乌鸦传媒

A first-in-class peptide-drug conjugate had "clinically meaningful" activity in heavily pretreated multiple myeloma, a prospective clinical evaluation showed.

Melflufen (melphalan linked to flufenamide) plus dexamethasone produced objective responses in 29% of patients who had received a median of five prior regimens. Median response duration was 5.5 months.

Treatment was associated with high rates of hematologic toxicity, however, though it was manageable in most patients, Paul G. Richardson, MD, of Dana-Farber Cancer Institute in Boston, and coauthors reported in the Journal of Clinical Oncology.

"The results from suggest that melflufen has the potential to be an important therapeutic option in RRMM (relapsed/refractory multiple myeloma) by providing a novel mechanism of action, clinically meaningful efficacy, and manageable safety when combined with dexamethasone in heavily pretreated patients," the authors concluded. "Based on these results, the efficacy and safety of melflufen plus dexamethasone versus pomalidomide (Pomalyst) plus dexamethasone are being further evaluated in OCEAN, a randomized, global, phase III multicenter study for patients in earlier relapse.

"Studies of melflufen plus dexamethasone in combination with bortezomib (Velcade) or daratumumab (Darzalex) are also ongoing, with promising results to date."

Recent approval of numerous new therapies have yet to provide a cure for multiple myeloma, and almost all patients relapse at some point. The near-inevitability of relapse creates an ongoing need for new therapies that provide clinically meaningful activity.

Switching classes of drugs at relapse has earned priority consideration among specialists, but the strategy is complicated by the increasingly frequent use of novel agents with therapies administered in earlier treatment lines, Richardson and colleagues noted. Consequently, multiclass drug resistance can occur as early as second-line therapy.

Patients with poor-prognosis disease characteristics -- high-risk cytogenetics, extramedullary disease, and multiclass resistance -- constitute a high unmet need, they continued. Moreover, patients with RRMM often have multiple comorbidities associated with age, disease burden, or cumulative toxicities of prior treatment.

Melflufen targets aminopeptidases and selectively releases alkylating agents into tumor cells. In contrast to prior aminopeptidase-targeting drugs that directly inhibited aminopeptidase activity, melflufen focuses on increased aminopeptidase activity and selectively targets release of cytotoxic drugs into tumor cells.

In a small dose-finding study, melflufen produced an objective response rate (ORR) of 31%, media duration of response of 8.4 months, median progression-free survival (PFS) of 5.7 months, and median overall survival (OS) of 20.7 months. Evaluation of the drug continued in an open-label HORIZON trial involving heavily pretreated, poor-prognosis RRMM.

Investigators at 17 sites enrolled patients who had received two or more prior lines of therapy (including an immunomodulator and a proteasome inhibitor) and who were refractory to pomalidomide and/or an anti-CD38 antibody. Treatment consisted of melflufen on day 1 of each cycle, plus once-weekly dexamethasone, for continuous 28-day cycles until disease progression or development of unacceptable toxicity. The primary endpoint was ORR, defined as partial response or better.

Data analysis comprised 157 patients, who had a median age of 65. Three fourths of the study population had triple-refractory disease, a third had extramedullary disease, and a majority were refractory to previous alkylator therapy.

During a median follow-up of 14 months, 28 patients had partial responses (PRs), 17 had very good partial responses (VGPR), and one met criteria for stringent complete response, representing an ORR of 29%. An additional 25 (16%) patients had minimal response, resulting in a clinical benefit rate (CBR) of 45%. Median PFS was 4.2 months and median OS was 11.6 months.

A prespecified analysis of patients with triple-refractory disease yielded an ORR of 26% (18 PR and 13 VGPR), and 16 (13%) patients had minimal response to produce a CBR of 39%. Median PFS was 3.9 months and median OS was 11.2 months.

In the overall and triple-refractory analyses, responding patients had median PFS of 8.5 months (both groups) and median OS of 17.6 and 16.5 months.

Treatment-related adverse events (TRAEs) occurred in 95% of the patients. Grade ≥3 treatment-emergent adverse events (TEAEs) included neutropenia in 79% of patients, thrombocytopenia in 76%, and anemia in 43%. The most common grade ≥3 nonhematologic TEAEs were pneumonia (10%) and hypophosphatemia (5%). Overall, the safety profile was consistent with previous clinical evaluations of melflufen, the authors said.

'Goldilocks Solution'

"These findings build substantially on previously reported results but in a population that is more aligned with current treatment practice in the relapsed and refractory as well as highly resistant disease setting," they said in a discussion of the findings.

Melflufen brings a lot of potential to the myeloma clinical space, said Joshua Richter, MD, of the Icahn School of Medicine at Mount Sinai in New York City. Over the past several years, upfront melphalan followed by transplantation and early use of cyclophosphamide-containing regimens have given way to immunodulator-containing triplet regimens, which provide durable remissions. As a result, many patients enter second, third, or fourth relapse without prior exposure to an alkylator.

"We know that melphalan is still the best alkylator," Richter told 乌鸦传媒. "The classic ways to use it are as high-dose therapy with a transplant or a low dose for older, frailer patients. Melflufen is like the Goldilocks solution: Not too hot, not too cold. It's just right. It's not blow-you-out-of-the-water stuff, like a transplant, and it's good for older, frailer patients, but still has some power behind it.

"I think in a myeloma algorithm where more patients are alkylator naive than they've ever been, this drug may have a really great role in the relapse setting."

A downside to melflufen is the current need for administration through a central venous line, Richter added. If the FDA approves the drug with central-line administration, a peripherally adiministered formulation will likely follow soon afterward.

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