Regimen Yields Deep Responses in High-Risk Smoldering Myeloma

Combination treatment with the proteasome inhibitor carfilzomib plus the immune-modulatory agent lenalidomide and dexamethasone (CRd) resulted in high rates of minimal residual disease (MRD) negativity with tolerable side effects in patients with newly diagnosed or smoldering high-risk multiple myeloma, according to the results of a pilot study published recently in JAMA Oncology.

“The present study confirms and expands our knowledge of effective, non-intensive anti-multiple myeloma therapy, building on previous studies of CRd in relapsed multiple myeloma and newly diagnosed multiple myeloma,” wrote study author Neha Korde, MD, of the Multiple Myeloma Section, Lymphoid Malignancies Branch, National Cancer Institute, and colleagues. “Taken together, our results provide further evidence for the role for proteasome inhibitor–immunomodulatory drug combination therapy in newly diagnosed multiple myeloma and demonstrate that MRD evaluation may be an important tool for measuring the depth of response.”

The study included 45 patients with newly diagnosed multiple myeloma and 12 with high-risk smoldering myeloma enrolled between 2011 and 2013. Patients were assigned to eight 28-day cycles of carfilzomib 20/36 mg/m² on days 1, 2, 8, 9, 15, and 16; lenalidomide 25 mg on days 1 to 21; and dexamethasone 20/10 mg on days 1, 2, 8, 9, 15, 16, 22, and 23. Extended dosing of lenalidomide was made available to patients who achieved stable disease.

The researchers evaluated patients for grade 3 or greater neuropathy and at least very good partial response.

None of the patients with newly diagnosed disease had grade 3 or worse neuropathy. Of the patients with high-risk smoldering disease, the most commonly occurring adverse event was lymphopenia and gastrointestinal disorders.

Very good partial response was achieved by all patients with smoldering disease.

The researchers also evaluated MRD negativity, an endpoint associated with improved survival. They found that 100% of patients with newly diagnosed disease, and 92% of patients with high-risk smoldering disease had MRD negativity using multiparametric flow cytometry. Using next generation sequencing, 14 of 21 patients with newly diagnosed disease and 9 of 12 patients with smoldering disease had MRD negativity.

In those patients with newly diagnosed disease, MRD negativity compared with positivity was associated with a 12-month progression-free survival of 100% vs 79% by flow cytometry (P < .001) and 100% vs 95% for next-generation sequencing (P = .02).

In an editorial that accompanied the article, Pieter Sonneveld, MD, PhD, of Erasmus MC Cancer Institute, Rotterdam, praised the researchers use of serial response assessment using MRD criteria and imaging techniques.

“The careful and consistent documentation provides us with the full impact of a highly effective regimen such as CRd. By monitoring the MRD status during and after treatment, it became evident that 12-month progression-free survival was 100% in patients who became MRD negative by flow cytometry and next-generation sequencing,” Sonneveld wrote. “These data confirm that with the introduction of highly effective drug combinations, traditional response criteria become less valid because these do not sufficiently assess the deepness of response. New ways of response evaluation such as MRD and PET/CT negativity should be introduced for clinical trials and ultimately also in clinical practice.”