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Fonseca Discusses Integrating Biology and Treatment in Multiple Myeloma

Caroline Seymour
Published: Thursday, Apr 19, 2018

Rafael Fonseca, MD
Rafael Fonseca, MD
Although findings from the phase III ALCYONE trial demonstrated the superiority of daratumumab (Darzalex) in combination with bortezomib (Velcade), melphalan, and prednisone (VMP) versus VMP alone, Rafael Fonseca, MD, explains that optimizing frontline therapy for patients with newly diagnosed multiple myeloma remains a work in progress.

The introduction of immunomodulatory drugs (IMiDs), such as lenalidomide (Revlimid), pomalidomide (Pomalyst), and proteasome inhibitors like bortezomib (Velcade) and carfilzomib (Kyprolis), has given physicians a firm backbone on which to base clinical trials as “there is [still] huge attrition between lines of therapy,” said Fonseca.

Ongoing trials are investigating and will soon reveal the use of daratumumab with lenalidomide, bortezomib, and dexamethasone (RVD), as well as daratumumab with carfilzomib, lenalidomide, and dexamethasone (KRd). Regimens such as rituximab (Rituxan) plus RVD and rituximab plus KRd are also being explored.

“We have the information, but we don't yet have the wisdom. I wouldn't be surprised if in a few years from now, we piece everything together in a way that is practical and useful for patients,” Fonseca said.  

In an interview during the 2018 OncLive® State of the Science Summit™ on Multiple Myeloma and Myeloproliferative Neoplasms, Fonseca, a hematologist at Mayo Clinic, discussed the integration of biology and treatment selection for patients with newly diagnosed multiple myeloma.

OncLive: How does the presentation of multiple myeloma differ from other hematologic malignancies?

Fonseca: Myeloma mainly affects people in their 60s and 70s, though it can affect younger individuals. Traditionally, patients present with symptoms of hypercalcemia, renal problems, renal insufficiency, anemia, and bone. Destructive bone lesions are one of the dangerous hallmarks of myeloma. However, renal failure is more dangerous because it is not always reversible. Bone damage can result in compression fractures and, despite our best efforts, can lead to lifelong pain so we want to intervene before that happens. 

What are some prognostic markers?

By definition, every patient with myeloma will have genetic abnormalities. High risk is determined by fluorescence in situ hybridization (FISH), but many people are not using FISH correctly. They’re sending the bone marrow without consideration for sorting or otherwise marking of the cells. Pathology labs are looking at the nuclei of the bone marrow, which doesn’t provide the right information.

The correct information is important for physicians to think about high-risk markers, subsequent maintenance strategies, and counseling approaches. Induction chemotherapy is a highly effective treatment, but leaves no viable plasma cells behind. Therefore, physicians who see patients who have received 1 or 2 cycles of induction therapy have lost the opportunity to look at plasma cells following treatment. Consequently, there is no opportunity to know if a FISH report is normal or not. 

How can physicians ensure that FISH is used correctly?

There needs to be standardization in clinical practice. We have made an effort to disseminate this information in the United States and worldwide. Why waste your money if you’re not going to use FISH properly?

I also talked about what we’ve learned from next-generation sequencing (NGS) and identified some of the gaps. That's just working its way into the clinic as a prognostic marker. I also spoke about some of the specific genetic subtypes. Venetoclax (Venclexta) is a new oral agent that can be effective for patients with translocation t(11;14). It’s quite unique in that it predominantly works against t(11;14). For those patients it works for, it works very well.

Are there other agents, besides venetoclax, that you're excited about for newly diagnosed patients?

We are very excited with the canonical set of agents such as IMiDs [with] lenalidomide and pomalidomide, and the addition of the proteasome inhibitors bortezomib and carfilzomib. We are very happy to have them as the backbone. The question right now is whether or not we’re going to use monoclonal antibodies in frontline therapy with agents like daratumumab; the answer is yes, but we don’t yet have the clinical trial data.




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