High Dose Therapy & Stem Cell Transplant for Multiple Myeloma
by Dr. C.D. Buckner M.D. updated by Dr. C.H. Weaver M.D. 9/20/2018
High-dose chemotherapy and bone marrow or blood stem cell transplantation (SCT) remains the best treatment available for selected patients with certain types of cancer including lymphomas and multiple myeloma. The SCT process was developed more than 36 years ago and was considered such a major development of biomedical science that the individuals responsible were awarded the Nobel Prize for Medicine in 1990. Continued refinement has made SCT safer, more widely available and possible in older patients.
The Basic Strategy
Higher doses of chemotherapy and radiation therapy kill more cancer cells than lower doses in certain types of cancer. Unfortunately, the higher doses of therapy used to destroy cancer cells also damage normal cells. The body’s normal cells that are most sensitive to destruction by high-dose therapy are the blood-producing stem cells in the bone marrow. To “rescue” the bone marrow and hasten blood cell production and immune system recovery, high-dose therapy is followed by an infusion of stem cells.
Stem cell transplants are classified based on which individual donates the stem cells and from where the stem cells are collected. Stem cells may come from the patient (autologous), an identical twin (syngeneic), or someone other than the patient or a twin (allogeneic). Allogeneic stem cells are further classified by whether the individual donating the stem cells is related or unrelated to the patient.
Stem cells can be collected from bone marrow, peripheral blood, or umbilical cord blood. There are important advantages and disadvantages to using stem cells collected from these different sources.
High-dose chemotherapy and SCT is part of the overall treatment for many individuals with multiple myeloma. To deliver high-dose chemotherapy, stem cells must be collected before treatment and infused into the patient after treatment. The stem cell infusion supports the recovery of the patient’s bone marrow.
HOVON Trial: Autologous Stem Cell Transplant Remains Superior to Novel Agents for Treatment of Multiple Myeloma
The phase III HOVON clinical trial confirmed that autologous stem cell transplantation (ASCT) should still be the treatment of choice in younger patients with newly diagnosed multiple myeloma.(1)
The clinical trial evaluated a total of 1,266 patients who were less than 65 years of age with newly diagnosed multiple myeloma between February 2011 and April 2014. All patients were treated with induction therapy consisting of Velcade (bortezomib)–cyclophosphamide–dexamethasone chemotherapy and then were assigned to receive additional standard dose chemotherapy or high dose melphalan chemotherapy and ASCT and directly compared.
All patients received maintenance therapy with Revlimid (lenalidomide) until disease progression or intolerable side effects.
The study revealed that ASCT treated patients had a 24 percent lower risk of disease progression compared to chemotherapy.
Transplant is Also Superior for Older Patients with Myeloma
According to a recent study older patients treated withe ASCT have similar disease response and survival as younger patients. In addition, older patients had superior survival compared with non-transplanted older patients.
The retrospective study compared 132 patients with newly diagnosed myeloma (103 patients aged 65 years or younger; 29 patients older than 65 years) who underwent transplant with a group of 23 similar non-transplanted patients aged 65 years to 70 years.
The older patients experienced similar side effects to the younger patients except when treated with high dose melphalan where greater hematologic toxicity and blood transfusion support was required. The overall survival duration averaged 59 months for older transplant recipients compared to 30 months for those treated with conventional dose therapy.
Transplant eligibility should be based on the individual biological fitness of each patient irrespective of chronological age.(2)
Mini-Transplants Show Promise for Older Patients with Multiple Myeloma
Less toxic cancer treatment followed by an allogeneic stem cell transplant are showing promise for older patients with advanced blood and bone marrow cancers such as multiple myeloma.
Stem cell transplants may use the patient’s own stem cells that were collected prior to cancer treatment (an autologous transplant) or stem cells donated by another person (an allogeneic transplant).
Because of the toxicities of high-dose allogeneic stem cell transplant, this treatment approach is often reserved for younger patients. In recent years, however, several transplant centers have evaluated less toxic regimens, including lower doses of chemotherapy, radiation, and/or biologic therapy prior to an allogeneic transplant. The less toxic regimens kill some cancer cells and suppress the patient’s immune system so that it won’t attack the donor cells. Once the donor cells are infused into the patient, they can recognize the patient’s cancer cells as foreign and mount an attack against the cancer. This approach is sometimes referred to as a “mini-transplant" or a "reduced intensity transplant (RIT)."
To evaluate the safety and effectiveness of mini-transplants among older patients with advanced hematologic cancer, researchers conducted a study among 372 patients between the ages of 60 and 75. Patients were treated with low-dose total body irradiation alone or combined with fludarabine. Patients then received an allogeneic stem cell transplant from a related or unrelated donor.
- Five-year overall survival was 35%.
- Five-year survival without a worsening of the cancer was 32%.
- Treatment outcome was generally similar regardless of the patient’s age.
These results are encouraging and suggest that mini-transplants are a viable treatment option for older patients with advanced hematologic cancers that may benefit more from an allogeneic than an autologous stem cell transplant. Patients with newly diagnosed multiple myeloma should strongly consider having a consultation at a cancer center with expertise in stem cell transplantation to ensure they are aware of the most recent use of this procedure.(3)
Autologous Transplants for Induction Failures
Most of the randomized trials and phase II studies have restricted stem cell transplants to patients responding to induction therapy. The rationale for this approach has never been convincing since refractory patients are more in need of intensive therapy than are responding patients. Dr. Powles from the Royal Marsden Hospital presented data suggesting that patients refractory to induction therapy fare as well as responding patients to high-dose therapy with ASCT.4 They treated 33 of 64 primary refractory patients with an ASCT and the remainder with standard dose chemotherapy or high-dose chemotherapy without an ASCT. Following ASCT the median survival was 6.8 years with 15/33 currently alive while only 1/17 receiving high-dose therapy without an ASCT were alive. These authors suggest that ASCT should be performed on all patients with primary refractory myeloma.(7)
- Barlogie B, Kyle R, Anderson K, et al. Comparable Survival in Multiple Myeloma (MM) with High Dose Therapy (HDT) Employing MEL 140 mg/m2 + TBI 12 Gy Autotransplants Versus Standard Dose Therapy with VBMCP and No Benefit from Interferon. Proceedings of the 45th annual meeting of the American Society of Hematology. Blood 2003;102:42a, abstract number 135.
- Blade J, Sureda A, Ribers J, et al. High-Dose Therapy Autotransplantation/Intensification Versus Continued Conventional Chemotherapy in Multiple Myeloma Patients Responding to Initial Chemotherapy. Definitive results from PETHEMA after a Median Follow-up of 66 months. Proceedings of the 45th annual meeting of the American Society of Hematology. Blood 2003;102:42a, abstract number 137.
- Barlogie B, Jacobson J, Sawyer J, et al. Increased CR Frequency as a Strategy Toward Extending Event-Free Survival (EFS) and Overall Survival (OS) in Multiple Myeloma (MM): 4-Year Results of Total Therapy II (TT II) Versus Total Therapy (TT I). Proceedings of the 45th annual meeting of the American Society of Hematology. Blood 2003;102:42a, abstract number 13
- Cavo M, Palumbo A, Zweegman S, et al. Upfront autologous stem cell transplantation (ASCT) versus novel agent-based therapy for multiple myeloma (MM): A randomized phase 3 study of the European Myeloma Network (EMN02/HO95 MM trial). Abstract #8000. Presented at the 2016 American Society of Clinical Oncology Annual Meeting, Chicago, IL, June 3, 2016.
- Marini C, Maia T, Bergantim R, et al. Real-life data on safety and efficacy of autologous stem cell transplantation in elderly patients with multiple myeloma [published online October 27, 2018]. *Ann Hematol.*doi: 10.1007/s00277-018-3528-x
- Sorror ML, Sandmaier BM, Storer BE et al. Long-term outcomes among older patients following nonmyeloablative conditioning and allogeneic hematopoietic cell transplantation for advanced hematologic malignancies. JAMA. 2011;306:1874-1883.
- Powles R, Sirohi B, Kukarni S, et al. Primary Refractory (PRef) Myeloma: Recommendations for Treatment. Proceedings of the 45th annual meeting of the American Society of Hematology. Blood 2003;102:686a, abstract number 2542.
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