Expert Evaluates Evolving Options in Newly Diagnosed Myeloma

Ravi Vij, MD

Transplant remains the standard of care for eligible patients with newly diagnosed multiple myeloma, although the optimal induction regimen and value of consolidation is still debated, explained Ravi Vij, MD.

However, in patients who are ineligible for transplant, Vij noted that proteasome inhibitors and monoclonal antibodies are showing promise in the frontline setting and may obviate the need for melphalan altogether.

Although bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (VRd) is the preferred induction regimen, according to Vij, the combination of carfilzomib (Kyprolis), lenalidomide, and dexamethasone (KRd) has already entered the pipeline, following multiple studies that have demonstrated a deeper depth of response. The head-to-head trial comparing the 2 competing strategies has completed accrual and will likely read out within the next 2 years (NCT01863550).

In patients ineligible for transplant, a recent news release announced that results of the phase III MAIA trial showed that the addition of daratumumab (Darzalex) to lenalidomide and dexamethasone (DRd) decreased the risk of disease progression or death by 45% compared with lenalidomide/dexamethasone (Rd) alone. In the interim analysis of the MAIA study, the median progression-free survival (PFS) had not been reached with the triplet versus 31.9 months in the Rd arm (HR, 0.55; 95% CI, 0.43-0.72; P <.0001).

This follows the May 2018 FDA approval of daratumumab in combination with bortezomib, melphalan, and prednisone for the treatment of patients with newly diagnosed disease who are ineligible for autologous stem cell transplant.

“We’re certainly making tremendous progress in the frontline treatment of multiple myeloma,” said Vij. “A lot of things that are going on in the relapsed/refractory space could also move into frontline development in the years to come, from promising new small molecules to perhaps, in the future, bispecific T-cell engagers and chimeric antigen receptor-T cell therapy.”

OncLive^®: Can you provide an overview of newly diagnosed multiple myeloma treatment?

In an interview during the 2018 OncLive^® State of the Science Summit^TM on Hematologic Malignancies, Vij, professor of Medicine, Division of Oncology, Section of Bone Marrow Transplant, Washington University School of Medicine in St. Louis, Siteman Cancer Center, discussed emerging treatment options for patients with newly diagnosed multiple myeloma.Vij: We've made tremendous strides in the treatment of patients with multiple myeloma. The paradigm that has evolved for multiple myeloma is one of continuous therapy. [First, we need to] determine whether a patient is transplant eligible or not. Stem cell transplant remains the standard of care for eligible patients. Most institutions would deem a stem cell transplant to be part of their initial therapy given the superior PFS that continues to be demonstrated. The paradigm for transplant-eligible patients is to give an induction period of treatment, though the optimal induction regimen is not known. The most popular regimen is VRd, which was shown to be superior to lenalidomide and dexamethasone in a study conducted by the SWOG Cancer Research Network. Though that study was not meant for patients who were proceeding to get transplants, it informed the decision that the use of 3 drugs is better than 2.

The use of our novel agents in the frontline setting is what continues to be explored. The substitution of bortezomib with carfilzomib is one thing that a lot of investigators are pursuing. Even off study, it has started to become a regimen that some institutions have adopted. The use of carfilzomib is primarily driven by studies that have shown a better depth of response when given with or without a transplant compared with what has been achieved historically. Frontline KRd is being compared with VRd in a randomized study, which has completed accrual. Hopefully, that will better inform our decision on which 3-drug regimen is optimal.

Very soon, we will probably move into the era of 4-drug treatments. The use of monoclonal antibodies and our 3-drug backbone is where the field is going to move. Daratumumab and elotuzumab (Empliciti) are both being explored in frontline trials. The trial data at this time are fairly preliminary. It is only a matter of time before 4-drug regimens best 3-drug regimens in comparative studies. Certainly, this will add to the cost of the regimen. However, some feel that the drug cost may be justifiable if one can give a finite period of therapy and thereby avoid the cost associated with the more extended therapy that we give today.

Once these patients have undergone transplant, maintenance therapy is the standard. Most patients get lenalidomide as maintenance therapy. It is probably not enough to use lenalidomide alone for high-risk patients. Patients who have deletion of 17p or other chromosome abnormalities, such as t(14;20) or t(14;60), could benefit from the addition of a proteasome inhibitor. For example, we are using bortezomib twice monthly with lenalidomide as maintenance therapy, although there are no randomized data to suggest that dual maintenance therapy is better. There was a trial conducted at Emory University looking at an extended period of VRd posttransplant, which showed that there were fairly impressive rates of PFS.

In the posttransplant setting, another thing that has been explored is the use of consolidation. The use of consolidation remains experimental. A large US study called the STAMINA trial did not demonstrate a benefit in PFS nor did the use of tandem transplant. However, another study done by the European Myeloma Network showed an improvement in PFS with the addition of a second transplant and with the use of consolidation therapy.

What does the landscape look like for patients who are ineligible for transplant?

The contradictory results of these 2 studies may be predicated on the regimens that were used before transplant. It remains a matter of conjecture as to why these divergent results were produced. In most institutions, consolidation is not a routine part of management. However, if patients don't achieve a very good partial response, a lot of investigators and treating physicians consider the use of consolidation on a case-by-case basis to deepen the response following transplant.The other part of this involves patients who are transplant-ineligible; that constitutes the majority of patients, especially those seen in a community setting. We’ve certainly made progress in this group of patients, though perhaps not as much as has been achieved for those who are transplant-eligible. The old standard used to be the 2-drug regimen of melphalan and prednisone.

Trials done in the late 1990s and early 2000s concentrated on the addition of thalidomide (Thalomid) to melphalan and prednisone (MPT). It became the standard for a time in Europe, but it never got really popular in the United States. A regimen consisting of lenalidomide with melphalan and prednisone was also explored, but it was not found to be superior to MPT. The use of bortezomib with melphalan and prednisone in the VISTA trial showed a PFS and an overall survival advantage and became the standard in Europe until recently. However, the United States never took to that regimen because we wanted to avoid the use of melphalan, even in elderly patients.

In the United States, we had access to lenalidomide, even in frontline treatment. Lenalidomide/dexamethasone has been a popular frontline regimen. The use of this regimen as frontline therapy has been validated by a 3-arm study looking at MPT compared with lenalidomide and dexamethasone either for a finite period of time or until progression. The study examining the use of lenalidomide/dexamethasone followed by lenalidomide until progression met its primary endpoint and is now the standard of care for those who are truly older and frailer.

Some patients who are between the ages of 70 and 80 could get a transplant, but for the vast majority who cannot, they are still able to get a regimen that is a little more intense than lenalidomide and dexamethasone. In that regard, VRd-light, which is dose-reduced bortezomib, lenalidomide, and dexamethasone is a standard that has evolved. Although only a small group of patients have been treated on a prospective trial, it seems logical to do.

Most recently, the ALCYONE study looked at adding daratumumab to bortezomib, melphalan, and prednisone in a randomized trial versus bortezomib, melphalan, and prednisone—the previous standard. The study reached its primary endpoint in improvement in depth of response and PFS. There will be some utility to this regimen but given the fact that melphalan is not a very desirable drug, either people will omit it and see if they can get insurance approval or give bortezomib with steroids and dexamethasone alone.

Genmab. Genmab announces positive topline results in phase III MAIA study of daratumumab in front line multiple myeloma. Published October 30, 2018. https://bit.ly/2JqFyEM. Accessed October 30, 2018.