Multiple Myeloma (MM) is a cancer originating from plasma cells, a type of white blood cell, that accumulates in the bone marrow. This uncontrolled proliferation of abnormal plasma cells interferes with the production of normal blood cells and causes damage to the bones and kidneys. For patients considered medically fit, a major decision revolves around the role of high-dose chemotherapy followed by an autologous stem cell transplant (ASCT). This intensive procedure has long represented a standard approach, but its necessity and optimal timing are continually being re-evaluated in the context of newer, highly effective drug therapies. The decision to pursue a transplant is highly personalized and depends on the specific characteristics of the patient and their disease.
Understanding Autologous Stem Cell Transplantation (ASCT)
Autologous stem cell transplantation allows for the safe administration of high-dose chemotherapy, which would otherwise be lethal to the bone marrow. The term “autologous” signifies that the patient’s own stem cells are used, distinguishing it from an allogeneic transplant, which uses donor cells. The process begins with stem cell mobilization, where a growth factor drug, often granulocyte colony-stimulating factor (G-CSF), encourages hematopoietic stem cells to move from the bone marrow into the circulating bloodstream.
Once mobilized, the stem cells are collected from the blood through apheresis, a process similar to donating blood. A machine filters out the stem cells, and the remaining blood components are returned to the patient. These harvested cells are then frozen and stored in a cryopreservation unit until the day of the transplant.
The patient next undergoes a conditioning regimen, typically involving a single, high dose of the chemotherapy drug melphalan. This potent treatment is designed to kill myeloma cells but also destroys the healthy blood-forming cells in the bone marrow. Finally, the stored stem cells are thawed and re-infused intravenously, where they migrate back to the bone marrow to begin engraftment and restore the body’s ability to produce new, healthy blood cells.
Necessity and Timing of Transplantation
For many years, high-dose melphalan with ASCT has been considered the standard of care, or consolidation therapy, for eligible patients with newly diagnosed MM. The primary goal of the transplant is to achieve a deeper, more durable remission, measured by an improvement in progression-free survival (PFS). The intensive conditioning regimen is generally more effective at eliminating residual disease than conventional chemotherapy.
The question of necessity has become complex with the introduction of highly effective novel agents. Newer triplet and quadruplet drug regimens can now achieve very deep responses even without a transplant. Randomized trials comparing upfront ASCT (early in the treatment course) with deferred ASCT (saving it for a later relapse) have shown a significant benefit in PFS for the upfront approach. For instance, one study showed a median PFS of 50 months with upfront ASCT versus 36 months for the deferred group.
Despite the PFS benefit, these studies have not always demonstrated a difference in overall survival (OS) between the two approaches. This suggests that the transplant may not need to be performed immediately to maximize a patient’s lifespan, provided the deferred transplant can be successfully performed at the time of relapse. Deferring the transplant allows patients to benefit from a longer period of continuous therapy with novel agents and avoid the immediate short-term toxicities associated with ASCT. Furthermore, a patient who achieves minimal residual disease (MRD) negativity after initial non-transplant therapy may be a strong candidate for deferring the procedure.
Determining Patient Eligibility and Risk
The decision to proceed with ASCT is based on a comprehensive assessment of the patient’s ability to tolerate the intensive procedure, not just their age. The clinical team evaluates a patient’s physiological age and overall fitness, which is considered more important than their chronological age. While patients under 65 were historically the primary candidates, many centers now successfully transplant individuals up to 75 years of age, or even older, based on their performance status.
A patient’s performance status, often measured by the ECOG scale, must be good (typically 0 to 2) to ensure they can physically withstand the high-dose chemotherapy. The presence of significant comorbidities, particularly in the heart, lungs, or kidneys, is a major factor that can lead to a patient being deemed ineligible for ASCT. Adequate organ function, such as an ejection fraction greater than 50% for cardiac function, is necessary to minimize the risk of serious complications.
The characteristics of the myeloma itself also influence the decision, particularly the presence of high-risk cytogenetics—specific chromosomal abnormalities in the myeloma cells. Patients with high-risk features, such as deletion 17p or translocation (4;14), often receive a stronger recommendation for upfront ASCT. The intense consolidation offered by the transplant may be necessary to overcome the aggressive nature of these specific subtypes and achieve a durable response.
Non-Transplant Treatment Strategies
For patients who are not candidates for ASCT due to age or comorbidities, or who choose to defer the procedure, modern medicine offers highly effective non-transplant strategies. These approaches rely on continuous therapy with novel therapeutic agents that have significantly improved outcomes in recent years. The current standard for non-transplant eligible patients involves combination regimens, often called triplets, which are significantly more effective than older chemotherapy-based treatments.
These triplet regimens typically combine a proteasome inhibitor with an immunomodulatory drug and a steroid. Common combinations include lenalidomide, bortezomib, and dexamethasone (VRd) or daratumumab, lenalidomide, and dexamethasone (DRd). Proteasome inhibitors work by disrupting the cellular machinery responsible for degrading proteins, leading to myeloma cell death. Immunomodulatory drugs modify the immune system and exert direct anti-myeloma effects.
Monoclonal antibodies, like daratumumab, represent another class of agents that directly target proteins on the surface of myeloma cells, such as CD38, to initiate an immune response. For many patients, especially those who are older or frail, continuous therapy with these combinations can provide disease control comparable to a transplant approach without the associated high-intensity risks. The goal in this setting is to maintain a deep, long-term remission through ongoing, tolerable treatment.