Better understanding of the molecular basis of multiple myeloma has yielded a growing list of treatments for this challenging plasma cell cancer—including carfilzomib, pomalidomide, panobinostat, ixazomib, elotuzumab, and daratumumab in recent years, with more in development.

But with more treatment options have come more complex clinical decisions and new questions about optimal combinations and timing of different agents. Advances in risk stratification can help move the field toward personalized medicine—as can an anticipated role for immune checkpoint inhibitor-based combination therapies.

“The treatment paradigm for myeloma continues to evolve rapidly with the introduction of new drugs, including new classes of drugs,” Shaji Kumar, MD, of the Division of Hematology, Mayo Clinic in Rochester, MN, told Cancer Therapy Advisor.

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As understanding of myeloma’s molecular-biological underpinnings has improved, there has emerged a growing appreciation for just how heterogeneous this clonal plasma cell cancer can be.

“We better understand now how different myeloma is; not all patients have exactly the same disease, and we understand more about the basic biology of what allows a malignant plasma cell to survive,” said Sagar Lonial, MD, FACP, professor and chair, Department of Hematology & Medical Oncology at the Emory University School of Medicine, and chief medical officer of the Winship Cancer Institute of Emory University in Atlanta, GA.

“At the same time, we’ve had a lot of preclinical and clinical work undertaken with new classes of agents,” he added.

“Until about the year 2000, all we really had was combination chemotherapy and steroids. You could change the chemotherapy drug, but the outcomes were not appreciably different. We learned the same lesson over and over again: more chemotherapy wasn’t necessarily better.”

The field started to make real headway, however, once enough was known about the molecular biology of myeloma to start targeting disease processes directly. The introduction of immunomodulatory drugs (IMiDs) and proteasome inhibitors have helped prolong overall survival (OS) rates, from a 5-year OS of just under 35% from 1998 to 2001 to 45% a decade later.1

The biggest advances have come for treating newly diagnosed myeloma. The overall approach remains familiar terrain: initial induction therapy (with stem-cell transplant if eligible), followed by consolidation and maintenance therapy—and eventually, in most cases, the treatment of relapse or refractory disease. But the options available for each of these steps are expanding, and the field has started to move, perhaps modestly, toward personalized treatment plans.

The goal of initial therapy remains to debulk disease, improve patient function and alleviate symptoms, and to achieve remission.

“That third goal of initial therapy is to achieve a deep and quick response in a way that doesn’t limit stem cell mobilization, because even in an era of great drugs, high-dose therapy and autologous stem cell transplantation [ASCT] continue to offer patients benefits,” said Dr Lonial. “Most large randomized controlled trials that compare transplantation versus no transplantation show that remission is longer for patients that have ASCT, and most studies show survival benefits as well.”

As myeloma advances, it becomes more genetically heterogenous, increasing the risk of drug resistance.

“One important goal of treatment is to maximize the duration of first remission,” noted Dr Lonial. “We know that the time of initial presentation is when the disease is at its most sensitive to treatment—you’re more likely to make a big impact for long-term control if you hit the disease effectively, early on.”

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The current gold standard for achieving those initial-therapy goals in newly diagnosed patients is the 3-drug “RVD” (Revlimid-Velcade-Dexamethasone) regimen, in Dr Lonial’s opinion. “In the French trial followed by randomized early versus late transplantation doesn’t show a survival benefit yet—but the follow-up has been very short.”

“Recent phase 3 trials have clearly demonstrated a role for a combination of proteasome inhibitor and an IMiD in the initial management of myeloma, provided the patient can tolerate a more intense regimen,” agreed Dr Kumar. “The continuing role of cell transplant as an effective consolidation therapy has been highlighted by a large randomized French trial comparing early versus late high-dose therapy following VRD induction.”