The expert reference panel supported publication of this protocol on the basis of the information summarised below. The committee was most strongly influenced by the prospective, randomised French cooperative study that compared melphalan 140 mg/m2 plus 8 Gy total body irradiation (TBI) vs. high dose melphalan 200 mg/m2 (HDM) in 282 newly diagnosed, previously untreated, symptomatic patients, less than 65 years of age.r The melphalan 200 mg/m2 regimen was better tolerated with less toxicities overall. The median duration of event-free survival (EFS) was similar in both arms (21 months), but survival at 45 months was significantly better in patients receiving melphalan 200 mg/m2 (65% vs. 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
HDM 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 the MD Anderson Cancer Center, of patients with renal failure, dialysis dependence and myeloma undergoing HDM and ASCT, found all-grade organ toxicities were higher in the melphalan 200 mg/m2 group compared to 140 mg/m2. Therefore, the lower melphalan dosing schedule may be preferred in this groupr
Conditioning regimens in primary systemic amyloidosis (AL) are based on adaptations of HDM. 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, HDM 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.
A summary of the evidence supporting this protocol is below.
Evidence Level (NHRMC) |
Study |
Study Design |
Disease |
Is the conditioning regimen consistent with the protocol? |
Comments |
II |
Moreau, P. et al. 2002 (IFM 9502)r |
Multicentre, randomised clinical trial |
Multiple myeloma |
Yes |
--- |
II |
Child, J. A. et al. 2003 (MRC7 Trial)r |
Multicentre, randomised clinical trial |
Multiple myeloma |
Yes |
--- |
II |
Blade, J. et al. 2005 (PETHEMA group)r |
Multicentre, randomised clinical trial |
Multiple myeloma |
No |
Results were combined for HDM 200 mg/m2 and TBI + HDM 140 mg/m2 |
II |
Palumbo, A. et al. 2014 (RV-MM-209 trial)r |
Multicentre, Randomised, open-label trial with a 2-by-2 factorial design |
Multiple myeloma |
Yes |
Compared HDM vs MPR with or without lenalidomide maintenance |
II |
Gay, F. et al. 2015r |
Multicentre, randomised open-label trial |
Multiple myeloma |
Yes |
--- |
II |
Attal, M. et al. 2017 (IFM 2009)r |
Multicentre, randomised clinical trial |
Multiple myeloma |
Yes |
First use of proteasome inhibitor-based induction |
II |
Skinner, M. et al. 2004r |
Longitudinal analysis of clinical effectiveness |
AL Amyloidosis |
Yes |
|
Efficacy
A summary of the evidence supporting the effect of this protocol is below.
Study |
No. of patients |
NRM/TRM |
Response |
Relapse Rate |
OS |
Median PFS/DFS (months |
Comments |
Moreau, P. et al. 2002 (IFM 9502)r |
142 |
Not reported |
CR = 35%
VGPR = 20%
PR = 39% |
Not reported |
45 months = 65% |
Not reported |
--- |
Child, J. A. et al. 2003 (MRC7 Trial)r |
201 |
Not reported |
CR = 44%
PR = 42% |
Not reported |
4 year = 55% |
32 |
--- |
Blade, J. et al. 2005 (PETHEMA group)r |
81 |
3.7% (3) |
CR = 30%
PR= Not reported |
Not reported |
Median OS = 65 months |
42 |
Results were combined for HDM 200 mg/m2 and TBI + HDM 140 mg/m2 |
Palumbo, A. et al. 2014 (RV-MM-209 trial)r |
141 |
“Toxic effects did not contribute to early death”
(No numbers reported) |
CR= 23.4%
VGPR=35.5%
PR =34% |
Not reported |
4 year = 82% |
43 |
Maintenance lenalidomide improved median 5-year OS and PFS in transplant groups |
Gay, F. et al. 2015r |
127 |
“No increase in serious adverse events or treatment-related deaths was noted” |
CR = 35%
VGPR = 44%
PR= 17% |
Not reported |
4 year = 86% |
43 |
--- |
Attal, M. et al. 2017 (IFM 2009)r |
350 |
1.7% (6) |
CR = 59%
VGPR = 29%
PR = 11% |
Not reported |
4 year = 81% |
50 |
--- |
Skinner, M. et al. 2004r |
701 |
13% |
CR = 40%
PR = 60%
|
8% |
5 years = 61% |
Not reported |
--- |
* OR=overall response; CR= complete response; PR=partial response; SD=stable disease; VGPR=very good partial response; R=refractory; NRM=non-relapse mortality; TRM=treatment-related mortality; OS=overall survival; DFS=disease-free survival; RD=refractory disease
Toxicity
A summary of the toxicities associated with this protocol are included in the table below.
Study |
Mucositis |
VOD/SOS |
Lung/IPS |
Infection* |
Comments |
Moreau, P. et al. 2002 (IFM 9502)r |
Grade 3-4: 30% |
0% |
Grade 3-4: 1.4% |
Not reported |
--- |
Child, J. A. et al. 2003 (MRC7 Trial)r
|
Not reported |
Not reported |
Not reported |
Not reported |
--- |
Blade, J. et al. 2005 (PETHEMA group)r |
Not reported |
Not reported |
Not reported |
See comments |
N=216
1 pt died of pneumonia, 2 died of neutropenic sepsis |
Palumbo, A. et al. 2014 (RV-MM-209 trial)r |
18.4% |
Not reported |
Not reported |
16.3% |
Mucositis was included under gastrointestinal (GI) events which also assessed rates of nausea, vomiting and diarrhoea |
Gay, F. et al. 2015r |
Grade 3: 19% |
Not reported |
Not reported |
26% |
Mucositis was included under GI events |
Attal, M. et al. 2017 (IFM 2009)r |
Grade 3-4: 17% |
Not reported |
Not reported |
20% |
--- |
Skinner, M. et al. 2004r |
Not reported |
Not reported |
Not reported |
11% |
N=277 who completed treatment with high dose melphalan. Other complications include GI Bleed 9%, renal failure requiring dialysis 5%, |
*Infection: includes neutropenic sepsis, invasive fungal infection (IFI) and viral reactivation/disease where reported
Transplant related toxicityr
© Blood 2002
G/GM-CSF=granulocyte-macrophage colony stimulating factor; HDM140=high dose melphalan 140 mg/m2; HDM200=high dose melphalan 200 mg/m2