Multiple Myeloma Therapy on Cusp of New Era, but Much Is Left to Prove, Review Says

The time has come for multiple myeloma (MM) treatment to evolve so as to better account for new treatment and assessment, according to a new review article, but the authors also wrote that pragmatism should remain at the forefront of clinicians’ minds.

Writing in the journal Cancers, corresponding author Jill Corre, of University Institute Cancer Toulouse Oncopole in France said high-risk patients should benefit from the most intensive and efficient therapeutic combinations, and they said the technology is already emerging to make that happen.

Corre and colleagues began by reviewing recent advances that can help identify high-risk patients at diagnosis. For instance, they noted that investigators are increasingly realizing that age and frailty are two different things, and the former might not imply the latter. They also noted that, while cytogenetics clearly have “huge” prognostic value, not all cytogenetic abnormalities have the same importance, and differing combinations of abnormalities can lead to different prognoses. They said newer prognostic scoring systems can help better risk stratify patients, and thus improve outcomes.

The authors then outlined a series of therapeutic advances, noting that regimens including bortezomib (Velcade) were initially seen as the best option for high-risk patients. However, they said newer combinations of drugs like proteasome inhibitors and immunomodulatory drugs also appear to be effective in patients with high-risk cytogenetics. In patients ineligible for autologous stem cell transplantation, triplets seem to be superior to doublets in high-risk cases, they said.

Even as treatments have improved, the authors cautioned that outcomes for patients remain heterogeneous with different depths and durations of response. Existing response criteria are limited, they said, handicapping physicians’ ability to adapt treatment based on an individual patient’s apparent complete response (CR), or lack thereof.

“[D]espite achieving a CR and even stringent complete response, most patients relapse, reflecting a persistent disease undetectable with standard methods, namely the minimal residual disease (MRD),” they wrote.

Next-generation flow cytometry and next-generation sequencing have each provided the ability to detect MRD, which the authors said could open up new avenues of dynamic, response-based therapy.

“Different clinical trials are ongoing to assess if MRD could help in clinical decision-making at various stages of treatment,” they said.

Though Corre and colleagues wrote that MRD integration into clinical proactive is a near-term possibility, they also examine longer-run potential changes in MM treatment. One of the most exciting possibilities, they said, is using molecular characteristics to bring targeted therapy to MM. However, the investigators said the prospect of such a therapy remains uncertain.

The closest thing to a “convincing” targeted therapy for MM, the authors said, is the BCL2 inhibitor venetoclax (Venclexta). However, Corre and colleagues argued the drug does not actually have a clear target. It has led to objective responses in multi-refractory patients harboring the t(11;14) translocation, but the authors said no biological link between CCND1 and BCL-2 has been clearly highlighted.

“The presence of t(11;14) may only be an imperfect surrogate marker of high BCL2 expression,” they said, “with some patients without t(11;14) also displaying good-quality response, and some with t(11;14) being refractory.”

On the other hand, the authors said there have been examples of drugs that appear to be particularly effective in cases with specific cytogenetic profiles, such as bortezomib for patients with t(4;14).

With potential evolution of MM therapy on the horizon, the authors said physicians and patients will increasingly face a set of complex choices. They said better risk stratification, response assessment, and the discovery of molecular characteristics will lead to new treatment options, but the authors also cautioned physicians that such options will be based on clinical-trial settings, rather than real-world cases.

Thus, the investigators concluded, a “pragmatic” approach that factors in patient quality of life and views risk-based and response-based strategies as complimentary, rather than oppositional, will be necessary.

“In the ever-changing field of myeloma treatment, risk and response assessment is like a compass,” they wrote, “it sets the course for treatment decisions, but real-life clinical practice steers the ship.”

Reference

Cazaubiel T, Mulas O, Montes L, et al. Risk and Response-Adapted Treatment in Multiple Myeloma. Cancers (Basel). 2020;12(12):E3497. Published 2020 Nov 24. doi:10.3390/cancers12123497