Treatment of multiple myeloma

Joint Bone Spine 70 (2003) 175–186 www.elsevier.com/locate/bonsoi

Review

Treatment of multiple myeloma Didier Clerc a,*, Jean-Paul Fermand b, Xavier Mariette a a

Rheumatology department, Hôpital de Bicêtre, Le Kremlin-Bicêtre, France b Hematology department, Hôpital Saint-Louis, Paris, France Received 3 June 2002; accepted 17 October 2002

Abstract Conventional chemotherapies are no longer the only treatment in multiple myelomatosis. High-dose chemotherapy and autologous transplantation are not curative but do increase relapse-free survival time in young patients. Thalidomide is efficacious in refractory and relapsing myeloma and its evaluation is going on. Curative and preventive treatments of skeletal events, infections and anemia improve quality of life. All together, these strategies imply therapeutic knowledge and choices but allow an about 5-year-long median survival time in modern studies. Treatment options for myeloma now include, not only conventional chemotherapy regimens, but also novel symptomatic drugs and strategies that increase survival and/or quality of life, although they fail to provide a cure. In parallel with this expansion of the treatment armamentarium, physicians must acquire the knowledge needed to select the best treatment for the individual patient. After reviewing the rationale, effectiveness, and safety of each of these treatments, we will discuss the indications that we believe are legitimate. © 2003 Éditions scientifiques et médicales Elsevier SAS. All rights reserved. Keywords: Myeloma; Chemotherapy; Bisphosphonates

1. Background We will start by briefly reviewing the classification, course, and prognosis of myeloma. 1.1. Classification The Durie and Salmon classification scheme (Table 1) distinguishes three stages based on estimated tumor burden, with two subclasses per stage, A and B, based on serum creatinine levels. Although most myeloma patients present with symptoms related to bone, bone marrow, or renal involvement, an increasing number of cases are being diagnosed upon evaluation of a laboratory test abnormality discovered fortuitously. These asymptomatic forms [1] are usually, stage 1 in the Durie-Salmon scheme. They may contribute about 15–20% of myeloma cases. “Indolent myeloma” [2] and “smoldering myeloma” [3] are terms used to designate asymptomatic disease. * Corresponding author. E-mail address: [email protected] (D. Clerc). © 2003 Éditions scientifiques et médicales Elsevier SAS. All rights reserved. DOI: 10.1016/S1297-319X(03)00018-6

Table 1 Classification scheme developed by Durie and Salmon (from Ref. [21]) Stage I

Criteria Myeloma with low tumor burden All of the following: • Hemoglobin > 10 g/dl • Serum calcium < 120 mg/l(3 mmol/l) • Normal bone X-ray or solitary lesion • Low monoclonal component production Serum IgG < 50 g/l Serum IgA < 30 g/l Urine light chain <4 g/24 h II Myeloma with intermediate tumor burden Myeloma that fits neither I nor III III Myeloma with high tumor burden One or more of the following: • Hemoglobin < 8.5 g/dl • Serum calcium > 120 mg/l (3 mmol/l) • Advanced lytic bone lesions • High monoclonal component production Serum IgG > 70 g/l Serum IgA >50 g/l Urine light chain>12 g/24 h Sub-classification based on renal function A Serum creatinine < 20 mg/l B Serum creatinine > 20 mg/l

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Table 2 Response criteria (from Ref. [21]) Complete remission Undetectable levels of serum and urinary monoclonal component (immunofixation, urine concentration) Less than 5% marrow plasmacytosis, with no dystrophic plasma cells Partial remission Greater than 50% drop in serum monoclonal component levels Greater than 75% drug in urinary light chain levels No new osteolytic lesions, and normal serum calcium At least partial relief from bone pain and anemia Minimal partial 25–50% decrease in serum monoclonal component remission levels 50–75% decrease in urinary light chain levels No new osteolytic lesions, and normal serum calcium At least partial relief from bone pain and anemia Failure Smaller than 25% change in serum monoclonal component levels 50% or smaller change in urinary light chain levels No change in the other parameters Progression One or more of the following: • Greater than 25% rise in serum monoclonal component • Greater than 50% increase in urinary light chain levels • Development of one or more osteolytic lesions • Progression of the anemia, development of hypercalcemia • Development of extra-skeletal malignant lesions

1.2. Course The treatment response [4] is defined on the basis of serum or urinary levels of monoclonal component (Table 2). Chemotherapy is stopped when a partial or complete remission is obtained and the monoclonal component level then remains stable, i.e., within 20% of the lowest post treatment value, for at least 6 months: this is the plateau phase. All patients eventually go on to have a relapse. In patients with no response after 3-6 months of specific treatment (primary refractory myeloma) and in those with disease progression (relapsing myeloma), the treatment regimen should be changed.

In this consistently fatal disease, the main criteria for evaluating treatment effectiveness are overall and diseasefree survival and quality of life. 1.3. Prognosis Numerous pretreatment factors predictive of survival have been identified including age, Durie and Salmon stage, estimated tumor burden irrespective of malignant cell kinetics, b2-microglobulinemia (which reflects both tumor burden and renal function), plasma cell labeling index (which is independent from tumor burden), C-reactive protein levels (which mirror IL-6 production and correlate with the labeling index), and serum albumin. Other factors are renal failure, type and level of monoclonal component, severityof anemia, presence of hypercalcemia, bone marrow plasma cell counts, morphology and phenotype of malignant plasma cells, and cytogenetic features. Along these last, deletion of chromosome 13 has been shown recently to confer a poor prognosis [5]. This deletion can be looked for routinely in the marrow using conventional cytogenetics or the more effective fluorescence in situ hybridization (FISH) method. Cell kinetics can be evaluated by studying the S phase of the malignant plasma cells by flow cytometry, which can also be used to determine DNA ploidy [6]. Several classification schemes [7–10] use various combinations of age, serum b2-microglobulin, C-reactive protein, albumin, and chromosome 13 abnormalities to identify patient subsets with different prognoses (Table 3). After treatment, the response to chemotherapy and achievement of a complete remission are major predictors of survival. Evaluation of the risk of disease progression in patients with asymptomatic myeloma (Table 4) relies on the hemoglobin level, monoclonal component, and presence of structural bone abnormalities [11]. Several studies [12–14] emphasize the adverse prognostic significance of abnormal findings from magnetic resonance imaging (MRI) of the thoracic and lumbar spine.

Table 3 Prognostic classification based on serum b2-microglobulin (b2m) and albumin [7]; CRP and b2m [8]; b2m, serum albumin, and age [9]; and chromosome 13 abnormalities and b2m [10] Criteria

Prognostic classification and median survival Low risk Intermediate risk Criteria Survival (months) Criteria b2m > 6 mg/l, serum b2m, serum albumin b2m < 6 mg/l, serum 55 albumin > 30 g/l albumin > 30 g/l b2m and CRP 54 b2m or CRP b2m CRP < 6 mg/l > 6 mg/l Does not fit either of b2m, serum albumin, b2m < 6 mg/l, serum >48 age albumin > 30 g/l, the other two sets of age < 60 years criteria >111 Abnormal Normal Abnormal, chromosome 13 or chromosome 13, 2m chromosome 13, b2m >2.5 mg/l b2m < 2.5 mg/l

Survival (months) 28.5 27 28.5

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High-risk Criteria Serum albumin < 30 g/l b2m and CRP > 6 mg/l b2m > 6 mg/l, serum albumin < 30 g/l, age > 60 years Abnormal chromosome 13, b2m > 2.5 mg/l

Survival (months) 4 4 12.7

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D. Clerc et al. / Joint Bone Spine 70 (2003) 175–186 Table 4 Risk of disease progression in untreated patients with asymptomatic myeloma [11] Risk Low risk

Intermediate risk

High-risk

Criteria All of the following: • Normal skeletal X-rays and MRI • IgG, IgA < 30 g/l • Urinary light chains <0.05 g/24 h • Hemoglobin > 10.5 g/dl • Normal skeletal X-rays and MRI • IgG, IgA > 30 g/l and/or urinary light chains >0.05 g/24 h One or more of the following: • osteolytic X-ray lesion(s) and/or abnormal MRI • IgG, IgA > 30 g/l and urinary light chains >0.05 g/24 h

2. Conventional treatments 2.1. Conventional chemotherapy 2.1.1. Single-drug induction chemotherapy The alkylating agents melphalan and cyclophosphamide are the mainstay of induction therapy. Duration of survival is comparable with these two drugs [15,16], regardless of the route of administration (oral or IV 600 mg/m2 every 3 weeks) of cyclophosphamide. Cross-resistance is the rule, although there have been a few reports suggesting effectiveness of cyclophosphamide after failure of melphalan [17]. Nitrosoureas, carmustine (BCNU), and belustine (CCNU) offer similar effectiveness but are more toxic and, consequently, are not appropriate for single-drug chemotherapy. Whether adding a glucocorticoid to the chemotherapy regimen improves survival remains unclear. An uncontrolled study by Alexanian et al. [18] compared intermittent oral melphalan, continuous oral melphalan, and intermittent oral melphalan plus prednisolone 1 mg/kg/d on alternate days or

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2 mg/kg/d for 4 d every 6 weeks. Adding prednisolone increased the response rate to 61%, as compared to 32% and 17% with intermittent and continuous melphalan, respectively, and increased median survival to 24 months as compared to 17–18 months without prednisolone. However, controlled studies [19,20] found no evidence that adding a glucocorticoid to the alkylating agent significantly increased survival. Despite these uncertainties, combined melphalan and prednisolone therapy is the induction chemotherapy regimen of reference in patients older than 65 years of age (Table 5). Treatment modalities and dosage are dependent on the renal excretion and highly variable digestive absorption of alkylating agents, their side effect and effectiveness profiles, and patient age. Melphalan should be taken on an empty stomach, and the dosage should be reduced by one-third in patients older than 70 years of age and in those with renal failure. A 25% dosage reduction is in order if marked bone marrow depression is noted on D14 (leukocytes < 1000/mm3 and platelets < 50 000/mm3). The course should be postponed for 1 week if the leukocyte count is < 3000/mm3 and/or the platelet count is ≤ 100 000/mm3. If this situation occurs repeatedly, the dosage should be decreased. On the contrary, in patients who remain free of side effects but have no treatment response, the dosage should be increased by 25%. The duration of induction therapy depends on the time needed to reach the plateau phase but is usually 12–18 months. The remission rate is about 40–60%, but only about 5% of patients achieve a complete remission. Duration of the plateau phase is about 2 years and survival about 3 years. 2.1.2. Combination induction chemotherapy Combination induction chemotherapy consists in combined or alternating use of a glucocorticoid, melphalan (M) and/or cyclophosphamide (C), vincristine (V), and a ni-

Table 5 Main conventional chemotherapy regimens. With all these regimens, the treatment is given at 28-d intervals MP Melphalan Prednisone VMCP Vincristine a Melphalan Cyclophosphamide Prednisone VAD Vincristine Doxorubicin Dexamethasone VAMP Vincristine Doxorubicin Methylprednisolone a

Route

Dosages

Days

Per os

9 mg/m2/d 60 mg/m2/d

D1 through D4 D1 through D4

IV Per os IV Per os

1.4 mg/m2 b 6 mg/m2/d 600 mg/m2 80 mg/m2/d

D1 D1 through D4 D1 D1 through D4

Continuous IV Continuous IV Per os

0.4 mg/24 h 9 mg/m2/24 h 40 mg/d

D1 through D4 D1 through D4 D1 through D4, D9 through D12, D17 through D20

Continuous IV Continuous IV IV

0.4 mg/24 h 9 mg/m2/24 h 400 mg/d

D1 through D4 D1 through D4 D1 through D4

Most patients receive thalidomide at some time during the course of their disease; consequently, vincristine is best avoided as primary treatment, since vincristine may exacerbate the neurological toxicity of subsequent thalidomide therapy. b No more than 2 mg per IV injection.

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trosourea (CCNU or BCNU) or the anthracycline doxorubicin, better known as adriamycin (A). The most widely used combinations are VMCP (Table 5), VBMCP (B = BCNU) or M2, and VBAP or ABCM. Vincristine is probably best avoided because its neurotoxicity may add to that of thalidomide, a drug now often used later in the course of the disease. Combinations of vincristine, adriamycin, and dexamethasone or methylprednisolone raise specific problems that are discussed further on. Combination induction chemotherapy has generated considerable interest and controversy. Only seven trials found a significant increase (of about 20%) in remission rates with combination therapy; the response time was usuallyshorter. However, with the exception of one trial [24], survival was comparable, a finding confirmed by a recent metaanalysis [25]. Combination induction therapy is indicated in patients who require rapid cytoreduction. Otherwise, the choice between single-drug and combination chemotherapy depends on the setting, the patient, and the physician. Single-drug therapy is given orally, which is convenient, but the intravenous injections that are necessary with combination chemotherapy may be associated with better compliance and monitoring. Furthermore, a venous port is needed also for bisphosphonate therapy (see below). 2.1.3. VAD and VAMP regimens VAD [26] combines adriamycin and vincristine injected intravenously by an electric pump from D1 through D4 and oral dexamethasone (Table 5). Gastrointestinal toxicity and infections are common with this regimen. Consequently, variants have been suggested, such as VAMP, in which methylprednisolone is substituted for dexamethasone (400 mg/d IV from D1 through D4). When used for induction therapy [27], this regimen provides a 15–20% increase in the response rate, with a large proportion of complete responses, but fails to improve response duration or survival. The response time is shorter, a valuable advantage in patients who require prompt cytoreduction because of renal failure (another advantage here being the extrarenal excretion of the drugs), severe hypercalcemia, neurological compression, or planned transplantation in a young patient. Apart from these situations, and despite the limited bone marrow toxicity, this regimen has no advantages over conventional chemotherapy for induction treatment, and the use of adriamycin carries a risk of cardiac toxicity. VAD and VAMP are useful in patients with myeloma refractory to induction therapy or with a relapse within 6 months of discontinuation of induction chemotherapy [28,29]. The mean response rate in this situation is about 50%, with variations across studies, criteria, and clinical settings (from 30% to 70%). Response rates are higher in patients with relapsing myeloma (50–75%) than in those with primary refractory myeloma (30–50%). In this last situation, dexamethasone alone provides a similar response

rate of about 40% [28]. In responders, survival is increased by about 1 year. 2.1.4. Other rescue chemotherapy regimens Two etoposide-based regimens [30,31] have been found effective in myeloma refractory to VAD: etoposidedexamethasone-cytarabine-cisplatin and, above all, cyclophosphamide (3 g/m2)-etoposide (900 mg/m2) combined with growth factor treatment. Response rates of up to 30% have been obtained with cyclophosphamide-etoposide, although the median duration of remission did not exceed 6 months. High-dose melphalan [32–34] (single intravenous injection of 100–140 mg/m2) produces an 80% response rate with 20–30% of complete responses, a median survival of 47 months, and a 9-year survival rate of about 35%. Given the major bone marrow toxicity and high early mortality rate (10–20%), this regimen cannot be used without stem cell support. 2.2. High-dose glucocorticoid therapy As mentioned above, dexamethasone is being increasingly used in combination with chemotherapy regimens. In an open trial [35] of previously untreated myeloma, the objective response rate with dexamethasone alone was 51% in patients with a low tumor burden and 37% in those with an intermediate or high tumor burden. This treatment may be particularly useful in very elderly patients, in patients with myeloma-related pancytopenia, and in patients requiring early localized radiation therapy. However, these impressive response rates should be interpreted with caution because dexamethasone decreases the half-life of immunoglobulins. Furthermore, a trial conducted by the French Myeloma Task Force [36] in myeloma patients aged 65–75 years showed that overall and disease-free survival times were significantly shorter in the group given dexamethasone only than in the groups given melphalan and dexamethasone or prednisone. As underlined above, dexamethasone alone and VAD produce similar response rates in patients with primary refractory myeloma. In a study by Alexanian et al. [37], the response rate with dexamethasone alone was 25% (20 mg/m2every morning from D1 through D4, from D9 through D12, and from D17 through D21, then repetition of the cycle after a 14-d rest period). The complication rate was substantially lower (4%) than with VAD, and median survival was 4–14 months. Lower dosages can be used (e.g., 40 mg for 4 d at 28-d intervals). Combined use of dexamethasone and interferon a (IFNa) or thalidomide are discussed below. 2.3. Interferon ␣ The results of trials with IFNa have discouraged the use of this drug as single-drug induction therapy, in combination with one or more conventional induction chemotherapy agents, or as treatment for primary refractory myeloma or relapsing myeloma [38,39]. Adding IFNa to dexamethasone

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does not improve outcomes in previously untreated myeloma [40], and the now old results in refractory myeloma [41–44] require confirmation. The main issue is the place of IFNa therapy as maintenance therapy during the plateau phase. Mandelli et al. [44] found an increase in overall survival in patients given IFNa, but this difference was neither maintained over time nor replicated by others. Other studies [45,46] found a significant increase in duration of the plateau phase, and a recent metaanalysis [47] showed a small but statistically significant increase (4%) in 3-year survival. However, the overall effect remains modest compared to the high cost, adverse effects, and constraints related to IFNa therapy. 3. New anti-tumor treatments Although large strides have been made toward unraveling the pathogenesis of myeloma [48], apart from improvements in symptomatic treatments, the most notable advances in the treatment of myeloma result from the introduction of highdose chemotherapy and thalidomide. 3.1. High-dose chemotherapy with stem cell support Melphalan as a single high-dose injection (140 mg/m2) has been shown to provide very high response rates, indicating a dose-response effect in myeloma [49]. To reduce the duration and complications of the profound myelosuppression associated with this treatment, which causes earlydeath in 10-20% of patients, hematopoietic stem cell support should be used. In addition, this approach allows total body irradiation [50]. The development over the last 15 years of high-dose chemotherapy combined with stem cell support has radically changed the treatment of myeloma in younger patients. As compared to autologous stem cell support, use of allogeneic cells offers the theoretical advantage of a graft vs. myeloma response [51]. However, because side effects are common and severe with allogeneic transplantation, this approach should be reserved to younger patients (< 50 years) with an HLA-identical family member. Even then, the high rate of septic and nonseptic complications associated with graft vs. host disease results in a mortality rate of 30–50% [52]. Autologous stem cell support is used far more widely. The mortality rate is less than 2%. Peripheral blood stem cells are now preferred over marrow cells [50]. Numerous phase II studies suggest that high-dose chemotherapy followed by stem cell support may be more effective than conventional chemotherapy [53–55]. However, this has been confirmed by only one randomized trial, which was conducted in 200 patients younger than 65 years of age, with newly diagnosed myeloma [56]. In the intention-to-treat analysis, patients randomized to high-dose chemotherapy and stem cell support had better outcomes: estimated 5-year survival was 52% vs. 12% (P = 0.03), and 5-year relapse-free survival was 28%

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vs. 10%, P = 0.01). In another randomized trial, primary high-dose chemotherapy provided similar survival to conventional chemotherapy followed by rescue high-dose chemotherapy: in both arms, median survival was longer than 5 years, but time without symptoms, treatment, and treatment toxicity (TWiSTT) was significantly longer with primary high-dose chemotherapy [57]. The age cutoff above which the risks of high-dose chemotherapy may outweigh the benefits remains controversial. Most groups reserve high-dose chemotherapy for patients younger than 65 years. Furthermore, in older patients, less intensive variants of high-dose chemotherapy regimens are often used [58]. In a randomized study [59] comparing conventional chemotherapy and highdose chemotherapy (without irradiation) in patients aged 55–66 years, both relapse-free survival and TWiSTT were longer with high-dose chemotherapy. However, overall survival in the patients given high-dose chemotherapy was as expected (median, 55 months) and was not longer than in the conventional treatment arm (51 months). In the conventional arm, median survival was longer than in earlier studies, probably as a result of advances in symptomatic treatments, including widespread use of bisphosphonates. Although the ability of high-dose therapy with stem cell support to increase survival remains in doubt, this treatment is now recommended to the overwhelming majority of patients younger than 65 years of age who have newly diagnosed myeloma. The reference conditioning regimen is melphalan in a dose of 200 mg/m2. Adding low-dose total body irradiation (8 grays) has more disadvantages than benefits [60]. Repeated high-dose chemotherapy does not seem to confer substantial benefits. Purging the stem cell harvests may have negative effects [61]: thus, CD34 selection eliminates not only contaminating tumor cells but also T cells, increasing the time to hematological reconstitution and the risk of infection. None of the treatments used to date, including multiple cycles of high-dose chemotherapy (total therapy), have proved capable of providing a cure. Clearly, other treatment modalities need to be developed. Immunological treatments are sparking considerable interest. Active immunotherapy designed to elicit an immune response against the tumor to destroy residual foci after high-dose chemotherapy and stem cell support seems the most promising approach to date. Furthermore, use of pretransplantation immunosuppressive nonmyeloablative treatments to optimize immunological anti-tumor responses in allogeneic transplant recipients is being extensively studied. 3.2. Thalidomide Another approach consists in identifying new compounds with direct or indirect effects on myeloma cells. The fortuitous discovery that thalidomide has anti-tumor effects in myeloma is a major advance [63]. Folkman, a pioneer in the field of tumor neoangiogenesis, hypothesized that the teratogenic properties of thalidomide so tragically revealed by an epidemic of birth defects in the

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late 1950s might result from inhibition of blood vessel development. In several experimental systems, thalidomide showed anti-angiogenic effects [63]. Thalidomide if one of the first anti-angiogenic drugs to be identified. The antitumor effects of thalidomide are being studied in various cancers. The first trial of thalidomide in myeloma, reported by Barlogie et al. [64], included 169 patients with progressive disease despite at least one prior treatment course. Twothirds of patients had received one or two high-dose treatments followed by autologous stem cell support [65]. Thalidomide given alone in a starting dose of 200 mg/d increased by 2-week steps to 800 mg/d (based on tolerance) provided an objective response (at least 25% decrease in the monoclonal immunoglobulin (MIg) level) in 36% of patients. The percentage of excellent responses (≥ 75% fall in MIg) was 20% and a very small number of patients (2%) apparently achieved a complete remission. These responses were often accompanied with a substantial reduction in bone marrow infiltration and attendant cytopenia, sometimes with an increase in levels of normal immunoglobulins, and usually with a marked improvement in clinical status. Most responses occurred within the first treatment month. Duration of the remissions was fairly short (median, 6 months) but reached about 20 months in about one in four or five patients. These results are clearlysuperior over those obtained with other drugs used as single-drug therapy under similar conditions. They have been confirmed by other studies done in the US and in Europe [66–68]. The body of available data militates in favor of a dose-response effect, but there is some evidence that thalidomide may be helpful, even in low dosages (including 50 mg/d). This is important because dosages above 600, or even 400 mg/d, usually produce side effects that preclude long-term use. Clinical data on thalidomide in combination with chemotherapy are promising, albeit preliminary. Thalidomide and high-dose sequential glucocorticoid therapy (e.g., dexamethasone 20–40 mg/d for four consecutive days once or twice a month) seem to have synergistic effects, since responses have been obtained in about 50% of patients who had a history of resistance to dexamethasone and subsequently failed to respond to thalidomide alone [69]. Thalidomide is being evaluated in earlier-stage myeloma, either at diagnosis to increase the rate of very good responses to conventional or high-dose chemotherapy or as maintenance or consolidation therapy to increase the duration of remission. However, early and prolonged thalidomide therapy may be poorly tolerated. The many side effects of thalidomide [70] include peripheral nervous system toxicity proportional to the treatment duration and dosage. In addition, particularly when used in combination with chemotherapy and/or glucocorticoid therapy, thalidomide may be associated with a high risk of thromboembolic events. Although thalidomide was initially used in myeloma because of its anti-angiogenic properties, its immunomodulating and anti-inflammatory effects may be useful also [62].

Efforts to develop more potent and potentially less toxic analogs have produced two groups of compounds. Selective cytokine inhibitory drugs (SelCIDs) inhibit the effects of cytokines, particularly TNFa, whereas immunomodulatory drugs (ImiDs) selectively activate Th1 cells. Studies comparing the effects of thalidomide and its analogs on cultured myeloma cells suggest that ImiDs may be more effective than thalidomide and SelCIDs [71]. Clinical studies have started with some of these agents in the US, opening up the possibility that a new class of drugs with activity in myeloma will be available in the near future.

4. Symptomatic treatments 4.1. Anemia Anemia is present at diagnosis in 60–70% of patients and results from multiple and often intertwined factors including bone marrow invasion by the malignant cells, treatmentrelated bone marrow suppression, renal failure, hemodilution, a relative erythropoietin deficiency, or more rarely hemolysis. Severe anemia (< 7–8 g Hb/dl) and/or symptomatic anemia require red blood cell transfusions. Although effective treatment of the myeloma is usually followed by a return of hemoglobin levels toward normal values, persistent anemia and/or a need for repeated transfusions may require erythropoietin therapy. On average, subcutaneous erythropoietin in a dosage of 150–300 U/kg two to three times a week increases the hemoglobin level by 2 g/dl or more within 4 weeks in 50–60% of patients [72–74]. In responders, dosage reduction to 100 U/kg twice a week maintains the initial gain in quality of life. 4.2. Infection Infection is the leading cause of death in myeloma patients. Both the disease itself and the drugs used to treat it contribute to the occurrence of infections. The risk is highest during the first 3 months of chemotherapy and during relapses. Most infections in myeloma patients are bacterial. Earlydiagnosis and treatment are imperative. Febrile neutropenia requires prompt evaluation to look for a cause. Treatment with probabilistic broad-spectrum non-nephrotoxic antibiotics should be started immediately. Routine prophylactic antibiotic therapy has been found effective [75] but is rarely used. Immunization against pneumococcal infections and influenza is of uncertain effectiveness in myeloma patients and is not usually performed. Polyvalent immunoglobulins showed efficacy in a randomized trial [76] but this study was conducted in patients at the plateau phase, whereas the risk of infection is highest during the active phases of the disease. 4.3. Renal failure Tubulointerstitial nephropathy related to light chain deposition is the main cause of renal failure in myeloma patients.

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Amyloidosis and Randall disease are far less common. The many factors that can precipitate or worsen renal failure should be looked for and prevented: they include dehydration, hypercalcemia, non-steroidal anti-inflammatory drug use, iodine injection, urinary tract infection, and hyperuricemia. The treatment rests on rehydration, alkalinization of urine, and, if the renal dysfunction is severe, hemodialysis. In patients whose creatinine levels remain high despite a response to anticancer therapy, hemodialysis should be continued. Melphalan is difficult to use in patients with severe renal failure. Either a combination of cyclophosphamide and highdose glucocorticoid therapy or a VAD or VAMP type regimen can be given instead. Stem cell transplantation is usually considered inappropriate in patients whose creatinine levels are greater than 300 µmol/l. 4.4. Consequences of malignant osteolysis Malignant osteolysis can cause pain, peripheral or spinal fractures, and hypercalcemia, and can contribute to neurological compromise. 4.4.1. Pain Pain should be treated as recommended by the World Health Organization. Many patients require opioids. In responders, chemotherapy is the most effective means of relieving pain. Radiation therapy is appropriate in patients with a painful myeloma focus despite chemotherapy. Short-course radiation therapy provides faster pain relief and causes less delay in administration of chemotherapy. Glucocorticoid therapy in a dosage of about 1-2 mg/kg/d is usually given simultaneously, particularly when the irradiated lesion is in the spine. Repeated courses of radiation therapy in areas of active hematopoiesis eventually increase the risk of hematological side effects from chemotherapy, particularly in older patients. Irradiation of one half of the body to ensure pain relief is exceptionally used. Bracing can contribute to alleviate the pain caused by vertebral fractures. More recently vertebroplasty has been used, generally in combination with radiation therapy. 4.4.2. Fractures Peripheral fractures usually require surgery. Most patients also receive radiation therapy. Surgeryand/or radiation therapy should be considered to prevent fracturing in areas rendered vulnerable by severe osteolytic lesions. 4.4.3. Hypercalcemia Hypercalcemia requires rehydration with isotonic saline and administration of antiosteoclastic agents. The classic combination of calcitonin and glucocorticoid therapy has been superseded by bisphosphonate therapy. Four bisphosphonates have been approved for use in this indication: clo-

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dronate, pamidronate, ibandronate [77], and zoledronate [78]. As compared to pamidronate, zoledronate can be administered in a shorter period of time (15 min) and is associated with higher rates of serum calcium normalization and a longer time with normal calcium levels [78]. Failure of bisphosphonate treatment is uncommon and requires forced diuresis by furosemide, usually in an intensive care unit. 4.4.4. Bisphosphonates: adjuvant treatment in malignant osteolysis Most studies of bisphosphonates in myeloma used etidronate, clodronate, pamidronate, or zoledronate. Etidronate was not found effective. 4.4.4.1. Clodronate. Several studies found that potential (IM or IV) clodronate was effective [79–81], at least on some parameters. However, the most promising results were obtained with the oral route. The first controlled trial, done by Delmas et al. [82], produced encouraging results but included only 13 patients. In a Finnish study, 350 patients undergoing primary melphalan-prednisone therapy for myeloma were randomized to clodronate (2400 mg/d orally) or a placebo. Follow-up was 24 months. The clodronate group had fewer patients with progression of osteolytic lesions (P = 0.026) and more patients with complete pain relief (P < 0.01). However, there were no significant effects on pain severity, analgesic use, the incidence of new vertebral and extra vertebral fractures, the percentage of patients with a corrected serum calcium level greater than 2.65 mmol/l, or survival [83]. A more recent German study [84] in 157 patients used a lower dosage of clodronate (1.6 g/jour) for a shorter period of time (1 year). No evidence of a bone response was found, but pain improved and analgesic use decreased. The best designed trial [85] was part of the VIth MRC multiple myeloma trial. A randomized double-blind placebocontrolled design was used to evaluate the efficacy of oral clodronate therapy (1600 mg/d) in 536 patients with untreated myeloma. Clodronate given continuously throughout all the phases of the disease was associated with lower incidences of hypercalcemia (5.1% vs. 10.1%, P = 0.06), extra vertebral fractures (6.8% vs. 13.2%, P = 0.04), and vertebral fractures (38% vs. 55%, P = 0.01) during the study period (median survival, 2.8 years in each group). After 2 years, significant decreases were found in the percentages of patients with spinal pain (P < 0.01) or a decline in general health (P < 0.25). Data obtained in this population after a median follow-up of 8.6 years were published in 2001 [86]: they confirm the earlier data but show no difference in survival between the clodronate group and the placebo group. However, surprisingly, the a posteriori analysis showed a statistically significant increase in survival in the subset of patients who were free of fractures at study inclusion (median survival, 59 vs. 37 months; 5-year survival, 46% vs. 35%) in the clodronate group.

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4.4.4.2. Pamidronate. The Myeloma Aredia Study Group [87] is a multicenter randomized placebo-controlled trial in 392 patients with myeloma and at least one osteolytic lesion. The patients were assigned at random to a placebo or to pamidronate 90 mg intravenously every 4 weeks for nine cycles. The patients were stratified according to whether they received first-line (stratum 1) or second-line (stratum 2) chemotherapy. Addition of pamidronate was associated with a significant reduction in the percentage of patients with one or more new skeletal events (24% vs. 41%, P < 0.001). The difference remained significant when the two strata were analyzed separately and was more marked in stratum 2 patients, suggesting that pamidronate may remain useful when chemotherapy becomes less effective. Other parameters that showed statistically significant differences in favor of pamidronate included time to development of a new skeletal event and to a need for radiation therapy, proportions of patients with new fractures or hypercalcemia, and differences between final and baseline analgesic use and ECOG performance scores. However, pamidronate was not associated with improvements in radiological osteolytic lesions. Further data were obtained after 21 cycles [88]. The beneficial effects of pamidronate therapy persisted, but the reduction in the number of fractures was not greater than at the 9-month time point; however, after 21 cycles, survival in stratum 2 patients was significantly longer with pamidronate (21 months vs. 14 months, P = 0.041). No statistically significant differences in survival were found in stratum 1 or in the overall study population. Despite promising preliminary results [89], oral pamidronate has not been found effective in improving the bone lesions associated with myeloma [90]. 4.4.4.3. Zoledronate. As compared to pamidronate, the new generation heterocyclic bisphosphonate zoledronate is a far more potent inhibitor of bone resorption, both in vitro and in several animal models. In myeloma patients, the two drugs have shown similar overall efficacy and safety [90–92]. Zoledronate can be administered in only 15 min, as compared to 2 h for pamidronate. Zoledronate was compared to pamidronate in a prospective randomized double-blind trial [93] in 1643 patients with bone metastases from breast cancer (n = 1130) or stage III myeloma (n = 513). Zoledronate was given in a dosage of 4 mg intravenously and pamidronate in a dosage of 90 mg intravenously every 3–4 weeks. The primary evaluation criterion was occurrence during the 13-month study of at least one skeletal event (pathological fracture, neurological compression, or treatment of a bone lesion by radiation or surgery). Similar proportions of myeloma patients met this criterion in the two treatment groups (47% with zoledronate and 49% with pamidronate). In the overall study population, the two groups showed no statistically significant differences for most of the secondary evaluation criteria: percentages of patients with each skeletal event or hypercalcemia, time to

occurrence of these events, skeletal morbidity rate, pain severity, analgesic use, ECOG performance status, and median survival (not achieved with zoledronate, 802 d with pamidronate). However, zoledronate patients were significantly less likely to require radiation treatment for bone lesions (15% vs. 20% of patients, P = 0.031; 0.47 vs. 0.71 events/year: P = 0.018). 4.5. The RANK-RANK-L system The ligand for the receptor that activates the nuclear factor of kappaB (RANK-L) is expressed at the surface of myeloma cells and/or bone marrow stromal cells, and the corresponding receptor (RANK) is expressed at the surface of osteoclasts. The interaction between RANK and RANK-L leads to osteoclast differentiation and activation. Animal studies [5] have been conducted to look for compounds capable of halting osteoclastogenesis by inhibiting the RANK/RANK-L system. Phase I trials are ongoing with two such compounds, osteoprotegerin [94], a naturally occurring soluble factor that binds RANK-L, and antibody to RANK-L. Preliminary results [94] show a larger decrease in bone resorption markers with osteoprotegerin (3 mg/kg/d) than with pamidronate (90 mg). 5. Therapeutic indications The increasing number of available treatments is making treatment decisions more difficult. With the sole exception of allogeneic transplantation, none of the available chemotherapy regimens, not even high-dose chemotherapy with autologous transplantation, can cure myeloma. However, these regimens increase the duration of survival and the quality of life. Treatment selection rests in large part on quality-of-life considerations. In the future, new treatments or treatment combinations will probably provide hope for a definitive cure. The first step is to find ways of achieving complete remission. We will discuss therapeutic indications by attempting to answer the questions most often raised in clinical practice. 6. Is treatment appropriate in patients with asymptomatic stage I or II myeloma? In patients with at least one radiographic bone lesion, the median time to disease progression is 1 year. Consequently, there is general agreement that treatment should be started promptly in this situation. When there are no radiographic bone lesions, however, median time to progression varies widely and can exceed 5 years. MRI is the best predictive tool. However, there is no evidence that early treatment is beneficial in patients with MRI lesions not visible by plain radiography. Thus, watchful waiting is appropriate in this situation, with more closely spaced evaluations in patients with MRI abnormalities. A study evaluating bisphosphonate therapy in these patients would be useful.

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7. Primary chemotherapy in patients with symptomatic myeloma 7.1. Conventional chemotherapy or intensive chemotherapy with autologous stem cell support? This issue is a focus of heated debate in which opinions are often expressed with more confidence that compelling data would indicate. Autologous stem cell support is associated with a higher rate of remission, including apparently complete remission, as compared to conventional chemotherapy. Hematologists, based on their culture and on their experience with leukemias and lymphomas, consider that complete remission should be the main goal of treatment, as a prerequisite to achieving a cure. In myeloma patients, however, even complete remissions are consistently followed by relapses. As mentioned above, a single study showed better survival with autologous stem cell support than with conventional chemotherapy. Two other studies are ongoing. With the MAG91 regimen [59], autologous stem cell support was not superior over conventional chemotherapy in patients aged 55–65 years. In patients 55 years of age or younger, survival was similar with autologous stem cell transplantation done early or only at the first relapse (MAG90 regimen). In both studies, relapse-free survival was longer with autologous stem cell transplantation. 7.2. What is the best strategy in everyday practice? In patients younger than 60 years of age, high-dose chemotherapy with autologous stem cell support should be offered either as the primary treatment or at the first relapse. At present, the simplest strategy is VAD (three to four cycles) to reduce the tumor burden followed by stem cell harvesting after mobilization by cyclophosphamide. High-dose chemotherapy is usually started immediately after this procedure. However, some patients choose to start with conventional chemotherapy, reserving high-dose chemotherapy for their first relapse. In patients older than 65 years of age, the toxicity of autologous stem cell support seems unacceptable as compared to expected benefits. In patients aged 60–65 years, the choice between conventional and high-dose chemotherapy rests mainly on the patient’s wishes and physiological age. 7.3. Which chemotherapy regimen is best for the primary treatment of patients older than 65 years? No combination chemotherapy regimens have been found more effective than the melphalan-prednisone combination (melphalan, 10 mg/m2 from D1 through D4; prednisone, 1-2 mg/kg from D1 through D4), which remains the treatment of reference. We often use the melphalan-cyclophosphamideprednisone combination in the following dosages: melphalan, 6 mg/m2 from D1 through D4; cyclophosphamide,

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600 mg/m2 IV on D1; and prednisone, 2 mg/kg/d from D1 through D4. This combination provides a faster response than melphalan alone and allows reevaluation of the patient every 4 weeks at the time of the brief intravenous cyclophosphamide infusion, which can, if appropriate, be combined with an intravenous bisphosphonate infusion. 7.4. What is the best high-dose treatment regimen? Does total body irradiation still have a place? Total body irradiation increases the risk of toxicity. Adding medium-intensity total body irradiation (8 grays) has not been associated with improved survival. Consequently, single-drug treatment (melphalan, 200 mg/m2) appears preferable. 7.5. When should allogeneic transplantation be considered? Early studies with allogeneic transplantation in myeloma patients were disappointing, mainly because toxicity was greater than in other indications. However, allogeneic transplantation should be considered in patients who are younger than 50 years of age and have an HLA-compatible sibling. Furthermore, nonmyeloablative allogeneic transplantation (mini-transplantation) can be considered in patients younger than 65 years of age who experience a relapse after high-dose chemotherapy with autologous stem cell support.

8. The plateau phase: is maintenance therapy in order? None of the treatments studied to date have been found effective in increasing survival when used at the plateau phase. Interferon therapy proved disappointing and has now been almost completely discarded. Studies are needed to identify agents capable of preventing or delaying the relapse that eventually puts an end to the plateau phase. Thalidomide deserves investigation in this indication.

9. Second- and third-line treatments? Classically, VAD or VAMP is used as second-line treatment and dexamethasone-thalidomide as third-line treatment (dexamethasone, 40 mg/d from D1 through D4 at 28-d intervals; and thalidomide, 200 mg/d). Now, these treatments are often given in the reverse order, particularly in elderly patients at high risk for cardiac or infectious side effects with VAD. The potential usefulness of thalidomide added to induction chemotherapy or second-line chemotherapy is under evaluation.

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10. Adjuvant treatments

11. Conclusions

10.1. Should bisphosphonates be given routinely?

Valuable gains have been made in the treatment of myeloma over the last decade. Although high-dose chemotherapy with autologous stem cell support fails to cure the disease, it substantially improves relapse-free survival in younger patients. The introduction of new treatments for preventing and managing skeletal events has noticeably improved quality of life. The anemia can be corrected. Median survival in most of the recent studies is 5 years and qualityof life is far better than in the past. It can be hoped that thalidomide, RANK-L inhibitors, new allogeneic transplantation techniques, and proteasome inhibitors will provide further decisive progress within the next 10 years.

We have shown [95,96] that bone mass increased by about 4% per year in patients who responded to conventional or high-dose chemotherapy and that this increase was sustained throughout the remission (yielding a 12% increase over 3 years). Furthermore, improved survival with bisphosphonate therapy has been shown only in patients with relapsing disease. We suggest the following indications: • bisphosphonates should be given to all patients with relapsing disease or with no response to chemotherapy; • at diagnosis, bisphosphonates should be used only in patients with severe bone involvement; in the other patients, provided there is a response to chemotherapy, bisphosphonate therapy may not be appropriate, for preventing skeletal events. Thus, in the above-mentioned study conducted by the MRC [85], survival was better in patients with no fracture at diagnosis, but this finding requires confirmation because it is based on an analysis of subgroups that were not defined beforehand; • at the plateau phase, there is no evidence that bisphosphonate therapy may be beneficial in patients with a good response to chemotherapy. 10.2. Which bisphosphonates should be used? The best results have been obtained with pamidronate (90 mg IV every 4 weeks) or zoledronate (4 mg IV every 4 weeks). Either drug can be used. However, in patients who are not receiving intravenous chemotherapy, long-term clodronate therapy (1600 mg/d) can be given. 10.3. How should infections be prevented? Infection is the leading cause of death in myeloma patients.Prophylactictreatmentwithsulfamethoxazole-trimethoprime is useful for preventing Pneumocystis carinii pneumonia and several bacterial infections in patients on high-dose dexamethasone therapy. However, sulfamethoxazole-trimethoprime is not the best treatment against Streptococcus pneumoniae , which is the most common organism in myeloma patients. Prophylactic amoxicillin treatment and pneumococcal immunization deserve evaluation.

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10.4. Should erythropoietin be given? [14]

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