Doxil

Plasma cell dyscrasias are a spectrum of B cell derived, plasma cells abnormalities. At one end they include monoclonal gammopathy of undetermined significance (MGUS) and extramedullary plasmacytomas and at the other end are the plasma cell leukemias. Multiple myeloma (MM) is the prototype of a tumor of differentiated plasma cells frequently accompanied by monoclonal (M) protein production and either diffuse osteoporosis or single or multiple osteolytic bone lesions. It accounts for approximately 1% of all malignant diseases and 10% of hematologic malignancies. The annual incidence of myeloma is 3-4 per 100,000 people. The median age of patients with MM is 65 years. The incidence is slightly higher in males than females, twice as high in African Americans as in whites, and lowest in Asian populations. MM mortality rates are increasing in the elderly. These increases may be related to differences in the gene pool of successive elderly cohorts, as adversity to human survival (mainly mortality due to infections) has declined drastically.

ETIOLOGY

Both genetic and environmental factors have been implicated but the cause of MM remains unknown. A genetic predisposition is suggested by reports of familial clusters of two or more first-degree relatives with MM and also by a significantly higher incidence of MM among African Americans. Environmental risk factors may be exposure to radiation, sheet metal work, and mineral oils used as laxatives or for dermatitis.

Clinical Manifestations, Diagnosis, and Prognostic Factors

The clinical features and etiology and management of manifestations of MM are summarized in Table 1.

The diagnosis of MM needs a combination of clinical, pathological and laboratory evidence. Table 2 summarizes the method of evaluating patients with MM. Table 3 summarizes the criteria for making the diagnosis.

Without therapeutic intervention the median survival is approximately 7 months, which increases to 2.5-3 years with conventional chemotherapy. Only 3.5% of patients survive more than 10 years. The Dune-Salmon clinical staging system attempts to estimate the tumor burden in the patient. This staging system is mostly based on the manifestations of the disease and presence of renal failure (Table 4). Patients with a low tumor load and creatinine

Beta-2 microglobulin ([beta]2M) and C-reactive protein (CRP) levels have prognostic significance in MM. Since the predictive value of CRP and [beta]2M are independent, a combination of these two parameters has been used for stratification of patients into risk groups (Table 5).

Additional risk factors include the following: The plasma cell labeling index (PCLI) measures the proliferative activity of plasma cells. The median survival of MM patients with a PCLI or = 3%. Unfavorable karyotypes, e.g., translocations or abnormalities involving 11q or partial or complete deletion of chromosome 13 reflect a particularly poor outcome in patients receiving autotransplants. Elevated LDH levels are associated with a median survival of only 9 months and a low response rate (20%) to standard chemotherapy. Plasmablastic myeloma (> or = 2% plasmablastic myeloma cells in the bone marrow), presence of monoclonal plasma cells in the peripheral blood and especially plasma cell leukemia (an absolute plasma cell count in the peripheral blood of > or =2.0 _ 10^sup 9^/L are among the poor prognostic factors.

On the other hand, patients with smoldering myeloma (serum myeloma protein level >3 g/dl but 10% atypical plasma cells in the bone marrow, without anemia, renal insufficiency, hypercalcemia, or multiple skeletal lesions) are usually asymptomatic and have a better prognostic outcome. They should not be treated until there is clear evidence of disease progression or symptomatic disease (median time to progression to myeloma is 26 months). MGUS is characterized by the presence of a serum M protein of

APPROACH TO THERAPY FOR SYMPTOMATIC MYELOMA

Patients with asymptomatic myeloma usually have low tumor burden and should be monitored closely. Symptomatic patients or those with anemia, recurrent infections, hypercalcemia, or renal insufficiency require treatment. For patients requiring treatment, sufficient evidence from both the French randomized and a pair-mate comparison is available that high dose chemotherapy is superior to standard dose treatment in terms of complete response rate and event-free and overall survival. Peripheral blood stem cell transplants can be performed safely up to age 70 and in patients with renal failure as well. Usually patients will receive one to three cycles of chemotherapy prior to stem cell mobilization to improve the patients general condition and to attain a significant tumor reduction. This is best achieved with the VAD regimen. Pulse high dose dexamethasone may be superior because of the rapidity of response and its stem cell sparing capacity. Patients who are not candidates for high-dose chemotherapy should be treated for at least 12 months or until a plateau phase (stable M protein for at least two months) has been obtained. Because of the high treatment-related mortality, allogeneic bone marrow transplantation should probably only be performed in patients with poor prognostic factors or failure to achieve at least a 50% reduction in M protein.

CYTOTOXIC THERAPY

Standard Dose Therapy.

Oral melphalan and prednisone have remained the standard therapy for symptomatic myeloma. They provide control of symptoms and tumor reduction by > or =50% in approximately half the patients. One of the most popular combination regimens is vincristine added to Adriamycin^sup R^ and prednisone (VAD). There is no clear advantage of combination chemotherapy over melphalan plus prednisone. VAD-based regimens in previously untreated myeloma patients result in a 55% response rate with near-maximum response occurring after two cycles of treatment. High dose dexamethasone alone in refractory myeloma has 15% less response rate but is equally effective as VAD in terms of survival. By adding cyclophosphamide to VAD (CVAD), 40% of VAD-resistant myeloma patients show an objective response.

Patients responding to standard chemotherapy have a much better survival than nonresponders (43 months vs. 19 months) with no survival advantage for complete responders over partial responders. Most responders attain a plateau phase, that is, a state of tumor quiescence. The duration of this plateau phase is variable and has direct survival impact with longest survival in patients with prolonged plateau phase. Response rate for refractory/relapsed MM remains very low. A recent report suggest that a regimen including doxil (D), vincristine (V), dexamethasone (d) and thalidomide (T) (DVd-T) for relapsed/refractory MM can be very effective in this group.

Autologous Stem Cell Transplantation.

Because minor dose increases in alkylating agents, as used in the combination chemotherapies, had not resulted in improvement of overall survival, it appeared worthwhile to try more pronounced escalation. This was first piloted by McElwain et al. using a dose of 100-140 mg/m^sup 2^ of melphalan. Three of 5 previously untreated patients achieved a biochemical and bone marrow complete remission, compared to a 3% complete response rate with standard therapy. However, the procedure-related mortality was high at 15-20%, mainly due to prolonged aplasia, a problem correctable with a bone marrow transplant. Bone marrow transplantation allowed further intensification of therapy: the dose of melphalan could be escalated to 200 mg/m^sup 2^ or total body irradiation could be added to melphalan at 140 mg/m^sup 2^. Further progress was made by supporting high dose chemotherapy with mobilized peripheral blood stem cells (PBSC) to shorten aplasia further. With peripheral blood stem cell support, transplant-related mortality is

The most important prognostic variables for event-free and overall survival after autotransplant are cytogenetics, duration of standard-dose therapy, and the [beta]2M level prior to the first transplant. Although it is still unclear whether MM patients can be cured with autotransplants, based on the lack of a plateau in the survival curves, it seems likely that in the low-risk group of patients (i.e., those with favorable cytogenetics,

Tandem transplants: Double transplants

Barlogie et al. at the University of Arkansas advocate tandem autologous stem cell transplants 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 transplants. Mortality rates were 3% during induction, 1% with the first transplant, and 4% with the second transplant. By intent-to-treat analysis, the CR rate was 26% with the first transplant and 41% after the second transplant. Overall survival with this approach was 68 months. Data from 4 different randomized trials on this treatment strategy were presented recently. The most mature trial reported an increase in response rates and event-free survival with tandem transplantation. The final results of these trials will clarify this important issue.

Triple transplants

To decrease the toxicities of high dose therapy even further and to increase dose intensity of melphalan delivered, we initiated a pilot, phase I/II study in which three courses of melphalan, also know as 1-phenylalanine mustard (1-PAM), at 100mg/m^sup 2^ were given at 21-day intervals (1-PAMx3). One day after each treatment, previously collected PBSC were infused. Nine consecutive patients with MM were enrolled to determine the tolerance to and efficacy of the 3 transplants in the outpatient setting. Five pts were judged to be standard risk (at least a partial response to 4 cycles of VAD) and 4 patients, who required additional chemotherapy (the DCIE regimen; BritJHematol 1997;96:746-8) to achieve at least a partial response, were adjudged to be at high risk. Post-transplant consolidation therapy with interferon, thalidomide, or rituximab was given. Recovery of blood counts after the last course of therapy was at a median of 10 days for granulocytes > 500/[mu]L and 19 days for platelets > 20,000/[mu]L. At a median follow-up for survivors of 24 months, Kaplan-Meier actuarial estimates are: 1) probability of relapse - 22% (Figure 1), 2) relapse free survival - 65% (see Figure 2), and 3) overall survival - 65%. Standard risk patients have done considerably better than high risk patients (data not shown). Taken together these results are comparable to those reported by the ABMTR for single autologous transplants with 200mg/m^sup 2^ of 1-PAM. The major differences in our approach are that it is delivered in the outpatient setting and it delivers 50% more melphalan in the same time period (2 months) as it takes to recover from a single transplant. Furthermore, the patients tolerated post-transplant consolidation.

Consolidation therapy after transplant

Several approaches have been suggested after autotransplant to eliminate minimal residual disease in order to prevent clinical recurrence. These include interferon, thalidomide (with or without dexamethasone), monoclonal antibodies, or combination chemotherapy. It is too early to determine if any of them will have an effect on survival. Some are discussed briefly below along with an interesting new drug for MM.

Interferon-alpha

Encouraging results had been reported with interferon-alpha therapy as maintenance therapy after 12 cycles of standard treatment with prolongation of response and survival in MM patients responding to conventional chemotherapy sparking interest in using interferon after transplant even though subsequent studies failed to show a survival advantage. Prolonged interferon-alpha treatment prior to autologous transplantation makes collection of adequate amounts of peripheral stem cells very difficult.

Thalidomide with and without dexamethasone

Recently thalidomide, an agent with antiangiogenic properties, has emerged as an active agent for relapsed and refractory myeloma. In the first trial of thalidomide in relapsed myeloma most patients had failed stem cell transplantation. The overall response rate defined as a decrease in monoclonal protein levels by 25% or more was 32%. An update to this study confirms the activity of thalidomide in 169 patients with relapsed myeloma with overall survival at 2 years of 48%. Several similar studies have confirmed these results with response rates between 25% to 35% for relapsed myeloma. The median response duration is approximately 9 to 12 months. The mechanism of thalidomide antitumor activity and teratogenicity is still unclear and may also be related to immunomodulation, inhibition of tumor necrosis factor alpha production, free radical-mediated oxidative damage to DNA, or effects on cell surface adhesion molecules.

Monoclonal antibodies

The anti-CD20 antibody, rituximab, has been suggested as a candidate for treatment of MM. Myeloma cells are either negative or weakly positive for CD20 antigen. A group from Italy recently suggested that maintenance therapy with anti-CD20 monoclonal antibody after autologous stem cell transplantation in MM may be associated with early relapse. CD52 on the other hand is expressed on MM cell lines and the preliminary results of at least one study suggests that the anti-CD52 antibody, alemtuzumab, significantly reduced tumor in 3 out of 4 chemotherapy resistance cases.

Clarithromycin (Biaxin(R))

An unexpected and surprising activity of this agent in newly diagnosed and previously treated MM patients was reported recently by Durie et al. Patients received a dose of 500 mg of clarithromycin twice daily. Thirty patients were enrolled with the longest follow-up being 1 year. Six patients had a > or =75% and seven had a > or =50% reduction in M protein associated with improvement in clinical status. Responses were also observed in patients failing standard or high-dose chemotherapy.

SUMMARY

Despite all the new advances, treatment of multiple myeloma remains very challenging. Table 6 summarizes the outcomes of some of the commonly used treatments from different clinical trails. Treatment with conventional chemotherapy alone resulted in median survival from 18 to 30 months. Aggressive treatments like VBMCP (vincristine, bleomycin, melphalan, cyclophosphamide, predisone) although resulting in higher response rates, resulted in higher treatment-related mortality and did not have any effect on median and 5 year survival. High dose chemotherapy with stem cell support increased the median survival to around 60 months and resulted in durable complete responses in a significant number of the patients. Some of the newer and promising treatments for multiple myeloma are summarized in Table 7.

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Mehrdad Abedi, MD, and Gerald J. Elfenbein, MD

Mehrdad Abedi, MD, is Assistant Professor of Medicine, Boston University School of Medicine.

CORRESPONDENCE:

Mehrdad Abedi, MD

Adele R. Decof Cancer Center

Roger Williams Medical Center

825 Chalkstone Avenue

Providence, RI 02908

Phone: (401) 456-5312

Fax: (401) 456-5759

mabedi@rwmc.org

Copyright Rhode Island Medical Society Aug 2003
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