Review: MM Outcomes Greatly Improving, but New Agents Still Needed

A new paper outlines major shifts in the treatment paradigm of multiple myeloma (MM) and suggests that additional evolution of clinical practice is on the horizon.

However, the review article also suggests that, despite the development of novel agents, autologous stem cell transplantation (ASCT) continues to play a central role in management of the disease.

Writing in the journal Advances in Cell and Gene Therapy, corresponding author Saad Z. Usmani, MD, of Atrium Health, and colleagues, note that overall survival for MM has nearly quadrupled in the past 2 decades, thanks to novel agents at all stages of treatment.

Usmani and colleagues wrote that updates to the consensus definition of active myeloma, as well as a revision of the international staging system, have made it easier to stratify patients and inform treatment decisions. Given that the disease remains incurable, the primary goals of treatment are to control the disease, prevent complications, and reduce the risk of early death.

The investigators noted that the current treatment paradigm is dependent upon whether the patient is eligible for ASCT. If so, patients should generally receive 4 cycles of induction chemotherapy before proceeding to high-dose melphalan and then ASCT. Which induction therapy to use will depend on the individual’s risk level, they wrote. For standard-risk patients, a triplet drug combination that includes novel agents is the preferred option. For high-risk patients, recent data has supported the inclusion of the proteasome inhibitor carfilzomib (Kyprolis) with lenalidomide (Revlimid) and dexamethasone (KRd).

However, head-to-head data comparing KRd with VRd (substituting bortzomib [Velcade] for carfilzomib), are not yet available.

In patients who are transplant-ineligible, the authors suggest 6 to 8 cycles of induction chemotherapy, followed by maintenance therapy. They recommend the RVd (lenalidomide, bortezomib, and dexamethasone) regimen for high-risk patients, and DRd (daratumumab [Darzalex], lenalidomide, and dexamethasone) for standard-risk patients.

The authors write that maintenance therapy has become the standard-of-care following transplant. In their practice, Usmani and colleagues say patients with standard cytogenetics typically receive single-agent lenalidomide, while patients with high-risk cytogenetics receive bortezomib or a combination of the two.

However, despite the advances, Usmani and colleagues say better agents are still needed.

“Clonal evolution and heterogeneity are well-established concepts in the pathogenesis of all hematological malignancies, and MM is no exception,” they wrote. “It has been suggested that with repeated exposure to chemotherapy a strong pressure is exerted on MM cells leading to the selection of clones that are inherently resistant to front-line agents.”

Aside from new therapies, the authors say future advances can be divided into 3 categories: changes to the management of patients with high-risk smoldering myeloma; the evaluation of the benefits of quadruplet chemotherapy; and efforts to incorporate new drugs into the frontline setting after the drugs demonstrate efficacy in a relapsed setting.

Though Usmani and colleagues wrote that much has changed, they said ASCT continues to be an “essential” part of therapy for transplant-eligible patients who are newly diagnosed with MM.

“Alternatively, a tailored or personalized approach that utilizes [measurable residual disease] status might provide a more accurate methodology for evaluation to new therapies, and single out patients who may not require maintenance therapy or ASCT after induction,” they concluded.

Reference:

Hamadeh I, Atrash S, Fisher AM, et al. Advances & future prospects in newly diagnosed multiple myeloma patients. Adv Cell Gene Ther. Published online June 24, 2020. doi:10.1002/acg2.96