Multiple Myeloma : Treatment Options for an Incurable Disease

Transcription

1 Update Article Multiple Myeloma : Treatment Options for an Incurable Disease SR Pandit Abstract Multiple myeloma remains a challenge for the treating physician, with extremely low complete response rates (5-10%) to conventional induction therapy. High dose therapy with autologous hematopoietic stem cell transplant results in improved response, event-free and overall survival and should be considered the standard of care for patients who are candidates for transplantation. Several newer treatment option are now available. INTRODUCTION Multiple myeloma (MM) is an incurable malignancy caused by neoplastic proliferation of a clone of malignant plasma cells. It comprises 10% of all hematological malignancies. Most patients with MM are symptomatic at presentation and will require prompt treatment. However, MM is asymptomatic in some (about 10-15%) at diagnosis, and in these patients, treatment can be delayed. Despite significant progress in the understanding of the pathophysiology of this disease and the development of newer treatment options, MM continues to remain an incurable disease and is a challenge to the treating physician. Progress achieved with conventional chemotherapy has been minimal over the past 3 decades or so since the initial description of melphalan-based chemotherapy. With conventional chemotherapy, the 5-year median survival rate is approximately 25%, with about 10% of patients living longer than 10 years. MM is a disease of the elderly, with the onset usually seen in the 7 th decade of life or later. This is a patient population with a high prevalence of other chronic diseases like hypertension and diabetes mellitus amongst others, which increase the incidence of pre-existing renal dysfunction and thereby make it difficult for these patients to be able to tolerate more aggressive treatment options like peripheral blood stem cell transplantation (PBSCT). However autologous transplantation following induction therapy has been shown to improve both survival and response rates in newly diagnosed MM and should be considered the standard approach for newly diagnosed patients who do not have other significant co-morbidities precluding Assistant Professor of Medicine, Division of Neoplastic Diseases and Related Disorders (Hematology-Oncology), 9200 W. Wisconsin Avenue, Medical College of Wisconsin, Milwaukee, Wisconsin (WI) , USA. Received : ; Accepted : this option. The following section includes a brief review of the clinical presentation and staging of MM followed by a more detailed discussion of the various treatment options. CLINICAL PRESENTATION MM should be suspected in any patient with unexplained anemia, renal dysfunction with or without bone pains. More than 60% of patients have anemia at presentation and a similar number of patients can present with bone pains and demonstrate lytic bone lesions on a skeletal X-ray survey. Hypercalcemia is seen in about one-fourth of the patients at presentation. Almost all patients will have demonstrable monoclonal paraproteinemia (98% to 99% of cases with immunoelectrophoresis of serum or urine, serum electrophoresis will detect about 75% of cases) with 60% showing monoclonal IgG protein, 20% IgA and 10% being light-chain excretors only. Only 1-2% of patients are non-secretors. Renal dysfunction is seen approximately in one-third of MM patients at presentation and in up to 50% of patients at some stage in their disease. The most common cause of renal failure results from a form of interstitial nephritis called myeloma kidney and is due to the development of light chain tubular casts. 1 Patients presenting with this entity most commonly have IgA lambda paraprotein with lambda light-chain Bence Jones proteinuria and clinically have either acute or chronic renal failure. Other possible etiologies for renal failure include hypercalcemia and hypercalciuria causing pre-renal azotemia due to volume depletion from osmotic diuresis, hyperuricosuria, light chain deposition disease (LCDD, which is seen more commonly with kappa light chains), associated AL amyloidosis (more commonly associated with lambda light chains) or from calcium deposition in the kidney. 2-5 Other factors such as hyperviscosity syndrome, concomitant infections or the use of JAPI VOL. 53 DECEMBER 2005

2 nephrotoxic medications may exacerbate renal dysfunction. Renal dysfunction in MM is an independent poor prognostic factor for survival since these patients are more likely to have a higher tumor burden, manifested as severe anemia, hypercalcemia, Bence Jones proteinuria and lytic bone disease. 6 STAGING AND PROGNOSTIC FACTORS The commonly used Durie-Salmon classification system divides newly diagnosed MM patients into 3 stages based on laboratory parameters and the presence or absence of lytic bone lesions as follows: Stage I - hemoglobin > 10 g/dl, serum calcium < 12 mg/dl, normal X-ray or solitary lytic lesion, IgG < 5 g/ dl or IgA < 3 g/dl, Bence Jones protein < 4 g/24h. Stage II - Not fitting stage I or III. Stage III - hemoglobin < 8.5 g/dl, serum calcium > 12 mg/dl, more than 3 lytic bone lesions, IgG > 7 g/dl or IgA > 5 g/dl, Bence Jones protein > 12 g/24h. Subclassification A - normal renal function (serum creatinine < 2 mg/dl) Subclassification B - abnormal renal function (serum creatinine > 2 mg/dl) The 5-year survival for each of these stages I, II and III are estimated at 25-40%, 15-30% and 10-25% respectively. In addition a number of poor prognostic factors which are associated with a shorter survival and/or inferior response to chemotherapy have been identified and include a high beta-2 microglobulin (especially > 6 mg/ dl), elevated C-reactive protein, chromosome 13 abnormalities, high plasma cell labelling index, high bone marrow microvessel density and increased soluble IL-6 receptor level. TREATMENT a) Supportive measures - MM patients frequently have renal insufficiency at presentation, and a significant number of these patients show improvement in renal function in response to vigorous rehydration, correction of hypercalcemia and discontinuation of the use of nephrotoxic drugs (e.g. NSAIDs, ACE inhibitors). For the control of hypercalcemia, bisphosphonates (Pamidronate, Zolendronic acid) are used for the effective control. Pamidronate is administered at a dose of mg intravenously as a 2-hour infusion and repeated at intervals of 2-4 weeks as necessary. Zoledronic acid is administered at a dose of 4 mg intravenously as a 15 minute infusion and would especially be advantageous in the out-patient setting given a much shorter infusion time. In addition to control of hypercalcemia, the use of bisphosphonates has been shown to reduce the incidence of skeletal-related events and improve the quality of life in MM patients. 7,8 Limited clinical data is available regarding the use of bisphosphonates in patients with renal impairment, and therefore those patients with evidence of deterioration in renal function while on therapy should be appropriately evaluated. b) Conventional chemotherapy - commonly used standard regimens for the initial treatment of MM includes melphalan and prednisone (MP), vincristine, adriamycin and dexamethasone (VAD) or a combination of vincristine, BCNU, melphalan, cyclophosphamide and prednisone (VBMCP). As initial therapy, the response rates with each of these regimens ranges from 50-60% with comparable median survivals. 9 In potential transplant patients the preferred regimen for initial therapy is VAD (vincristine 0.4 mg/m 2 and doxorubicin 10mg/m 2 daily given as continuous IV infusion for 96 hours alongwith oral dexamethasone 40 mg on days 1-4, 9-12 and with repeat cycles every 4-5 weeks). This is because one of the major toxicities of alkylator-based regimens like MP or VBMCP is myelosuppression which may cause prolonged cytopenias and/or in myelodysplasia/acute leukemia. 10,11 Therefore alkylator-based chemotherapy like MP (standard melphalan dose is 8-10 mg/m 2 given orally with prednisone 100 mg/ day orally on days 1-4 of a 5 week cycle). Patients who present with renal failure usually have a higher tumor burden and consequently more aggressive disease, and therefore trying to achieve more rapid control of the disease with regimens like VAD might be necessary. No dose modification is necessary in the presence of renal impairment, but close monitoring for hematological toxicity is necessary since these patients might not be able to adequately tolerate the more aggressive regimens. Patients treated successfully with initial therapy enter a plateau phase or a state of tumor quiescence. 12 Achievement and the duration of the plateau phase determines duration of survival. 13 Characteristics of a plateau phase include a low plasma cell labeling index, low levels of proliferation markers like serum thymidine kinase, normal levels of oncoproteins, normal nucleotide transporters, and sil-6 receptors. 12 Escape from this phase is associated with a variety of biologic abnormalities like the emergence of the multi-drug resistant phenotype, nucleotide transporter dysfunction, chromosomal abnormalities, oncogene activation and/or tumor gene inactivation. 12 Different treatment modalities have been evaluated as maintenance therapy to prolong the progression-free survival (PFS) including maintenance chemotherapy, interferon, and corticosteroids. Continuation of melphalan- JAPI VOL. 53 DECEMBER

3 based treatment after a stable response has been achieved prolongs the duration of initial response but does not increase overall survival. 14 Interferon-a (IFN) has been shown to prolong the duration of remission in some studies, but has failed to show prolongation of overall survival. 15,16 Since IFN has significant side effects, the clinical benefit of prolonging the initial remission remains questionable. More recently, there is considerable interest in thalidomide as maintenance therapy. c) High-dose therapy with Autologous Hematopoietic Stem Cell Transplant (AHSCT) - has been shown to improve both response rates and survival in patients with newly diagnosed MM. A randomized French Myeloma Intergroup trial of 200 newly diagnosed patients under 65 years of age treated with either high dose therapy with autologous transplantation or conventional chemotherapy reported superior outcomes for the transplant arm including overall response rate (ORR; 81% versus 57%), event-free survival (EFS; 28% versus 10%) and overall survival (OS; 52% versus 12%). 17 This indicates that autologous transplantation following induction therapy should be the standard of care for newly diagnosed patients who do not have other significant co-morbidities precluding this option. However MM continues to remain an incurable disease with almost all patients relapsing even after transplantation. This has led to the evaluation of the role of tandem transplantation and maintenance therapy. The French group recently reported the final analysis of their prospective randomized trial comparing single versus double auto-transplants in 399 patients under 60 years of age with the doubletransplant arm showing a statistically significant improvement in event-free survival and overall survival at 7 years.18 Transplant-related mortality (TRM) is remarkably low with AHSCT. d) Allogeneic transplantation - As indicated above, the use of high dose therapy with autologous transplantation has been shown to be superior to conventional therapy. However there does not appear to be a plateau in the disease-free survival indicating that cures even with tandem autologous transplantation are unlikely. Allogeneic transplantation offers the advantages of a providing tumor-free grafts and the benefit of a graft-versusmyeloma effect. 19,20 However allogeneic transplantation has been associated with a significantly high transplant-related mortality (TRM) ranging from 24-57% in various reported studies, and would possibly be an option in a small minority of patients (5-10%) who have HLA compatible donors, are younger (under 60 years of age) and have extremely poor prognostic features. e) Donor lymphocyte infusion (DLI) - In MM, it has been shown that immunoreactive T lymphocytes can induce clinical remissions in relapses following allogeneic transplant. 19,20 Lokhorst et al reported a trial demonstrating the efficacy of DLI in patients with relapsed disease (52 DLI in 27 patients) patients responded (52%) including 6 CRs (22%). The median survival for the whole group was 18 months; 5 patients remained in remission at a median of 31 months post-dli. DLI was associated with significant GVHD: 56% acute and 26% chronic. Similar findings were updated by this group reporting data on 39 patients receiving 68 DLI, with acute GVHD and chronic GVHD seen in 47% and 33% patients, respectively. 27 Graft-versus host disease remains a problem after DLI in myeloma. f) Non-myeloablative transplants ( mini transplants ) - Given the proven efficacy of immunoreactive donor T lymphocytes in inducing a graft-versus-myeloma effect, and to try reduce the excessively high transplant-related mortality associated with conventional allogeneic transplants, the current trend is to utilize non-myeloablative transplants ( mini-transplants ) for a number of hematologic malignancies including MM. The basis of the mini-transplant is to provide sufficient immune suppression to allow donor engraftment and subsequent graft-versus-tumor effect. 28 Preliminary data showed a high rate of complete remission, even in heavily treated patients with resistant disease. Lalancette et al reported on 50 patients with multiple myeloma undergoing nonmyeloablative transplants. 29 All patients engrafted, 20 of 27 evaluable patients achieved 95% donor engraftment: new complete response (CR) was observed in 16 patients with the relapse incidence at one year being 13%. Transplant-related mortality at one year was 32%, and the actuarial survival at one and two years was 54% and 40%, respectively. Another recently reported series by Badros et al on 16 poor-risk multiple myeloma patients who received a non-myeloablative conditioning regimen (with Melphalan 100 mg/m 2 ) followed by DLI in 14/16 patients (given either to attain full donor chimerism or to eradicate residual disease) had a 75% overall response rate with 5 sustained CRs (1 year follow-up). 30 However 10 patients developed acute GVHD with most progressing to chronic GVHD and 3 patients died of GVHD complications. Other series of patients receiving non-myeloablative transplants utilizing different conditioning regimens have been reported with the transplant-related mortality (TRM) in the range of 17-38% The transplant-related mortality is lower than that observed with conventional allogeneic transplant but remains substantially higher than autologous transplant (10-67%). However, non-myeloablative transplants are probably not sufficient in producing JAPI VOL. 53 DECEMBER 2005

4 cures in multiple myeloma. The efficacy of posttransplant maintenance therapy has not yet been established. Post-transplant immunomodulation either by anti-idiotype vaccines, DNA vaccines, or idiotype-pulsed dendritic cells is an area of intense interest. However these studies are still in the early stages and whether this type of immune enhancement will result in a clinically relevant outcome remains to be proven. g) Thalidomide - has been shown to have antimyeloma activity. Prominent vascularization of the bone marrow has been described in MM which correlates with a high plasma cell labelling index and disease activity, and independently confers a poor prognosis. 34 A phase II trial with thalidomide in 89 patients with relapsed or refractory MM showed an overall response rate of 32% with 2 patients having a complete remission. 35 Thalidomide was given at a starting daily dose of 200 mg and increased by 200mg every 2 weeks for 6 weeks up to a final dose of 800 mg/day. The most common side effects were constipation, weakness and somnolence. The Mayo clinic group recently reported a trial using the combination of thalidomide plus dexamethasone in 50 patients with newly diagnosed MM with an overall response rate of 64%. 36 h) Newer therapies - including farnesyl transferase inhibitors and amino- bisphosphonates (aimed at preventing Ras activity or processing), IL-6 signalling inhibitors, anti-il-6 monoclonal antibodies, 2-medroxyestradiol and arsenic trioxide amongst others are being investigated in Phase I/II clinical trials. Rituximab (anti-cd 20 monoclonal antibody) reportedly has activity against multiple myeloma. 37 CONCLUSION In addition, a recently reported final analysis of a prospective randomized trial showed a statistically significant improvement in event-free survival and overall survival with double auto-transplants as compared to single auto-transplants. However, no plateau is appreciated even after tandem transplant. Allogeneic transplants are associated with excessive transplant-related mortality and would be an option in a very selective younger patient population. Nonmyeloablative transplant (mini-allograft) trials have shown prompt allogeneic engraftment and in reducing transplant related mortality but longer follow-up is needed to compare survival data with other standard therapies. Donor Lymphocyte Infusion (DLI) has shown impressive response rates even in refractory/relapsed myeloma but GVHD seems to be a significant factor contributing to transplant-related mortality. An optimal treatment is yet to be developed for this otherwise incurable disease. A combination of the above mentioned treatments to develop a strategy which utilizes optimal cytoreduction (autologous transplant), immunoablation by alloreactive T lymphocytes (non-myeloablative therapy with DLI) followed by long-term maintenance with immunomodulating agents to prevent disease recurrence (thalidomide with or without corticosteroids, cytokines, vaccines) may ultimately provide the optimal control and potential cure for this challenging disease. REFERENCES 1. Soloman A, Weiss DT, Kattine AA. Nephrotoxic potential of Bence Jones proteins [see comments]. N Eng J Med 1991;324: Khamlichi AA, Rocca A, Touchard G, et al. Role of light chain variable region in myeloma with light chain deposition disease: evidence from an experimental model. Blood 1995;86: Pozzi C, Fogazzi GB, Banfi G, et al. Renal disease and patient survival in light chain deposition disease. Clin Nephrol 1995;43: Kyle RA. Monoclonal proteins and renal disease. Annu Rev Med 1994;45: Clark AD, Shetty A, Soutar R. Renal failure and multiple myeloma: pathogenesis and treatment of renal failure and management of underlying myeloma. Blood Reviews 1999;13: Sakhuja V, Jha V, Varma S, et al. Renal involvement in multiple myeloma: a 10-year study. Renal Failure 2000;22: Berenson JR, Lichtenstein A, Porter L, et al. Long-term pamidronate treatment of advanced multiple myeloma reduces skeletal events. J Clin Oncol 1998;16: Berenson JR, Hillner BE, Kyle R, et al. American Society of Clinical Oncology clinical practice guidelines: The role of bisphosphonates in multiple myeloma. J Clin Oncol 2002;20: Alexanian R, Dimopoulos MA. Management of multiple myeloma. Semin Hematol 1995;32: Tricot G, Jagannath S, Vesole D et al. Peripheral blood stem cell transplant for multiple myeloma: identification of favorable variables for rapid engraftment in 225 patients. Blood 1995;85: Govindarajan R, Jagannath S, Flick JT et al. Preceding standard therapy is the likely cause of MDS after autotransplants for multiple myeloma. Br J Haematol 1996;95: Joshua DE, Brown RD, Gibson J. Multiple myeloma: why does the disease escape from plateau phase? Br J Haematol 1994;88: Divanen TM for the Finnish leukemia group. Plateau phase in multiple myeloma: an analysis of long-term follow-up of 432 patients. Br J Haematol 1996;92: Belch A, Shelley W, Bergsagel D, et al. A randomized trial of maintenance versus maintenance melphalan and prednisone in responding multiple myeloma patients. Br J Cancer 1988;57: Westin J, Rodjer S, Turesson I, et al. IFN alpha-2b versus no maintenance treatment during the plateau phase in multiple myeloma: a randomized study. Br J Haematol 1995;89: Browman GP, Bergsagel DE, et al. Randomized trial of IFN maintenance in multiple myeloma: a study of the Canada Clinical Trials group. J Clin Oncol 1995;13: Attal M, Harousseau JL, Stoppa AM, et al. A prospective randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe JAPI VOL. 53 DECEMBER

5 Francais du Myelome. N Eng J Med 1996;335: Attal M, Harousseau JL, Facon T, et al. Double autologous transplantation improves survival of multiple myeloma patients: Final analysis of a prospective randomized study of the Intergroupe Francophone du Myelome (IFM 94). Blood 2002;100:abstract Tricot G, Vesole DH, Jagannath S et al. Graft-versus-myeloma effect: proof of principle. Blood 1996;87: Lokhorst HM, Schattenberg A, Cornelissen JJ et al. Donor lymphocyte infusions for relapsed multiple myeloma after allogeneic stem-cell transplantation: predictive factors for response and long-term outcome. J Clin Oncol 2000;18: Gahrton G, Apperley J, Bacigalupo A, et al. An overview of allogeneic stem cell transplantation in multiple myeloma. VIIIth International Myeloma Workshop, S14, May 2001, Banff, CAN. 22. Bensinger WI, Buckner CD, Anasetti C, et al. Allogeneic marrow transplantation for multiple myeloma: an analysis of risk factors on outcome. Blood 1996;88: Ballen K, King R, Carston M, Reece D, Giralt S, Vesole D, et al. Outcome of unrelated transplants in patients with multiple myeloma. Blood 2000;96:abstract 1780, 414a. 24. Mehta J, Ayers D, Mattox S, et al. Allogeneic bone marrow transplantation in multiple myeloma: single-center experience of 97 patients. Blood 1997; 90: abstract 993, 225a. 25. Huff CA, Noga SJ, Jones RJ et al. Allogeneic bone marrow transplantation: Role of T cell depletion and graft versus host disease. Blood 2000; 96: abstract 862,202a. 26. Cheung B, Ackers C, Powles R, et al. Allogeneic peripheral blood stem cell Transplantation for patients with multiple myeloma single centre experience. Blood 2000;96:abstract 5276,352b. 27. Lokhorst H. Graft versus myeloma. Clinical and basic aspects. VIIIth International Myeloma Workshop, S20, May 2001, Banff, CAN. 28. Champlin R, Khouri I, Kornblau S, et al. Reinventing bone marrow transplantation: nonmyeloablative preparative regimens and induction of graft-versus-malignancy effect. Oncology 1999;13: Lalancette M, Rezvani K, Szydlo R et al. Excellent outcome of non-myeloablative stem cell transplant (NMSCT) for good risk myeloma: the EBMT experience. Blood 2000;96: abstract Badros A, Barlogie B, Morris C, et al. High response rate in refractory and poor-risk multiple myeloma after allotransplantation using a nonmyeloablative conditioning regimen and donor lymphocyte infusions. Blood 2001;97: Peggs KS, Williams CD, Chopra R, D Sa S, et al. Nonmyeloablative allogeneic transplantation with adjuvant dose escalated donor lymphocyte infusions for multiple myeloma. Blood 2000;96:abstract 3379,781a. 32. Schaefer H, Bader P, Hebart H et al. Mini-allografts as salvage therapy in patients with heavily pretreated multiple myeloma. Blood 2000;96:abstract 5066, 306b. 33. Giralt S, Weber D, Aleman A, et al. Non-myeloablative conditioning with fludarabine/melphalan for patients with multiple myeloma. Blood 1999;94:abstract 1549, 347a. 34. Vacca A, Ribatti D, et al. Bone marrow angiogenesis and progression in multiple myeloma. Br J Haematol 1994;87: Singhal S, Mehta J, Barlogie B, et al. Anti-tumor activity of thalidomide in refractory multiple myeloma. N Engl J Med 1999;341: Rajkumar SV, Hayman S, Gertz MA, et al. Combination therapy with thalidomide plus dexamethasone for newly diagnosed myeloma. J Clin Oncol 2002;20: Hussein MA, Karam MA, McLain DA, et al. Biologic and clinical evaluation of Rituxan in the management of newly diagnosed multiple myeloma. Blood 1999;94:abstract Announcement INDO-FRENCH CME on "IV immunoglobulin (IVIG) in autoimmune and inflammatory disorders: Current situation and future prospects" on January 28, Organised by Department of Medicine, JIPMER, Pondicherry. Eminent research scientists and clinicians from France and India will speak about their experience, current guidelines and future prospects for clinical usage of IVIG. The CME will benefit practicing physicians, pediatricians, neurologists, nephrologists, hematologists, rheumatologists, immunologists, critical care specialists and their postgraduate students. For further details contact : Prof RP Swaminathan / Dr VS Negi; Department of Medicine, JIPMER, Pondicherry - 6. Phone : / ivigcme@jipmer.edu. Registration form and other details can be downloaded from our institute website JAPI VOL. 53 DECEMBER 2005