As Myeloma Options Increase, So Do Challenges

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As Myeloma Options Increase, So Do Challenges

Recent expansion of treatment options for multiple myeloma has created a good news/bad practice environment for clinicians and patients.

Most patients achieve a partial response or better with currently available front-line therapies. Truly refractory disease is increasingly uncommon but “not quite rare,” said Robert Z. Orlowski, MD, PhD, of MD Anderson Cancer Center in Houston, during the Society of Hematologic Oncology virtual meeting.

Higher response rates have been accompanied by earlier use of new agents. As a consequence, management of relapsed and refractory disease has become more challenging.

“The good news is that there are lots of options [for relapsed/refractory disease],” said Orlowski. “The bad news is that there are lots of options.”

Current National Comprehensive Cancer Network guidelines include 38 different regimens for relapsed/refractory myeloma, 13 of which have category 1 recommendations, meaning the advice has support from randomized, phase III clinical trials. “It can therefore be difficult to try to pick out which options are the best.”

Triplets Represent New Standard

Many of the influential phase III trials have shown that combination therapy can achieve high response rates in relapsed disease, even when they involve agents previously used to treat the patient, Orlowski continued. As an example, the OPTIMISMM trial involved patients who had received as many as three prior regimens.

Investigators randomized patients to pomalidomide (Pomalyst), bortezomib (Velcade), and dexamethasone or to bortezomib and dexamethasone. Patients who received the three-drug combination had a 39% reduction in the hazard ratio (HR) for disease progression or death as compared with those assigned to the two-drug regimen.

The phase III ICARIA trial involved patients who had received at least two prior lines of therapy (including an immunomodulator and a proteasome inhibitor) and had disease progression within 60 days on their most recent therapy. They were randomized to pomalidomide plus dexamethasone or to the same two drugs with isatuximab (Sarclisa). Treatment with the triplet regimen led to an overall response rate (ORR) of 60% versus 35% for the two-drug regimen, representing almost a three-fold increased likelihood of response (OR 2.795, P<0.0001).

Continuing the theme of adding a new drug to an existing regimen, the CANDOR trial compared carfilzomib (Kyprolis) and dexamethasone with or without the addition of daratumumab (Darzalex). The three-drug regimen was associated with a statistically significant 37% reduction in the hazard for disease progression or death (P=0.0027). Median progression-free survival (PFS) with two drugs was 15.8 months but not reached in the cohort that received daratumumab.

“You can see the triplets moving ahead and beating out the doublets,” said Orlowski. “Really, a triplet regimen should be the standard of care in the relapse setting, unless you have a patient that you feel is frail and maybe will not tolerate a triplet, in which case a doublet may be appropriate.”

More Options on the Horizon

Emerging therapies will likely provide even more options for patients with relapsed/refractory myeloma. Belantamab mafodotin-blmf (Blenrep) — a monoclonal antibody against B-cell maturation antigen, linked to the cytotoxic agent auristatin F — was added to lenalidomide and dexamethasone in a preliminary evaluation of patients who had received at least one prior regimen. The results showed that 14 of 18 patients had at least a partial response, one had a minor response, and the remaining three patients had stable disease.

The BCL-2 inhibitor venetoclax (Venclexta) was added to bortezomib and dexamethasone for a randomized trial involving 300 patients who had received as many as three prior regimens. Once again, the three-drug regimen prevailed, resulting in a 37% reduction in the hazard for progression or death. The data were particularly impressive for patients whose disease was associated with t(11;14) translocation, who had an 81% reduction in the PFS hazard and a nonsignificant 28% reduction in the survival hazard, Orlowski noted.

The nuclear export inhibitor selinexor (Xpovio) was added to bortezomib and dexamethasone and compared with the standard two-drug regimen in 400 patients with progressive myeloma and as many as three prior regimens. The triplet therapy led to a median PFS of 14 months versus 9.5 months with bortezomib and dexamethasone (P=0.0075). The selinexor regimen was most effective in patients with deletion 17p.

Chimeric antigen receptor (CAR) T-cell therapy targeting B-cell maturation antigen (BCMA) will offer yet another option for patients with relapsed/refractory myeloma. In a preliminary study involving 30 patients, the autologous therapy resulted in a median PFS of 11.8 months. Orlowski said the therapy could become available in the U.S. by the end of 2020 for treatment of refractory disease.

“There are already clinical trials looking at its use in earlier lines of therapy, which would include one to three prior lines, so this may be an option to consider for this group of patients in the future” he said.

The bispecific antibody CC-93269 also targets BCMA, along with the CD3 antigen on T cells, and showed promise in a preliminary evaluation involving 30 patients with relapsed/refractory myeloma. The therapy had dose-dependent activity, including objective responses in eight of nine patients who received the highest doses of the antibody.

Clinicians face a number of challenges to make optimal use of available therapies in patients who have received one to three prior regimens, said Orlowski. For example, multiple monoclonal antibodies have proven efficacious in triplet regimens, but no data have emerged to suggest a preferable drug or appropriate sequence.

Results from clinical trials suggest potential for individualizing therapy on the basis of molecular characteristics, such as t(11;14) translocation and deletion 17p. In the absence of biomarker evidence, guidance should come from traditional clinical characteristics, said Orlowski, including fitness, frailty, risk of neuropathy, presence or absence of diabetes, and cardiac risk.

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    Charles Bankhead is senior editor for oncology and also covers urology, dermatology, and ophthalmology. He joined MedPage Today in 2007. Follow

Disclosures

Orlowski disclosed relevant relationships with CARsgen Therapeutics, Celgene, Exelixis, Janssen Biotech, Sanofi-Aventis, Takeda, BioTheryX, Amgen, Bristol-Myers Squibb, EcoR1 Capital, Forma Therapeutics, Genzyme, GlaxoSmithKline, Ionis Pharmaceuticals, Juno Therapeutics, Kite Pharma, legend Biotech, Molecular Partners, Regeneron, Servier, STATinMED Research, and Asylia Therapeutics.

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