Treatment for multiple myeloma has evolved significantly, with long-term survival increasingly within reach for many patients. Achieving optimal outcomes requires not only addressing symptoms but also tailoring therapies to match the heterogeneity of this complex disease.
Defining Optimal Outcomes in Myeloma
For patients newly diagnosed with multiple myeloma, optimal outcomes start with a clear set of goals. "The primary goals of initial treatment are straightforward: relieve symptoms like anemia, bone pain, or kidney failure; control the disease as long as possible; and minimize side effects," explained Natalie S. Callander, MD, of the University of Wisconsin Carbone Cancer Center in Madison.
Callander emphasized that getting patients into remission is now a critical objective, a stark contrast to the era when remission was often considered unattainable.
Multiple myeloma, historically treated as a single disease, is increasingly recognized as a heterogeneous condition. "If you look at another lymphoid disease, non-Hodgkin lymphoma, there are clear histologic subtypes," Callander said. "Multiple myeloma was long considered a single entity, but we now understand that different genetic and clinical features influence prognosis and treatment response."
Advances in molecular testing, such as cytogenetic analysis of plasma cells, have allowed clinicians to stratify patients based on risk, and tailor therapy accordingly. Importantly, the focus on achieving deep remission has also redefined success. Beyond simply controlling the disease, clinicians aim to eliminate detectable abnormal plasma cells through multi-pronged therapy.
"The bar has been raised," said Callander. "Today, the goal is MRD [minimal residual disease] negativity -- finding no residual disease even with sensitive molecular tests. That's where we're trying to get every patient."
With these refined benchmarks, myeloma treatment now prioritizes both immediate symptom management and long-term disease control, setting the stage for personalized approaches to care. However, according to Nisha Joseph, MD, of Emory University School of Medicine in Atlanta, providers do not always know who the long-term survivors will be.
"It tends to be standard-risk patients who respond well early, but some high-risk patients also achieve MRD negativity and stay there," said Joseph. "It's not always who you think it's going to be."
High-Risk Myeloma: Identification and Challenges
Although identifying high-risk multiple myeloma patients is critical for determining the most effective treatment approach, it remains a significant challenge due to the disease's complexity. Callander explained that "there are certain patterns we can see upfront -- cytogenetic markers like 17p deletions or translocations involving chromosome 14. These can indicate whether a patient is likely to have a longer remission or if their disease might progress more quickly."
Such markers, along with clinical indicators like elevated beta-2 microglobulin and extramedullary disease, are critical in stratifying patients by risk.
However, not all high-risk patients are easily identifiable. Patients referred to as "functional high-risk" initially present with low-risk features but relapse rapidly after treatment. "On paper, these patients should do well," said Joseph. "But within 18 months, they're back, and we're often left wondering why. They lack the typical high-risk genetic or clinical features, making them especially difficult to predict."
The Revised International Staging System has provided a framework for risk stratification, incorporating both laboratory findings and genetic abnormalities. Yet, even with these tools, clinicians face challenges in predicting individual outcomes, especially for patients who may develop new genetic mutations during relapse.
"We're getting better at identifying high-risk features, but it's not perfect," Callander acknowledged. "Patients with two or more high-risk cytogenetic features, for example, are at the greatest risk of relapse and typically require more aggressive, continuous treatment."
This inability to fully predict functional high-risk cases underscores the complexity of multiple myeloma. While genetic and clinical markers guide treatment strategies, ongoing research into the mechanisms of resistance and relapse is essential to refine risk assessment and improve outcomes for these difficult-to-treat patients.
"Current methods, like cytogenetics or FISH [fluorescence in situ hybridization], often fall short in predicting outcomes," Joseph said. "We need to move toward whole-genome sequencing and a deeper look at the biology to appropriately re-stratify these patients."
Optimizing Therapy for Long-Term Success
Advances in multiple myeloma treatment have shifted the focus toward more intensive, personalized approaches aimed at achieving deep remission and prolonging survival. Quadruplet regimens, which combine drugs targeting multiple myeloma from multiple biological angles, are increasingly becoming the standard for initial therapy.
"If you're attacking something, you don't just shoot an arrow at it," Callander said. "You throw a grenade, fire a torpedo, and drown it all at once. The idea is to hit the disease hard to reduce the chance of resistant clones emerging."
Joseph noted that "with the number of drugs that we now have -- each targeting different mechanisms -- we may already have the tools to achieve a quote-unquote cure. The key is sequencing and combining them synergistically to get a deep response and sustain it."
Achieving MRD negativity has become a primary benchmark for success. However, while high-risk patients often benefit from long-term maintenance therapy to sustain remission, there is growing interest in de-escalation strategies for low-risk patients. "For those with less aggressive disease, we're exploring treatment-free intervals," Callander said. "The idea is to intensify early treatment to achieve a deep remission, then give patients a break from therapy to improve their quality of life."
Joseph pointed to the patients "that we are over-treating because we're trying to ensure we're not under-treating those who really need it. The challenge is identifying who never needs that much treatment in the first place."
The role of autologous stem cell transplantation (ASCT) also continues to be debated. While some studies suggest quadruplet drug regimens can achieve similar remission rates without a transplant, Callander emphasized that ASCT remains a cost-effective and potent option, especially for high-risk patients. "Transplants add value, particularly for patients with high-risk disease, where achieving deeper remission is crucial," she said.
Ongoing trials comparing ASCT to cellular therapies, like CAR T-cell therapy, may eventually reshape this paradigm, but for now, ASCT remains an integral part of multiple myeloma treatment.
With long-term survival increasingly achievable for patients with multiple myeloma, treatment strategies are evolving to balance effectiveness with quality of life. Continued research into risk stratification and novel therapies promises to refine this balance, bringing the field closer to delivering personalized, durable care for all patients.
"The goal in the absence of a true cure is a functional cure -- achieving a deep, durable response that allows patients to reach their natural lifespan without myeloma causing their death," Joseph said.