Noopur S. Raje, MD, professor of medicine at Harvard Medical School and director of the Multiple Myeloma Program at Massachusetts General Hospital, discusses recent findings with melflufen in relapsed/refractory multiple myeloma.

Melflufen is a novel alkylating agent with less toxicity, says Raje. The phase 2 HORIZON trial enrolled patients with relapsed/refractory multiple myeloma who were refractory to pomalidomide (Pomalyst) and/or an anti-CD38 monoclonal antibody. The combination of melflufen and dexamethasone was effective in patients with triple-refractory disease and the median duration of response was also significant, says Raje. 

These results underscored that in a particularly difficult population to treat, the old alkylating agent still had efficacy. The trial included many patients who already had melphalan and many had received prior high-dose chemotherapy; even so,some notable efficacy was observed. This is a good weapon to have in the treatment armamentarium, especially in the triple-refractory patient population where response rates can be dismal, concludes Raje.

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Noopur S. Raje, MD, discusses recent findings with melflufen in relapsed/refractory multiple myeloma.

Dr. Raje on Efficacy With Melflufen in Triple-Refractory Myeloma

Noopur S. Raje, MD, professor of medicine at Harvard Medical School and director of the Multiple Myeloma Program at Massachusetts General Hospital, discusses remaining questions in multiple myeloma. 

On the heels of recent advances with BCMA-directed therapies, future research efforts should focus on developing novel combination​s and ​refining sequencing strategies, says Raje. 

Additionally, smoldering myeloma remains an area of controversy, Raje explains. ​Eliminating the definition of smoldering myeloma, and instead focusing on whether a patient has myeloma, could help streamline the treatment algorithm.

Ultimately, better risk stratification is critical, Raje concludes. 

Noopur S. Raje, MD, discusses remaining questions in multiple myeloma. 

 Dr. Raje on Remaining Questions in Multiple Myeloma  

Noopur S. Raje, MD, a professor of medicine at Harvard Medical School and director of the Multiple Myeloma Program at Massachusetts General Hospital, discusses quadruplet therapies that have been examined in multiple myeloma.

Three-drug combinations have been accepted as a standard of care in the up-front and relapsed settings for multiple myeloma, says Raje. The questions that arise now is: Can the field do better, and can quadruplets therapies be used? Typically a quadruplet regimen would be comprised of a 3-drug backbone with the addition of a monoclonal antibody. That is where the quadruplet regimen of carfilzomib (Kyprolis), lenalidomide (Revlimid), and dexamethasone (KRd) plus isatuximab (Sarclisa) comes into play, notes Raje. The quadruplet was examined in the 

 and results showed an 100% overall response rate, with a very high proportion of patients achieving minimal residual disease (MRD) negativity. Other trials are ongoing, a handful of which have already been presented.

For example, in 2019, data from the phase 3 CASSIOPEIA trial with bortezomib, thalidomide (Thalomid), and dexamethasone (VTd) plus daratumumab (Darzalex) were reported, adds Raje. VTd was used in the trial because it is the standard of care in Europe, as lenalidomide was not yet approved there. Again, very high response rates and MRD negativity were reported with this regimen.

The depth of remission or response is very clear with these 4-drug combinations. Similarly, in the United States, the phase 2 GRIFFIN trial evaluated bortezomib, lenalidomide, and dexamethasone plus daratumumab. These data were presented by Peter Voorhees, MD, of Levine Cancer Institute, at the 2019 ASH Annual Meeting and showed a very high response rate with deep responses and MRD negativity, concludes Raje.

Noopur S. Raje, MD, discusses the quadruplet therapies that are currently available for patients with multiple myeloma.

Dr. Raje on the Effectiveness of Quadruplet Therapies in Multiple Myeloma

Noopur S. Raje, MD, professor of medicine at Harvard Medical School and director of the Multiple Myeloma Program at Massachusetts General Hospital, discusses the ​design of the randomized phase 3 E​NDURANCE (E1A11) trial in ​newly diagnosed multiple myeloma.

, ​findings from the study showed that carfilzomib (Kyprolis), lenalidomide (Revlimid), and dexamethasone (KRd) did not significantly improve progression-free survival compared with bortezomib (Velcade), lenalidomide, and dexamethasone (VRd) in patients with newly diagnosed multiple myeloma who were not intended for up-front autologous stem cell transplant. 

​The trial randomized ​patients to receive KRd (n = 545) ​versus VRd (n = 542), says Raje. Notably, these are 2 of the most commonly used induction regimens in this space, Raje concludes.

Noopur S. Raje, MD, discusses the ​design of the randomized phase 3 E​NDURANCE trial in ​newly diagnosed multiple myeloma.

Dr. Raje on the Design of the ENDURANCE Trial in Newly Diagnosed Multiple Myeloma

Noopur S. Raje, MD, director, Center for Multiple Myeloma, Massachusetts General Hospital Cancer Center, and professor of medicine, Harvard Medical School, highlights the different options available for patients with relapsed multiple myeloma.

There are several options available to those with relapsed disease, says Raje; it really depends on where in their relapse they are. For example, there have been multiple FDA approvals in the context of relapse after 1-3 lines of treatment.

It’s important to recognize what the nature of the relapse is and what kind of treatment the patient received prior to the relapse. For example, did the patient relapse on lenalidomide maintenance? Did the patient receive a triplet combination upfront?

The majority of patients will relapse on lenalidomide maintenance because that is the standard of care in the frontline treatment of multiple myeloma. When this happens, there are several pomalidomide (Pomalyst)-based combinations to choose from. The agent has been approved for use in combination with agents such as elotuzumab (Empliciti) or daratumumab, (Darzalex), says Raje.

Furthermore, a Biologics License Application for isatuximab in this setting has recently been accepted by the FDA. The BLA is based on data from the phase III ICARIA-MM trial which showed that the addition of isatuximab to pomalidomide and low-dose dexamethasone led to a greater than 40% reduction in the risk of disease progression or death versus pomalidomide and dexamethasone alone.

There’s ongoing work with pomalidomide and ixazomib (Ninlaro), and there’s phase II data on pomalidomide in combination with carfilzomib (Kyprolis) as well. Therefore, depending on the nature of the relapse, there are my options available. The agent can either be used with a monoclonal antibody or you can use it with a proteasome inhibitor in this context, concludes Raje.

Noopur S. Raje, MD

Articles

Dr. Raje on Efficacy With Melflufen in Triple-Refractory Myeloma

Dr. Raje on Remaining Questions in Multiple Myeloma

Dr. Raje on the Effectiveness of Quadruplet Therapies in Multiple Myeloma

Dr. Raje on the Design of the ENDURANCE Trial in Newly Diagnosed Multiple Myeloma

Dr. Raje Highlights Treatment Options for Relapsed Multiple Myeloma