The first trial to show the benefit of high dose (HD) therapy in multiple myeloma was the IFM90 trial, comparing conventional dose chemotherapy with HD therapy (Total Body Irradiation [TBI] 8 Gy and melphalan 140 mg/m2) and autologous stem cell transplantation (ASCT) that found significantly increased response rate, event-free survival and overall survival (OS) with HD therapy.r The benefit was most marked for patients who achieved complete response (CR) or very good partial response (VGPR) with a 5 year survival of 72%.
The use of the HD of melphalan (200 mg/m2) dose is primarily based upon a 1995 prospective, randomised French cooperative study, that compared melphalan 140 mg/m2 plus 8 Gy TBI versus melphalan 200 mg/m2 in 282 newly diagnosed, previously untreated, symptomatic patients less than 65 years of age.rThe melphalan 200 mg/m2 regimen was better tolerated with less toxicities overall.The median duration of event-free survival was similar in both arms (21 months) but survival at 45 months was significantly better in patients receiving melphalan 200 mg/m2 (65% versus 45 %).r
Similar results were seen for melphalan 200 mg/m2 conditioning pre-ASCT in the various studies that followed. Studies using higher doses of melphalan, the addition of alkylating agents or more intensive preparative regimens have not demonstrated significant improvements either in terms of response rates or in OS.rrrrrrrrrr
Of note is the phase III study of the Italian group comparing HD melphalan (200 mg/m2) with intermediate dose (100 mg/m2). Median progression free survival (PFS) was superior in the 200 mg/m2 group (31.4 v 26.1 p= 0.01) but with no difference in OS.r
As such ASCT with melphalan 200 mg/m2 conditioning continues to be regarded as standard of care in patients aged under 65 diagnosed with multiple myeloma. It remains to be shown whether this will stay the case as the use of multi-agent chemotherapy regimens incorporating biological agents increases and as more highly efficient new drugs become available. At this stage, however, available evidence suggests that ASCT upgrades the response to novel agents (e.g. bortezomib/lenalidomide) containing induction regimens, and that ASCT and novel agents are complementary rather than alternative. This has been confirmed with the publication of the results of a multinational randomised study comparing consolidation utilising cyclophosphamide - dexamethasone- lenalidomide with melphalan 200 mg/m2 and ASCT.rGroups were further randomised to receive maintenance post consolidation with lenalidomide and prednisone or lenalidomide alone. The group receiving melphalan 200 mg/m2 and ASCT had a significantly better median PFS (43.2 months v 28.3 months) and at 3 years, a significantly better OS (86% v 73%). Lenalidomide maintenance had no effect on either PFS nor OS at 3 years.rA conceptually similar phase III study evaluating consolidation with oral melphalan, prednisone and lenalidomide versus HD melphalan 200 mg/m2 as well as post consolidation maintenance therapy with or without lenalidomide has been published. Once again HD melphalan and ASCT appears to be a superior consolidative intervention with demonstrably better PFS and OS (median PFS 43 v 22.4 months; OS at 4 yrs. 86.1 % v 65.3%). Moreover in this trial, lenalidomide maintenance was associated with improved PFS but not OS.r
While tandem melphalan-conditioned ASCT has been demonstrated to confer a survival advantage in studies by the French and Italian groups, this was only in patients who had a VGPR with the first transplant.rr The results of these studies are also made more difficult to interpret in light of the recent introduction of novel agents as part of induction, consolidation and/or maintenance therapy in myeloma. It has been established, for example, that a similar benefit to tandem transplantation can be obtained with thalidomide as maintenance post ASCT.r
Long term follow up of the German single v tandem ASCT study confirms overall non inferiority of single ASCT v tandem ASCT for both PFS and OS. Again tandem ASCT improved CR and n CR response rates compared to single ASCT.r
HD melphalan and ASCT has also been evaluated in the group of patients with myeloma and dialysis dependent end stage renal failure. A large retrospective analysis from MD Anderson of patients with renal failure, dialysis dependence and myeloma undergoing HD melphalan and auto-SCT found all grade organ toxicities were higher in the melphalan 200 mg/m2 group compared to 140 mg/m2. As such the lower melphalan dosing schedule may be preferred in this group.r
The EBMT Chronic Malignancies Working Party published a report which aimed to compare outcomes in patients receiving melpahlan 200 mg/m2 vs 140 mg/m2 as conditioning before ASCT.r This study included 1964 ASCT episodes.The key findings of the study included;
- Patients undergoing ASCT and in <PR, melphalan 200 mg/m2 was favoured in terms of OS, PFS and relapse risk
- Patients undergoing ASCT and in VGPR/CR, melphalan 140 mg/m2 was favoured in terms of OS, PFS and relapse risk
- Melphalan 200 mg/m2 does not overcome the effects of poor-risk cytogenetics or advanced ISS stage
It concluded that dose selection is still physician driven. Even though age, renal function and overall performance status were a consideration for reducing to melphalan 140 mg/m2, there was no interaction found between these parameters, melphalan dose and OS. The data supports current practice and understanding that ASCT is safe and effective in fit older patients. Remission status at the time of first transplant should be considered when deciding on the melphalan dose.r Further research is required for melphalan 140 mg/m2 conditioning in ASCT in combination with novel therapies as an alternative transplantation regimen.
Primary Systemic Amyloidosis
Auto-BMT is associated with a high response rate in patients with primary systemic amyloidosis (AL), followed by a significant amelioration of organ damage in most responding patients. Unfortunately, ASCT is associated with a high toxicity, reflecting underlying organ damage secondary to amyloid deposition.
Conditioning regimens in AL are based on adaptations of HD melphalan. The usual melphalan dose is 200 mg/m2 although a ‘risk-adapted’ approach, with dose reduction to 140 mg/m2 used in higher-risk patients in order to reduce transplant-related toxicity.r Criteria for defining ‘high-risk’ patients are; age >60, increased creatinine level, performance status (PS) 2 or compensated cardiac failure. Reduced dose melphalan has been associated with a decreased response rate in some studiesr but not in others.r
Overall, HD melphalan results in significant responses (VGPR and CR) in 50-60% of patients, with complete responses (defined by a negative immunofixation and normal free immunoglobulin light chain) in about one third of patients.
Median time to achieve a response is 3-4 months, although organ responses (which follow haematological responses in most patients) can take up to 2 years. Unlike most series in patients with myeloma, the overall relapse rate is low, especially among patients who achieve a CR after ASCT. In the Boston series reported by Skinner et al, the relapse rate at 10-years post-SCT in patients who achieved a CR was 21%.r Together, the high response rates and low relapse rates in patients with AL who survive ASCT translate into long-term (3-5 year) survival rates of 45-60% in most large series. (Table 1)
Unfortunately, ASCT with melphalan conditioning is also associated with a high risk of mortality and morbidity in patients with AL, with most series demonstrating a treatment related mortality (TRM) of 11-43%. (Table 1) Cardiac arrhythmias, cardiac failure, cardiogenic shock, gastrointestinal bleeding and infection are the most frequent complications causing early TRM, while renal insufficiency and renal failure develop in up to 20% of those who survive ASCT.
Several factors have been shown to be predictive of TRM and transplant outcome in AL including;
- cardiac involvement (as indicated by clinical features – congestive cardiac failure, thickened intraventricular wall on cardiac echocardiography, and/or elevated cardiac biomarkers – cardiac troponins cTnT and cTnI, and pro-brain natriuretic peptide NT-proBNP)r
- renal failurer
- involvement of more than two organsr
- higher pre-transplant levels of serum free light chains (FLC)r
- degree of response achieved after transplantrr
- poor performance statusr
Longer term follow up of various AL amyloidosis cohorts suggest improving TRM in more recent time periods with overall improving post transplant survival. Transplantation in specialised centres performing a critical number of autografts per annum (>4) and HD melphalan conditioning appears to be other important factors in reducing TRM and long term survival.r
Table 1: Outcome of patients with primary amyloidosis undergoing autologous transplant
||No of patients
||Overall response rate (CR) %
||Overall survival (%)
||13 (100 day)
||60 (3 year)
| CIBMTR (multicentre)r
18 (30 day)
27 (1 year)
66 (1 year)
56 (3 year)
| UK (multicentre)r
||23 (100 day)
||50 (5 year)
||11 (100 day)
||60 (5 year)
|French Intergroup (MAG-IFM)r
||21 (100 day)
||45 (3 year)
||7.5 (100 day)
||60;43;30 (@ 5,10, 15 years)
While long-term survival appears to be prolonged after ASCT, especially in patients who achieve a CR after transplant, there are few studies that have directly compared ASCT with standard dose chemotherapy, and the results of these are conflicting. Recently the 20 year updated experience of the Boston group has been published confirming the importance of a haematologic CR in determining long term survival.r
A case-control study conducted by the Mayo Clinic, which compared ASCT with standard therapy, showed better survival in the intensively treated group, with a 4-year survival of 71% vs 41%.r However this study was a non-randomised retrospective review and many of the patients in the ‘control’ arm received only melphalan and prednisolone. In contrast, a recent RCT comparing HD melphalan with standard dose melphalan and dexamethasone showed a better outcome in patients not randomised to ASCT when analysed on an intention-to-treat basis.rHowever the results of this study must be interpreted with caution as it included only 50 patients in each arm and only two-thirds of those randomised to HD therapy actually underwent ASCT. Indeed, when the analysis was restricted to those who actually received the assigned therapy there was no difference found between the two arms.
The benefit offered by ASCT and the population who benefits most from ASCT therefore still remains to be clarified. Moreover, it remains unclear what difference treatment with new agents, including bortezomib and the immunomodulators (thalidomide and lenalidomide) will make to outcomes of patients with AL amyloidosis.
Multiple Myeloma Survivalrr
© Blood 2002
Figure 1: IFM95 Comparison of 200 mg/m2 melphalan vs. 8 Gy TBI with melphalan 140 mg/m2 as conditioning regimens: overall survival according to treatment arm. While the median duration of event-free survival was similar in both arms (21 months), survival at 45 months was significantly better in patients receiving melphalan 200 mg/m2, 66% versus 46 % (P= 0.05).
Figure 2: IFM95: overall survival after relapse according to treatment arm. There was a trend toward a better outcome for patients treated with 200 mg/m2 melphalan compared with 8 Gy TBI plus melphalan 140 mg/m2 as conditioning regimes. Post relapse treatment was not standardised. Half the patients in arm B received a second cycle of intensive therapy with autologous haematopoietic cell transplantation compared with only 25% in arm A.r
Figure 3: PFS and OS in patients undergoing autoSCT vs MPR consolidation and lenalidomide maintenance v no maintenancer
© New England Journal of Medicine 2014
Figure 4: Cumalative incidence of relapse after autologous stem cell transplantation for patients who received conditioning with melphalan 140 mg/m2 (MEL140) or 200 mg/m2 (MEL200). All comparisons are adjusted for: age at transplant, renal function, prior proteasome inhibitor treatment, gender, status of disease, and Karnofsky score.20
© haematologica 2018
AL Amyloidosis Survivalr
Figure 4: Kaplan-Meier estimates of overall survival. A) Overall survival in 629 AL amyloidosis patients receiving HD melphalan and autografting. B) OS according to CR versus no CR
© Blood 2015
Transplant related toxicityr
© Blood 2002