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Current Therapy for Multiple Myeloma

      Multiple myeloma is an incurable plasma cell malignancy that accounts for 10% of all hematologic cancers. For decades the mainstay of therapy has been the use of melphalan and prednisone; with this regimen, the median survival is approximately 3 years. Recently, important advances were made that have substantially altered the manner in which patients with myeloma are treated. Newly diagnosed patients with good performance status are now treated with autologous stem cell transplantation, resulting in improved survival. Because of the increasing use of transplantation as initial therapy, several therapeutic issues have emerged: the role of tandem transplantation, early vs delayed transplantation, and the role of allogeneic transplantation. The pronounced activity of thalidomide in patients with refractory myeloma represents another important advance. This has prompted the study of several novel agents in the treatment of myeloma, at least 2 of which appear promising. Supportive care measures also have improved, including the use of bisphosphonates to prevent osteolytic lesions. The purpose of this review is to summarize recent advances and provide an evidence-based approach to the treatment of multiple myeloma.
      CR (complete response), DVT (deep venous thrombosis), GVHD (graft-vs-host disease), VAD (vincristine, doxorubicin (Adriamycin), dexamethasone), VBMCP (vincristine, carmustine (BCNU), melphalan, cyclophosphamide, prednisone)
      Multiple myeloma is a clonal plasma cell disorder characterized by the presence of a monoclonal protein in the serum or urine, osteolytic lesions, increased plasma cells in the bone marrow, anemia, and hypercalcemia.
      • Bataille R
      • Harousseau JL
      Multiple myeloma.
      It accounts for 1% of all malignancies and 10% of malignant hematologic neoplasms.
      • Bataille R
      • Harousseau JL
      Multiple myeloma.
      • Jemal A
      • Thomas A
      • Murray T
      • Thun M
      Cancer statistics, 2002 [published correction appears in CA Cancer J Clin. 2002;52:119].
      In 2002, approximately 14,600 new patients in the United States will be diagnosed as having myeloma, and more than 10,800 will die of the disease.
      • Jemal A
      • Thomas A
      • Murray T
      • Thun M
      Cancer statistics, 2002 [published correction appears in CA Cancer J Clin. 2002;52:119].
      The annual incidence is approximately 4 per 100,000 population. The incidence rates in Europe are slightly lower: approximately 3 per 100,000 in the United Kingdom, Sweden, and the Netherlands and 2.5 per 100,000 in Denmark, France, and Spain.
      • Herrinton LJ
      • Weiss NS
      • Olshan AF
      The epidemiology of myeloma.
      The incidence is lower in Asian countries: less than 1 per 100,000 in China and the Philippines.
      • Herrinton LJ
      • Weiss NS
      • Olshan AF
      The epidemiology of myeloma.
      The incidence in black persons is almost twice that of white persons.
      At present, there is no cure for myeloma, and median survival with standard therapy is approximately 3 years. A state-of-the-art, evidence-based approach to the treatment of symptomatic, newly diagnosed multiple myeloma is presented in this review.

      MANAGEMENT OF SYMPTOMATIC MULTIPLE MYELOMA

      Symptomatic multiple myeloma is defined by the presence of increased monoclonal plasma cells in the bone marrow, presence of a serum or urinary monoclonal protein, and symptoms related to 1 or more of the following features: osteolytic lesions, anemia, hypercalcemia, or renal failure. Other causes of anemia, renal failure, and hypercalcemia must be considered and excluded.
      A schematic approach to the management of patients with newly diagnosed, symptomatic multiple myeloma is shown in Figure 1. Of importance, a subset of patients may have mild anemia or small osteolytic lesions on skeletal survey, with minimal or no symptoms. These patients can be observed without therapy until definite evidence of progression, based on the results of 2 randomized trials that showed no significant improvement in overall survival in patients who received immediate treatment with melphalan plus prednisone compared with those who received treatment at progression.
      • Hjorth M
      • Hellquist L
      • Holmberg E
      • Magnusson B
      • Rodjer S
      • Westin J
      • Myeloma Group of Western Sweden
      Initial versus deferred melphalan-prednisone therapy for asymptomatic multiple myeloma stage I—a randomized study.
      • Grignani G
      • Gobbi PG
      • Formisano R
      • et al.
      A prognostic index for multiple myeloma.
      It is also based on the toxic effects of therapy and the fact that some patients may not experience disease progression for many months with no therapy.
      • Greipp PR
      • Kyle RA
      Staging, kinetics, and prognosis of multiple myeloma.
      • Kyle RA
      • Greipp PR
      Smoldering multiple myeloma.
      Figure thumbnail gr1
      Figure 1Approach to the treatment of newly diagnosed, symptomatic myeloma. *Induction therapy is given for 3 to 4 cycles. MP = melphalan plus prednisone; VAD = vincristine, doxorubicin (Adriamycin), dexamethasone; VBMCP = vincristine, carmustine (BCNU), melphalan, cyclophosphamide, prednisone.
      Once a decision is made that therapy is indicated, the next issue is to determine whether the patient is a candidate for autologous stem cell transplantation because survival is superior with this strategy.
      • Attal M
      • Harousseau J-L
      • Stoppa A-M
      • Intergroupe Français du Myélome
      • et al.
      A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma.
      Patients who are not candidates for autologous stem cell transplantation because of advanced age, poor performance status, pronounced renal failure, or comorbidity should receive standard-dose alkylator-based therapy with melphalan (an alkylating agent) and prednisone or a suitable alternative therapeutic regimen. The rest of the patients are treated with early or delayed autologous stem cell transplantation.

      Conventional-Dose Chemotherapy

      For decades, the simple oral regimen of melphalan plus prednisone has remained the cornerstone of therapy for myeloma. The overall response rate with this regimen is about 50%.
      Myeloma Trialists' Collaborative Group
      Combination chemotherapy versus melphalan plus prednisone as treatment for multiple myeloma: an overview of 6,633 patients from 27 randomized trials.
      Melphalan is administered orally at a dose of 0.15 mg/kg daily for 7 days. Prednisone is administered orally at a dose of 60 mg/d during the same 7 days. The treatment is repeated every 6 weeks. An alternative schedule is to administer melphalan, 9 mg/m2 per day, for 4 days in combination with prednisone, 100 mg/d, on the same 4 days, with the treatment repeated every 4 weeks. The white blood cell count and platelet count must be obtained 2 to 3 weeks after initiation of therapy and before re-treatment. Based on these counts, the dose of melphalan for subsequent cycles is adjusted to produce mild cytopenia at mid cycle. Patients are treated in this manner for 1 year or up to 6 months after a plateau phase has been achieved. The complete response (CR) rate with this strategy is less than 10%, and the median survival is about 3 years.
      • Kovacsovics TJ
      • Delaly A
      Intensive treatment strategies in multiple myeloma.
      The 5-year survival rate is approximately 25%.
      Myeloma Trialists' Collaborative Group
      Combination chemotherapy versus melphalan plus prednisone as treatment for multiple myeloma: an overview of 6,633 patients from 27 randomized trials.
      Many investigators have sought to improve the results obtained with melphalan plus prednisone by using more complex multiagent chemotherapy. Unfortunately, these more aggressive combination chemotherapeutic regimens such as vincristine, carmustine (BCNU), melphalan, cyclophosphamide, and prednisone (VBMCP) result in superior response rates (60%-70%) but no substantial survival benefit.
      Myeloma Trialists' Collaborative Group
      Combination chemotherapy versus melphalan plus prednisone as treatment for multiple myeloma: an overview of 6,633 patients from 27 randomized trials.
      • Alexanian R
      • Dimopoulos M
      The treatment of multiple myeloma.
      • Oken MM
      • Harrington DP
      • Abramson N
      • Kyle RA
      • Knospe W
      • Glick JH
      Comparison of melphalan and prednisone with vincristine, carmustine, melphalan, cyclophosphamide, and pred-nisone in the treatment of multiple myeloma: results of Eastern Cooperative Oncology Group Study E2479.
      Similarly, the addition of interferon to initial therapy produces slightly better response rates with no clinically meaningful improvement in survival.
      Myeloma Trialists' Collaborative Group
      Interferon as therapy for multiple myeloma: an individual patient data overview of 24 randomized trials and 4012 patients.
      As a result, melphalan and prednisone remain the best choice for initial therapy for patients who are not candidates for stem cell transplantation.
      Alternatives to melphalan and prednisone are useful when a more rapid reduction of tumor burden is needed or when melphalan and prednisone are ineffective. A good alternative is VBMCP, as is the regimen of vincristine, doxorubicin (Adriamycin), and dexamethasone (VAD).
      • Alexanian R
      • Barlogie B
      • Tucker S
      VAD-based regimens as primary treatment for multiple myeloma.
      High-dose dexamethasone alone produces a response in 45% of patients with myeloma.
      • Alexanian R
      • Dimopoulos MA
      • Delasalle K
      • Barlogie B
      Primary dexamethasone treatment of multiple myeloma.
      It is thought that highdose dexamethasone accounts for most of the activity of the VAD regimen, with much less toxicity. Dexamethasone is administered at a dose of 40 mg/d orally on days 1 through 4, 9 through 12, and 17 through 20 every 5 weeks. Dexamethasone has the advantage over melphalan of not causing alky lator-mediated stem cell damage. However, toxicity may be higher, including severe proximal muscle weakness and increased risk of opportunistic infections.

      Autologous Stem Cell Transplantation

      High-dose therapy followed by autologous stem cell transplantation improves response rate and survival in patients with myeloma, but the strategy is not curative.
      • Harousseau JL
      • Attal M
      The role of autologous hematopoietic stem cell transplantation in multiple myeloma.
      • Barlogie B
      • Jagannath S
      • Epstein J
      • et al.
      Biology and therapy of multiple myeloma in 1996.
      • Gertz MA
      • Pineda AA
      • Chen MG
      • et al.
      Refractory and relapsing multiple myeloma treated by blood stem cell transplantation.
      Response rates exceed 75% to 90%,
      • Kovacsovics TJ
      • Delaly A
      Intensive treatment strategies in multiple myeloma.
      • Alexanian R
      • Dimopoulos M
      The treatment of multiple myeloma.
      and CR rates range from 20% to 40%.
      • Attal M
      • Harousseau J-L
      • Stoppa A-M
      • Intergroupe Français du Myélome
      • et al.
      A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma.
      • Barlogie B
      • Jagannath S
      • Epstein J
      • et al.
      Biology and therapy of multiple myeloma in 1996.
      A French randomized trial in 200 previously untreated patients with myeloma showed improved survival with autologous bone marrow transplantation compared with conventional chemotherapy, with 5-year survival rates of 52% and 12%, respectively.
      • Attal M
      • Harousseau J-L
      • Stoppa A-M
      • Intergroupe Français du Myélome
      • et al.
      A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma.
      Thus, the current standard of care is autologous stem cell transplantation for eligible patients younger than 65 years with good performance status and adequate renal function. Preliminary data from a recent randomized trial by the Spanish Cooperative Group have not yet confirmed a similar difference in overall survival.
      • Blade J
      • Sureda A
      • Ribera JM
      • et al.
      High-dose therapy autotransplantation/intensification vs continued conventional chemotherapy in multiple myeloma patients responding to initial treatment chemotherapy: results of a prospective randomized trial from the Spanish Cooperative Group PETHEMA [abstract].
      Based on this study and others, there are concerns regarding the true efficacy of stem cell transplantation, especially with the emergence of novel active agents such as thalidomide and the proteasome inhibitor PS-341.
      Age older than 65 years alone is not a contraindication for transplantation.
      • Siegel DS
      • Desikan KR
      • Mehta J
      • et al.
      Age is not a prognostic variable with autotransplants for multiple myeloma.
      Such patients are candidates for transplantation if they have good functional status and limited comorbidity.
      The process of transplantation involves 3 to 4 cycles of induction therapy to minimize tumor burden, then peripheral blood stem cell collection using apheresis techniques (harvest), followed by high-dose myeloablative therapy (conditioning regimen), and finally reinfusion of stem cells (rescue). Peripheral blood stem cells are preferred over bone marrow because they result in more rapid engraftment and minimize discomfort to the patient compared with that from bone marrow collection. The standard conditioning regimen is melphalan, 200 mg/m2. Total body irradiation is not used, based on the results of a French randomized trial showing increased toxicity with no significant survival benefit.
      • Moreau P
      • Facon T
      • Attal M
      • Intergroupe Francophone du Myélome
      • et al.
      Comparison of 200 mg/m2 melphalan and 8 Gy total body irradiation plus 140 mg/m2 melphalan as conditioning regimens for peripheral blood stem cell transplantation in patients with newly diagnosed multiple myeloma: final analysis of the Intergroupe Francophone du Myélome 9502 randomized trial.
      Similarly, stem cells are not purged of contaminating myeloma cells or enriched for CD34+ cells, based on the results of a large randomized trial that showed no clinical benefit.
      • Stewart AK
      • Vescio R
      • Schiller G
      • et al.
      Purging of autologous peripheral-blood stem cells using CD34 selection does not improve overall or progression-free survival after high-dose chemotherapy for multiple myeloma: results of a multicenter randomized controlled trial.
      Controversial issues in the treatment of myeloma with stem cell transplantation are discussed subsequently.
      Optimum Pretransplantation Induction Regimen.—Although infusional VAD is considered the standard pretransplantation induction therapy, it is cumbersome to administer and is associated with substantial toxicity. Lack of response to initial VAD (primary refractory disease) does not portend poor survival after transplantation, and patients are treated with transplantation regardless of response status to VAD.
      • Rajkumar SV
      • Fonseca R
      • Lacy MQ
      • et al.
      Autologous stem cell transplantation for relapsed and primary refractory myeloma.
      • Singhal S
      • Powles R
      • Sirohi B
      • Treleaven J
      • Mehta J
      Response to induction chemotherapy is not essential to obtain survival benefit from high-dose melphalan and autotransplantation in myeloma [abstract].
      The best strategy for managing patients who have progressive disease with induction therapy is unclear. Alternative induction regimens with new agents may be an option and need to be studied. It is clear that dexamethasone accounts for a significant proportion of the activity of VAD, and although the response rate may be lower, there is no effect on overall survival.
      • Alexanian R
      • Dimopoulos MA
      • Delasalle K
      • Barlogie B
      Primary dexamethasone treatment of multiple myeloma.
      There is no difference in engraftment or stem cell collection with dexamethasone alone compared with VAD.
      • Anagnostopoulos A
      • Aleman A
      • Williams P
      • et al.
      Autologous stem cell transplantation (ASCT) after nonmyelosuppressive induction therapy with dexamethasone alone is safe and effective for newly diagnosed multiple myeloma (MM) pts who receive high dose chemotherapy (HDC) [abstract].
      Therefore, dexamethasone is an appropriate alternative to VAD as pretransplantation induction therapy.
      Recently, there was interest in thalidomide as induction therapy. A Mayo Clinic study of 50 patients with previously untreated myeloma showed a response rate of 64% with use of the combination of low-dose thalidomide (200 mg/d) and pulsed dexamethasone.
      • Rajkumar SV
      • Hayman SR
      • Gertz MA
      • et al.
      Combination therapy with thalidomide plus dexamethasone (Thal/Dex) for newly diagnosed myeloma (MM) [abstract].
      This regimen may be a suitable oral alternative to infusional chemotherapy with VAD as initial treatment of myeloma in preparation for stem cell transplantation. An Eastern Cooperative Oncology Group randomized phase 3 trial of thalidomide plus dexamethasone vs dexamethasone alone as induction therapy for newly diagnosed myeloma is ongoing in the United States (P.R.G., oral communication, June 2002).
      Prolonged alkylator therapy before transplantation results in poor engraftment. Hence, alkylating agents should be avoided in patients who are candidates for stem cell transplantation.
      • Goldschmidt H
      • Hegenbart U
      • Wallmeier M
      • Hohaus S
      • Haas R
      Factors influencing collection of peripheral blood progenitor cells following high-dose cyclophosphamide and granulocyte colony-stimulating factor in patients with multiple myeloma.
      • Kroger N
      • Zeller W
      • Hassan HT
      • et al.
      Successful mobilization of peripheral blood stem cells in heavily pretreated myeloma patients with G-CSF alone.
      Early vs Delayed Transplantation.—Autologous stem cell transplantation for myeloma is often performed early in the course of the disease, after 3 to 4 cycles of induction chemotherapy. However, it is possible to delay transplantation until relapse without compromising survival, provided hematopoietic stem cells are harvested and cryopreserved early in the course of disease before alkylator therapy. Data from 2 French randomized trials that compared early vs delayed transplantation indicate no significant difference in outcome between the 2 strategies.
      • Fermand JP
      • Ravaud P
      • Chevret S
      • et al.
      High-dose therapy and autologous peripheral blood stem cell transplantation in multiple myeloma: up-front or rescue treatment? results of a multicenter sequential randomized clinical trial.
      • Facon T
      • Mary JY
      • Harousseau JL
      • et al.
      Front-line or rescue autologous bone marrow transplantation (ABMT) following a first course of high dose melphalan (HDM) in multiple myeloma (MM): preliminary results of a prospective randomized trial (CIAM protocol) [abstract].
      The results of another large US multicenter randomized trial addressing this issue were recently obtained, analysis of which is awaited (P.R.G., oral communication, June 2002). The choice between the 2 options currently is based on patient preference and other clinical conditions and risk factors.
      Single vs Tandem Transplantation.—At present the role of tandem (double) transplantation in myeloma is unclear. With tandem transplantation, patients receive a second planned transplant after recovery from the first procedure. Barlogie et al
      • Barlogie B
      • Jagannath S
      • Vesole DH
      • et al.
      Superiority of tandem autologous transplantation over standard therapy for previously untreated multiple myeloma.
      • Vesole DH
      • Barlogie B
      • Jagannath S
      • et al.
      High-dose therapy for refractory multiple myeloma: improved prognosis with better supportive care and double transplants.
      • Tricot G
      • Jagannath S
      • Vesole DH
      • et al.
      Hematopoietic stem cell transplants for multiple myeloma.
      • Desikan R
      • Barlogie B
      • Sawyer J
      • et al.
      Results of high-dose therapy for 1000 patients with multiple myeloma: durable complete remissions and superior survival in the absence of chromosome 13 abnormalities.
      at the University of Arkansas advocate tandem autologous stem cell transplantation to improve CR rates and survival. In a study of 231 patients with newly diagnosed myeloma, they showed that more than 70% of patients are able to go through induction therapy and both transplantations successfully.
      • Barlogie B
      • Jagannath S
      • Desikan KR
      • et al.
      Total therapy with tandem transplants for newly diagnosed multiple myeloma.
      The mortality rates were 3% during induction, 1% with the first transplant, and 4% with the second transplant. With use of an intent-to-treat analysis, the CR rate was 26% with the first transplant and 41% after the second transplantation. Overall survival with this approach was 68 months. These results have prompted several studies of tandem stem cell transplantation in myeloma.
      Preliminary data from 4 different randomized trials on this treatment strategy were presented recently.
      • Dalton WS
      • Bergsagel PL
      • Kuehl WM
      • Anderson KC
      • Harousseau JL
      Multiple myeloma.
      These trials indicate a slight increase in response rates and possibly event-free survival with tandem transplantation. However, only 1 of the 4 trials has thus far shown any improvement in overall survival with tandem transplantation.
      • Dalton WS
      • Bergsagel PL
      • Kuehl WM
      • Anderson KC
      • Harousseau JL
      Multiple myeloma.
      The final results of these trials will clarify this important issue. Because the role of tandem transplantation is not settled, it is wise to harvest enough stem cells for 2 transplantations. At Mayo Clinic, Rochester, Minn, a single transplantation is done with half of the stem cells collected, and the other half are cryopreserved for transplantation at relapse. A recent study by Sirohi et al
      • Sirohi B
      • Powles R
      • Singhal S
      • et al.
      High-dose melphalan and second autografts for myeloma relapsing after one autograft: results equivalent to tandem autotransplantation [abstract].
      suggests that this strategy produces results equivalent to those reported with tandem transplantation.
      Role of Allogeneic Transplantation.—Autologous stem cell transplantation has 2 drawbacks. First, the harvested stem cells are inevitably contaminated by tumor cells. Second, there is no possibility of an immunologically mediated graft-vs-myeloma effect. Allogeneic transplantation eliminates the problem of tumor cell contamination of the stem cells. Furthermore, using donor lymphocyte infusions, several investigators found a graft-vs-myeloma effect in myeloma with allografting.
      • Cavo M
      • Benni M
      • Cirio TM
      • Gozzetti A
      • Tura S
      Allogeneic bone marrow transplantation for the treatment of multiple myeloma: an overview of published reports.
      • Tura S
      • Cavo M
      Allogeneic bone marrow transplantation in multiple myeloma.
      • Lokhorst HM
      • Schattenberg A
      • Cornelissen JJ
      • Thomas LL
      • Verdonck LF
      Donor leukocyte infusions are effective in relapsed multiple myeloma after allogeneic bone marrow transplantation.
      Studies show that allogeneic transplantation leads to prolonged disease-free survival in a relatively small percentage of patients.
      • Bensinger WI
      • Buckner CD
      • Anasetti C
      • et al.
      Allogeneic marrow transplantation for multiple myeloma: an analysis of risk factors on outcome.
      • Cavo M
      • Bandini G
      • Benni M
      • et al.
      High-dose busulfan and cyclophosphamide are an effective conditioning regimen for allogeneic bone marrow transplantation in chemosensitive multiple myeloma.
      However, the high treatment-related mortality rate (approximately 30%) and significant toxicity from graft-vs-host disease (GVHD) have limited the role of this procedure in the treatment of myeloma. As a result, we rarely recommend conventional allogeneic bone marrow transplantation for the treatment of myeloma.
      There is interest in studying nonmyeloablative (“mini”) allogeneic transplantation for selected patients with myeloma, either immediately after autologous stem cell transplantation
      • Molina A
      • Sahebi F
      • Maloney DG
      • et al.
      Non-myeloablative peripheral blood stem cell (PBSC) allografts following cytoreductive autotransplants for treatment of multiple myeloma (MM) [abstract].
      or at relapse. Maloney et al
      • Maloney DG
      • Sahebi F
      • Stockerl-Goldstein KE
      • et al.
      Combining an allogeneic graft-vs-myeloma effect with high-dose autologous stem cell rescue in the treatment of multiple myeloma [abstract].
      recently reported results in 32 patients treated with autologous stem cell transplantation followed by a nonmyeloablative allogeneic transplantation. They used melphalan, 200 mg/m2, as the conditioning regimen for autologous transplantation and mycophenolate, cyclosporine, and total body irradiation (200 cGy) as conditioning agents for the nonmyeloablative allogeneic transplantation. All allografts were from HLA-identical sibling donors. The response rate to therapy was 84%, with a relatively low day-100 treatment-related mortality rate of 6%. However, the high incidences of acute (45%) and chronic (55%) GVHD tempered enthusiasm for this approach. A recent study by Badros et al
      • Badros A
      • Barlogie B
      • Siegel E
      • et al.
      Improved outcome of allogeneic transplantation in high-risk multiple myeloma patients after nonmyeloablative conditioning.
      also confirmed the high incidence of GVHD with this approach, with rates of 58% for acute GVHD and 29% for chronic GVHD. Treatment-related mortality was 29%. Until further refinements are made and additional confirmatory studies are completed, the role of allogeneic stem cell transplantation as initial therapy for myeloma must be considered investigational.

      Maintenance Therapy

      The role of maintenance therapy after either conventional-dose melphalan plus prednisone therapy or stem cell transplantation is investigational. Several studies show that interferon alfa as maintenance therapy prolongs the plateau phase in patients with myeloma.
      • Shustik C
      Interferon in the treatment of multiple myeloma.
      • Mandelli F
      • Avvisati G
      • Amadori S
      • et al.
      Maintenance treatment with recombinant interferon alfa-2b in patients with multiple myeloma responding to conventional induction chemotherapy.
      • Browman GP
      • Bergsagel D
      • Sicheri D
      • et al.
      Randomized trial of interferon maintenance in multiple myeloma: a study of the National Cancer Institute of Canada Clinical Trials Group.
      • Westin J
      • Rodjer S
      • Turesson I
      • Cortelezzi A
      • Hjorth M
      • Zador G
      • Cooperative Study Group
      Interferon alfa-2b versus no maintenance therapy during the plateau phase in multiple myeloma: a randomized study.
      However, others have failed to show such an effect, and overall survival was not prolonged.
      • Salmon SE
      • Crowley JJ
      • Grogan TM
      • Finley P
      • Pugh RP
      • Barlogie B
      Combination chemotherapy, glucocorticoids, and interferon alfa in the treatment of multiple myeloma: a Southwest Oncology Group study.
      • Peest D
      • Deicher H
      • Coldewey R
      • et al.
      A comparison of poly-chemotherapy and melphalan/prednisone for primary remission induction, and interferon-alpha for maintenance treatment, in multiple myeloma: a prospective trial of the German Myeloma Treatment Group.
      • Ludwig H
      • Cohen AM
      • Polliack A
      • et al.
      Interferon-alpha for induction and maintenance in multiple myeloma: results of two multicenter randomized trials and summary of other studies.
      A large randomized trial in the United States evaluating the role of interferon alfa as maintenance therapy for myeloma is awaiting analysis (P.R.G., oral communication, June 2002). The Myeloma Trialists’ Collaborative Group recently completed a meta-analysis of interferon alfa therapy for myeloma.
      Myeloma Trialists' Collaborative Group
      Interferon as therapy for multiple myeloma: an individual patient data overview of 24 randomized trials and 4012 patients.
      The analysis included 12 maintenance trials with 1543 patients. Maintenance therapy with interferon alfa was associated with a slight increase in overall survival by about 4 months with the benefit restricted to the smaller trials. Given the cost, adverse effects, and minimal benefits, interferon alfa is not routinely used as maintenance therapy.
      Prednisone at low doses has been studied as maintenance therapy and is promising.
      • Salmon SE
      • Crowley JJ
      • Balcerzak SP
      • et al.
      Interferon versus interferon plus prednisone remission maintenance therapy for multiple myeloma: a Southwest Oncology Group Study.
      In a recently published randomized trial, progression-free survival after initiation of maintenance therapy was significantly longer in patients receiving 50 mg of prednisone orally every other day compared with those receiving a lower dose of 10 mg every other day, with median progression-free survival times of 14 vs 5 months, respectively.
      • Berenson JR
      • Crowley JJ
      • Grogan TM
      • et al.
      Maintenance therapy with alternate-day prednisone improves survival in multiple myeloma patients.
      A similar difference was seen in overall survival, with median times of 37 vs 26 months, respectively.
      Clinical trials currently are being designed for further study of the role of low-dose prednisone, as well as thalidomide, dendritic cell vaccination, and other novel approaches as maintenance therapy after stem cell transplantation or conventional chemotherapy.

      Supportive Care Strategies

      Myeloma is characterized by osteolytic lesions, fractures, and osteoporosis that cause pronounced pain. Anemia, infections, hypercalcemia, and renal failure are other common complications. As a result, supportive care measures are important in management.
      Bisphosphonates to Prevent Myeloma Bone Disease.—Recent studies
      • Kyle RA
      The role of bisphosphonates in multiple myeloma.
      show that bisphosphonates (such as pamidronate or zoledronic acid) can delay or prevent osteolytic lesions, osteoporosis, and vertebral compression fractures. The goal is to prevent or delay skeletal events.
      • Kyle RA
      The role of bisphosphonates in multiple myeloma.
      Randomized trials show that pamidronate at a dose of 90 mg intravenously over 4 hours every month reduces skeletal complications and improves the quality of life of patients with myeloma.
      • Berenson JR
      • Lichtenstein A
      • Porter L
      • Myeloma Aredia Study Group
      • et al.
      Efficacy of pamidronate in reducing skeletal events in patients with advanced multiple myeloma.
      • Berenson JR
      • Lichtenstein A
      • Porter L
      • Myeloma Aredia Study Group
      • et al.
      Long-term pamidronate treatment of advanced multiple myeloma patients reduces skeletal events.
      Zoledronic acid is as effective as pamidronate with a much shorter infusion time (15 minutes).
      • Rosen LS
      • Gordon D
      • Antonio BS
      • et al.
      Zoledronic acid versus pamidronate in the treatment of skeletal metastases in patients with breast cancer or osteolytic lesions of multiple myeloma: a phase III, double-blind, comparative trial.
      • Berenson JR
      • Rosen LS
      • Howell A
      • et al.
      Zoledronic acid reduces skeletal-related events in patients with osteolytic metastases [published correction appears in Cancer. 2001;91:1956].
      Based on these studies, we now recommend that all patients with myeloma-related bone disease receive bisphosphonate therapy monthly as supportive care, for an indefinite period. The role of bisphosphonates in patients who have no evidence of bone disease is unclear and needs further investigation.
      Treatment of Anemia.—Anemia is a source of distress for patients, resulting in fatigue and poor performance status. Reversible causes of anemia such as iron, folate, or vitamin B12 deficiency must be identified and treated. Anemia is often secondary to bone marrow involvement and renal dysfunction. Treatment of the underlying disease and improvement in renal function often lead to improvement in hemoglobin concentration. Erythropoietin therapy can improve the anemia associated with myeloma and is well tolerated.
      • Mittelman M
      • Zeidman A
      • Fradin Z
      • Magazanik A
      • Lewinski UH
      • Cohen A
      Recombinant human erythropoietin in the treatment of multiple myeloma-associated anemia.
      • Musto P
      • Falcone A
      • D'Arena G
      • et al.
      Clinical results of recombinant erythropoietin in transfusion-dependent patients with refractory multiple myeloma: role of cytokines and monitoring of erythropoiesis.
      Erythropoietin therapy should be considered for myeloma patients with symptomatic anemia who are receiving myelosuppressive chemotherapy or have severe renal dysfunction. Blood transfusions are indicated for patients with severe anemia who do not receive substantial benefit from other therapies.
      Management of Infections.—Patients with myeloma are prone to infectious complications due to suppressed humoral and cell-mediated immunity from the disease and the added effects of therapy. The principal organisms involved are Streptococcus pneumoniae and Haemophilus influenzae.
      • Kelleher P
      • Chapel H
      Infections: principles of prevention and therapy.
      Herpes zoster activation is also common and requires antiviral therapy to prevent dissemination. Patients with severe hypogammaglobulinemia and recurrent infections may benefit from monthly intravenous immunoglobulin infusions.
      • Chapel HM
      • Lee M
      • Hargreaves R
      • Pamphilon DH
      • Prentice AG
      • UK Group for Immunoglobulin Replacement Therapy in Multiple Myeloma
      Randomised trial of intravenous immunoglobulin as prophylaxis against infection in plateau-phase multiple myeloma.
      Patients should be vaccinated against S pneumoniae and H influenzae, although immune responses to vaccines are attenuated in myeloma.
      • Kelleher P
      • Chapel H
      Infections: principles of prevention and therapy.
      Annual influenza vaccine is also recommended.
      For patients receiving high-dose corticosteroid regimens, prophylactic therapy against Pneumocystis carinii with trimethoprim-sulfamethoxazole must be considered.
      • van der Lelie J
      • Venema D
      • Kuijper EJ
      • et al.
      Pneumocystis carinii pneumonia in HIV-negative patients with haematologic disease.
      Fungal infections can occur with high-dose corticosteroid therapy, but no data are available on the role of antifungal prophylaxis. A large randomized trial is ongoing in the United States to determine the role of prophylactic antibiotics in myeloma patients undergoing chemotherapy (P.R.G., oral communication, June 2002).
      Management of Hypercalcemia.—The current treatment of hypercalcemia in myeloma is aggressive hydration and corticosteroid therapy. Bisphosphonates are given if no response occurs or if the hypercalcemia is severe. A single dose of pamidronate, 60 to 90 mg intravenously over 2 to 4 hours, will normalize the calcium levels within 24 to 72 hours in most patients.
      • Gucalp R
      • Theriault R
      • Gill I
      • et al.
      Treatment of cancer-associated hypercalcemia: double-blind comparison of rapid and slow intravenous infusion regimens of pamidronate disodium and saline alone.
      Zoledronic acid (4 mg intravenously over 15 minutes) may be more potent than pamidronate in the treatment of hypercalcemia and is a good alternative.
      • Major P
      • Lortholary A
      • Hon J
      • et al.
      Zoledronic acid is superior to pamidronate in the treatment of hypercalcemia of malignancy: a pooled analysis of two randomized, controlled clinical trials.
      With the advent of bisphosphonates, true refractory hypercalcemia is rare. Occasionally, salmon calcitonin, 4 IU/kg every 12 hours, is used if a rapid reduction in serum calcium is needed. A skin test (0.1 mL of a 10 IU/mL dilution, intracutaneous) to rule out hypersensitivity is performed before salmon calcitonin is administered.
      Management of Renal Failure.—Patients with myeloma are prone to renal failure from various causes. Prompt treatment of myeloma with chemotherapy is critical for the control of renal failure and prognosis.
      • Alexanian R
      • Barlogie B
      • Dixon D
      Renal failure in multiple myeloma: pathogenesis and prognostic implications.
      The most common reversible causes of renal failure in patients with myeloma are hypercalcemia and dehydration. Light chain cast nephropathy (myeloma kidney) is an important cause of renal failure that requires treatment with hydration and institution of chemotherapy to control the light chain production. Alkaline diuresis may be helpful. Selected patients with excess light chain excretion in the urine and evolving acute renal failure due to cast nephropathy may benefit from plasmapheresis. Data from a small randomized trial showed that plasmapheresis can lead to recovery of renal function.
      • Johnson WJ
      • Kyle RA
      • Pineda AA
      • O'Brien PC
      • Holley KE
      Treatment of renal failure associated with multiple myeloma: plasmapheresis, hemodialysis, and chemotherapy.
      Pain Control Measures and Orthopedic Interventions.—Narcotic analgesics may be needed to control bone pain from osteolytic lesions or fractures. Splinting or other orthopedic interventions such as vertebroplasty can also reduce pain. Physical therapy and activity should be encouraged because there is a high risk of deep venous thrombosis (DVT) in the first 6 months after myeloma diagnosis, likely a result of immobilization. Mild degrees of pain can be controlled with acetaminophen-codeine, acetaminophen-oxycodone, or similar preparations. Nonsteroidal anti-inflammatory agents can precipitate renal failure or exaggerate corticosteroid-induced gastritis in patients with myeloma and should generally be avoided.
      • Yussim E
      • Schwartz E
      • Sidi Y
      • Ehrenfeld M
      Acute renal failure precipitated by non-steroidal anti-inflammatory drugs (NSAIDs) in multiple myeloma.
      • Wu MJ
      • Kumar KS
      • Kulkarni G
      • Kaiser H
      Multiple myeloma in naproxen-induced acute renal failure [letter].
      For severe pain, oral morphine sulfate administered as a sustained-release preparation with an immediate release form available for breakthrough pain is effective. Alternatives to morphine include hydromorphone or transdermal fentanyl. Radiation therapy to limited areas is indicated to control pain that is refractory to narcotics and to prevent or treat spinal cord compression. Orthopedic interventions and/or radiation may also be needed to prevent or treat pathologic fracture in susceptible long bones with large lytic lesions. In general, it is wise to limit the amount of radiation that is administered because radiation to large areas of bone can limit the amount of systemic chemotherapy that can be administered. The dose of radiation must be individualized, and some patients may require doses lower than the traditional 30 Gy administered in 10 fractions.
      • Shrieve DC
      The role of radiotherapy.

      Treatment of Relapse

      Therapy for relapsed myeloma is inadequate. Typically, patients who have relapse are treated with chemotherapeutic regimens such as VAD, VBMCP, pulsed methylprednisolone, or dexamethasone. Remissions with such therapy are usually short-lived. In selected patients with refractory disease, stem cell transplantation may be beneficial.
      • Vesole DH
      • Crowley JJ
      • Catchatourian R
      • et al.
      High-dose melphalan with autotransplantation for refractory multiple myeloma: results of a Southwest Oncology Group phase II trial.
      The choice of therapy depends on several factors, including the nature of the relapse, response to initial therapy, number of prior treatment regimens, age, performance status, and patient preference.
      In general, patients who have relapse several months after remission induced by alkylator-based therapy should receive the same regimen. However, high-dose corticosteroids may be a reasonable option if the response duration after alkylator-based therapy is brief or for patients who have relapse shortly after stem cell transplantation. A second transplant is probably futile in patients who have relapse very early after the initial procedure. The choice of therapy for relapsed myeloma is based on weighing the risks and benefits of each option, and the final decision should consider the patient's wishes. No standard therapy exists for relapsed myeloma, and depending on the clinical situation any or all of the approaches mentioned in Table 1 can be considered. Patients refractory to 1 regimen may respond to another. At each step, based on the clinical situation, palliative and supportive care must also be considered.
      Table 1Therapeutic Options for Patients With Relapsed Myeloma
      ModalityComment
      Autologous stem cell transplantationFor eligible patients in whom cryopreserved stem cells are available or for patients who have received minimal alkylator therapy in whom stem cells can be collected
      Alkylator-based therapyMelphalan plus prednisone or combination chemotherapeutic regimens such as VBMCP (vincristine, carmustine [BCNU], melphalan, cyclophosphamide, prednisone)
      CorticosteroidsHigh-dose corticosteroid-based therapy such as dexamethasone alone, VAD (vincristine, doxorubicin [Adriamycin], dexamethasone), or methylprednisolone
      ThalidomideAs single agent or in combination with corticosteroids or chemotherapy
      Investigational therapyIn approved clinical trials including miniallogeneic transplantation and novel agents such as PS-341 and CC-5013
      Supportive care onlyPain control, bisphosphonates, erythropoietin, transfusions

      Thalidomide

      Recently thalidomide, an agent with antiangiogenic properties,
      • D'Amato RJ
      • Loughnan MS
      • Flynn E
      • Folkman J
      Thalidomide is an inhibitor of angiogenesis.
      emerged as an active agent for relapsed and refractory myeloma. Singhal et al
      • Singhal S
      • Mehta J
      • Desikan R
      • et al.
      Antitumor activity of thalidomide in refractory multiple myeloma [published correction appears in N Engl J Med. 2000;342:364].
      at the University of Arkansas conducted the first trial investigating the activity of thalidomide in relapsed myeloma. In most patients, stem cell transplantation had failed. The overall response rate defined as a decrease in monoclonal protein levels by 25% or more was 32%. Paraprotein responses were accompanied by improvements in anemia and other symptoms. The median duration of response was not achieved after 14.5 months of follow-up. An update to this study confirms the activity of thalidomide in 169 patients with relapsed myeloma.
      • Barlogie B
      • Desikan R
      • Eddlemon P
      • et al.
      Extended survival in advanced and refractory multiple myeloma after single-agent thalidomide: identification of prognostic factors in a phase 2 study of 169 patients.
      Overall survival at 2 years was 48%, and eventfree survival was 20%.
      Several studies have confirmed these results and showed a 25% to 35% response rate with thalidomide therapy for relapsed myeloma.
      • Rajkumar SV
      • Witzig TE
      A review of angiogenesis and antiangiogenic therapy with thalidomide in multiple myeloma.
      The median response duration is approximately 9 to 12 months.
      • Rajkumar SV
      • Fonseca R
      • Dispenzieri A
      • et al.
      Thalidomide in the treatment of relapsed multiple myeloma.
      • Rajkumar SV
      Current status of thalidomide in the treatment of cancer.
      The usual initial dose is 200 mg/d, increased after 2 weeks to 400 mg/d. Most patients will respond to these dose levels, and further dose escalation usually is not needed. However, some patients will require a higher dose (up to 800 mg/d) to achieve or sustain a response.
      The return of thalidomide to clinical practice as an effective agent in the treatment of myeloma represents a major comeback by a drug with a notorious past.
      • Rajkumar SV
      • Kyle RA
      Thalidomide in the treatment of plasma cell malignancies [editorial].
      Thalidomide was first marketed in the late 1950s as a sedative in more than 40 countries. In the United States, the Food and Drug Administration was concerned about peripheral neuropathy, and the drug was not approved for clinical use. In 1961, the severe teratogenic potential of the drug was recognized, and thalidomide was taken off the market. However, thalidomide never really disappeared. The drug was soon found to be effective in the treatment of erythema nodosum leprosum. Over the past 10 years, other uses emerged, such as the treatment of acquired immunodeficiency syndrome-related cachexia and oral ulcers, aphthous ulcers in Behcet disease, and chronic GVHD. In 1998, the Food and Drug Administration approved the drug for use in erythema nodusum leprosum, with substantial precautions.
      • Rajkumar SV
      • Witzig TE
      A review of angiogenesis and antiangiogenic therapy with thalidomide in multiple myeloma.
      The study of thalidomide in myeloma was prompted by 2 factors: the understanding that angiogenesis (new vessel formation) is critical for the proliferation and metastases of most malignant neoplasms, including myeloma,
      • Folkman J
      Seminars in Medicine of the Beth Israel Hospital, Boston: clinical applications of research on angiogenesis.
      • Vacca A
      • Di Loreto M
      • Ribatti D
      • et al.
      Bone marrow of patients with active multiple myeloma: angiogenesis and plasma cell adhesion molecules LFA-1, VLA-4, LAM-1, and CD44.
      • Rajkumar SV
      • Fonseca R
      • Witzig TE
      • Gertz MA
      • Greipp PR
      Bone marrow angiogenesis in patients achieving complete response after stem cell transplantation for multiple myeloma.
      • Rajkumar SV
      • Leong T
      • Roche PC
      • et al.
      Prognostic value of bone marrow angiogenesis in multiple myeloma.
      and the knowledge that thalidomide possessed potent antiangiogenic properties.
      • D'Amato RJ
      • Loughnan MS
      • Flynn E
      • Folkman J
      Thalidomide is an inhibitor of angiogenesis.
      However, the mechanism of its antitumor activity and teratogenicity is still unclear and may also be related to immunomodulation,
      • Rajkumar SV
      • Witzig TE
      A review of angiogenesis and antiangiogenic therapy with thalidomide in multiple myeloma.
      inhibition of tumor necrosis factor a production, free radical-mediated oxidative damage to DNA, or effects on cell surface adhesion molecules.
      • Rajkumar SV
      • Witzig TE
      A review of angiogenesis and antiangiogenic therapy with thalidomide in multiple myeloma.
      Because of its severe teratogenicity, the use of thalidomide in pregnant women is absolutely contraindicated. Women of childbearing age must undergo pregnancy testing before therapy is initiated and every 2 to 4 weeks during treatment. They must abstain from sexual intercourse or use 2 highly effective contraceptive methods during treatment. Men must abstain from sexual intercourse or use a condom while receiving treatment even if they have had a successful vasectomy. All patients must continue these measures for at least 1 month after the last dose of the drug. Breast-feeding is contraindicated. In the United States, all patients, physicians, and pharmacists must participate in the System for Thalidomide Education and Prescribing Safety program that explains these risks and precautions before therapy is initiated.
      • Zeldis JB
      • Williams BA
      • Thomas SD
      • Elsayed ME
      S.T.E.P.S.: a comprehensive program for controlling and monitoring access to thalidomide.
      The most common adverse effects of thalidomide are sedation, fatigue, constipation, and rash. Because severe constipation is a common problem, laxatives are recommended prophylactically. If a rash occurs, the drug should be discontinued and reinstituted at a lower dose after the rash clears. Thalidomide also causes peripheral neuropathy, generally after chronic use over a period of several months. There is also increasing concern about the relationship between thalidomide therapy and DVT. The incidence of DVT is approximately 1% to 2% in patients receiving thalidomide alone, 10% in patients receiving thalidomide in combination with dexamethasone, and about 25% in patients receiving the agent in combination with other cytotoxic chemotherapeutic agents, particularly doxorubicin.
      • Barlogie B
      • Desikan R
      • Eddlemon P
      • et al.
      Extended survival in advanced and refractory multiple myeloma after single-agent thalidomide: identification of prognostic factors in a phase 2 study of 169 patients.
      • Osman K
      • Comenzo R
      • Rajkumar SV
      Deep venous thrombosis and thalidomide therapy for multiple myeloma [letter].
      • Zangari M
      • Anaissie E
      • Barlogie B
      • et al.
      Increased risk of deep-vein thrombosis in patients with multiple myeloma receiving thalidomide and chemotherapy.
      The role of prophylactic low-dose warfarin or low-molecular-weight heparin for high-risk patients receiving thalidomide in combination with other regimens remains unclear. Also, because some myeloma patients are predisposed to DVT due to their malignancy and reduced mobility from osteolytic lesions, the precise contribution of thalidomide to the incidence of DVT remains to be determined.
      Other less common but important adverse effects of thalidomide include edema, bradycardia, neutropenia, increased liver enzymes, menstrual irregularities, impotence, hyperglycemia or hypoglycemia, and hypothyroidism.

      Novel Agents

      Given the activity of thalidomide in myeloma, investigations are under way to identify safer and more active analogues. Immunomodulatory drugs represent a class of thalidomide analogues that show promise in laboratory studies. Two recently completed phase 1 trials with an immunomodulatory drug (CC-5013) have shown significant activity in heavily pretreated patients with refractory disease.
      • Richardson PG
      • Schlossman RL
      • Hideshima T
      • et al.
      A phase 1 study of oral CC5013, an immunomodulatory thalidomide (Thal) derivative, in patients with relapsed and refractory multiple myeloma (MM) [abstract].
      • Zangari M
      • Tricot G
      • Zeldis J
      • Eddlemon P
      • Saghafifar F
      • Barlogie B
      Results of phase I study of CC-5013 for the treatment of multiple myeloma (MM) patients who relapse after high dose chemotherapy (HDCT) [abstract].
      Confirmatory phase 2 trials with this agent are ongoing.
      The proteasome inhibitor PS-341 is another active agent in refractory myeloma. A recent multicenter trial with PS-341 in patients with refractory myeloma showed a response rate of 50%.
      • Richardson PG
      • Berenson J
      • Irwin D
      • et al.
      Phase II study of PS-341, a novel proteasome inhibitor, alone or in combination with dexamethasone in patients with multiple myeloma who have relapsed following front-line therapy and are refractory to their most recent therapy [abstract].
      A confirmatory phase 3 trial comparing PS-341 with high-dose dexamethasone in the treatment of refractory myeloma is ongoing (M. Q. Lacy, MD, oral communication, June 2002).
      Other active areas of investigation include dendritic cell vaccination, 2-methoxyestradiol, farnesyl transferase inhibitors, flavopiridol, and inhibitors of angiogenic cytokines.

      FUTURE DIRECTIONS

      After 3 decades of alkylator- and corticosteroid-based therapy, major strides are being made in the treatment of myeloma, and several novel agents have emerged. Future studies will seek to define the role of these novel agents, improve transplantation-conditioning regimens, and develop effective maintenance therapy. Nonmyeloablative allogeneic transplantation is promising. These advances are still short of the eventual goal of a cure. However, the momentum clearly is in favor of dramatic strides in the next decade.

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