High-dose chemotherapy: Autologous bone marrow or peripheral stem cell transplantation
The failure of conventional therapy to cure the disease has led investigators to test the effectiveness of much higher doses of drugs such as melphalan. The development of techniques for harvesting hemopoietic stem cells, from marrow aspirates or the peripheral blood of the patient, and infusing these cells to promote hemopoietic recovery made it possible for investigators to test very large doses of chemotherapy.
Based on the experience of treating thousands of patients in this way, it is possible to draw a few conclusions, including the following:
- The risk of early death caused by treatment-related toxic effects has been reduced to less than 3% in highly selected populations.
- Chemotherapy patients can now be treated as outpatients.
- Extensive prior chemotherapy, especially with alkylating agents, compromises marrow hemopoiesis and may make the harvesting of adequate numbers of hemopoietic stem cells impossible.
- Younger patients in good health tolerate high-dose therapy better than patients with a poor performance status.[69,70,71]
- Upon review of eight updated trials encompassing more than 3,100 patients, at 10 years' follow-up, there was a 10% to 35% event-free survival (EFS) rate and a 20% to 50% OS rate.
Single autologous bone marrow or peripheral stem cell transplantation
While some prospective randomized trials, such as the U.S. Intergroup trial SWOG-9321, have shown improved survival for patients who received autologous peripheral stem cell or bone marrow transplantation after induction chemotherapy versus chemotherapy alone,[73,74,75][Level of evidence: 1iiA] other trials have not shown any survival advantage.[76,77,78,79][Level of evidence: 1iiA]
Two meta-analyses of almost 3,000 patients showed no survival advantage.[80,81][Level of evidence: 1iiA]
Even the trials suggesting improved survival showed no signs of a slowing in the relapse rate or a plateau to suggest that any of these patients had been cured.[73,74,75,82] The role of ASCT has also been questioned with the advent of novel induction therapies with high complete-remission rates.[83,84]
Tandem autologous bone marrow or peripheral stem cell transplantation
Another approach to high-dose therapy has been the use of two sequential episodes of high-dose therapy with stem cell support (tandem transplants).[85,86,87,88,89]
- A meta-analysis of six randomized clinical trials enrolling 1,803 patients compared single autologous hematopoietic cell transplantation with tandem autologous hematopoietic cell transplantation.
- There was no difference in OS (HR = 0.94; 95% CI, 0.77–1.14) or in EFS (HR = 0.86; 95% CI, 0.70–1.05).[Level of evidence: 1A]
- In a trial of 194 previously untreated patients aged 50 to 70 years, the patients were randomly assigned to either conventional oral melphalan and prednisone or VAD for two cycles followed by two sequential episodes of high-dose therapy (melphalan 100 mg/m2) with stem cell support.
- With a median follow-up of more than 3 years, the double transplant group had superior EFS (37% vs. 16% at 3 years, P < .001) and OS (77% vs. 62%, P < .001).[Level of evidence: 1iiA]
- Three different groups have compared two tandem autologous transplants with one autologous transplant followed by a reduced-intensity conditioning allograft from an HLA-identical sibling; treatment assignment was based on the presence or absence of an HLA-identical sibling. The results have been discordant for survival in these nonrandomized trials.
- One study showed a survival advantage for the two tandem autologous transplants.
- One study showed a survival advantage for the autologous transplant followed by an allogeneic transplant.
- One study showed no difference in OS.[91,92,93,94][Level of evidence: 3iiiA]
- A trial of 195 patients younger than 60 years with newly diagnosed myeloma randomly compared two tandem transplants with a single autologous stem cell transplant followed by 6 months of maintenance therapy with thalidomide.
- With a median follow-up of 33 months, the thalidomide maintenance arm showed a benefit in PFS (85% vs. 57% at 3 years, P = .02) and OS (85% vs. 65% at 3 years, P = .04).[Level of evidence: 1iiA]