Treatment of Recurrent Multiple Myeloma
Treatment of Recurrent Multiple Myeloma
Medically reviewed by Dr. C.H. Weaver M.D. Medical Editor (08/2018)
Recurrent multiple myeloma is defined as myeloma that has persisted despite treatment or returned following initial treatment. With current therapy, curing patients with recurrent multiple myeloma is uncommon; recent advances incorporating new precision medicines, immunotherapy, stem cell transplantation, and maintenance therapy however have prolonged survival by several years.
Doctors are personalizing care by finding the genetic alterations within the cancer that drive its growth and use medicines that specifically counteract the cancerous effects of those genes. In addition, these “targeted therapies” are designed to treat only the cancer cells and minimize damage to normal, healthy cells. The ability to test a patients’ cancer for individual differences at the genetic level, and to make treatment decisions based on those differences is the hallmark of precision medicine.
There is a steadily increasing number of newer precision medicines and immunotherapies that are being used as standard treatment of patients with recurrent multiple myeloma. These newer medicines have improved outcomes significantly. The only potentially curative treatment for multiple myeloma remains high-dose therapy followed by a stem cell transplant using donor cells (allogeneic stem cell transplant).
About This Treatment Information
The following treatment overview summarizes the standard of care and recent advances in the treatment of recurrent multiple myeloma. Optimal treatment of multiple myeloma incorporates ongoing advances in precision medicine with chemotherapy, high-dose therapy and stem cell transplant, and maintenance therapy. Participation in a clinical trial utilizing new, innovative therapies should be considered and may provide the most promising treatment for select individuals. Learn more Strategies to Improve Treatment.
Standard Therapies for Multiple Myeloma
Most patients with recurrent multiple myeloma will have already been treated with chemotherapy or a stem cell transplant. The main goal of treatment for recurrent disease is to induce a complete or near complete disappearance of myeloma cells in order to prolong survival and improve symptoms. Treatment selection depends on patient age, general medical condition, and prior therapy.
The following medicine’s are approved by the U.S. Food and Drug Administration as treatment for multiple myeloma: These medicines are typically used in combinations to attain the best results.
- Precision Medicines
- Darzalex® (daratumumab)
- Farydak® (panobinostat)
- Empliciti® (elotuzumab)
- IMiDs (immunomodulatory drugs)
- Pomalyst® (pomalidomide)
- Proteasome inhibitors
- Alkylating agents (chemotherapy)
- Steroids (e.g., dexamethasone and prednisone)
Combinations typically consist of medicines not used as initial treatment and often combine an IMiD plus a proteasome inhibitor or precision medicine with dexamethasone. Determining optimal combination regimens is ongoing in clinical trials.
High-dose Therapy and Stem Cell Transplant for Recurrent Multiple Myeloma
High-doses of chemotherapy are more effective at killing cancer cells than lower doses. However, high-dose therapy destroys many other cells in the body. A dangerous side effect of administering high-dose therapy is damage to the cells in the bone marrow that develop into mature blood cells, called stem cells.
Without functioning stem cells in the bone marrow, the body cannot produce red blood cells, white blood cells or platelets, which leaves patients vulnerable to infection and bleeding, and unable to supply adequate oxygen to their tissues.
However, bone marrow function can be restored after high-dose therapy by replacing the damaged stem cells with healthy ones. This is a procedure known as a stem cell transplant.
There are two possible sources of stem cells for transplantation; they may be collected from the patient prior to undergoing high-dose therapy or they may be collected from a donor. A stem cell transplant that utilizes the patient’s own cells is called an autologous stem cell transplant. When the stem cells are from a donor the procedure is called an allogeneic stem cell transplant.
In general, autologous transplants are performed much more frequently than allogeneic transplants. This is due to the fact that there are relatively few patients with suitable donors and because allogeneic transplants are associated with more treatment-related complications.
High-dose Therapy and Autologous Stem Cell Transplant (ASCT) for Progressive or Relapsed Multiple Myeloma
ASCT is a treatment that is often reserved until multiple myeloma recurs after initial treatment or progresses with treatment. Results of clinical trials indicate that patients did not live longer if they opted for this treatment early in their disease course as opposed to waiting until their myeloma recurred.16,17
Following a first ASCT, some patients may undergo a second one. This is known as a tandem, or double, transplant. Studies have suggested that patients who do not achieve a complete or very good anti-cancer response to the first ASCT are the most likely to benefit from a second ASCT.18
It is important to note that undergoing transplantation later in the treatment strategy is more likely to be successful if it is planned for. Stem cells must be collected prior to any other initial treatment because the bone marrow becomes damaged even with conventional-dose chemotherapy.
High-Dose Therapy and Allogeneic Stem Cell Transplant for Progressive or Relapsed Multiple Myeloma
An allogeneic stem cell transplant involves stem cells collected from a donor. Compared to autologous transplant, a transplant of donor cells is associated with more side effects and a greater risk of death. The benefit of allogeneic transplant, however, is the chance for long-term survival; patients who undergo a donor transplant following cancer recurrence after conventional-dose treatment appear to have a better chance of surviving 10 years or more compared to patients who undergo an autologous SCT.19 Thus, patients accept more upfront risks with an allogeneic transplant in exchange for the chance of long-term survival.
In an attempt to reduce treatment-related side effects, which can be significant, some researchers have explored the role of reduced-intensity allogeneic stem cell transplantation. A small study conducted in patients with poor-risk, relapsed, or refractory multiple myeloma suggested that an ASCT followed by a reduced-intensity allogeneic transplant may be an effective treatment approach for selected patients.20
Maintenance therapy is the ongoing use of chemotherapy or another treatment for months to years to help lower the risk of recurrence after initial therapy has induced a myeloma remission. Some studies evaluating maintenance therapy using Velcade® in elderly patients have reported a delay in the time to cancer recurrence, but not all have ultimately increased overall survival.10,21,6 The use of Revlimid® maintenance after ASCT has also been shown to delay the time to cancer recurrence and prolong survival. Revlimid® is also associated with an increase in the risk of developing myelodysplasia or acute leukemia from 3% to 7%22,23
Managing Complications & Side Effects of Myeloma
The treatment of multiple myeloma is focused on controlling the underlying disease (the increased number of abnormal plasma cells). Managing the symptoms and other medical problems resulting from the increased numbers of plasma cells and abnormal proteins is equally important. The following are complications of multiple myeloma that have specific treatments available:
Bone complications: In 70% of multiple myeloma cases, the bones develop multiple holes, which explains why the disease is referred to as “multiple” myeloma. The holes are referred to as osteolytic lesions, which cause the bones to be fragile and subject to fractures. Osteolytic lesions are caused by the rapid growth of myeloma cells, which push aside normal bone-forming cells, preventing them from repairing general wear and tear of the bones. Under normal circumstances, cells called osteoclasts destroy dead and dying bone. Multiple myeloma causes the secretion of osteoclast-activating factor, a substance that stimulates osteoclasts.
Multiple myeloma involving the bone can cause pain, fracture and other significant problems for patients. Management of bone involvement is an integral part of the overall treatment strategy for multiple myeloma. The first objective of treatment of bone complications is to prevent new bone disease from developing or progression from existing bone lesions to occur.
Bisphosphonate drugs can effectively prevent loss of bone that occurs from metastatic lesions, reduce the risk of fractures, and decrease pain. Bisphosphonate drugs work by inhibiting bone resorption, or breakdown. Bone is constantly being “remodeled” by two types of cells: osteoclasts, which break down bone; and osteoblasts, which rebuild bone. Although the exact process by which bisphosphonates work is not completely understood, it is thought that bisphosphonates inhibit osteoclasts and induce apoptosis (cell death) in these cells, thereby reducing bone loss. There is also evidence that these drugs bind to bone, thereby blocking osteoclasts from breaking down bone.
Bisphosphonate drugs that are FDA-approved for the treatment of cancer-related skeletal complications include Zometa® (zoledronic acid) and Aredia® (pamidronate). Of these two drugs, Zometa appears to demonstrate the strongest activity. An added benefit of Zometa is that it is administered in a dose ten times lower than Aredia, which considerably reduces the administration time from several hours to 15 minutes, resulting in a more convenient regimen for patients.24
Patients with progressive bone involvement from multiple myeloma may experience worsening pain and/or fracture of the bone from the progressive cancer. Low-dose radiation therapy, as well as analgesics, can help control the pain from bone progression of multiple myeloma.
To learn more about bone complications and bone health, go to the Bone Complications and Cancer.
Hypercalcemia: Many multiple myeloma patients develop hypercalcemia, which is an increased level of calcium in the bloodstream. Hypercalcemia results from the destruction of bone from osteolytic lesions or sometimes from the development of generalized osteoporosis, in which all the bones are soft and porous and have lost calcium. Hypercalcemia in patients with multiple myeloma causes fatigue, lethargy and other symptoms. Severe hypercalcemia is a medical emergency requiring immediate treatment. Typically, hypercalcemia is treated with bisphosphonates and hydration.
Decreased blood cell production: The multiplication of the plasma cells in the bone marrow eventually crowds out and suppresses the normal production of blood cells. This may cause a significant decrease in red blood cells, causing anemia; in platelets, causing abnormal bleeding and in white blood cells, causing neutropenia.
Anemia: Anemia, or a decrease in the red blood cell hemoglobin concentration necessary for the transport of oxygen to the body’s organs, is a common complication of multiple myeloma. Anemia may cause patients to experience tiredness, fatigue, shortness of breath and/or a reduced tolerance to activity.
Infections: The depletion of normal white blood cells compromises the patient’s immunity in several ways. First, the number of monocytes and granulocytes are greatly reduced so that the patient is at risk from infections. Second, the delicate and complex balance between the different types of lymphocytes is distorted. Patients with multiple myeloma often have reduced levels of normal immunoglobulin necessary to fight certain types of infections. Patients experiencing recurrent infections may need to have immunoglobulin levels replenished.
Kidney dysfunction: In 75% of patients, the plasma cells also produce monoclonal incomplete immunoglobulins, called light chains. These are excreted in the urine and are the so-called Bence Jones proteins. Bence Jones proteins are named after a British physician, Henry Bence Jones (1813-1873), who first discovered them. Bence Jones proteins may deposit in the kidney, clogging the tubules. Ultimately, this damages the kidney and can cause renal failure. Hypercalcemia may exacerbate kidney problems because excess calcium in the bloodstream causes excessive fluid loss and dehydration. Because the abnormal proteins produced by the plasma cells are eliminated from the body through the urine, they may accumulate in the kidneys and cause kidney dysfunction. In addition to treating the underlying cancer, it is important for patients to maintain adequate oral intake of fluids to help avoid kidney failure and avoid using over-the-counter medications such as non-steroidal anti-inflammatory drugs that can worsen kidney function.
Strategies to Improve Treatment
Advances in precision medicine are leading to the development of more effective treatments for multiple myeloma. Advances require that these new and innovative therapies be evaluated with cancer patients in clinical trials. Patients should discuss the role of clinical trials in the management of their condition with their doctor.
Multiple Myeloma News: The Daily Cancer News reports on all advances in the management of multiple myeloma that are most important to patients; visit the news to stay current with developments in the treatment of multiple myeloma.
Precision Medicine- Cancer used to be diagnosed solely by a visual microscopic examination of tumor tissue and all patients received the same chemotherapy. Now, doctors are personalizing care by finding the genetic alterations within the cancer that drive its growth and use medicines that specifically counteract the cancerous effects of those genes. In addition, these “targeted therapies” are designed to treat only the cancer cells and minimize damage to normal, healthy cells. The ability to test a patients’ cancer for individual differences at the genetic level, and to make treatment decisions based on those differences is the hallmark of precision medicine.
Antibody-drug conjugate, GSK2857916-combines an antibody that recognizes myeloma cells by attaching to the protein BCMA and the drug monomethyl auristatin F (MMAF), which kills the cells after they’re recognized. This is the first time this drug has been studied in humans, and the primary purpose of the study was to find a dose that is safe.25
Second-generation CD38 antibody, MOR202 Darzalex, a CD38 antibody, has been shown to work well against myeloma. Early-phase investigations into a new antibody, MOR202, have preliminary results suggesting that the drug is effective against myeloma.26
CAR-T, or chimeric antigen receptor T-cells- is a new form of cancer immunotherapy in which a patient’s own T cells are removed and then engineered to identify and kill malignant multiple myeloma cells. The use of a patient’s own immune cells to fight cancer is proving to be a promising therapeutic approach in the treatment of some lymphomas.
One characteristic of a cancer cell is its ability to evade an attack by a person’s immune system. Immune cells are constantly surveying the body for potential threats, such as a bacteria or virus. Once the immune system detects such a threat, it initiates an attack against it.
One method of stimulating the immune system to detect cancer cells is referred to as chimeric antigen receptor T cell (CAR-T) therapy. Using this type of treatment, researchers take a sample of blood from the patient, and collect certain immune cells called T-cells.
Through laboratory processes, the collected T-cells are reprogrammed to recognize and attack the patient’s cancer cells. Once the T-cells multiply and reach a certain number in the laboratory (usually hundreds of millions to billions), they are re-infused into the patient. The infused T-cells then circulate throughout the body, attacking the patient’s cancer cells.
- CTL019 CAR T-cell Therapy-engineers a patient’s own T cells to teach them to recognize and attack myeloma cells. CTL019 is designed to attack myeloma stem cells, a cell type that can give rise to many more myeloma cells. A pilot study reported that this approach was safe and feasible a phase 2 trial evaluating this approach is ongoing.27
- BCMA CAR T-cell Therapy-teaches T cells to recognize myeloma cells through a protein called B-cell maturation antigen (BCMA). This approach was reported to have promise in treating myeloma in patients who had already failed other therapies. There are several ongoing trials with BCMA as a target.28
Zolinza (vorinostat) is a histone deacetylase (HDAC) inhibitor which works by increasing the production of proteins that slow cell division and cause cell death. Some studies have indicated an improvement with progression-free survival with the use of zolinza in refractory multiple myeloma.29
Maintenance therapy: The administration of relatively low doses of anticancer drugs after an ASCT could extend the time before cancer progression or prevent relapses. Dexamethasone and interferon are two drugs that have been investigated as maintenance therapy, but benefits remain uncertain.
Researchers conducted a Phase III clinical trial in 614 patients under the age of 65 who had undergone ASCT for initial treatment of multiple myeloma and then treated either Revlimid® or a placebo. Treatment with Revlimid® delayed the progression of myeloma but did not prolong overall survival.
Progression-free survival was 46 months with Revlimid® and 24 months with placebo. Overall survival is ~ 81 months in both groups.30
Allogeneic Stem Cell Transplant
Reduced Intensity Allogeneic Stem Cell Transplant: In an attempt to reduce treatment-related side effects, some researchers have explored the role of reduced-intensity (RIC) allogeneic stem cell transplantation. This approach carries a lower risk than conventional allogeneic stem cell transplant, but has also been linked with a higher risk of relapse.31,32 Nevertheless, one small study has reported that ASCT followed by RIC allogeneic stem cell transplantation resulted in better overall survival than tandem ASCT.33
High-dose therapy followed by allogeneic stem cell transplant is currently the only potentially curative treatment for multiple myeloma. The high risk of serious complications, however, has prompted researchers to explore an alternative procedure known as a reduced-intensity allogeneic stem cell transplant. In a study of 24 patients with poor-risk, relapsed, or refractory multiple myeloma, the approach of starting with an autologous stem cell transplant and then performing a reduced-intensity allogeneic stem cell transplant (with stem cells from an unrelated donor) produced promising response rates with a lower risk of death from treatment.34
Donor lymphocyte infusions: Recent studies have indicated that patients with multiple myeloma who experience a recurrence after an allogeneic transplant achieved high response rates to donor lymphocyte infusions. Researchers from several transplant centers in Europe evaluated 27 patients with multiple myeloma who had a recurrence following treatment with HDC and an allogeneic SCT.
All of these patients received infusions of donor lymphocytes after recurrence of the cancer. Over half of the patients experienced a partial or complete disappearance of myeloma following the infusion. Unfortunately, graft-versus-host disease, a side effect caused by donor cells attacking healthy tissue of the patient, affected over 75% of these patients. The results of this study suggest that donor lymphocyte infusions may be beneficial to patients with multiple myeloma who have a recurrence after HDC and allogeneic stem cell transplant.35
1 Richardson P, Mitsiades C, Schlossman R et al. The treatment of relapsed and refractory multiple myeloma. Hematology 2007. American Society of Hematology Education Program Book; 317 – 323.
2 Singhal S, Mehta J, Desikan R et al. Antitumor activity of thalidomide in refractory multiple myeloma. New England Journal of Medicine. 1999;341:1565-1571.
3 Alexanian R, Dimopoulos M. The treatment of multiple myeloma. New England Journal of Medicine. 1994;330:484-489.
4 Dimopoulos M, Spencer A, Attal M, et al.: Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N Engl J Med 357 (21): 2123-32, 2007.
5 Weber DM, Chen C, Niesvizky R, et al.: Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. N Engl J Med 357 (21): 2133-42.
6 Mateos MV, Oriol A, Martínez-López J, et al.: Maintenance therapy with bortezomib plus thalidomide or bortezomib plus prednisone in elderly multiple myeloma patients included in the GEM2005MAS65 trial. Blood 120 (13): 2581-8, 2012
7 San Miguel J, Weisel K, Moreau P, et al. Pomalidomide plus low-dose dexamethasone versus high-dose dexamethasone alone for patients with relapsed and refractory multiple myeloma (MM-003): a randomised, open-label, phase 3 trial. Lancet Oncology. Published early online September 3, 2013. doi:10.1016/S1470-2045(13)70380-2
8 Richardson PG, Sonneveld P, Schuster M et al. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. New England Journal of Medicine. 2005. 352:2487-98.
9 Richarson PG, Hideshima T, Mitsiades C, Anderson KC. The emerging role of novel therapies for the treatment of relapsed myeloma. Journal of the National Comprehensive Cancer Network. 2007;5:149-162.
10 Bringhen S, Larocca A, Rossi D, et al.: Efficacy and safety of once-weekly bortezomib in multiple myeloma patients. Blood 116 (23): 4745-53, 2010
11 Kumar S, Berdeja J, Niewsvizky R, et al. Safety and tolerability of ixazomib, an oral proteasome inhibitor, in combination with lenalidomide and dexamethasone in patients with previously untreated multiple myeloma: an open-label phase 1/2 study. The Lancet Oncology, Volume 15, Issue 13, Pages 1503 – 1512. December 2014.
12 Usmani S, Weiss B, Plesner T, et al. Clinical efficacy of daratumumab monotherapy in patients with heavily pretreated relapsed or refractory multiple myeloma. Blood. 2016; doi:10.1182/blood-2016-03-705210. Available at: . Accessed June 29, 2016.
Clinical efficacy of daratumumab monotherapy in patients with heavily pretreated relapsed or refractory multiple myeloma
A pooled analysis of 2 daratumumab monotherapy trials showed no new safety signals, an ORR of 31%, and rapid, durable, and deep responses.
13 Lokhohrst H, Plesner T, Laubach J, et al. Targeting CD38 with daratumumab monotherapy in multiple myeloma. New England Journal of Medicine. 2015; August 26, 2015DOI: 10.1056/NEJMoa1506348.
14 San-Migule J, Hungira V, Yoon S-S, et al. Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma: a multicentre, randomised, double-blind phase 3 trial. The Lancet Oncology, Volume 15, Issue 11, Pages 1195 – 1206, October 2014.
15 Richardson PGG, Moreau P, Jakubowiak AJ et al. Elotuzumab with lenalidomide and low-dose dexamethasone in patients with relapsed multiple myeloma: a randomized phase II study. Paper presented at: 2011 Annual Meeting of the American Society of Clinical Oncology; June 3-7, 2011; Chicago, IL. Abstract 8014. Meeting of the American Society of Clinical Oncology; June 3-7, 2011; Chicago, IL. Abstract 8014.
16Fermand J-P, Ravaud P, Chevret S, et al. High-Dose Therapy and Autologous Peripheral Blood Stem Cell Transplantation: UP-Front or Rescue Treatments? Results of a Multicenter Sequential Randomized Trial. Blood. 1998;92:3131-3136.
17 Barlogie B, Kyle RA, Anderson KC et al. Standard chemotherapy compared with high-dose chemoradiotherapy for multiple myeloma: final results of phase III US Intergroup Trial S9321. Journal of Clinical Oncology. 2006;24:929-936.
18 Kyle RA, Rajkumar SV. Multiple Myeloma. Blood. 2008;111:2962-2972.
19 Bjorkstrand B. European Group for Blood and Marrow Transplantation Registry studies in multiple myeloma. Semin Hematol. 2001;38:219-225.
20 Georges GE, Maris MB, Maloney GD et al. Nonmyeloablative unrelated donor hematopoietic cell transplantation for the treatment of patients with poor-risk, relapsed, or refractory multiple myeloma. Biol Blood Marrow Transplant. 2007;13:423-432.
21 Mateos MV, Oriol A, Martínez-López J, et al.: Bortezomib, melphalan, and prednisone versus bortezomib, thalidomide, and prednisone as induction therapy followed by maintenance treatment with bortezomib and thalidomide versus bortezomib and prednisone in elderly patients with untreated multiple myeloma: a randomised trial. Lancet Oncol 11 (10): 934-41, 2010
22 Attal M, Lauwers-Cances V, Marit G, et al.: Lenalidomide maintenance after stem-cell transplantation for multiple myeloma. N Engl J Med 366 (19): 1782-91, 2012.
23 Palumbo A, Hajek R, Delforge M, et al.: Continuous lenalidomide treatment for newly diagnosed multiple myeloma. N Engl J Med 366 (19): 1759-69, 2012.
24 Ross JR, Saunders Y, Edmonds PM, et al. Systematic Review of Role of Bisphosphonates on Skeletal Morbidity in Metastatic Cancer. British Medical Journal 2003; 327:469-471.
25 Maude S, Pulsipher M, Boyer M, et al. Efficacy and Safety of CTL019 in the First Phase II Multicenter Trial in Pediatric Relapsed/Refractory Acute Lymphoblastic Leukemia: Results of an Interim Analysis. Proceedings from the 2016 annual meeting of the American Society of Hematology. Abstract #2801.
26 Boldajipour B, Galetto R, Sommer C, et al. Preclinical Evaluation of Allogeneic Anti-BCMA Chimeric Antigen Receptor T Cells with Safety Switch Domains and Lymphodepletion Resistance for the Treatment of Multiple Myeloma. Proceedings from the 2016 annual meeting of the American Society of Hematology. Abstract #381.
27 Cohen A, Popat R, Trudel S, et al. First in Human Study with GSK2857916, and Antibody Drug Conjugated to Microtubule-Disrupting Agent Directed Against B-Cell Maturation Antigen (BCMA) in Patients with Relapsed/Refractory Multiple Myeloma (MM): Results from Study BMA117159 Part 1 Dose Escalation. Proceedings from the 2016 annual meeting of the American Society of Hematology. Abstract #1148.
28 Raab M, Chatterjee M, Goldschmidt H, et al. A Phase I/II Study of the CD38 Antibody MOR202 Alone and in Combination with Pomalidomide or Lenalidomide in Patients with Relapsed or Refractory Multiple Myeloma. Proceedings from the 2016 annual meeting of the American Society of Hematology. Abstract #1152
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30 Attal M, Lauwers-Cances V, Marit G et al. Lenalidomide Maintenance After Stem-Cell Transplantation For Multiple Myeloma: Follow-Up Analysis Of The IFM 2005-02 Trial. Presented at the 55th ASH Annual Meeting and Exposition. New Orleans, LA. December 7-10, 2013. Abstract 406.
31 Kyle RA, Rajkumar SV. Multiple Myeloma. Blood. 2008;111:2962-2972.
32 Harousseau J-L. Role of stem cell transplantation. Hematology/Oncology Clinics of North America. 2007;21:1157-1174.
33 Bruno B, Rotta M, Patriarca F et al. A comparison of allografting with autografting for newly diagnosed myeloma. New England Journal of Medicine. 2007;356:1110-1120.
34 Georges GE, Maris MB, Maloney GD et al. Nonmyeloablative unrelated donor hematopoietic cell transplantation for the treatment of patients with poor-risk, relapsed, or refractory multiple myeloma. Biol Blood Marrow Transplant. 2007;13:423-432.
35 Lokhorst HM, Schattenberg A, Cornelissen JJ et al. Donor lymphocyte infusions for relapsed multiple myeloma after allogeneic stem-cell transplantation: predictive factors for response and long-term outcome. Journal of Clinical Oncology. 2000;18:3031-3037.