Introduction

High-dose intravenous melphalan was explored in myeloma in the 1980s, originally without^{1, 2} and then with autologous marrow transplantation.³ Relapse after autotransplantation is almost inevitable in myeloma, making the disease somewhat unique among hematologic malignancies, where there is often an expectation of cure after an autograft. While relapse relatively early after autotransplantation is a problem in acute leukemia, there is a plateau on the survival curve after a few years. In contrast, myeloma patients continue to relapse with the passage of time showing no plateau in the survival curve. Figure 1 illustrates this interesting phenomenon by comparing event-free (EFS) and overall (OS) survival after melphalan-based conditioning regimens and autotransplantation in first-remission acute leukemia^{4, 5, 6} and myeloma.⁷ Although autotransplantation is not curative in myeloma in the conventional sense in the vast majority of patients, there are significant benefits with the therapy in terms of prolongation of survival with good—indeed normal—quality of life.

Figure 1.

Autologous transplantation in first remission acute leukemia versus myeloma with no prior exposure to alkylating agents illustrating the lack of events after 4 years in acute leukemia compared to continued occurrence of events in myeloma at 10 years.

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We first proposed the term 'operational cure'⁸ for a small minority of patients who were in a continuous first CR 10 years or longer after high-dose therapy. It is now widely appreciated that survival after relapse following autotransplantation can be prolonged, and excellent responses including CR can be achieved in a reasonable proportion of patients. Even this 'discontinuous CR' (multiple episodes of remissions punctuated by courses of therapy)⁹ can be accompanied by good quality of life. We therefore propose using the term 'operational cure' for any survival with good quality of life beyond 10 years. Long-term follow-up studies of high-dose therapy with single⁷ or tandem¹⁰ transplantation show that one-third of the patients are alive at 10 years—and can be considered to be operationally cured.

The effect of age

The traditional upper age limits for high-dose therapy in the early 1990 s—50 years and then 60 years—were initially broken in myeloma when patients in their 60s and 70s underwent autotransplantation.^{11, 12} Although disease-specific biologic features are the major determinants of prognosis in myeloma, age also makes a modest contribution to outcome in patients receiving high-dose melphalan (Figure 2). EFS is not affected as much as OS by age, probably reflecting the fact that all age groups benefit nearly equally from transplantation but older individuals tolerate or respond to salvage therapy poorly—and also die of other causes.

Figure 2.

The effect of age on overall survival (P<0.0001) and event-free survival (P=0.021) after 200 mg/m² melphalan and autotransplantation.

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The median age at diagnosis in myeloma is 67 years. The median age at the time of autotransplantation in myeloma in published reports is usually at least a decade less than that. The bulk of the available literature therefore addresses the outcome of 'young' patients—those under the age of 65 years. This study reviews high-dose therapy in this group of patients.

Questions about high-dose therapy and autotransplantation

Table 1 shows questions surrounding autotransplantation. In addition to reviewing published data to answer these questions, we have provided additional analyses on selected subgroups of patients from the Royal Marsden Hospital (RMH) (Figures 1, 2, 3, 4, 5 and 6). Aggregate results of the outcome of these 451 patients (410 aged <65 years) were published recently.⁷ Over half of these patients received induction therapy (VAMP or C-VAMP) at RMH, and the rest received variable induction therapy elsewhere. All underwent a planned single autograft after 200 mg/m² melphalan between February 1985 and October 2001 at RMH, and were followed up through December 2003.

Figure 3.

Survival from the time of the salvage second autograft for patients relapsing after the first autograft: the effect of time to disease progression (P=0.002) (age at first autograft <65 years).

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Figure 4.

Outcome of 242 patients under 65 years of age who had attained partial remission after induction chemotherapy, and were alive without disease progression 100 days following an autograft with 200 mg/m² melphalan. The outcome of patients attaining CR after the transplant is superior.

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Figure 5.

Identification of subgroups with excellent and very poor prognosis (age <65 years at the time of transplantation). 'Best' includes albumin >4 g/dl and 2-microglobulin <2 mg/l, and 'worst' includes albumin <4 g/dl and 2-microglobulin 4 mg/l. These represent values just before autotransplantation.

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Figure 6.

The effect of time to disease progression after autograft on survival following relapse in patients under 65 years of age at the time of the transplant.

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Table 1 - High-dose chemotherapy and autotransplantation in myeloma: the questions.

Full table

Is high-dose chemotherapy with autotransplantation beneficial?

High-dose and conventional-dose chemotherapy have been compared prospectively in a number of studies.^{13, 14, 15, 16, 17} Table 2 summarizes the prospective randomized studies comparing transplantation to no transplantation. Three of the five studies showed benefit from high-dose therapy with higher response rates, and longer EFS and OS. An update of the British Myeloma VII study showed that the benefit for autotransplantation in terms of OS (P=0.0004) and EFS (P=0.0001) was maintained with longer follow-up.¹⁸

Table 2 - Randomized studies comparing high-dose therapy to conventional-dose therapy in patients under 65 years.

Full table

The Spanish study¹⁶ showed no benefit from high-dose therapy at all. The reasons for this may have been one or more of the following: only patients responding to induction therapy were included, eight additional cycles of VBMCP-VBAD chemotherapy were administered to the conventional therapy group after initial induction, 18% of patients in the conventional therapy group underwent transplantation, and 30% of patients in the high-dose therapy group received 140 mg/m² melphalan with total-body irradiation; a regimen shown to be inferior to 200 mg/m² melphalan.^{19, 20, 21, 22}

The French GMA study¹⁷ showed a trend towards better EFS and better quality of life as measured by time without symptoms, treatment and treatment toxicity (TwiSTT) with high-dose therapy. However, OS was not better in the transplant group. The reasons for lack of difference in OS may have been similar to those discussed above for the Spanish study.

The heterogeneity of treatment approaches shown in Table 2 makes comparison between studies difficult. However, it is noteworthy that in the studies summarized in Table 2, between 10 and 26% of patients randomized to high-dose therapy did not receive it, and between 9 and 23% of patients randomized to conventional-dose therapy underwent autotransplantation; either as primary therapy or as salvage therapy. Since the studies were analyzed on an intent-to-treat basis, the net effect of crossover between groups is to reduce the magnitude of the difference made by high-dose therapy.

The Dutch prospective HOVON 24 study²³ has not been included in the table because its design is more akin to a single versus tandem transplantation study (see below). All patients received 3–4 cycles of VAD induction chemotherapy followed by randomization to an autograft with cyclophosphamide-TBI or no transplant. All patients received high-dose cyclophosphamide and underwent stem cell collection after randomization. Subsequently, both groups received 140 mg/m² melphalan in two divided doses 2 months apart without stem cell support. This was followed by an autograft in the high-dose therapy group. There was no difference in overall response rates, EFS or OS between the arms in this study in the preliminary report.

When should transplantation be performed?

Autotransplantation can be performed as consolidation therapy after initial induction (as discussed above; 'early') or for disease that has relapsed following an initial response ('late'). Two randomized studies have addressed the early versus late transplant question.^{24, 25}

In the French study,²⁴ 185 patients were randomized to early (n=91) or late (n=94) high-dose therapy after undergoing stem cell apheresis during recovery from 1 to 2 courses of CHOP. The late transplant group received 1–20 cycles of VMCP (median 8), and 73 (90% of those eligible) received high-dose therapy for primary refractory or relapsed disease. Eighty-nine (98%) of the early transplant group underwent transplantation as planned. The conditioning regimen comprised BCNU, etoposide, 140 mg/m² melphalan and TBI. The 4-year OS was 66% in the early group and 61% in the late. The median OS exceeded 5 years in both groups. The median EFS was significantly longer (39 months) in the early group compared to 13 months in the late. The average TwiSTT duration was better for early (28 months) than for late (22 months) transplantation.

In the US Intergroup study,²⁵ patients received 3–4 cycles of VAD chemotherapy followed by randomization to transplant (n=261) or no transplant (n=255), and then high-dose cyclophosphamide and stem cell collection. Since stem cells were collected in all randomized patients and there was a provision for salvage autotransplantation at relapse in the non-transplant group (although this was not mandatory), this was really an early versus late transplant study. The conditioning regimen comprised 140 mg/m² melphalan and 12 Gy TBI, and 213 (82%) of the patients randomized to autotransplantation underwent the procedure. The non-transplant group patients received VMCP maintenance therapy until progression. Outcomes from the time of randomization were comparable for the transplant and non-transplant groups: 7-year EFS and OS were 17 and 38% in autograft group, and 14 and 38% in the non-transplant group. Follow-up was available on 157 patients relapsing on the non-transplant arm; 87 (55%) of whom underwent autotransplantation as salvage therapy. The median OS of these patients from the time of relapse was 30 months, compared with 23 months for the 70 relapsing patients who did not receive a salvage autograft (P=0.13). No quality of life studies were done; an important point to consider because patients in the non-transplant arm remained on therapy for longer periods of time. Use of a TBI-based conditioning regimen was an obvious factor contributing to poor outcome of the autografted group in this study. Other concerns are high patient attrition rates through stages of therapy, a significant proportion of patients lost to follow-up, and lack of information on the conditioning regimen used for salvage transplantation.

The disadvantages of waiting until relapse include a longer time on chemotherapy, possible organ deterioration (for example, renal failure) should the disease relapse explosively, and a higher risk of eventual myelodysplastic syndrome if treated with low-dose alkylating agent therapy. The advantage of waiting is avoidance or postponement of transplantation in a small proportion of patients who may survive for several years without disease progression.

Myeloma patients at all phases of the disease can potentially benefit from high-dose therapy, albeit to a variable extent.^{2, 26} As with any malignant disease, when a given therapeutic modality is used later in the disease (that is, with more advanced disease), its absolute benefit diminishes due to the emergence of resistance.

What is the role of tandem transplantation?

The University of Arkansas Total Therapy 1 program comprised remission induction with 2–3 cycles of VAD, high-dose cyclophosphamide with GM-CSF for stem cell mobilization, EDAP (etoposide, dexamethasone, cytarabine, cisplatin) intensification, followed by tandem autotransplantation (two elective procedures a few months apart) and maintenance therapy with interferon-2b.²⁷ The conditioning regimen was 200 mg/m² melphalan for the first transplant. Patients achieving partial remission (PR) received the same regimen for the second transplant, whereas those not attaining PR received melphalan-TBI or melphalan-cyclophosphamide. Of 231 patients enrolled, 13% had only one transplant and 71% completed both. The overall CR and PR rates were 41 and 42% for the entire group of patients, and 51 and 44% for the 165 patients completing two transplants. Long-term follow-up of the study¹⁰ showed median OS and EFS of 68 and 31 months, and 15-year actuarial OS and EFS probabilities of 17 and 7% respectively. Despite limitations such as patient selection, these are extraordinary results.

The question of single versus double transplantation is a contentious one, and has been explored in one published study²⁸ and several ongoing studies from which preliminary data are available.^{29, 30, 31, 32} These have been summarized in Table 3.

Table 3 - Randomized studies comparing single versus double autotransplantation.

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While the Dutch HOVON 24 study (see above) showed no difference between the no transplant ('single intensive') and the transplant ('double intensive') arms initially,²³ longer term follow-up of 303 randomized patients altered this finding.³³ 81% of all patients received both cycles of intermediate-dose melphalan, and 79% of patients randomized to double-intensive therapy underwent an autograft. CR rate was higher with double-intensive therapy (28% versus 13%; P=0.002), but the overall response rate was comparable. Median EFS was 22 months in the double intensive arm and 20 months in the single-intensive arm (P=0.014). However, OS was comparable (median 55 versus 50 months; P=0.39), possibly because a high proportion of patients from the single-intensive arm underwent autotransplantation at first relapse.

In the IFM 96 study,²⁸ patients who did not have at least a very good partial response after the first transplant had a significant benefit from the second; with 7-year OS rates being 11% in the single-transplant group and 43% in the double-transplant group (P<0.001). Patients who had at least a very good partial response did not appear to benefit significantly from the second autograft. However, even in this subgroup, the OS curves appear as if they are starting separate at the 6-year mark in favor of the double-transplant group.

In the Bologna 96 study,^{29, 30} patients who did not attain CR or near-CR after the first transplant had longer EFS and OS if they were in the double-transplant group. Interestingly, this benefit was seen even in patients who did not attain CR or near-CR after having received the second transplant. Patients who were in CR or near-CR after the first transplant did not appear to benefit significantly from a second transplant.

In the MAG95 study,³² OS was superior (P=0.04) after tandem transplantation compared with single in the subgroup of patients receiving unmanipulated stem cells—the use of which is standard practice now; CD34+ selection/purging having been abandoned.

It is not known if tandem transplantation is superior to one transplant followed by a second transplant as salvage therapy of relapsed disease. A second high-dose therapy procedure is thought to be an effective salvage treatment for relapse after prior autotransplantation in selected patients.^{34, 35} As Figure 3 shows, a second autograft is worth considering as salvage therapy in patients whose disease has progressed 2 years after the first autograft. Findings of a randomized study from Tunisia suggest that tandem transplantation and salvage autotransplantation for disease relapsing after one transplant are equivalent.³⁶ However, this study has not been published yet, and the median follow-up of under 2 years is too short to allow any definitive conclusions to be drawn. Additionally, the 2-year survival rates appear to be lower than expected.

A reasonable approach may be to consider tandem autotransplantation in patients who are not in CR or near-CR after the first transplant. In those who are in CR or near-CR, the second transplant could be a salvage procedure in the future rather than an elective tandem procedure. However, until there are longer-term data from the IFM 96 study as well as mature data from the other ongoing studies that can answer the question definitively, there is no evidence to support a dogmatic stand that a planned second autograft should not be performed in patients who are in CR or near-CR after the first transplant.

Is response to induction therapy important?

Most myeloma patients are autografted before they have attained CR, and most patients attaining CR do so as a result of the transplant. The prognosis of patients with primary refractory disease is poor if they are treated with conventional-intensity therapy. High-dose chemotherapy improves their outcome.^{37, 38} We have shown that patients with primary refractory disease can benefit from autotransplantation to the same extent as those with responsive disease,³⁹ because outcome is dependent upon the final response after the transplant independent of response to induction chemotherapy. These data have been confirmed by other groups.⁴⁰

However, whether patients not responding to induction chemotherapy should proceed immediately to stem cell collection and autotransplantation or receive salvage therapy to attain a response is unknown. We believe that a patient who is refractory to simple induction therapy such as pulse dexamethasone could benefit from the addition of a drug such as thalidomide, lenalidomide or bortezomib to derive a response before stem cell collection and transplantation, or from proceeding straight to stem cell collection and transplantation. The path chosen should be dictated by logistics. By contrast, a patient initially treated with more powerful induction chemotherapy such as thalidomide–dexamethasone should probably proceed immediately to stem cell collection and transplantation if the disease is unresponsive.

A pilot study showed that patients undergoing stem cell collection at the time of diagnosis after a single 5-day pulse of high-dose methylprednisolone and then receiving high-dose melphalan and autotransplantation as primary therapy did as well as those receiving several cycles of induction chemotherapy and then undergoing transplantation with the disease under some control.⁴¹ This observation calls into some question the contribution of induction chemotherapy to disease control if a transplant is planned. However, induction therapy is clearly essential to stabilize organ function and to improve performance status while the logistics of stem cell collection and transplantation are being organized.

What is the role of new agents before autotransplantation?

Large phase II investigations of high-dose therapy have used standard cytotoxic combinations such as VAD²⁷ or VAMP/C-VAMP⁶ for induction. The Arkansas induction therapy approach after Total Therapy 1 changed to single-agent dexamethasone⁴² with the supposition that the intensity of post-induction therapy nullified any difference that induction therapy may have made. It was subsequently shown that VAD and dexamethasone were equivalent for induction in patients subsequently undergoing autotransplantation.⁴³

Based on a randomized study that showed significantly higher response rates with the combination of thalidomide and dexamethasone compared to dexamethasone alone, the combination has become standard first-line therapy despite significantly greater toxicity and expense.⁴⁴ However, the equivalent survival in the two arms⁴⁴ suggests that subsequent autotransplantation overcame any early differences.⁴⁵ Post-autograft EFS and OS of patients induced with VAD, dexamethasone and thalidomide–dexamethasone was identical in a retrospective study.⁴⁶ A Greek cooperative randomized study has been reported to show superior OS and EFS after autotransplantation in the thalidomide arm, but no details are available currently.⁴⁷

In some patients, thalidomide may have a temporary inhibitory effect on stem cell mobilization with G-CSF. The drug, if used, should be stopped at least 4 weeks before mobilization. Deep vein thrombosis is a major problem in patients receiving thalidomide or lenalidomide with dexamethasone for induction. Prophylactic or therapeutic anticoagulation, in addition to the inconvenience, expense and risk of bleeding, makes subsequent management such as insertion of a large-bore apheresis catheter difficult.

Data exist showing excellent activity of lenalidomide and bortezomib in newly diagnosed myeloma with lack of detrimental effect on stem cell collection. However, in patients who are to undergo autotransplantation, any beneficial effect of using one of the three new agents for induction is not apparent and cannot be recommended as a routine. Indeed, data from the Arkansas Total Therapy 2 study⁴⁸ show that patients getting thalidomide from the beginning of therapy and continuing it all the way through have better response rates and EFS than patients not receiving thalidomide: however, their post-relapse survival is much poorer leading to OS rates that are comparable. These results should lend a strong note of caution against widespread inclusion of novel agents in pre-transplant treatment regimens outside of clinical trials.

Unless a patient is on clinical trial involving one of the new agents, our standard approach is to use three 4- or 5-week cycles of pulse dexamethasone for induction. Thalidomide or bortezomib are added if there is inadequate response to the first or second cycle. After a total of three cycles of therapy, stem cells are mobilized with CDEP (cyclophosphamide, dexamethasone, etoposide, cisplatin). Patients with high-risk disease (high lactate dehydrogenase (LDH), high plasma cell labeling index, plasma cell leukemia) are treated with aggressive combination chemotherapy from the beginning.

Should maintenance therapy be used post-transplant?

Since autotransplantation is not curative in myeloma, the use of post-transplant maintenance therapy to prolong the duration of disease control is logical. An early randomized study showed significantly longer EFS with interferon-, OS was comparable.⁴⁹ Based on this study, the use of interferon became widespread (Tables 2 and 3). However, the drug is myelosuppressive and causes significant constitutional symptoms leading to poor quality of life. With the availability of new drugs such as thalidomide⁵⁰ and a recent study showing no benefit for interferon maintenance,²⁵ interferon has fallen out of favor.

The use of corticosteroids as maintenance therapy is reasonable in patients whose disease is not known to be steroid-refractory. Although direct evidence in autografted patients is lacking, a study of prednisone maintenance in conventionally treated patients⁵¹ provides rationale for this approach. Thalidomide^{52, 53, 54} with or without prednisone has been used as maintenance therapy after autograft. A recent randomized study showed better EFS and OS in patients receiving thalidomide maintenance after autotransplantation.⁵⁵ However, the benefit was confined to patients not in CR or a very good PR after the autograft suggesting that thalidomide may have helped through elimination of detectable disease rather than suppressing minimal residual disease. In patients with disease known to be responsive to steroids pre-transplant, it is unclear if steroids or thalidomide should be used.

Neither thalidomide nor corticosteroids have a role in patients with disease not responding well to thalidomide–dexamethasone induction. In such patients and in those who cannot tolerate steroids or thalidomide, bortezomib at the dose of 1.3 mg/m² once every 4 weeks is being evaluated. In our experience, this is tolerated well and is convenient. However, there are no data on efficacy.

Periodic post-transplant intensive chemotherapy has been explored.^{56, 57, 58} While this is tolerated well, there is no compelling evidence showing benefit. Immunotherapeutic approaches in the setting of minimal residual disease after autotransplantation such as idiotype vaccination⁵⁹ have not yet been shown to be beneficial.

Is the extent of the final response relevant?

Does the achievement of CR affect outcome? There is no definite answer to this question because results of some high-dose therapy studies show better outcome for patients achieving CR,^{48, 57} whereas others do not.^{25, 27, 60} The most important difficulty with evaluating the contribution of CR to outcome in a group of patients is the differential impact of disease biology on attainment of CR and response duration. For example, some powerful adverse risk factors such as elevated LDH and IgA isotype are associated with a higher likelihood of attaining CR but lower response duration.

Figure 4 shows the outcome of patients who had achieved PR after induction chemotherapy, and then underwent an autograft after 200 mg/m² melphalan. After excluding patients relapsing or dying of toxicity within 100 days, it is clear that those achieving CR eventually have a better outcome than those staying in PR. Age, albumin and 2-microglobulin levels were comparable for the two groups, but no other prognostic factor information was available.

Should the goal of therapy in every myeloma patient therefore be to achieve CR? Since CR, despite the limitations of its definition and its heterogeneity in myeloma, represents maximal cytoreduction, it is logical to pursue CR as a goal in practice. However, the magnitude of therapy required to achieve CR should be considered in making decisions. No data exist currently to support stopping the standard sequence of therapy (that is, eliminating high-dose chemotherapy altogether) and proceeding to maintenance therapy in a patient attaining CR with induction. However, in a patient who is in CR at the time of the first autograft or attains CR after the first autograft, it may be reasonable to avoid a second transplant and start maintenance therapy as an alternative to tandem transplantation. It is unclear if patients not achieving CR even after a second transplant benefit from additional intensive therapy after transplantation (not just maintenance therapy) specifically aimed at achievement of CR.

What are the factors affecting outcome?

Several adverse prognostic factors have been identified (Table 4).⁴⁵ The most widely available of these are albumin and 2-microglobulin, which have been combined to generate an 'International Staging System'. The median survival of high-dose chemotherapy-treated patients with ISS stages I, II, and III, on an intent-to-treat basis, is 90, 61 and 40 months respectively.⁶¹ These survival durations have been measured from the start of initial therapy, and therefore are approximately 6 months longer than those measured from the time of transplantation.

Table 4 - Adverse prognostic factors.

Full table

The poor post-transplant outcome of some subgroups of patients—such as those with del(13) or 13q- detected on metaphase karyotyping^{62, 63}—is sometimes construed as a lack of benefit of high-dose therapy. This is incorrect. Such an interpretation requires data showing no difference in outcome between conventional- and high-dose therapy in these subgroups—and not simply data showing poor outcome after high-dose therapy. It is possible that these subgroups may have an even poorer outcome after conventional-dose therapy. Unfortunately, none of the studies (Table 2) has compared the impact of cytogenetics and other prognostic factors in the context of chemotherapy intensity. A more reasonable interpretation of the available data is that autotransplantation does not eliminate the difference between good- and poor-risk patients, and that further improvement in the outcome of such patients requires a change in strategy.

Extreme regression analysis is an interesting method to identify small subgroups of patients with very good or very poor prognosis.⁶⁴ An example of such an analysis is shown in Figure 5, where the combination of pre-transplant albumin >4 g/l and 2-microglobulin <2 mg/l identified 45 of 410 (11%) with the best OS (median 13.7 years), the combination of 2-microglobulin >4 mg/dl and albumin <4 g/dl identified another 40 (10%) patients with the worst OS (median 1.5 years), and the remaining 325 patients had an intermediate outcome (median OS 6.4 years).

Interestingly, the duration of response after a single autograft (EFS length) is a determinant of OS after disease progression. Figure 6 shows the outcome of 252 patients experiencing disease progression up to 1 year (n=58), 1–2 years (n=64), 2–5 years (n=95), and more than 5 years (n=35) following an autograft. Patients experiencing disease progression within 100 days or non-relapse events have been excluded. It is clear that survival after relapse is much better in patients with longer prior EFS suggesting that these patients had more favorable disease biology to begin with and that this advantage persisted after relapse. This is in contrast to the Total Therapy 2 study where patients enjoyed longer EFS on the thalidomide arm but had shorter OS following relapse.⁴⁸ The patients shown in Figure 6 had not been treated with novel agents before relapse. This suggests that prior exposure to novel agents such as thalidomide, particularly long-term continuous exposure, may modify the biological nature of the disease adversely in some way.

Gene expression profiling may eventually turn out to be the most important prognostic predictor in myeloma. However, data available currently are limited and inconsistent.

Who should undergo transplantation?

Most patients with symptomatic myeloma that requires initiation of treatment could potentially benefit from high-dose therapy and autotransplantation. Older age^{11, 12} and renal failure,^{65, 66, 67, 68} traditional barriers to transplantation, do not constitute absolute contraindications to intensive therapy these days. Decisions to proceed or not can rarely be absolute, and the final assessment of risks versus benefits is unique to each individual requiring careful analysis—and cannot be made by a cursory review of limited information.

Patients with significant, active, concomitant, and unrelated medical conditions that are likely to become aggravated as a result of or are likely to be impediments to intensive therapy should probably not undergo transplantation. This could include severe cardiomyopathy, ischemic heart disease, cerebrovascular disease, marked liver impairment, and pulmonary problems. Older individuals and those with renal failure do experience greater morbidity than others. A case could be made for deferring high-dose therapy in such patients if they have responded very well to induction therapy. However, lack of adequate response to first- or second-line induction therapy would counterbalance any worry about greater morbidity with transplantation in such patients. After all, it is easier to justify high-risk approaches if there are no superior alternatives.

The risk of transplantation in terms of prolonged pancytopenia and the likelihood of life-threatening complications increases significantly if an adequate number of progenitor cells is not infused. Most published work in myeloma and other diseases suggests that 2 10⁶ CD34+ cells per kg constitutes the minimum acceptable dose for a transplant. The lack of an adequate number of cells is a relative contraindication.

What about small, selected patient subgroups with poor outcome following autotransplantation such as those shown in Figure 5? An excellent case can be made for enrolling such patients on clinical trials exploring novel treatment approaches as an alternative to standard autotransplantation. However, in the absence of access to appropriate studies, proceeding with high-dose therapy is appropriate until alternatives proven to be superior are found.

What is the optimum technique for performing autografts?

Exposure to as little as 6 months of therapy with alkylating agents can affect stem cell collection and post-transplant hematologic recovery adversely. Stem cell-damaging agents such as melphalan and the nitrosoureas should either not be used in patients who may be candidates for autotransplantation, or stem cells should be collected before commencement of such therapy. Extensive local radiation—particularly to the pelvis—can also compromise stem cell collection. Unlike most hematologic malignancies, patients with myeloma may undergo more than 1 autograft—and sometimes more than 2.⁶⁹ They may also benefit from chemotherapy for post-transplant relapse, an intervention that could result in prolonged pancytopenia. It is therefore important to collect enough stem cells before embarking upon the first autograft to ensure that possible future needs are taken care of. It is difficult to collect stem cells in patients with myeloma who have already undergone autotransplantation.⁷⁰

There is no place for CD34+ selection to reduce tumor cell contamination, because this approach has no beneficial effect on relapse rates and survival.⁷¹ Indeed, it may increase morbidity by delaying immune reconstitution.³²

High-dose melphalan is the best conditioning regimen for myeloma.^{19, 20, 21, 22} The usual dose is 200 mg/m² although a reduction in dose to 140 mg/m² or so is appropriate under certain circumstances such as renal failure or poor performance status to improve the safety profile. The higher melphalan dose is appropriate for most patients under 70 years^{11, 12, 72} but for those aged 70 or older,⁷³ a reduction in the dose is usually warranted.

There may be place for exploration of alternative regimens in patients who have undergone a first autograft using 200 mg/m² melphalan and have attained limited incremental response after the transplant. In a recent study of tandem transplantation in high-risk myeloma patients, the melphalan doses for the first and second autografts was 200 and 220 mg/m², respectively.⁷⁴ Half the patients received a murine anti-interleukin-6 antibody in a randomized fashion with the second transplant. This had no impact on response rates, EFS or OS. Before this strategy is discarded, it may be worth exploring in patients with lower-risk disease. Amifostine has been shown to reduce mucositis in myeloma patients after 200 mg/m² melphalan without increasing relapse.⁷⁵ A small (n=24) pilot study has shown encouraging results using amifostine cytoprotection with 280 mg/m² melphalan and autotransplantation in myeloma.⁷⁶ This approach merits additional study.

When the disease burden is estimated after transplantation to determine response, it is important to wait for about 8 weeks or so as paraprotein may take several weeks to clear.⁷⁷ The standard criteria for evaluation of response remain those proposed by the EBMT, IBMTR, and ABMTR.⁷⁸ The new international criteria⁷⁹ are yet to be validated because the role of newer laboratory techniques such as the serum-free light chain assay in assessing response remains to be determined.^{80, 81}

How should relapsed disease be treated?

The majority of autografted myeloma patients eventually experience relapse (Figure 1).^{7, 10} Appropriate management of relapsed disease is critical to improving the duration of 'discontinuous remission' and extending 'operational cure' as discussed earlier. Broadly, the salvage therapy approaches that are used in patients with relapsed disease include newer agents such as thalidomide, bortezomib, and lenalidomide, more conventional approaches such as high-dose dexamethasone, and melphalan-prednisone, and repeat high-dose chemotherapy with autotransplantation or allogeneic hematopoietic stem cell transplantation. Clinical trials of investigational agents are always reasonable options if no other promising approach is available.

The appropriate therapy for a given situation depends on the nature of the disease, age, organ function, bone marrow function, prior treatment, the availability of stem cell donors, and access to novel agents.^{26, 45, 82} A detailed discussion of this is beyond the scope of this study. A therapeutic trial of thalidomide, bortezomib or lenalidomide is essential after relapse in all patients. Similarly, autotransplantation is essential at some stage of the disease in most patients younger than 65–70 years.

As Figure 3 shows, a repeat autograft is worth considering in patients whose disease had remained under control for at least 2 years following the initial autograft. Selected patients relapsing after a year may also benefit from salvage autotransplantation.⁸³ Third autografts have been used as salvage therapy in patients with available cells and adequate performance status. Allogeneic transplantation has also been used as salvage therapy after 1–2 prior autografts.⁸⁴

Can new agents replace autotransplantation?

The discovery of the dramatic activity of thalidomide in relapsed and/or refractory myeloma,^{50, 85} and 20% 7-year survival in patients with near-terminal disease⁴⁵ transformed the treatment of recurrent myeloma. This was followed by the development of two other active agents, bortezomib⁸⁶ and lenalidomide.^{87, 88}

These agents are also very active in untreated disease leading to speculation that these newer agents may replace high-dose chemotherapy. Only a prospective, randomized study can answer this question. The limited available evidence suggests that median response durations in patients treated with frontline thalidomide-dexamethasone⁸⁹ and bortezomib-dexamethasone⁹⁰ are of the order of 18–24 months—and are thus shorter than the response durations seen after autotransplantation. It is therefore premature to consider abandonment of the use of high-dose therapy.

As thalidomide has improved the survival of autograft recipients relapsing in the thalidomide era compared to those relapsing before its availability,¹⁰ it is logical to expect that the sequential use of autografts and novel agents would be superior to the use of novel agents without high-dose therapy. For an individual patient, it is important to plan therapy in a manner that uses all active agents—chemotherapeutic or otherwise—appropriately and sequentially as none of the treatments need be mutually exclusive.

References

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