New Regimens for Multiple Myeloma: Selecting the Right Treatment for the Right Patient

At the 2020 NCCN hematologic malignancies conference, Shaji Kumar, MD, Consultant and Professor of Medicine, Division of Hematology, Mayo Clinic Cancer Center, Rochester, MN, discussed the “bonanza of treatment regimens for multiple myeloma.”

Although several new agents and combination regimens have extended survival in patients with multiple myeloma, this cancer remains an incurable chronic disease, according to Dr Kumar.

“Treatment of myeloma requires a long-term strategy. The key is delivering the best ‘package’ of treatment at a given stage. Optimal combinations and sequencing are critical, and a risk-stratified approach should be used,” Dr Kumar said.

Newly Diagnosed Multiple Myeloma

“With initial therapy, the intent is to attain as deep a remission as possible,” Dr Kumar noted.

The triplet regimen of bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (VRd) is considered standard therapy for newly diagnosed patients. Several studies have attempted to improve on this regimen by substituting newer drugs for the individual components of VRd—for example, replacing bortezomib with carfilzomib (Kyprolis) or with ixazomib (Ninlaro)—but these regimens were not superior to VRd.

In the MAIA study, a regimen of daratumumab (Darzalex) plus lenalidomide and dexamethasone improved outcomes in newly diagnosed, transplant-ineligible patients versus lenalidomide plus dexamethasone alone. This regimen replaced the proteasome inhibitor (bortezomib) with a monoclonal CD38-directed antibody (daratumumab). With the newer regimen, the rates of objective response, complete response, and minimal residual disease (MRD) negativity were superior, but overall survival (OS) data have not yet been reported.

Quadruplet Therapy Approaches

The strategy of quadruplet therapy with daratumumab plus VRd is currently being evaluated in the GRIFFIN study, but it is unclear whether survival will be improved.

The MASTER study evaluated a risk-adapted approach using daratumumab plus carfilzomib, lenalidomide, and dexamethasone (KRd). Patients who achieved MRD-negative status on 2 consecutive measurements discontinued the treatment. Nearly 90% of the patients attained stringent complete response, and almost 60% were MRD negative.

“This quadruplet approach needs to be replicated in a phase 3 trial,” Dr Kumar said.

Yet another quadruplet regimen is under investigation in the ALCYONE study; in this study, daratumumab is being added to bortezomib, melphalan, and prednisone (VMP) and is compared with the triple-drug VMP regimen alone. With the 4-drug regimen, a significant improvement was observed in the objective response rates and duration of response.

“Lenalidomide-dexamethasone is still a good combination for older patients who can’t tolerate quadruplet therapy,” Dr Kumar said.

Transplant-Eligible Newly Diagnosed Patients

Transplant-eligible, standard-risk patients should receive 4 cycles of VRd, followed preferably by autologous stem-cell transplant (ASCT), or VRd for 4 cycles, followed by lenalidomide maintenance therapy or delayed ASCT.

High-risk, transplant-eligible patients should receive 4 cycles of daratumumab plus VRd, followed by (or in tandem with) ASCT, and then bortezomib plus lenalidomide maintenance therapy until disease progression.

For newly diagnosed, standard-risk patients who are not eligible for transplant, VRd should be used for 12 months, followed by lenalidomide maintenance therapy or VRd for 12 months, followed by daratumumab plus lenalidomide maintenance therapy. For high-risk patients who are ineligible for transplant, VRd, followed by bortezomib plus lenalidomide maintenance therapy until disease progression, is recommended.

Relapsed or Refractory Disease

Dr Kumar expressed optimism about 2 newer drugs for the treatment of patients with relapsed or refractory multiple myeloma: selinexor (Xpovio), a selective inhibitor of nuclear export, and belantamab mafodotin-blmf (Blenrep), the first FDA-approved drug targeting B-cell maturation antigen (BCMA), which is expressed exclusively in multiple myeloma.

In the STORM study, selinexor plus dexamethasone improved the response rates and progression-free survival (PFS), with a promising OS of 8.6 months in patients with relapsed or refractory multiple myeloma who had received treatment with 3 different drug classes. The BOSTON study showed improved response rates and depth of response and improved PFS with selinexor plus bortezomib and dexamethasone versus bortezomib plus dexamethasone alone. Based on the results of these clinical trials, selinexor, in combination with dexamethasone, was approved in 2019 for the treatment of relapsed or refractory multiple myeloma.

“Another exciting drug targeting BCMA has been recently approved for the treatment of relapsed or refractory multiple myeloma—belantamab,” Dr Kumar added.

The multicenter, phase 2 DREAMM-2 trial investigated single-agent belantamab in patients with relapsed multiple myeloma. The overall response rate was 32% and 35% in the 2.5-mg/kg and 3.4-mg/kg dose arms. A very good partial response or better was achieved by 58% and 66% of patients, respectively.

“Ongoing trials are looking at which combinations are better with belantamab in relapsed or refractory patients,” Dr Kumar said.

The DREAMM-6 trial is exploring belantamab in combination with the standard-of-care therapies lenalidomide plus dexamethasone and bortezomib plus dexamethasone. In one arm of the study, patients with relapsed or refractory multiple myeloma who received the combination of belantamab, bortezomib, and dexamethasone had an overall response rate of 78%, with half achieving a deep response.

“A host of therapies are on the horizon, including immunotherapies, CAR [chimeric antigen receptor] T-cell, and BiTE [bispecific T-cell engager] therapies. Stay tuned for progress reports,” he advised.

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