In the early 1980s, McElwain and colleagues demonstrated that high-dose melphalan(Drug information on melphalan) (Alkeran, 100-400 mg/m2) was very effective in patients with aggressive (plasma cell leukemia) or refractory myeloma.[ 1] Other researchers subsequently confirmed these results.[2-4] Unfortunately, the duration of cytopenia associated with such treatment was excessive (3 to 4 weeks), leading to a treatment-related mortality rate of 10% to 20%.
To make this procedure safer, Barlogie et al introduced stem cell support with bone marrow,[5] based on the theory that although up to 30% of bone marrow could be composed of myeloma cells, the recovery of hematopoietic progenitor cells would be faster than the regrowth of myeloma cells, which have a low proliferative capacity. This constituted a new paradigm in stem cell transplantation, with the aim of therapy shifted from cure to prolonging life. However, support with bone marrow stem cells still causes delayed recovery.
The use of peripheral blood stem cells, mobilized with hematopoietic growth factors alone, or in combination with chemotherapy, drastically reduced the duration of cytopenia, especially after high-dose melphalan therapy, which is administered 24 hours prior to stem cell infusion. Profound cytopenia occurs 5 to 6 days posttransplant, with recovery of counts between days 10 and 12 posttransplant, leaving patients severely cytopenic for approximately 1 week.
This allowed further dose escalation of melphalan to 200 mg/m2 and made it possible to enroll patients aged ≥ 65 years in clinical trials. Results included an extremely low transplant-related mortality, similar to that observed with 6 months of VAD chemotherapy (vincristine, doxorubicin(Drug information on doxorubicin) [Adriamycin], dexamethasone(Drug information on dexamethasone)) or 12 months of melphalan/ prednisone(Drug information on prednisone) chemotherapy, and complete remissions in approximately 50% of newly diagnosed patients.
Tandem Transplants
Tandem transplants were introduced to keep transplant-related mortality low while maximizing the myeloma effect. Rather than administering multiagent chemotherapy over many days and causing a high rate of treatment-related morbidity, the idea was to provide two cycles of less intensive chemotherapy that would be better tolerated, particularly by older myeloma patients. Investigators speculated that two cycles of high-dose melphalan with a 3- to 6- month interval (waiting until patients had fully recovered from the toxicities of the first transplant) would be equally effective. It turned out that this approach was actually more effective than a single cycle of multiagent chemotherapy.
For the majority of myeloma patients, melphalan is the most effective drug and needs to be given at maximally tolerated doses. In multiagent chemotherapy regimens, the dose of melphalan is usually reduced to 100 to 140 mg/m2, compared to 400 mg/m2 in tandem melphalan transplants. The addition of totalbody irradiation to melphalan therapy has actually been shown to result in an inferior outcome.
We now know that drug resistance in the early stages of myeloma is conferred by the microenvironment providing ligands to receptors on the membrane of myeloma cells (eg, interleukin [IL]-6 receptor, IL-15 receptor, insulin-like growth-factor receptor, CD38, and CD40). These ligands cause the myeloma cells to upregulate antiapoptotic and angiogenesis- inducing factors, as well as transcription of factors related to proliferation. Although a fraction of myeloma cells are proliferative, the large majority are kept out of cycle by upregulation of p27 and p21, making these cells poor targets for any type of cytotoxic therapy. It is, therefore, unlikely that a single cycle of high-dose chemotherapy can eradicate all myeloma cells.
Total Therapy II
If cure is the objective, it will require multiple cycles of effective and non-cross-resistant chemotherapy, followed by tandem transplants and additional cycles of combination chemotherapy to eradicate any remaining myeloma cells (including those infused with the autotransplants). Such an approach is the basis of our Total Therapy II protocol, which also randomizes patients to receive or not receive thalidomide(Drug information on thalidomide) (Thalomid), to evaluate whether this immunomodulator acts synergistically with chemotherapy.
Our initial data suggest that such an approach in patients with a good prognosis (no deletion of chromosome 13 and normal lactate dehydrogenase [LDH] levels at diagnosis) will prove to be superior to the already excellent results obtained with Total Therapy I.[5] With the Total Therapy I protocol, such patients (76% of the entire group) had a median survival of 9.5 years. The median survival of good-prognosis patients on Total Therapy II will likely range between 11 and 12 years.
IFM-94 Protocol
It appears unlikely that any other approach will prove to be superior in these patients. However, it is possible that the addition of immunotherapy after transplantation or the administration of new effective drugs (IMiDs, PS341) may further delay disease progression and increase survival. The superiority of tandem transplants over a single transplant was demonstrated by the Intergroupe Français du Myélome (IFM)-94 trial.[ 6] The most recent update shows a significantly better event-free and overall survival for tandem transplants. The 6-year overall survival with a single transplant was 26% vs 46% with tandem transplants (P = .02).[7] The protocol of the IFM- 94 study, however, was suboptimal, with no alkylating therapy given prior to transplantation, and the total dose of melphalan in the tandem transplant arm was only 280 mg/m2.
Newer Treatment Modalities
For the 24% of newly diagnosed patients with either chromosome 13 abnormalities or elevated LDH levels, our more intensive Total Therapy II protocol does not appear to be superior, although this may be due to insufficient follow-up time. In these patients, it is appropriate to investigate new treatment modalities, such as a single autologous transplant followed by a nonmyeloablative allotransplant. Allotransplantation, through its immunologic graft-vs-myeloma effect, is very effective in controlling refractory myeloma in patients with deletion of chromosome 13.
However, there are two important caveats. First, durable disease control is only seen if the disease burden is minimal at the time of the nonmyeloablative allotransplant. For this procedure to be successful, it should be planned upfront to consolidate the tumor reduction obtained after an autotransplant, and should not be performed at the time of relapse. Second, we have only seen a significant graftvs- myeloma effect in the context of acute and/or chronic graft-vs-host disease, indicating that the target of the cytotoxic T cells is either a major or minor histocompatibility antigen and not a myeloma-associated tumor antigen; this is clearly different from chronic myeloid leukemia.
Conclusions
The fact that graft-vs-host disease is required for disease control, and that the graft-vs-host disease course is completely unpredictable, makes it unlikely that such an approach is the ultimate solution to the treatment of multiple myeloma. Given the clues from the allotransplant experience and the power of immunotherapy to destroy chemotherapy-resistant myeloma, we are now investigating immunologic approaches based on stronger and more immunogenic tumor antigens derived from gene array profiling, in the hope that they can be applied in the autologous rather than allogeneic setting.
