Autologous stem cell transplants refer to stem cells that are collected from an individual and given back to that same individual. Autologous transplants are also referred to as autografts, and are by far the most common type of transplant performed in myeloma patients today. With this type of transplant, the patient's stem cells are obtained prior to high-dose chemotherapy, frozen, and stored if necessary, and are then given back afterward.

Several studies have shown that high-dose chemotherapy with autologous stem cell transplantation improves the response rate, event-free survival (EFS), and overall survival (OS) in myeloma over that obtained with conventional chemotherapy. The first randomized trial comparing the two treatments was conducted by the Intergroup Francais du Myelome (IFM) and included 200 previously untreated patients under the age of 65. (Attal et al. N Engl J Med. 1996;335:91-97.) The IFM-90 study, as it was called, demonstrated the superiority of high-dose versus conventional-dose chemotherapy (see table below). Patients in this study had been followed for an average of 7 years.

Results of another large multicenter study demonstrating the superiority of high-dose versus conventional chemotherapy in patients with myeloma (MRC VII) were reported in 2003 and follow-up data was reported in 2004 (see table below). (Child et al. N Eng J Med. 2003;348:1875-1883; Morgan et al. Blood. 2004;104(11). Abstract 927.) The study, which was conducted in England between 1993 and 2000, included 407 patients who were less than 65 years of age and had received no previous treatment.

In this study, there was a trend toward a greater survival benefit in patients with a poor prognosis, which was defined by a high beta-2 microglobulin level.

In other studies, response rates of up to 75% to 90% have been seen and complete response rates have ranged from about 20% to 40%. For this reason, high-dose chemotherapy with autologous stem cell transplant is considered to be an appropriate treatment option for eligible patients who achieve a response or stable disease following conventional chemotherapy as their primary therapy.
Other studies are comparing the efficacy of more intensive conventional chemotherapy regimens and high-dose therapy/autologous transplant regimens. Results of one such study, the S9321 Intergroup Trial, suggest that an intensive chemotherapy regimen known as VBMCP (vincristine, BCNU, melphalan, cyclophosphamide, and prednisone) offers overall survival that is significantly improved over that seen with conventional chemotherapy and is similar to that seen with high-dose chemotherapy. (Barlogie et al. Blood. 2003;102(11). Abstract 135.)

Results of the Spanish PETHEMA study showed that high-dose therapy and transplant offered a higher complete response (CR) rate than did a standard chemotherapy regimen that included alternating VBMCP and VBAD (vincristine, BCNU, Adriamycin®, and dexamethasone). (Bladé et al. Blood. 2003;102(11). Abstract 137.) However, after a median follow up of 66 months, there was no difference in event-free and overall survival between the two treatments.

There are many important differences between these various studies. For example, in the PETHEMA trial, only patients responding to initial chemotherapy were randomized into the study. Therefore, direct comparisons cannot be made and further study is needed. High-dose chemotherapy and autologous stem cell transplant is a treatment option for both patients with newly-diagnosed disease and for those who have already received other treatments. High-dose chemotherapy and autologous transplant is considered by many to be a standard of care for patients up to the age of 65.

In general, patients with good performance status and adequate kidney function are eligible. In the past, high-dose chemotherapy and autologous stem cell transplantation was not considered an option in patients who were over 65 years of age because the procedure was thought to be too strenuous. However, older patients are eligible for the procedure as long as they meet the performance and function criteria.

Recent data from an Italian study also show that repeated, intermediate doses of melphalan chemotherapy (100 mg/m²) followed by an autologous stem cell transplant may be a more tolerable alternative to high-dose melphalan (200 mg/m²)/autologous stem cell transplant for elderly patients between the ages of 60 and 70, especially those who have other medical conditions. (Boccadoro et al. Haematologica. 2005;90(suppl. 1);18. Abstract PL.03.) The regimen was superior to melphalan-prednisone with regard to response rate (near CR, 25% vs. 6%, respectively), 3-year event-free survival (37% vs. 16%), and 3-year overall survival (77% vs. 62%).

Although in the past, high-dose chemotherapy/autologous stem cell transplant was not considered an option in patients with renal (kidney) failure, recent studies suggest that the procedure is feasible and effective in these patients with proper planning and dose modification. In patients with renal failure who achieve a remission, survival is comparable to that seen in myeloma patients with normal renal function. (Jagganath S. Hematology J. 2003;4(suppl 1):S62. Abstract P10.3.2.)

In certain instances, prior treatment with certain chemotherapy drugs (for example, the alkylating agents melphalan or BCNU [carmustine]) or with radiation therapy to the spine or pelvis may reduce the number of stem cells that can be collected for an autologous transplant. For this reason, an autologous transplant may not be an option for some patients who have received these therapies. Prior to an autologous stem cell transplant, patients first receive several cycles of conventional chemotherapy (induction therapy) to reduce the tumor burden. After induction therapy, the stem cells are collected. Patients may then go straight to high-dose chemotherapy and transplant ("early transplantation") or continue to receive chemotherapy until the myeloma relapses ("late transplantation").

In general, studies have shown that overall survival is similar for both early and late autologous transplants (see table below). However, early transplants are often preferred over late transplants because they minimize a patient's exposure to alkylating chemotherapy agents that can damage bone marrow. In addition, patients who achieve disease remission following transplant have a better quality of life, so there is the potential for improved quality of life earlier in the course of treatment with an early transplant. In addition, greater benefit may be achieved when a transplant is performed when a patient has received treatment for less than one year (Fassas et al. Leuk Lymphoma. 2003;44(5):749-758.) Therefore, the choice between an early or late transplant must be made based on a patient's particular case.

Achievement of a complete response (undetectable disease) or near complete response is a major favorable prognostic factor in myeloma. However, it is not clear whether achieving a complete response prior to autologous transplant improves overall outcome more so than achieving a complete response following transplant. However, patients who do not respond to initial therapy tend to have a poorer outcome following transplant. Representative studies that support the finding of improved outcome following transplant in patients who achieve a favorable response following initial therapy are listed below.

The use of autologous stem cell transplants in patients at other stages of disease are being investigated in clinical trials. Patients who respond or obtain stable disease after salvage therapy may also be eligible to receive an autologous transplant. A second autologous stem cell transplant is sometimes performed in patients who have relapsed after an initial stem cell transplant. Some myeloma centers now automatically collect enough stem cells for two transplants and reserve half of them for this potential future use. Autologous stem cell transplants have several advantages over other types of transplants. One is that the patient serves as his or her own source of stem cells. There is no need to find a donor and there is no risk of incompatibility. Autologous transplants are relatively safe procedures, with low rates of complications and infections compared with allogeneic transplants. In many instances, much of the procedure can be done on an outpatient basis. The mortality rate is 2% to 3% in patients with newly diagnosed myeloma.

Autologous transplants may not be an option for some patients. In certain instances, prior treatment with certain chemotherapy drugs (ie, melphalan or BCNU [carmustine]) or with radiation therapy to the spine or pelvis may reduce the number of stem cells that can be collected for an autologous transplant.

Following high-dose chemotherapy and autologous transplant, approximately 20% to 40% of patients achieve a complete response (CR). A number of studies, including the IFM-90 study, have shown that achievement of a CR in this context is associated with improved survival. Another example is a study involving 67 patients undergoing high-dose chemotherapy and autologous stem cell transplant for relapsed or primary refractory myeloma, which showed that overall survival after transplantation was significantly better among responders who achieved CR than those who did not (median survival, 24 vs. 11 months). (Rajkumar et al. Bone Marrow Transplant. 1999;23:1261-1266.) Attainment of a CR independently predicted better survival in a multivariate analysis.

Achievement of a CR was also associated with improved survival in a study of 68 consecutive patients with myeloma of high or intermediate tumor mass that had responded to initial therapy. (Alexanian et al. Bone Marrow Transplant. 2001;27:1037-1043.) Following high-dose therapy, the rate of CR increased from 6 to 37%, with median survival extended by 10 months. The survival of 21 patients with disease that converted from a partial response (PR) to CR following transplant (median 8.3 years) was significantly longer than that of similarly-treated patients who remained in PR (median 5.0 years). The authors identified CR as the major surrogate marker of long survival and the primary goal of high-dose treatment for patients in PR.

Since myeloma is not curable, patients will eventually have recurrence or progression (also referred to as relapse) of their disease. Individual patient factors play a role in the duration of response. Approximately 50% to 60% of patients who achieve a complete response have recurrence of their disease with 5 years; the rate of disease progression in patients who do not initially achieve a complete response is about 60% to 80%.*


Data from the myeloma registry of the European Group for Blood and Marrow Transplantation (EBMT) indicate that overall and progression-free survival 15 years post autologous transplant is approximately 5%. (Björkstrand et al. Haematologica. 2005; 90(suppl. 1):17. Abstract PL4.02.) This registry contains information on more than 15,000 autologous transplants performed in patients with myeloma at more than 500 centers since 1983. In the annual updates on registry data performed since 1994, favorable prognostic factors for autologous transplantation have repeatedly been lower age, response to chemotherapy, one line of primary induction treatment, stage I or II at diagnosis, and low beta-2-microglobulin at diagnosis.

Another drawback is that the transplant may be contaminated with tumor cells when a patient's stem cells are collected. However, recent studies indicate that this does not contribute to early relapse. (Unfortunately, a much larger number of myeloma cells may remain in a patient following high-dose chemotherapy, so the relative number of cells given back during an autologous transplant is small.) Further studies show that removing the tumor cells from an autograft does not provide any benefit with regard to survival. Researchers are investigating ways to improve the outcome of autologous transplants. One strategy is the use of novel therapies or other chemotherapy regimens to improve the outcome of initial therapy prior to transplant, which often leads to greater benefit following the transplant. Various types of high-dose chemotherapy regimens (also called conditioning regimens) are also being evaluated. Novel therapies are also being investigated for use in maintaining a response following transplantation. Researchers are also investigating the use of double or tandem transplants. A tandem autologous transplant incorporates a second autologous transplant to enhance the response rate and duration achieved with the first transplant. Radiolabeled bone-targeted therapies (radiopharmaceuticals) are also being used in conjunction with high-dose therapy as part of a conditioning regimen to improve response rates.

Promising preliminary results have been seen with strategies that incorporate the use of novel agents as induction therapy prior to transplant. However, the effect of these new strategies on survival has yet to be determined. Examples of these strategies, as well as their use as maintenance therapy following transplant, are summarized below.

Thalidomide-based regimens. The combination of thalidomide and dexamethasone is now a commonly used regimen for induction therapy prior to autologous stem cell transplant. A study comparing thalidomide-dexamethasone (thal-dex) and vincristine-doxorubicin-
dexamethasone (VAD), another commonly used induction regimen, showed that thal-dex significantly augmented tumor cytoreduction without increasing the toxicity or interfering with subsequent collection of peripheral blood stem cells. (Cavo et al. Blood. 2004;104(11). Abstract 1489.)

Find out more about thalidomide-based regimens as front-line therapy.

Velcade-based regimens. Exciting preliminary data have been reported in studies of Velcade in combination with various agents as induction therapy for myeloma. Examples of such regimens include Velcade-melphalan, Velcade-dexamethasone, and Velcade-
doxorubicin-dexamethasone (PAD). Preliminary results include response rates of up to 95% using various combinations and dosing regimens. A number of studies have shown there is no compromise of stem cell harvest following various Velcade-based regimens and side effects have been similar to that seen in studies in relapsed/refractory disease. These data support the potential utility of Velcade as front-line therapy in patients who are candidates for autologous stem cell transplant, but further studies are necessary to confirm these preliminary findings.

Find out more about Velcade-based regimens as front-line therapy.

Maintenance. A Phase II study showed that in a study of patients receiving thalidomide and prednisone as maintenance therapy following autologous transplant, one-year survival was 91%. (Stewart et al. Blood. 2004;104(11). Abstract 335.) A thalidomide dose of 200 mg was determined to be a tolerable maintenance dose. This regimen is being evaluated in a Phase III trial.

Find out more about:

• Tandem Autologous Transplants