Fonseca Discusses Integrating Biology and Treatment in Multiple Myeloma

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.

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

What are some prognostic markers?

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.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. 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.

How can physicians ensure that FISH is used correctly?

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. 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?

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

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.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.

Why have we not seen frontline daratumumab and VMP used as much?

What are some abnormalities aside from t(11;14) that have been identified with NGS?

What are the factors that determine a patient's eligibility for transplant?

Is there any other research you are working on that you would like to share?

The ALCYONE trial reported this with a bit of an older combination. It’s going to be a matter of time before we start doing that. The reality is that we'll have regimens like R-CHOP [rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone] as in lymphoma for myeloma; that may be rituximab with RVD or rituximab with KRd. As you start getting into complete responses of 50% or higher, you start seeing a sizable number of durable responses. We know that happens in a very small fraction of patients. We're striving to do that from the get-go. Daratumumab with VMP contains melphalan, and melphalan is rarely used in the United States with the exception of stem cell transplant. At the global level, it's going to be very important. Many countries around the world use that combination. There is a phase III clinical trial that shows improvement. How that converts to relevant practice in the United States is not going to be very complex. That may be in the form of daratumumab and something like bortezomib, cyclophosphamide and dexamethasone (CyBorD), which we don't use as much. That would be the equivalent with melphalan.Some of the mutations that have been identified are present in a sizable number of patients and could potentially serve as therapeutic targets. We have seen preliminary success in some of these efforts. We need to combine some of these targeted agents with some of the standard chemotherapeutic drugs. There are reports of single-agent activity with BRAF-targeted agents. The responses haven’t been durable, so we’re turning to combination approaches. We have a much better understanding of RAS mutations and NIK abnormalities, some of which may be related to IMiD sensitivity. The list of those mutations continues to grow.Many patients are eligible for transplant. It may be that 5 years from now, transplant will be gone, but as it stands patients who are eligible to undergo transplant should undergo the procedure. For the most part, anyone under the age of 75 who is otherwise healthy is eligible for transplant. We're fortunate that that age has moved from 65 to about 75. There is no question that the older the individual gets, the harder transplant becomes. We are more reluctant in patients over 75, even if they look fit. It’s an individualized decision based on the condition of the patient. We need to better understand how IMiDs work. One of the things they do is interfere with a cell's ability to detoxify. When plasma cells synthesize antibodies, they form these disulfide bonds that release hydrogen peroxide, which is very toxic to the cell. They need good mechanisms to dispose of them. Those mechanisms exist in the cells, but drugs like lenalidomide can inhibit them and self-poison the cell. It depends on the cell’s ability to produce proteins, which might explain why some of these drugs don't work in other tumor types. They tend to be less effective in more advanced disease when patients become non-secretors.

What is your preferred regimen?

In terms of treatment, you have to start with your best foot forward. Putting your best combination forward from the get-go is very important. I like to use the analogy between soccer and baseball. The strategy in soccer is to put your best players out from the beginning of the game. In baseball, you can have a pitcher who is going to save you in the seventh inning; that’s not the case in myeloma. You have to go for the best possible combination with the highest durability of response. There may not be a future line of therapy because of comorbidities, toxicities, or disease progression, so you shouldn’t save a therapy for later. Patient preferences also factor in.RVD is one of the preferred regimens for transplant-eligible and transplant-ineligible patients with newly diagnosed multiple myeloma. KRd is also used in patients who have high-risk markers. Even though we have 11 new drugs, things are getting a little bit simpler in terms of preferred regimens. I'm hoping we'll be able to further refine our treatments, even though it’s challenging.

Mateos M-V, DA Meletios, Cavo M, et al. Daratumumab plus bortezomib, melphalan, and prednisone for untreated myeloma. N Engl J Med. 2018;378:518-528. doi:10.1056/NEJMoa1714678.