New four-drug combination sets a new standard in myeloma care

New four-drug combination sets a new standard in myeloma care

A new four-drug combination is highly effective and safe in patients with newly diagnosed multiple myeloma. This is according to data presented at the annual meeting of the American Society of Clinical Oncology, held May 30 to June 3 in Chicago.

The data came from the preliminary clinical trial led by the Sylvester Comprehensive Cancer Center, part of the University of Miami Miller School of Medicine.

The randomized, multicenter trial is testing the effects of adding the targeted drug daratumumab to the standard therapy regimen called KRD (carmfilzomib, lenalidomide and dexamethasone).

“This study shows that daratumumab added to KRD is a new standard of care for patients who were previously candidates for KRD alone,” said Sylvester Myeloma Institute director and study leader C. Ola Landgren, MD, Ph.D., who will report the findings on June 3.

From Manhattan to move forward

The new clinical trial has its roots in the Manhattan Study, a smaller study also led by Landgren. In this study, newly diagnosed multiple myeloma patients were also treated with daratumumab added to KRD, a combination called DKRD.

The results of the Manhattan experiment were “spectacular,” Landgren said. Sensitive methods for assessing minimal residual disease (MRD) showed that 71% of patients had no detectable disease after completing their treatment. However, this study was a single-arm trial – all 41 patients received DKRD.

The preliminary study will be further compared by directly comparing KRD with DKRD in a large, multicenter, randomized (1:1) clinical trial in the USA

Improve results

Half of the 306 patients in the preliminary study were randomly assigned to receive KRD and half to receive DKRD.

The new results show that 59% of DKRD-treated patients were MRD negative after eight cycles of treatment, compared to 36% of KRD-treated patients.

The longer-term durability of the answer is an open question. However, the data so far is encouraging: at 32.7 months of follow-up, 86% of patients with DKRD showed progression-free survival, compared to 79% of patients on KRD.

Adding daratumumab to KRD did not add significant toxicities, Landgren added – in part due to excluding patients with underlying cardiovascular disease or patients who were frail. Before study enrollment, all patients were cleared according to the study protocol by standard laboratories, a standard examination and ECG and cardiac echo.

“If you give it to the right patients in the right way, it is an extremely safe and very effective therapy,” Landgren said.

The new four-drug combination utilizes a range of therapeutic targets and modalities. Carfilzomib (brand name Kyprolis) inhibits the protein degradation machinery in cells, and lenalidomide (Revlimid and other brand names) stimulates immune activity against tumors, among other things. Dexamethasone has effects on immunity and inflammation.

These three drugs can shrink the tumors enough for daratumumab to finish the job, Landgren said. Daratumumab targets the CD38 protein on multiple myeloma cells and induces tumor cell death.

Tumors from patients in the study will undergo detailed molecular testing. Questions include why tumors respond differently to drug regimens and why some develop resistance.

A new nursing standard

Newly diagnosed multiple myeloma patients at Sylvester and other cancer centers already routinely receive the four-drug DKRD combination.

“It has definitely changed my practice,” Sylvester physician Dickran Kazandjian, MD, CO-PI, said in the preliminary study. “Your best shot to get your best response is to treat first.”

Landgren's research has transformed clinical practice before. His studies led to the introduction of carmfilzomib as a less toxic replacement for bortezomib.

He and his team can transform clinical practice again. They are planning a new multiple myeloma trial that will test multiple drugs in combination with a bispecific T cell engager, a newer type of immunotherapy treatment.

The preliminary study also shows a trend in which more and more patients are forgoing prior transplantation as a result of achieving MRD negativity with modern, effective combination therapy alone.

Eligible patients in the study had stem cells collected after four cycles in case they needed a transplant after completing treatment. The patients who achieved MRD -negative status kept their stem cells in the -80°C freezer and postponed their transplantation. Instead, they moved directly to lenalidomide maintenance therapy according to the study protocol.

Landgren and Kazandjian credit Sylvester's clinical trial team with bringing the advance study to Sylvester sites throughout South Florida. Other institutions participating in the Advance study include MD Anderson Cancer Center, Memorial Sloan Kettering Cancer Center, Moffitt Cancer Center, Roswell Park Comprehensive Cancer Center, Huntsman Cancer Foundation and Stony Brook Cancer Center.

The National Cancer Institute estimates that by 2025, 36,110 people will be newly affected by multiple myelomas, the second most common blood cancer.

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