adding interferon to improve the durability of these remissions. An early study performed by Attal was a trial of ‘three-phase treatment’.45 Thirty-five patients were enrolled to receive induction chemotherapy with either VCMP or VAD; those in plateau went on to receive high dose melphalan (140 mg/m’) and total body irradiation (TBI) (8 Gy in 4 fractions) with unpurged bone marrow graft. Interferon was started in all patients post-transplant at a standard dose of 3 MU thrice-weekly when good haematological reconstitution was attained (granulocytes > 500/mm’, platelets > 75 OOO/mmi), and continued until relapse. Overall, the results were encouraging, with 43% of patients obtaining a CR, and these patients had a significantly higher chance of progression-free survival (85% at 33 months) than those in PR (24% at 33 months). Interferon was generally well tolerated and was started a median of 2.6 months post transplantation. It was transiently interrupted on three occasions due to thrombocytopenia (< 50 000/mm3), and although all patients experienced a statistically significant decrease in platelet count after 1 month of therapy this was not clinically significant. The Royal Marsden Group randomized 85 patients to receive interferon or no maintenance post autografting.“” The patients were induced with C-VAMP, consolidated with high dose melphalan (200 mg/m’) and unpurged autologous bone marrow transplant, and were randomized to interferon 3 MU/m’ thriceweekly to relapse, or no maintenance. Remission duration and survival were prolonged in those receiving

198 Blood Reviews Table 7

Interferon

after

The paucity of randomized data and small definitive conclusions impossible Interferon transplant

may be of benefit

At doses of up to 3 MU/m2 tolerated post-transplant The value of interferon is doubtful

Table 8

high dose therapies

after

numbers

in patients

who achieve

thrice-weekly,

interferon

an autograft

Interferon

after

allogeneic

bone marrow

make

Interferon is associated with a high frequency an allograft, and this is dose-related

CR post-

Further cautious randomized studies low dose interferon and in association

transplant

of GVHD

following

may be of use, possibly with with T cell depleted grafts

is well

if PR or less is achieved

interferon; median progression-free survival was 27 months in the control group and 39 months in the interferon group, with 53% of the patients who received interferon in remission 4 years after treatment. This benefit was confined to those who achieved CR, with no advantage shown for partial responders and non-responders to high dose melphalan. There was mild toxicity associated with interferon therapy, resulting in discontinuation of therapy in five patients. In contrast to these promising results, nonrandomized data from the French Registry did not show a benefit from maintenance therapy with interferon.47 This multicentre, retrospective analysis reviewed 133 patients with myeloma who underwent a variety of high dose regimes (mainly variants of high dose melphalan and TBI) following initial induction chemotherapy, and received unpurged autologous bone marrow or stem cell grafts. Of the 110 patients who achieved at least a PR after transplantation, 65 received maintenance with interferon 3 MU/m’ thriceweekly, with no improvement in remission duration or overall survival. There was, however, a trend in favour of improved remission duration for those in CR post autologous transplant who received interferon (40 vs 20 months, P = 0.10). These results are summarized in Table 7.

INTERFERON AFTER ALLOGENEIC TRANSPLANTATION The tantalizing prospect of cure in myeloma remains elusive, but allogeneic bone marrow transplantation offers the possibility of long-term survival (35% at 10 years).@ The EBMT data on 400 patients suggests that relapse occurs in more than 50% of patients who survive the procedure, including a significant proportion of those who enter CR. In view of the encouraging results of interferon maintenance in autografting, the EBMT undertook a pilot study of the feasibility and toxicity of interferon, commenced within 6 months of transplant, in seven patients with myeloma who had undergone allogeneic bone marrow transplantation

and had adequate haemopoietic reconstitution and no significant graft versus host disease (GVHD).49 All had received T cell replete marrow from HLAmatched sibling donors, conditioning with cyclophosphamide/TBI or cyclophosphamide/busulphan, and GVHD prophylaxis with cyclosporin A, and ‘short’ methotrexate, with or without prednisone. The trial was terminated due to significant acute GVHD, which developed at a dose of 3 MU of interferon thriceweekly, and was fatal in one patient. The dose schedule of 1 MU thrice-weekly did not induce GVHD, and haematological toxicity was minimal. Interestingly, the only patient who relapsed did not have GVHD. These results are summarized in Table 8. There are theoretical reasons why interferon could induce GVHD, such as the enhanced expression of MHC class II molecules, and the increase in activity of NK cells. The issue is obviously more complex than this, however, as interferon-induced GVHD is not seen in CML patients who receive both T cell replete and depleted grafts.5o It is tempting to speculate upon the potential for harnessing the interferon-induced GVH to produce a graft-versus-myeloma effect .

SALVAGE THERAPY CORTICOSTEROIDS

WITH INTERFERON

AND

Following the observation of in vitro synergism of interferon and dexamethasone16 several investigators have attempted to treat chemotherapy-resistant patients with this combination. The results vary with the patient group, and it is unclear whether successes were due to one or other agent, or the combination. One study matched primary resistant patients receiving interferon and dexamethasone with historical controls, and failed to show an advantage.s’ More encouragingly, the SWOG study, which looked at interferon maintenance therapy post induction, also chose to treat non- or partial responders to induction chemotherapy with interferon 5 MU thrice-weekly and dexamethasone 40 mg daily for 4 days twice a month.17 Forty-five per cent of the partial responders achieved a CR on this regime, and 32% of the nonresponders achieved a PR. The group as a whole reported less interferon-related toxicity than those receiving interferon alone. It is possible therefore that

Alpha

Table

9

Salvage

therapy

with

In-vitro

synergism

of interferon

Partial

remissions

arc possible

Steroids

in high doses appear

interferon and dexamethasone with

exists

9.

tolerance

IO.

this regime

to increase

interferon

in vitro synergism of interferon and dexamethasone exists and partial remissions are possible with this regime. These results are summarized in Table 9. CONCLUSION WHICH PATIENTS WITH MYELOMA FROM INTERFERON?

II.

12.

13.

BENEFIT

Despite numerous studies the exact role of interferon in myeloma is still not resolved, and it is hoped that the results of a large meta-analysis to be performed by the MRC (UK) Myeloma Trialists’ Collaborative Group will provide clarification. Currently, there seems little evidence that interferon alone can be used as a successful induction agent, and when combined with conventional chemotherapy the advantages of interferon therapy are at best modest. Furthermore, interferon in this setting may require chemotherapy dose reduction. The beneficial role of interferon in the maintenance of plateau phase is gaining credence, and its advantages appear maximized for most patients with an initial good prognosis or who attain plateau phase. Similarly, patients who achieve a complete remission after autologous transplantation appear to benefit from, and tolerate, interferon therapy. Finally, for those patients who are refractory to chemotherapy, the combination of interferon and dexamethasone is a feasible method of attempting to achieve a partial remission.

14.

15. 16.

17.

18.

19.

20. 21.

23. 24. 25.

REFERENCES I. Isaacs A, Lindenmann J. Virus interference. The interferon. Proc R Sot B 1957; 147: 258. 2. Mellstedt H, Bjorkholm M, Johansson B, Ahre A, Holm G, Strander H. Interferon therapy in myelomatosis. Lancet 1979; i: 245. 3. Reynold JEF (ed). Martindale: The Extra Pharmacopoeia. 3 1 st Edition. London: Royal Pharmaceutical Society, 1996.6533654. 4. Salmon SE, Durie BGM, Young Y et al. Effect of cloned leucocyte interferons in the human tumour stem cell assay. J Clin Oncol 1983; I: 217. 5. Trotta PP. Preclinical biology of alpha interferons Semin Oncol 1986; 13: 3. 6. Creasey AA, Bartholomew JC, Merigan TC. Role of G,,-G, arrest in the inhibition of tumour cell growth by interferon. Proc Natl Acad Sci USA 1980; 77: 1471. 7. Revel M, Kimci A, Shulman L. Role of interferon induced enzymes in the antiviral and antimitogenic effects of interferon. Ann N Y Acad Sci 1980; 350: 459. RM. Development of a 8. Samid D, Chang EH, Friedman transformed phenotype induced by a human RAS oncogene is

26.

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