Until recently, few advances have been made towards the goal of extending the duration and quality of life of the multiple myeloma patient. In the 70’s and 80’s, different combinations of standard dose chemo-therapy regimens were compared to the current standard of care (melphalan and prednisone) without demonstrating improved patient outcome. Although these more aggressive combination chemotherapy regimens (VMCP, M-2, VAD) often achieve higher response rates and act more quickly to suppress the myeloma clone, the final outcome, median overall survival, is not extended by these newer regimens as evident by numerous randomized trials. Most likely, this lack of improvement is due to the limitations of most cytotoxic chemotherapy, dose-limiting bone marrow toxicity. Without hematopoietic support, the mere substitution of different cytotoxic drugs had little chance of extending the survival of the myeloma patient.
In order to circumvent this dose-limiting feature, myeloablative chemotherapy followed by bone marrow transplantation has been tried. The concept being that much higher doses of drugs, which would normally cause irreversible bone marrow damage, could be used if the bone marrow was then regenerated with unexposed bone marrow reinfused following chemotherapy exposure. The first treated patients received a syngeneic transplant (donor bone marrow being supplied by an identical twin). Patients treated in this way have done well with long-term survivors of 14 years and more being documented without the development of progressive disease. Of interest, even in these long-term survivors, a measurable monoclonal protein has remained detectable suggesting that their condition was reverted to an MGUS-like state following the treatment. Since most patients are not fortunate enough to have an identical twin, allogeneic transplants (using a related sibling’s bone marrow) have been more commonly performed. With this form of therapy, long-term survivals have been achieved but at the expense of significant early treatment related mortality. In a recent report from Seattle, transplant 100 day mortality was 44% with only a 24% 4.5 year survival among patients treated in this way. Since standard allogeneic transplants can only be used in patients <55 years of age who have a sibling with a matching HLA type (25% likelihood per sibling) this procedure can only be offered to a subset of patients with multiple myeloma. Given the high early mortality rate related to the procedure, our group has recommended this form of therapy only rarely. In support of this recommendation, a SWOG sponsored study randomizing eligible patients to early or late autologous transplantation vs. allogeneic transplantation had the latter arm closed to further enrollment due to excess treatment related mortality.
Due to the toxicity and limited applicability of the aforementioned types of treatment, autologous transplantation of bone marrow became more commonly employed. In this procedure, one’s own bone marrow is harvested and frozen for future administration intravenously following myeloablative chemotherapy. The obvious disadvantage of this technique is that the harvested bone marrow is always contaminated with tumor cells. These contaminating myeloma cells, when reinfused into the patient following the high-dose chemotherapy, will likely re-seed the bone marrow and potentially contribute to disease recurrence. Nevertheless, this form of therapy was shown to be advantageous in the only controlled study to date. Dr. Attal and colleagues from France randomized 200 patients with Durie-Salmon stage II or III multiple myeloma to receipt of either 10 cycles of standard chemotherapy (VMCP/VBAP) vs. 2 cycles of standard chemotherapy followed by high-dose melphalan and an autologous bone marrow transplant. As of the most recent update of these results, six and seven year survival was more than doubled for those patients randomized to the autologous bone marrow transplant arm. Those patients 60 years of age and less were particularly benefited by the high-dose chemotherapy. A retrospective review of patient outcome from Scandinavia appeared to confirm the benefits of high-dose chemotherapy. Four-year survival was improved from 46% to 61% for those Nordic patients who received an autologous transplant when compared to a control group of patients who received standard chemotherapy. Finally, a French group compared early vs. late autologous transplantation. One hundred eighty-five patients were randomized to receive an autologous transplant at presentation (following some initial chemotherapy) or at the time of disease relapse. Overall survival was similar between groups. However, because of the additional chemotherapy needed to reattain a remission state following progressive disease, the quality of life was judged better for the patients who received early high-dose chemotherapy. A similar trial is accruing patients in the United States and should again address whether early versus late autologous transplantation is preferable.
Bone marrow was used as the hematologic support in early transplant studies but is rarely used today. The use of peripheral blood progenitor
cells (PBPCs) is advantageous because patients have a shortened duration of neutropenia and hospitalization, avoid the operating room for bone marrow harvesting, and receive a reduced load of reinfused tumor cells following cytoreductive chemotherapy. Our group compared myeloma tumor burden in PBPC and back-up bone marrow harvests from patients undergoing autologous transplantation. In almost every case, tumor burden was less in the PBPC product, translating into a median 14-fold reduction in contaminating tumor cells. Unfortunately, this reduction in tumor burden does not seem to have made a significant impact on progression-free or overall survival. The majority of patients continue to relapse within 4 years, with median survival times varying between 36 and 65 months.
In an attempt to improve these results, efforts have been made to eliminate contaminating tumor cells from the reinfused autograft product. We have previously demonstrated that the malignant cells in patients with myeloma do not express the stem cell antigen CD34. Consequently, a phase III study was initiated comparing CD34-selected autografts to unmanipulated PBPC autografts for patients with multiple myeloma. The CD34 selection procedure was safe, with equivalent neutrophil nadirs (median 12 days) and only a 2-day delay in platelet engraftment (median 11 days vs. 9 days). Infections were also comparable between groups. Using PCR analysis of myeloma-specific Ig gene sequence, the purging procedure resulted in a median 3.1 log reduction in autograft tumor burden. Nevertheless, no improvement in progression-free or overall survival has been noted to date. Consequently, the study demonstrates that the reinfusion of malignant cells is not a main contributor to disease relapse in patients following autologous transplantation.
Some centers have adopted a double autologous transplant approach as a method of further increasing dose-intensity and potential disease control. Comparisons of outcomes between centers using this approach and our own results show little apparent benefit in disease-free or overall survival. To more scientifically answer this question, French investigators have randomized over 400 patients to a single vs. double autologous peripheral blood stem cell transplant. To date, no significant difference in outcome has been noted although the follow-up remains short. Consequently, at the present time it seems that this added round of high-dose chemotherapy adds little if anything to patient outcome.
Two new transplant approaches are being studied that show promise. In an attempt to minimize the toxicity of allogeneic bone marrow transplantation, “mini” allogeneic transplants are being performed. In this procedure, the toxic consolidation chemotherapy of busulfan/cyclophosphamide or TBI/cyclophosphamide is eliminated. Typically, the consolidation chemotherapy is used to cytoreduce the tumor and recipient’s bone marrow to allow rapid donor marrow engraftment. Instead, immunosuppressive agents such as fludarabine are used to allow a gradual engraftment of the donor bone marrow and consequent graft versus myeloma effect. This approach does appear less toxic and can be used in more elderly patients. Nevertheless, chronic graft versus host disease remains problematic and it is unclear whether the graft versus myeloma effect is sufficient by itself to lead to long-term disease control.
Other centers have experimented with adding a bone seeking radiopharmaceutical to the standard melphalan that is used for autologous transplantation. Myeloma cells are typically radiosensitive tumors. However, the addition of external beam radiation to melphalan adds significant toxicity to the transplant procedure. To circumvent this problem, radioactive holmium has been conjugated to a bisphosphonate bone-seeking drug and given intravenously to patients undergoing autologous transplantation. Bone marrow doses of 40Gy can be given in this way without an apparent adverse effect on bone marrow engraftment or added non-hematologic toxicity. Phase II studies appear to suggest improved complete remission rates with this approach and a national Phase III trial is currently under development to compare this approach to standard high-dose melphalan in patients with multiple myeloma.
In summary, high-dose therapy with autologous transplantation is a beneficial therapeutic maneuver for the majority of patients <70 years of age with advanced (Durie-Salmon Stage II or III) multiple myeloma. Despite the inability to cure the disease using this approach, disease-free and overall survival are improved and patient quality of life is often benefited as well by the attainment of a prolonged state of time of minimal disease activity and avoidance of chemotherapy. It is hoped that further improvements in allogeneic transplantation methodology will make this option more successful and applicable. Finally, the use of improved forms of maintenance therapies (prednisone + thalidomide) may further prolong patient’s survival times and allow these patients to survive long enough to benefit from one of many promising new agents now undergoing clinical trial.