Surge in FDA-approved myeloma agents brings new therapeutic decision challenges

With a record number of FDA approvals granted for multiple myeloma drugs in the past year, the field is buoyed by the range of treatment options that stand to enhance survival and improve quality of life for patients.

However, the rapidly-expanding therapeutic armamentarium also carries complexities in selecting, combining and sequencing agents — leaving clinicians with a new set of decisions to optimize and personalize care.

“It is an embarrassment of riches in many ways, but it also poses challenges for us as clinicians,” said Saad Z. Usmani, MD, FACP, chief of plasma cell disorders at the Levine Cancer Institute at Carolina HealthCare System in Charlotte, and a HemOnc Today Editorial Board member.

Saad Z. Usmani

“The way that I think of this is you have to look at these bigger clinical trials and see which subsets really benefit,” he said.

Five different drugs are now available for the management of patients with multiple myeloma: carfilzomib (Kyprolis, Onyx Pharmaceuticals), daratumumab (Darzalex, Janssen), elotuzumab (Empliciti, Bristol-Myers Squibb), ixazomib (Ninlaro, Takeda Pharmaceuticals) and panobinostat (Farydak, Novartis).

Carfilzomib

In phase 3 results from the ENDEAVOR study, carfilzomib plus dexamethasone significantly extended PFS compared with bortezomib (Velcade, Millennium Pharmaceuticals) plus dexamethasone in patients with relapsed multiple myeloma.

Usmani noted IV carfilzomib could be used in combination with both lenalidomide (Revlimid, Celgene) and dexamethasone in relapsed or refractory populations who had already received one to three prior lines of therapy.

“If you have patients who perhaps have a higher burden of disease, and you want a quick response, carfilzomib with lenalidomide and dexamethasone might be a combination you choose,” he said.

Daratumumab

The first monoclonal antibody given the go-ahead for myeloma, daratumumab showed encouraging efficacy and favorable safety as a single agent in heavily pretreated, refractory patients in a phase 2 study and demonstrated a favorable benefit–risk profile with durable responses in the relapsed and/or refractory disease in combination with lenalidomide and dexamethasone.

“It’s going to take us a little bit of time in the community to get acclimatized on how best to give this drug,” Usmani said.

He highlighted some infusion reactions observed with the anti-CD38 agent are similar to those seen with the monoclonal antibody Rituxan (rituximab, Genentech) used to treat non-Hodgkin's lymphoma or chronic lymphocytic leukemia.

Elotuzumab

Interim results from a phase 3 study showed that adding the immunotherapeutic monoclonal antibody elotuzumab to lenalidomide and dexamethasone significantly prolonged PFS in relapsed or refractory populations.

By attaching to signaling lymphocyte activation molecule F7 (SLAMF7) — a surface microbe found on myeloma cells and natural killer cells — the agent is believed to both target myeloma cells directly as well as enhance the ability of natural killer cells.

“Elotuzumab has a better side effect profile than the proteasome inhibitors and may be a better combination choice with lenalidomide plus dexamethasone for patients who are older and perhaps have other comorbidities that preclude them from getting a proteasome inhibitor,” Usmani said.

Ixazomib

The first oral proteasome inhibitor to gain approval for the treatment of myeloma, ixazomib in combination with lenalidomide and dexamethasone significantly extended PFS with no increased toxicity in patients with relapsed and/or refractory disease in a phase 3 study.

Researchers believe the triplet regimen could confer favorable outcomes among high-risk patients with genetic alterations.

“Ixazomib may be suitable for patients who would prefer getting an oral regimen — as long as they qualify for lenalidomide and dexamethasone,” Usmani noted.

Panobinostat

In a subgroup analysis of the phase 3 PANORAMA 1 trial, patients with relapsed and refractory disease who had already received bortezomib and immunomodulatory drugs (IMiD) had significantly improved PFS when given the HDAC inhibitor panobinostat in conjunction with bortezomib and dexamethasone.

The analysis included data from patients previously treated with an IMiD, with bortezomib and an IMiD and with two or more prior lines of bortezomib and an IMiD, with the largest median PFS increase among the latter group.

“In patients who may have had an [IMiD] drug in the past, for whom you’re trying to switch the drug class, perhaps the panobinostat combination may be reasonable,” Usmani said. “But there are side effects associated with the drug of which we need to be careful.”

Disclosure: Usmani reports consulting for Celgene, Millennium, Onyx and Sanofi; research funding from ArrayBioPharma, Celgene, Onyx, Janssen, Pharmacyclics and Sanofi; and speaking honoraria from Celgene, Millennium, Onyx and Sanofi.