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Multiple Myeloma:Role of Allogeneic Transplantation

Multiple Myeloma:Role of Allogeneic Transplantation

ABSTRACT: An estimated 14,600 new cases of multiple myeloma will be diagnosed in the United States in 2002. Multiple myeloma remains an incurable disease despite significant improvements in complete response rates and overall survival through the use of autologous stem cell transplantation. Allogeneic transplantation offers the advantage of a tumor-free graft and a graft-vs-myeloma effect but has been associated with a high mortality rate from transplant-related complications—primarily graft-vs-host disease (GVHD). As immunotherapy for patients with relapsed myeloma, donor lymphocyte infusion has resulted in response rates of over 50%, but many of these responses are not durable. In addition, donor lymphocyte infusion is associated with a significant risk of moderate-to-severe GVHD. In an attempt to decrease the high transplant-related mortality of conventional allogeneic transplants and to employ the proven efficacy of immunoreactive donor T lymphocytes, the use of nonmyeloablative transplants or "mini-transplants" is increasing. This approach has succeeded in significantly reducing transplant-related mortality but still may not be sufficient in producing long-term remissions or cures in myeloma patients. A combination of an autologous transplant (to achieve maximal cytoreduction) and a mini-transplant with donor lymphocyte infusion (for the immunoablative effect of alloreactive T lymphocytes) followed by maintenance therapy (thalidomide [Thalomid], steroids, cytokines, vaccines) for long-term immunomodulation is being investigated as a potential cure for this challenging disease. [ONCOLOGY 16:1268-1276, 2002]

Multiple myeloma is an incurable plasma cell
dyscrasia arising from clonal B cells. Approximately 14,600 new cases of the
disease will be diagnosed in the United States in 2002.[1] Median survival with
conventional chemotherapy is about 36 months. Most patients with multiple
myeloma have symptoms from their disease at presentation and require prompt
therapy.

Pretransplant Chemotherapy

Conventional chemotherapy regimens in this setting have been
stagnant for many years; the preferred initial regimen for potential transplant
patients has long been infusional vincristine and doxorubicin with oral
dexamethasone for 3 to 4 months.[2] Alkylator-based chemotherapy regimens such
as MP (melphalan [Alkeran], prednisone) or VBMCP (vincristine, carmustine [BiCNU],
melphalan, cyclophosphamide [Cytoxan, Neosar], prednisone) represent other
commonly used standard regimens for initial treatment.[3,4]

In previously untreated patients, response rates with each of
these regimens range from 50% to 60%, with comparable median survivals.[5] The
major toxicity of alkylator-based therapy is myelosuppression, which may result
in prolonged cytopenias and/or myelodysplasia/acute leukemia.[6,7] In addition,
alkylator-based chemotherapy damages the stem cell compartment, decreasing the
ability to collect adequate peripheral blood stem cells. Hence, alkylator-based
chemotherapy may be more suitable for patients who are not considered candidates
for transplantation.

A recent report from the Mayo Clinic has demonstrated that
the combination of thalidomide (Thalomid) and dexamethasone pulsing resulted in
response rates exceeding 70%.[8] The benefit of maintenance therapy is as yet
uncertain. A number of poor prognostic factors associated with a short survival
and/or inferior response to chemotherapy have been identified. These include
elevated C-reactive protein and beta-2-microglobulin levels, abnormalities
involving chromosome 13, increased soluble interleukin (IL)-6 receptor levels,
high plasma cell labelling index, and high bone marrow microvessel density.

Autologous Stem Cell Transplantation

The use of high-dose therapy with autologous hematopoietic
stem cell transplantation has improved outcomes in patients with newly diagnosed
multiple myeloma. A randomized French trial of 200 newly diagnosed patients
under 65 years old conclusively demonstrated that high-dose therapy with
autologous hematopoietic stem cell transplant was superior to conventional
therapy. Rates of overall response (81% vs 57%), complete remission (22% vs 5%),
5-year event-free survival (28% vs 10%), and overall survival (52% vs 12%) were
all superior in the transplant group (all statistically significant, P < .05).[9]

Investigators at the University of Arkansas reported the
results of a pair-mate analysis comparing VAD chemotherapy (vincristine,
doxorubicin [Adriamycin], dexamethasone) to tandem high-dose therapy with
autologous hematopoietic stem cell transplant. They, too, showed superior
results in the high-dose therapy group (event-free survival: 49 vs
22 months, overall survival: 62+ vs 48 months).[10]

Thus, high-dose therapy with autologous hematopoietic stem
cell transplant is now considered the standard of care for newly diagnosed
multiple myeloma patients. For patients younger than 78 years (per Health Care
Financing Administration guidelines), an autologous peripheral blood stem cell
transplant should be considered as consolidation of induction therapy, if there
are no significant comorbidities precluding this option. It is preferable that
hematopoietic stem cells be collected before exposing the patient to alkylating
agents and/or prolonged periods (> 12 months) of chemotherapy.

Tandem high-dose therapy with autologous stem cell transplant
has shown improved event-free and overall survival in nonrandomized
studies,[11-13] and three randomized trials comparing single to tandem
transplants are awaiting final analyses. Even with tandem transplant, a plateau
on survival curves has not been achieved. Although approximately 50% of patients
who undergo high-dose therapy are alive at 5 years, the relapse rate continues
to increase over time.

In contrast to these studies, a retrospective Spanish
Registry study in 77 patients with mutliple myeloma (who were deemed
transplant-eligible but who received conventional chemotherapy) demonstrated a
5-year median survival rate similar to that seen in the above trials.[14] Thus,
patient selection may play an important role in response and survival with
different treatment options.

Allogeneic Transplantation

As suggested above, there does not appear to be a plateau in
disease-free survival after high-dose therapy with autologous hematopoietic stem
cell transplant, indicating that cures even with tandem autologous
transplantation are unlikely. This may be due to either infusion of stem cell
grafts contaminated with myeloma cells or the inability to eradicate minimal
residual disease. In an attempt to avoid tumor cell contamination in autografts,
three different groups have studied the use of highly purified CD34+ cells
(positive selection) to support single or tandem high-dose therapy. However,
these trials have failed to demonstrate a significant improvement in
progression-free or overall survival.[15,16,16a]

Allogeneic transplantation offers two advantages: the absence
of tumor-contaminating grafts and the benefit of a graft-vs-myeloma
effect.[16,17] However, allogeneic transplant is an option for a small minority
of patients (5%-10%) who have human leukocyte antigen (HLA)-compatible donors
and are under age 60.

EBMT Registry

The largest experience in allogeneic transplant data was
reported by the European Group for Blood and Marrow Transplantation (EBMT). They
initially reported on 266 patients with a 51% complete response, an overall
treatment mortality rate of approximately 40%, and actuarial survival rates of
30% at 4 years and 20% at 10 years. An update of the EBMT database in over 600
patients showed complete remission rates of 15% (by stringent criteria) with a
transplant-related mortality of 20% (1994-1998 data). The relapse rate after
the first 2 years was small, but late relapses continue to occur.[18]

Single-Institution Trials

The largest single-institution studies have been reported by
groups in Seattle (Bensinger et al) and Arkansas (Mehta et al). Bensinger et al
reported the results of a trial in which 106 patients underwent allogeneic
transplant.[19] Approximately 70% of these patients had chemotherapy-resistant
disease, and the majority were very heavily pretreated. The investigators
observed a 50% treatment-related mortality within the first 100 days and a 57%
overall treatment-related mortality at 1 year. At a median follow-up of 4 years,
23% were alive, but only 16% were progression-free.

These results are similar to findings reported by the
Arkansas group in patients with similar characteristics.[20] Table 1 shows
results of single-institution trials with allogeneic transplants in mutliple
myeloma.[18-23] Again, late relapses have been observed.

Larger Studies

Alternative donor transplants have equally poor outcomes as
those of HLA-identical sibling transplants. Ballen et al reported the National
Marrow Donor Program experience in 71 myeloma patients undergoing unrelated
donor transplant.[21] They reported a 40% transplant-related mortality. The
relapse rate was 35% at 3 years, and only 17% were alive at 5 years
posttransplant. Similarly poor results have been reported utilizing alternative
donors by the Seattle group.[19]

One of the debates surrounding the outcome of allogeneic
transplants concerns the fact that they have routinely been performed in heavily
pretreated patients, often after autologous transplant. This argument is not
supported by the North American Intergroup trial (S9321), which allowed
allogeneic transplantation in patients under 55 who had HLA-identical sibling
donors. Patients underwent allogeneic transplant following four cycles of VAD
and high-dose cyclophosphamide (4.5 g/m²).
This arm of the study was prematurely closed when the transplant-related
mortality reached 41% in the first 36 patients (R. Kyle, personal
communication).

Case-matched comparative studies between allogeneic and
autologous transplantation have been reported: All have shown superior outcomes
with autologous transplant, given a higher transplant-related mortality
associated with allogeneic transplant.[24-27] Of interest, Gahrton et al
compared the outcomes of syngeneic (n = 25), allogeneic (n = 125), and
autologous (n = 125) transplantation in the EBMT database. The overall
4-year survival from transplant with syngeneic transplantation was 77%, with
autotransplantation, 46%, and with allotransplantation, 31%.[24]

Recommending
Allogeneic Transplant

The selection of patients for allogeneic transplant entails a
difficult clinical decision. Heavily treated patients and those with
chemotherapy-resistant disease have a uniformly dismal outcome. Newly diagnosed
patients with chemotherapy-sensitive disease may derive long-term remissions and
potential cures. When the clinician is counseling his or her patient, it may be
difficult to recommend the allogeneic approach, with its 20% to 50% early
transplant-related mortality and less than 30% 5-year survival (compared with
the superior data for autologous transplant—less than 2% transplant-related
mortality and projected 5-year median survival of over 50%). Perhaps patients
with extremely poor prognostic features, chromosome 13 deletions, and elevated
beta-2-microglobulin may be candidates for allogeneic transplant.

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