Novel Frontline Approaches Induce Deep, Durable Responses in Multiple Myeloma

Michael A. Rosenzweig, MD, MS

Utilizing the oncology standard that "more is better," frontline treatment options for patients with multiple myeloma are expanding to include more novel agents and different combinations in order to obtain deeper responses, explained Michael A. Rosenzweig, MD, MS.

"Options for frontline treatment are increasing and obtaining deep responses is critically important to helping patients prolong the control of their disease," said Rosenzweig. "The longer we can control the disease, the more options patients will have in the future. While we are working hard to find a cure for multiple myeloma, if we can control the disease for a long period of time to turn this disease into a chronic disease, that is certainly a win."

In the past, multiple myeloma treatment was typically comprised of doublet therapies whereas today, triplet regimens have been successful enough to become the new standard of care. For example, the triplet of daratumumab (Darzalex), lenalidomide (Revlimid), and dexamethasone (DRd) became an option for transplant-ineligible patients after it was found to reduce the risk of disease progression or death by 44% versus lenalidomide/dexamethasone (Rd) alone. As different 3-drug regimens are tested, patients are experiencing greater tolerability, which allow for potentially higher efficacy, stronger disease control, and deeper responses, said Rosenzweig.

Trials exploring maintenance therapy, immunotherapy, and the need for transplant are also evolving the multiple myeloma paradigm. Although data have shown that transplantation still has a role in improving disease control, the line between patients who are eligible for the procedure versus those who are not is becoming blurred.

"In the past, we thought transplant-ineligible patients couldn't tolerate strong therapies that would induce deep responses, but what we are learning is that we can get deep responses with newer agents that are, in fact, well tolerated," said Rosenzweig.

In an interview during the 2019 OncLive^® State of the Science Summit™ on Hematologic Malignancies, Rosenzweig, assistant clinical professor of Hematology and Hematopoietic Cell Transplantation and hematologist/oncologist at City of Hope, discussed changes in the frontline setting of multiple myeloma.

OncLive: What are some key considerations to remember in the frontline treatment of multiple myeloma?

Rosenzweig: In 2019, obtaining deep responses is critically important in multiple myeloma treatment. The reason for that is, deeper responses have been shown to be improved upon less deep responses, as demonstrated by the data showing that minimal residual disease (MRD)-negative patients fare better than those who have MRD-positive disease. That's really important, because getting deep responses translates to longer progression-free survival (PFS). The longer we can control the disease, the more options patients will have in the future.

How has frontline treatment evolved over the years?

Over the years, frontline treatment for patients with multiple myeloma has evolved to include more therapies, more agents, and finding the right combination. We started with doublet therapies, which were the standard of care. Initially there was melphalan and prednisone, and then there was Rd. What we are learning is that triplet therapies are the standard we have evolved to. Now that triplet therapies are well-tolerated and are very effective, the question is, "How do we improve upon that success?" Are there new agents that we can incorporate into triplet therapies or maybe we can add to the existing triplet therapies with some of the newer agents?

What are some of the options available to transplant-eligible patients versus transplant-ineligible patients?

The line between transplant-eligible and transplant-ineligible [patients] is really becoming blurred because of how well tolerated the regimens for multiple myeloma are today. Even patients who are somewhat older and maybe too frail to tolerate a transplant can tolerate some of our most effective agents. Again, the distinction between what to do for transplant-eligible and transplant-ineligible [patients] [continues to blur] and just excludes our most intense therapy, which is autologous stem cell transplant (ASCT).

Could you discuss the FORTE trial and how those findings can impact this space?

In the FORTE trial, investigators explored induction chemotherapy followed by ASCT consolidation, which was then followed by further consolidation. The trial compared three different arms: carfilzomib (Kyprolis) and Rd (KRd) followed by transplant; carfilzomib, cyclophosphamide, and dexamethasone followed by transplant; and KRd that was followed by additional lines of treatment with KRd.

What the FORTE trial found is that the combination of carfilzomib being used in the induction setting is well-tolerated and very effective. As such, [this regimen is] one to consider upfront for patients with high-risk cytogenetics and those who are otherwise quite fit. In addition, results showed that KRd was superior to carfilzomib, cyclophosphamide, and dexamethasone in terms of response rates post-induction.

The other interesting finding had to do with the arm that included transplant with KRd compared with one without transplant. While both arms had similar responses and similar rates of disease control with MRD negativity, that rate of MRD seemed to be more persistent in the patients who went on to transplant. That teaches us that the proteasome inhibitor, immunomodulatory agent, and steroid combination remains an excellent regimen; it's the one to beat or the one to build upon. It also teaches us that transplant still has a role in this space, even in the setting of these highly active agents. Transplant can improve on even some of our most effective induction therapies.

Switching over to the MAIA trial, what were some of the key lessons learned?

The MAIA trial is exciting because it explores a triplet therapy compared with the standard doublet therapy in patients who are ineligible for transplant. When we added daratumumab, a monoclonal antibody that targets CD38, to Rd it was found to be very well tolerated. We can take patients who are somewhat frail, somewhat older, and transplant-ineligible and they will do quite well with DRd.

The response rates [seen with this triplet] are exciting. The median PFS was actually not met with the triplet compared with Rd alone. Also, more patients were able to achieve MRD negativity on the daratumumab arm. This just shows us that daratumumab is moving its way to the frontline setting as an agent that is effective and well tolerated. We are seeing that first in the transplant-ineligible population.

What work is being done with immunotherapy?

Immunotherapy is our newest way of attacking cancer, and it ranges from allogeneic stem cell transplantation, to CAR T-cell therapy, to monoclonal antibodies, to bispecific T-cell engagers. These therapies are exciting in that we are finding them to be effective even in patients who have had multiple lines of treatment and whose immune systems may not be as robust as patients who are diagnosed earlier. What's so exciting about that is we're inducing responses and achieving disease control in patients who have really exhausted all other options. Going forward, when we move immunotherapy options closer to the frontline setting, even at the time of induction, we will be able to control the disease even better than we currently are.

What strategies are being used in the maintenance setting?

Maintenance is part of our armamentarium for myeloma. Patients who receive maintenance over a long period of time have better disease control and their disease stays under control for longer than those who do not receive maintenance. What is happening in this space is that there are more options for patients. Lenalidomide has been shown to be beneficial to patients as a maintenance drug and continuing that maintenance until disease progression outweighs the risks that are involved. The question then is, "Can we improve upon that?"

Some of the other agents, including ixazomib (Ninlaro), which was examined in the TOURMALINE-MM3 study, [can be used] in the maintenance setting. [This drug] is superior to placebo; although we didn't compare ixazomib with Rd, it is another option for patients. Perhaps [it is an option for] patients who are intolerant of lenalidomide or for those who are at risk for neuropathy, as we would want to avoid bortezomib (Velcade) maintenance, which has been an option in the past.

Moving forward, other agents that are used in the relapsed/refractory setting, such as daratumumab, are making their way to the maintenance setting as well and these drugs are providing patients with more options and longer disease control with reduced toxicity. The goal of a maintenance therapy is to find an agent that works well but is not too toxic because patients are going to hopefully be on this medicine for a long time. We want to treat patients so that they can continue living their lives as normally as possible and avoid the toxicity of another agent that may be more detrimental to their health.

Facon T, Kumar SK, Plesner T, et al. Phase 3 randomized study of daratumumab plus lenalidomide and dexamethasone (D¬—Rd) versus lenalidomide and dexamethasone (Rd) in patients with newly diagnosed multiple myeloma (NDMM) ineligible for transplant (MAIA). Blood. 2018;132(suppl 1):LBA-2. doi: 10.1182/blood-2018-120737.