Multiple myeloma develops in 5-10 per 100 000 population in the U.S.A. and Europe each year. Although often regarded as a disease of later life, almost 50% of patients are under the age of 70 at the time of diagnosis. Cytotoxic drug treatment given at standard doses produces regression of the myeloma in >70% of patients, but complete remissions are unusual and the median survival in most reported series is 24-36 months [i],[ii],[iii]. Oral melphalan and prednisolone remain the most widely used treatment and a recent meta-analysis of 18 published trials has shown no survival advantage to combination chemotherapies [iv],[v],[vi]. In the absence of cure, and the desire to prolong the plateau phase, different biologic approaches have been investigated.

Rational for studying Interferon in Multiple Myeloma

Therapeutic intervention with cytokines is being evaluated in the management of a range of malignancies. The interferon's have a broad spectrum of action on cellular proliferation as well as immunoregulation. In patients with myeloma, interferon alpha has been demonstrated to have potent antiproliferative action and the capacity to modulate oncogene expression [vii],W .Also, it prolongs all phases of the cell cycle as well as overall cell generation time and markedly reduces the self-renewal capacity of myeloma-forming cells [viii]. Interest in the use of interferon in multiple myeloma was evoked after Mellsted et al who demonstrated its efficacy as a single agent in previously untreated myeloma [ix]. Several studies have since been undertaken using this cytokine in combination with chemotherapy to exploit its synergistic anti-tumor effect and others have used it as part of maintenance therapy [x],[xi],[xii],[xiii].

Interferon as a single agent in the treatment of Multiple Myeloma

The first study in which a-IFN was utilized as a single agent for induction therapy of previously untreated MM patients was published in 1979 I . In this study, 3 mega units of human leukocyte a-IFN were administered via daily intramuscular injection to four patients. All patients achieved a durable response lasting from 3 to 19 months I .This result and the increasing availability of a-IFN prompted several investigators to utilize this biologic response modifier in the treatment of MM. The results obtained in the early clinical studies show a wide response rate ranging from 20% to 100%, with an overall response rate of about 30% [xiv],[xv],[xvi].

Recently, the Myeloma Group of Central Sweden (MGCS) has reported the results of a randomized trial comparing the administration of human leukocyte a-IFN with the administration of oral melphalan and prednisone (MP). Forty-four percent of patients treated with MP achieved responses, whereas only 14% of the patients treated with a-IFN responded. However, in the IgA and Bence Jones myeloma subgroups, the response rate was similar in both treatment groups. Moreover, because the response rate to a second line treatment was better in the previously et-IFN-treated group than in the MP group, the overall survival duration was similar in both groups C .

Interferon in combination with induction chemotherapy

The Eastern Cooperative Oncology Group (ECOG) designed a study to evaluate the effect of adding alternating cycles of IFN or early intensification with high dose cyclophosphamide (HiCy) to the VBMCP regimen for the treatment of multiple myeloma patients. The ECOG entered previously untreated patients with active multiple myeloma on a study in which they were randomized to VBMCP (vincristine) (melphalan) (BCNU) (cyclophosphamide) (prednisone) or VBMCP + rIFN(alpha2), the latter given at 5 Mu/m² 3 times a week starting on Day 22 of each 6-week cycle after 2 initial cycles of VBMCP. Patients younger than 70 years were also randomized to a third treatment that substituted cyclophosphamide 600 mg/m²i.v. on Days 1-4 and prednisone 100 mg/m² p.o. on Days 1-4 for cycles 3 and 5 of VBMCP (VBMCP + HiCy). Treatment was continued for 2 years. Of the 653 patients entered, 628 were eligible for the study. All were evaluated for response. With median follow-up for surviving patients of 54 months, the median survival duration was 42 months-1 year longer than usually reported for melphalan combined with prednisone. A comparison of the three regimens revealed no significant difference in the rates of survival or objective response (OR). However, CRs were increased among patients treated with VBMCP + rIFN (alpha2) compared with VBMCP alone (18% vs. 10%, P = 0.03). Patients treated with VBMCP + rIFN (alpha2) had a longer response duration than patients treated with VBMCP alone (30 vs. 25 months, P = 0.035). There was a greater response rate with the IFN regimen among elderly patients (OR and CR = 67% and 31%, respectively) and patients with immunoglobulin A (IgA) myeloma (OR and CR = 83% and 29%, respectively). Severe infections were seen as often with VBMCP as with VBMCP + rIFN (a2) (13% vs. 15%), but they were more frequent with VBMCP + HiCy (25%). VBMCP + rIFN (alpha2) yields a higher rate of CR and a longer response duration than VBMCP alone but appears to make no difference in the rates of overall response or survival compared with VBMCP or VBMCP + HiCy. The superior ability of VBMCP + rIFN (alpha2) induction therapy to produce CR and more durable responses, as well as its activity in older patients and in those with IgA myeloma, suggest that this therapy has important biologic activity in myeloma and merits further clinical investigation [xvii].

The role of Interferon in the maintenance of plateau phase in myeloma patients

Interferon maintenance following conventional chemotherapy

IFN has primarily been studied as a maintenance treatment aimed at prolonging the plateau phase. The deployment of a-IFN as maintenance agent in multiple myeloma patients is the ability of a-IFN, both natural and recombinant, to shown a greater control of cell growth and differentiation than b-IFN and g-IFN [xviii],[xix],[xx]. This inhibitory effect is more evident in noncycling tumor cells (G₀ and G₁), and in some cases an accumulation of cells in G₀, accompanied by a decrease in transition to G₁ as well as the arrest of some cell types in G₀ [xxi],[xxii].

An Italian group compared IFN maintenance with no treatment, and the relapse rate after 33 months of follow-up was reduced from 56% to 24% [xxiii]. A recent MRC study found no survival benefit of IFN use in the first plateau phase, although opinion is divided on this issue, and a recent meta-analysis of 24 randomized trials involving 4000 patients showed that IFN produced a moderate improvement in relapse-free survival and a minor improvement in survival [xxiv],[xxv]. Survival was somewhat better when IFN was used at induction or maintenance (3-year survival: 53% v. 49%, p=0.0l). An effect of similar size was observed in both induction and maintenance trials, with increases in median survival of about 2 and 7 months respectively. In induction, complete (17% v. 14 %, p=0.08) and complete plus partial (58% v. 53%, p=0.0l) response rates were slightly better with IFN. Recurrence-free survival (RFS) was highly significantly better with IFN in both induction (p=0.0003) and maintenance (p<0.00001) trials: median RFS increased by about 6 months in both and 3-year RFS 7% and 12% better respectively, with some suggestion of a plateau beyond 4 years.

Interferon maintenance following autologous bone marrow transplantation

When Mandelli et al reported the results of the first trial of maintenance interferon in myeloma, the greatest benefit was reported in the patients with lowest tumor burden at the start of maintenance therapy W . On this basis, an ideal group of patients for investigation of the role of interferon maintenance would be those who have undergone high-dose chemotherapy and achieved CR. The majority of these patients have the lowest residual tumor burden so far seen in myeloma (i.e. CR), yet almost all patients are destined to relapse. This observation was the basis for the study by Cunningham et al [xxvi]. Eighty four patients with multiple myeloma entered on a trial where induction treatment consisted of vincristine, adriamycin and methyl prednisolone (VAMP) and VAMP plus cyclophosphamide (C-VAMP until maximum response was achieved. Autologous marrow stem cell support 6 weeks after the last chemotherapy cycle an autograft was planned. Randomization to the interferon arm was carried out at hematological recovery (WBC count >2 x 10⁹/L and platelets >100 x 10⁹/L) following autologous bone marrow transplant. Interferon alpha was given at a dose of 3 x 10⁶ units/m² subcutaneously three times a week. Bone marrow aspiration and a trephine biopsy were carried out before randomization to. This trial is the first reported use of interferon following high-dose chemotherapy, a situation whereby most patients are in complete remission and truly have minimal residual disease. Longer follow-up has failed to demonstrate the benefits of interferon alpha and may be due to patients in the control arm who have relapsed, subsequently receiving interferon (17/33), whereas only 4/31 patients who relapsed after interferon maintenance received further interferon. Thus the trial was really a 'cross over' of treatment negating survival benefit and was due to the design of the trial, which closed at the time of relapse. Ideally a subgroup analysis should be undertaken to determine if clinical variables such as myeloma type, patient age, etc., would help to identify patients who would definitely benefit from interferon therapy. This was not possible in this study, again due to the small number of patients accrued. Several authors have reported the use of interferon alpha following high-dose treatment, but all these studies are non-randomized. Attal et al have reported a 28% event-free survival and 52% overall survival at 5 years, in their high-dose treated patients. All their patients received interferon following high-dose treatment [xxvii]. Data from the French registry in a phase II non-randomized trial demonstrate a favorable trend for CR patients (37% CR rate) on interferon maintenance post high-dose treatment [xxviii].

Interferon following allogeniec bone marrow transplantation

Allogeniec transplantation has the advantage of graft versus myeloma, which could prolong plateau phase. Relapse continues to be a major cause of treatment failure, however. Byrne et al sought to improve complete remission (CR) rates by the use of a-IFN in patients not in CR when evaluated 4 months post allogeniec bone marrow transplant. They report five of 13 evaluable patients undergoing allogeniec sibling bone marrow transplantation for MM between 1990 and 1997 who met the criteria for adjuvant alpha-IFN therapy. A starting dose of 3 MU x 3/week was commenced at median time of day +126 (range day +112-224) post-transplant and was well tolerated. In contrast to other reports we observed no increased toxicity in terms of GVHD compared to those patients not receiving alpha-IFN therapy and only one patient treated with alpha-IFN has developed chronic GVHD. Durable CRs were achieved in two patients within 8 weeks of starting therapy whilst two other patients required a longer course of alpha-IFN to achieve CR (36 weeks and 30 weeks, respectively). One patient whose paraprotein was rapidly rising at the time of alpha-IFN therapy clinically relapsed despite 6 months of treatment. None of the patients who achieved CR following alpha-IFN therapy have relapsed and they concluded that a-IFN is a safe and effective adjuvant treatment for some patients in the achievement of CR following allogeniec transplantation for myeloma [xxix].

Summary of Treatment Results, Clinical Implications and future directions with new interferon's

A meta-analysis of individual patient data and one of published results of randomized trials on interferon treatment reveal a 6%-higher response rate to combined interferon chemotherapy, a significant prolongation of disease-free survival, and a survival benefit of 4% in the former and of 6 months in the latter metaanalysis. These benefits must be balanced against possible toxicity and financial costs of interferon. No specific characteristics could be derived that would allow to identify patients who are most likely to benefit from interferon treatment. However, in analogy to other cancers, low tumor load, excellent performance status, young age, and remission from high-dose chemotherapy seem to be factors associated with beneficial effects of interferon. More over, the dose and schedule of interferon might play a role in the quality of response. This randomized multicenter study was designed to compare two schedules of IFN maintenance therapy in order to assess the difference in effectiveness and tolerance. This prospective randomized multicenter study was attempted to assess the best schedule of IFN administration in the maintenance treatment of MM in plateau phase with regard to progression free survival (PFS) and toxicity. The second aim was defining the difference between the two schedules in overall survival (OS) and identifying the critical dose of IFN therapy needed to prolong plateau phase and survival. 52 patients affected with low-risk MM (i.e. with serum beta 2- microglobulin < 6.0 mg/L and serum albumin > 3.0 g/dL) were enrolled; 27 patients (group A) were randomly assigned to receive IFN alpha-2b 3 mega units (MU) subcutaneously three times a week and 25 patients (group B) 3 MU/day until disease progression. Median progression free survival (PFS) was 11.9 months in-group A and 38.3 months in-group B (p = 0.0038). Median survival was 63.2 months in-group A and 61.9 months in-group B (p = 0.489). However, those patients who were given an IFN dose > 30 MU/month experienced a significantly longer PFS and survival than the other patients. Seventeen patients (32.7%) discontinued therapy and sixteen patients (30.8%) reduced IFN alpha-2b dose because of severe side effects without having a significant difference between the two schedules. These results show that patients treated with IFN alpha 3 MU/day had significantly longer remission duration than patients treated with IFN alpha 3 MU three times weekly. Moreover, an IFN dose is probably critical for obtaining a longer survival in patients affected with low- risk MM. Since the patients' discomfort during a IFN maintenance therapy was frequently experienced the quality of their lives should be carefully taken into account [ax]. The development of IFN-a1 which is the predominant interferon subtype in naturally produced IFNs should resolve the issue of toxicity limiting the dose intensity [xxxi],[xxxii],[xxxiii],[xxxiv]. The pegelated forms of IFN also, will help resolve the inconveniences of daily injections. The studying of these new forms of IFN should overcome the quality of life issues that have limited the benefits of IFN in this disease.

References

[i] Osterborg, A., Ahre, A., Bjorkholm, M., Bjoreman, M., Brenning, G., Gahrton, G., Gyllenhammar, H., Johansson, B., Juliusson, G. & Jarnmark, M. (1989) Alternating combination chemotherapy (VCMP/VBAP) is not superior to melphalan/prednisolone in the treatment of multiple myeloma stage III: a randomized study from MGCS. European Journal of Haematology, 43, 54-62

[ii] MacLennan, I.C.M., Chapman, C., Dunn, J. & Kelly, K. (1992) Combined chemotherapy with ABCM versus melphalan for treatment of myelomatosis. Lancet, 339, 200-205.

[iii] Blade, J., San Miguel, J.F., Alcala, A. Maldonado, J., Sanz, M.A., Garcia-Conde, J., Moro, M.J., Alonso, C., Besalduch, J., Zubizarreta, A., Besses, C., Gonzallez-Brito, G., Hernandez-Martin, J., Fernandez-Calvo, J., Rubio, D., Ortega, F., Jimenez, R., Colominas, P., Faura, M.V., Font, L., Tortosa, J., Domingo, A., Fontanillas, N., Rozman, C. & Estape, J. (1993) Alternating combination VCMP/VBAP chemotherapy versus melphalan/prednisolone in the treatment of multiple myeloma: a randomized multicentric study of 487 patients. Journal of Clinical Oncology, 11, 1165-1171.

[iv] Alexanian, R., Haut, A., Khan, A.U., Lane, M., McKelvey, E.M., Migliore, P.J., Stuckey, W.J. & Wilson, H.E. (1969) Treatment for multiple myeloma: combination chemotherapy with different melphalan dose regimens. Journal of the American Medical Association, 208, 1680-1685.

[v] Gregory, W.M., Richards, M.A. & Malpas, J.S. (1992) Combination chemotherapy versus melphalan and prednisolone in the treatment of multiple myeloma: an overview of published trials. Journal of Clinical Oncology, 10, 334-342

[vi] McElwain, T.J. & Powles, R.L. (1983) High-dose intravenous melphalan for plasma cell leukemia and myeloma. Lancet, ii, 822-824.

[vii] Borden, E.C. & Ball, L.A., (1981) Interferons: biochemical, cell growth inhibitory and immunological effects. Progress in Hematology, 12, 299-339.

[viii] Bergsagel, D.E., Haas, R.H. & Messner, H.A. (1986) Interferon alfa-2b in the treatment chronic granulocytic leukemia. Seminars in Oncology, 13, (Suppl. 2), 29-34

[ix] Mellstedt, H., Ahre, A., Bjorkholm, M., Holm, G., Johansson, B. & Strander, H. (1979) Interferon therapy in myelomatosis. Lancet, i, 245-247

[x] Cooper, M.R., Dear, K., McIntyre, R., Ozer, H., Ellerton, J., Canellos, G., Bernhardt, B., Duggan, D., Faragher, D. & Schiffer, C. (1993) A randomized clinical trial comparing melphalan/prednisolone with or without interferon alfa-2b in newly diagnosed patients with multiple myeloma: a Cancer and Leukemia Group B study. Journal of Clinical Oncology, 11, 155-160

[xi] Osterborg, A., Bjorkholm, M., Bjorman, M., Brenning, G., Carlson, K., Celsing, F., Gahrton, G., Grimfors, G., Gyllenhammar, H., Hast, R., Johansson, B., Juliusson, G., Janmark, M., Kimby, E., Lerner, R., Linder, O., Merk, K., Nilsson, B., Ohrling, M., Paul, C., Simonsson, B., Smedmyr, B., Svedmyr, E., Stalfelt, A.M., Strander, H., Uden, A.M., Osby, E. & Mellstedt, H. (1993) Natural interferon-alpha in combination with melphalan/prednisolone versus melphalan/prednisolone in the treatment of multiple myeloma stages II and III: a randomized study from the Myeloma Group of Central Sweden. Blood, 81, 1428-1434.

[xii] Ludwig, H., Cohen, A.M., Polliack, A., Huber, H., Nachbaur, D., Senn, H.-J., Morant, R., Eckhardt, S., Gunczler, P., Seewann, H.L., Schuller, J., Rhyner, K., Cavalli, F. & Fritz, E. (1995) Interferon-alpha for induction and maintenance in multiple myeloma: results of two multicentre randomized trials and summary of other studies. Annals of Oncology, 6, 467-476.

[xiii] Salmon, S.E., Crowley, J.J., Grogan, T.M., Finley, P., Pugh, R.P. & Barlogie, B. (1994) Combination chemotherapy, Glucocorticoids, and Interferon alfa in the treatment of multiple myeloma: a Southwest Oncology Group study. Journal of Clinical Oncology, 12, 2405-2414

[xiv] Ahre A, Björkholm M, Mellstedt H, et al: Human leukocyte interferon and intermittent high-dose melphalan-prednisone administration in the treatment of multiple myeloma: A randomized clinical trial from the Myeloma Croup of Central Sweden. Cancer Treat Rep 68:1331, 1984

[xv] Ludwig H, Cortelezzi A, Scheithauer W, et al: Recombinant interferon alpha-2c versus polychemotherapy (VMCP) for treatment of multiple myeloma: A prospective randomized trial. Eur J Cancer Clin Oncol 22:1111, 1986

[xvi] Ahre A, Björkholm M, Osterborg A, et al: High dose of natural a-interferon (a-IFN) in the treatment of multiple myeloma. A pilot study from the Myeloma Croup of Central Sweden (MCCS). Eur J Haematol 41:123, 1988

[xvii] Oken MM, Leong T, Lenhard RE, Jr., Greipp PR, Kay NE, Van Ness B, Keimowitz RM, Kyle RA: The addition of interferon or high dose cyclophosphamide to standard chemotherapy in the treatment of patients with multiple myeloma: phase III Eastern Cooperative Oncology Group Clinical Trial EST 9486. Cancer 86: 957-968, 1999

[xviii] Blalock J, Ceorgiades JE, Langford MP, et al: Purified human immune interferon has more potent anticellular activity than fibroblast or leukocyte interferon. Cell Immunol 49:390, 1980

[xix] Borden EC, Hogan TF, Voelkel JC: Comparative antiproliferative activity in vitro of natural interferons alpha and beta for diploid and transformed human cells. Cancer Res 42:4948, 1982

[xx] Chadha KC, Srivastava BL: Comparison of the antiproliferative effects of human fibroblast and leukocyte interferons on various leukemic cell lines. J Clin Hematol Oncol 11:55, 1981

[xxi] Creasey AA, Bartholomew JC, Merigan TC: Role of G0-G1 arrest in the inhibition of tumor cell growth by interferon. Proc NatI Acad Sci USA 77:1471, 1980

[xxii] Horoszewicz JS, Leong SS, Carter WS: Non cycling tumor cells are sensitive targets for the antiproliferative activity of human interferon. Science 206:1091, 1979

[xxiii] Mandelli F, Avvisati G, Amadori S, Boccadoro M, Gernone A, Lauta VM, Marmont F, Petrucci MT, Tribalto M, Vegna ML, Dammacco F, Pileri A. Maintenance treatment with recombinant interferon alfa-2b in patients with multiple myeloma responding to conventional induction chemotherapy. N Engl J Med 1990; 322:1430-4.

[xxiv] Drayson MT, Chapman CE, Dunn JA, Olujohungbe AB, MacLennan IC. MRC trial of interferon-alfa 2b maintenance therapy in first plateau phase of multiple myeloma. Br J Haem 1998; 101:195-202.

[xxv] Wheatley J. Which myeloma patients benefit from interferon therapy? An overview of 24 randomized trials with 4000 patients. Br J Haem 1998; 102:140.

[xxvi] Cunningham D, Powles R, Malpas J, Raje N, Milan S, Viner C, Montes A, Hickish T, Nicolson M, Johnson P, Treleaven J, Raymond J, Gore M: A randomized trial of maintenance interferon following high-dose chemotherapy in multiple myeloma: long-term follow-up results. Br.J.Haematol. 102: 495-502, 1998

[xxvii] Attal, M., Harousseau, J.L., Stoppa, A.M., Sotto, J.J., Fuzibet, J.G., Rossi, J.F., Casassus, P., Maisonneuve, H., Facon, T., Ifrah, N., Payen, C. & Bataille, R. (1996) A prospective randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. New England Journal of Medicine, 335, 91-97

[xxviii] Harousseau, J.L., Attal, M., Divine, M., Marit, G., Leblond, V., Stoppa, A.M., Bourhis, J.H., Caillot, D., Boasson, M., Abgrall, J.F., Facon, T., Linassier, C., Cahn, J.Y., Larny, T., Troussard, X., Grabecos, N., Pignon, B., Auzanneau, G. & Bataille, R. (1995) Autologous stem cell transplantation after first remission induction treatment in multiple myeloma: a report of the French Registry on autologous transplantation in multiple myeloma. Blood, 85, 3077-3085

[xxix] Byrne JL, Carter GI, Bienz N, Haynes AP, Russell NH: Adjuvant alpha-interferon improves complete remission rates following allogeneic transplantation for multiple myeloma. Bone Marrow Transplant. 22: 639-643, 1998

[xxx] Offidani M, Olivieri A, Montillo M, Rupoli S, Centurioni R, Alesiani F, Marchegiani G, Pieroni S, Catarini M, Pelliccia G, Altilia F, Leoni P: Two dosage interferon-alpha 2b maintenance therapy in patients affected by low-risk multiple myeloma in plateau phase: a randomized trial. Haematologica 83: 40-47, 1998

[xxxi] Hawkins MJ, Borden EC, Fein S, Simon KJ. Evaluation of the clinical and biological effects of recombinant human interferon alpha rD(IFN-a(rD). Proc Am Soc Clin Oncol 2:50, 1983

[xxxii] Hawkins MJ, Borden EC, Edwards BS. Biological effect in man of recombinant human interferon alpha rD. Antiviral Res 1:33, 1983

[xxxiii] Quesada JR, et al. Clinical study of recombinant DNA-produced leukocyte interferon (Clone A) in an intermittent schedule in cancer patients. J Natl Cancer Inst 70:1041-1046, 1983.

[xxxiv] Quesada JR, Hawkins MJ, et al. A collaborative phase I-II study of recombinant DNA-produced leukocyte interferon (clone A) in metastatic breast cancer, malignant lymphoma and multiple myeloma. Am J Med 77:427-432, 1984.