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
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 celldyscrasia arising from clonal B cells. Approximately 14,600 new cases of thedisease will be diagnosed in the United States in 2002. Median survival withconventional chemotherapy is about 36 months. Most patients with multiplemyeloma have symptoms from their disease at presentation and require prompttherapy.
Conventional chemotherapy regimens in this setting have beenstagnant for many years; the preferred initial regimen for potential transplantpatients has long been infusional vincristine and doxorubicin with oraldexamethasone for 3 to 4 months. Alkylator-based chemotherapy regimens suchas MP (melphalan [Alkeran], prednisone) or VBMCP (vincristine, carmustine [BiCNU],melphalan, cyclophosphamide [Cytoxan, Neosar], prednisone) represent othercommonly used standard regimens for initial treatment.[3,4]
In previously untreated patients, response rates with each ofthese regimens range from 50% to 60%, with comparable median survivals. Themajor toxicity of alkylator-based therapy is myelosuppression, which may resultin prolonged cytopenias and/or myelodysplasia/acute leukemia.[6,7] In addition,alkylator-based chemotherapy damages the stem cell compartment, decreasing theability to collect adequate peripheral blood stem cells. Hence, alkylator-basedchemotherapy may be more suitable for patients who are not considered candidatesfor transplantation.
A recent report from the Mayo Clinic has demonstrated thatthe combination of thalidomide (Thalomid) and dexamethasone pulsing resulted inresponse rates exceeding 70%. The benefit of maintenance therapy is as yetuncertain. A number of poor prognostic factors associated with a short survivaland/or inferior response to chemotherapy have been identified. These includeelevated C-reactive protein and beta-2-microglobulin levels, abnormalitiesinvolving chromosome 13, increased soluble interleukin (IL)-6 receptor levels,high plasma cell labelling index, and high bone marrow microvessel density.
The use of high-dose therapy with autologous hematopoieticstem cell transplantation has improved outcomes in patients with newly diagnosedmultiple myeloma. A randomized French trial of 200 newly diagnosed patientsunder 65 years old conclusively demonstrated that high-dose therapy withautologous hematopoietic stem cell transplant was superior to conventionaltherapy. 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%) wereall superior in the transplant group (all statistically significant, P < .05).
Investigators at the University of Arkansas reported theresults of a pair-mate analysis comparing VAD chemotherapy (vincristine,doxorubicin [Adriamycin], dexamethasone) to tandem high-dose therapy withautologous hematopoietic stem cell transplant. They, too, showed superiorresults in the high-dose therapy group (event-free survival: 49 vs22 months, overall survival: 62+ vs 48 months).
Thus, high-dose therapy with autologous hematopoietic stemcell transplant is now considered the standard of care for newly diagnosedmultiple myeloma patients. For patients younger than 78 years (per Health CareFinancing Administration guidelines), an autologous peripheral blood stem celltransplant should be considered as consolidation of induction therapy, if thereare no significant comorbidities precluding this option. It is preferable thathematopoietic stem cells be collected before exposing the patient to alkylatingagents and/or prolonged periods (> 12 months) of chemotherapy.
Tandem high-dose therapy with autologous stem cell transplanthas shown improved event-free and overall survival in nonrandomizedstudies,[11-13] and three randomized trials comparing single to tandemtransplants are awaiting final analyses. Even with tandem transplant, a plateauon survival curves has not been achieved. Although approximately 50% of patientswho undergo high-dose therapy are alive at 5 years, the relapse rate continuesto increase over time.
In contrast to these studies, a retrospective SpanishRegistry study in 77 patients with mutliple myeloma (who were deemedtransplant-eligible but who received conventional chemotherapy) demonstrated a5-year median survival rate similar to that seen in the above trials. Thus,patient selection may play an important role in response and survival withdifferent treatment options.
As suggested above, there does not appear to be a plateau indisease-free survival after high-dose therapy with autologous hematopoietic stemcell transplant, indicating that cures even with tandem autologoustransplantation are unlikely. This may be due to either infusion of stem cellgrafts contaminated with myeloma cells or the inability to eradicate minimalresidual 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 inprogression-free or overall survival.[15,16,16a]
Allogeneic transplantation offers two advantages: the absenceof tumor-contaminating grafts and the benefit of a graft-vs-myelomaeffect.[16,17] However, allogeneic transplant is an option for a small minorityof patients (5%-10%) who have human leukocyte antigen (HLA)-compatible donorsand are under age 60.
The largest experience in allogeneic transplant data wasreported by the European Group for Blood and Marrow Transplantation (EBMT). Theyinitially reported on 266 patients with a 51% complete response, an overalltreatment mortality rate of approximately 40%, and actuarial survival rates of30% at 4 years and 20% at 10 years. An update of the EBMT database in over 600patients showed complete remission rates of 15% (by stringent criteria) with atransplant-related mortality of 20% (1994-1998 data). The relapse rate afterthe first 2 years was small, but late relapses continue to occur.
The largest single-institution studies have been reported bygroups in Seattle (Bensinger et al) and Arkansas (Mehta et al). Bensinger et alreported the results of a trial in which 106 patients underwent allogeneictransplant. Approximately 70% of these patients had chemotherapy-resistantdisease, and the majority were very heavily pretreated. The investigatorsobserved 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 theArkansas group in patients with similar characteristics. Table 1 showsresults of single-institution trials with allogeneic transplants in mutliplemyeloma.[18-23] Again, late relapses have been observed.
Alternative donor transplants have equally poor outcomes asthose of HLA-identical sibling transplants. Ballen et al reported the NationalMarrow Donor Program experience in 71 myeloma patients undergoing unrelateddonor transplant. They reported a 40% transplant-related mortality. Therelapse rate was 35% at 3 years, and only 17% were alive at 5 yearsposttransplant. Similarly poor results have been reported utilizing alternativedonors by the Seattle group.
One of the debates surrounding the outcome of allogeneictransplants concerns the fact that they have routinely been performed in heavilypretreated patients, often after autologous transplant. This argument is notsupported by the North American Intergroup trial (S9321), which allowedallogeneic transplantation in patients under 55 who had HLA-identical siblingdonors. Patients underwent allogeneic transplant following four cycles of VADand high-dose cyclophosphamide (4.5 g/m²).This arm of the study was prematurely closed when the transplant-relatedmortality reached 41% in the first 36 patients (R. Kyle, personalcommunication).
Case-matched comparative studies between allogeneic andautologous transplantation have been reported: All have shown superior outcomeswith autologous transplant, given a higher transplant-related mortalityassociated with allogeneic transplant.[24-27] Of interest, Gahrton et alcompared the outcomes of syngeneic (n = 25), allogeneic (n = 125), andautologous (n = 125) transplantation in the EBMT database. The overall4-year survival from transplant with syngeneic transplantation was 77%, withautotransplantation, 46%, and with allotransplantation, 31%.
The selection of patients for allogeneic transplant entails adifficult clinical decision. Heavily treated patients and those withchemotherapy-resistant disease have a uniformly dismal outcome. Newly diagnosedpatients with chemotherapy-sensitive disease may derive long-term remissions andpotential cures. When the clinician is counseling his or her patient, it may bedifficult to recommend the allogeneic approach, with its 20% to 50% earlytransplant-related mortality and less than 30% 5-year survival (compared withthe superior data for autologous transplantless than 2% transplant-relatedmortality and projected 5-year median survival of over 50%). Perhaps patientswith extremely poor prognostic features, chromosome 13 deletions, and elevatedbeta-2-microglobulin may be candidates for allogeneic transplant.
It has become increasingly apparent that a significant partof the curative potential of allogeneic transplants is related to alloreactive Tlymphocytes with activity against tumor cells. This is particularly true forB-cell malignancies and chronic myelogeneous leukemia, which is the prototype ofallogeneic T-cell immunoreactivity against tumor cells. The most compellingclinical evidence consists of (1) higher relapse rates in syngeneic transplantswith no graft-vs-host disease (GVHD); (2) the increased relapse rate in T-cell-depletedallografts resulting in reduced GVHD; and (3) the efficacy of donor lymphocyteinfusions resulting in complete remission in nearly 70% to 80% of patients withcytogenetic relapse.
The effectiveness of donor lymphocyte infusion in inducingremissions in recurrent disease following allogeneic transplant has beendemonstrated in most hematologic malignancies and some solid tumors, withsuccess rates ranging from approximately 10% to 15% in acute lymphocyticleukemia to 70% to 80% in chronic myelogenous leukemia. This principle hasalso been proven in patients who have relapsed after transplant from anunrelated donor.
In multiple myeloma, it has been proven that immunoreactive Tlymphocytes can induce clinical remissions in patients who have relapsedfollowing allogeneic transplant.[16,17] The largest trial to demonstrate theefficacy of donor lymphocyte infusion in multiple myeloma was conducted byLokhorst et al, who reported on 52 such procedures in 27 patients withrelapsed disease. A total of 14 patients responded (52%), including six completeresponses (22%). The median survival for the whole group was 18 months;five patients remained in remission at a median of 31 months post-donorlymphocyte infusion. Nevertheless, the procedure was associated with asignificant incidence of GVHDacute cases in 56% and chronic cases in 26%.
Similar findings were updated by this group, who reporteddata on 39 patients receiving 68 donor lymphocyte infusions, with acute GVHDseen in 47% of patients and chronic GVHD in 33%. Moreover, GVHD remains aproblem after donor lymphocyte infusion in myeloma. Favorable prognostic factorsreported by Lokhorst and colleagues were a T-cell dose exceeding 1.1 x108cells/kg, response to reinduction chemotherapy before donor lymphocyte infusion,and chemotherapy sensitivity prior to allotransplant. In an attempt to reducethe drawback of GVHD, Alyea and coworkers infused a purified donor lymphocytegraft consisting predominantly of CD4+lymphocytes after depleting CD8+lymphocytes. The treatment-related mortality was only 3%, and five of sixrelapsed myeloma patients responded.
Allogeneic transplant in multiple myeloma is associated withexcessive toxicity, with transplant-related mortality ranging from 20% to 50%.In addition, even in the most favorable group of patientsie, those who haveachieved complete remission prior to transplant, are less than 1 year fromdiagnosis, and have low beta-2-microglobulin levelsover 50% will relapsewithin 5 years. Thus, it remains to be proven whether allogeneic transplantalone is curative.
As discussed above, donor lymphocyte infusions asimmunotherapy for patients with relapsed disease results in response rates ofover 50%. Unfortunately, many of these responses are not durable. In addition,donor lymphocyte infusion is associated with a significant risk ofmoderate-to-severe GVHD.
Due to the excessively high transplant-related mortalityassociated with conventional allogeneic transplants and the proven efficacy ofimmunoreactive donor T lymphocytes in inducing a graft-vs-myeloma effect, thecurrent trend is to utilize nonmyeloablative transplants("mini-transplants") for many hematologic malignancies includingmultiple myeloma. The basis of the mini-transplant is to provide sufficientimmune suppression to allow donor engraftment and subsequent graft-vs-tumoreffect.
Preliminary data have shown a high rate of complete remissionafter nonmyeloablative transplantation, even in heavily treated patients withresistant disease. Atthe American Society of Hematology meeting in December 2000, a large number ofabstracts described nonmyeloablative therapy using different conditioningregimens. Table 2 summarizes some of these trials.[33-39]
The largest study of multiple myeloma patients undergoingnonmyeloablative transplants was reported by Lalancette et al, who presented theEBMT results in 50 patients. All patients engrafted, and 20 of 27 evaluablepatients achieved 95% donor engraftment. A new complete response was observed in16 patients, continuous complete response in 1, new partial response in 7, andcontinuous partial response in 12.
Transplant-related mortality at 1 year was 32%, and therelapse incidence at 1 year was 13%. Actuarial survival at 1 and 2 years was54% and 40%, respectively. Patients with good-risk features (complete responseor first or second partial response) had a 1-year overall survival,transplant-related mortality, and relapse rate of 83%, 13%, and 11%, compared tothe poor-risk group (beyond a second partial response or refractory), with 25%,67%, and 20%, respectively. Again, unfortunately, many of the observed responseswere not durable.
Another recently reported series from the Arkansas group on16 poor-risk multiple myeloma patients who received a nonmyeloablativeconditioning regimen (with melphalan, 100 mg/m²)followed (in 14 patients) by donor lymphocyte infusiongiven either to attainfull donor chimerism or to eradicate residual diseasehad a 75% overallresponse rate with five sustained complete responses at 1-year follow-up.However, 10 patients developed acute GVHD, and most of this group progressed tochronic GVHD. Three patients died of GVHD complications.
Although currently very popular within the transplantcommunity, nonmyeloablative transplants are probably not sufficient to producecures in multiple myeloma patients. The transplant-related mortality is lowerthan that observed with conventional allogeneic transplant but remainssubstantially higher than that seen after autologous transplant (10%-67%).Even with donor lymphocyte infusionwhether preemptive in high-risk patientsor for persistent disease/relapsedoes not produce durable remissions in themajority of patients.
The Seattle group reported an intriguing pilot trial ofautologous transplant (with melphalan, 200 mg/m²)followed by nonmyeloablative allogeneic transplant. This appealing strategymaximizes tumor cytoreduction with the autologous transplant to optimize theimmunoablative graft-vs-myeloma effect and eradicate minimal residual disease. Atotal of 32 patients completed the planned two transplants, and nearly 100%donor chimerism was achieved by day 56. The complete response rate was 53%, andthe transplant-related mortality, 16%. The median follow-up, however, was only202 days. The Eastern Cooperative Oncology Group has initiated amulti-institutional protocol (E4A98) utilizing the same approach.
The efficacy of posttransplant maintenance therapy has notyet been established. A variety of treatments have been utilized, includinginterferon-alpha, chemotherapy, corticosteroids, and immunotherapy.[12,13,40]There is growing interest in thalidomide, with or without corticosteroids, asmaintenance therapy, based on the cytoreductive activity of both types of agentsas monotherapy. Thalidomide has been known to have activity in relapsed multiplemyeloma, but has not been tested as posttransplant maintenance therapy.
An area of intense investigational interest is posttransplantimmunomodulation, achieved via anti-idiotype vaccines, DNA vaccines, or idiotype-pulseddendritic cells. Studies of anti-idiotype vaccines have demonstrated the abilityto generate humoral and/or cellular responses in some patients aftertransplantation. Whether this type of immune enhancement will result in aclinically relevant outcome remains to be proven.
Another immunomodulation modality involves the use oflymphocyte and/or dendritic cell stimulatory cytokines, such as IL-12, IL-2 (Proleukin),or granulocyte-macrophage colony-stimulating factor (GM-CSF, Leukine), eitheralone or in combination. These studies are in their infancy.
Multiple myeloma remains a challenge for the oncologist dueto the low proliferative rate of clonal plasma cells resulting in theprogressive development of chromosomal abnormalities. These malignant plasmacells demonstrate native chemotherapy resistance even at the time of diagnosis,and this, in turn, accounts for the extremely low complete response rates (5%-10%)to conventional induction therapy.
High-dose therapy with autologous hematopoietic stem celltransplantation results in improved response rates as well as increasedevent-free and overall survival. However, no plateau is appreciated even aftertandem transplant. Allogeneic transplants are promising but associated withexcessive transplant-related mortality. Nonmyeloablative transplant (mini-allograft)trials have been encouraging, showing prompt allogeneic engraftment and reducingtransplant-related mortality, but longer follow-up is needed to compare survivaldata with other standard therapies.
The use of donor lymphocyte infusion has shown impressiveresponse rates even in refractory/relapsed myeloma, but GVHD seems to be asignificant factor contributing to transplant-related mortality in this setting.Ultimately, a treatment strategy that utilizes maximal cytoreduction (autologoustransplant), immunoablation by alloreactive T lymphocytes (nonmyeloablativetherapy with donor lymphocyte infusion) followed by long-term immunomodulationto prevent disease recurrence (thalidomide with or without corticosteroids,cytokines, or vaccines) may provide the optimal control and potential cure ofthis challenging disease. In addition, we need to more fully understand theclinical implications of different prognostic factors, and use this informationto stratify suitable treatment approaches to individual patients.
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