Treating Precursor Disease May Stall Multiple Myeloma Progression

C. Ola Landgren, MD, PhD

Intervention in early or “smoldering” myeloma with a three-drug regimen led to complete responses (CRs) in a group of high-risk patients, suggesting a window of opportunity that may delay or prevent progression to a debilitating disease state, according to results of a small pilot study.

All 12 patients had attained at least a very good partial response after completing two cycles of carfilzomib, lenalidomide, and dexamethasone (CRd). After four cycles of therapy, 7 of the 12 had CR or stringent CR (sCR). Following completion of the eight planned cycles of therapy, all 12 patients had attained near CR (nCR), CR, or sCR, according to C. Ola Landgren, MD, PhD, at the 55th Annual American Society of Hematology meeting.

“What these results suggest is that if you treat early, every patient goes into complete response,” said Landgren, senior investigator in the Multiple Myeloma Section of the National Cancer Institute.

“Most striking to me, we evaluated patients for minimal residual disease, using very-high-quality assays, including multicolor flow cytometry of bone marrow, and we evaluated 3 million cells,” he continued. “We defined minimal residual disease as the identification of 20 events, and by that stringent criteria, 11 of 12 patients were negative for minimal residual disease.”

A precursor state consistently precedes development of multiple myeloma. The precursor condition, known variously as monoclonal gammopathy of unknown significance (MGUS); smoldering myeloma; or early myeloma, progresses to multiple myeloma within 5 years in 75% of cases.

Whether or not intervention in the precursor stage can prevent progression remains undetermined. Recently, the PETHEMA research group in Spain reported that treatment of smoldering myeloma was associated with significantly longer survival compared with an observation group (N Engl J Med. 2013;369:438-447).

Landgren and colleagues evaluated the safety and efficacy of intervention in high-risk smoldering myeloma, beginning with eight cycles of the CRd regimen. Patients with at-least stable disease as their best response continued on lenalidomide maintenance therapy for 2 years.

Response rate is the primary endpoint of the ongoing trial, and secondary endpoints include progression-free survival, response duration, and correlative studies focusing on minimal residual disease. Follow-up consists of periodic assessment of clinical biomarkers, FDG-PET/CT imaging, and the minimal residual disease studies (flow cytometry and VDJ gene sequencing of bone marrow aspirates).

Eleven of the 12 patients met the PETHEMA working group model for high-risk smoldering multiple myeloma, and the remaining patient met both PETHEMA and Mayo Clinic criteria.

Overall, the regimen has been well tolerated, according to Landgren. One patient discontinued after six cycles of therapy because of congestive heart failure. The most common grade ≥3 nonhematologic toxicities have been electrolyte imbalances and rash/pruritus in three patients each, liver enzyme (LFT) elevation and acute kidney injury in two patients each, and one case each of congestive heart failure, dyspnea, infection, venous thromboembolism, diarrhea, and hyperglycemia. Hematologic toxicity consisted of lymphopenia in five patients, thrombocytopenia in three, anemia in two, and neutropenia in one patient.

All 12 patients have maintained their best responses without evidence of progression to clinically symptomatic multiple myeloma. Additionally, 11 of the 12 patients had no minimum residual disease by eight-color flow cytometry analysis of bone marrow aspirates.

“In this pilot study, we treated high-risk asymptomatic myeloma—with a very high risk of transforming into multiple myeloma—with very potent therapy, and in 11 out of 12 patients, there is no detectable disease,” said Landgren. “It raises the question of whether early treatment should be the way to go.”

Investigators have begun enrolling 16 additional patients in an expansion-cohort evaluation of the CRd followed by lenalidomide extended-dose (CRd-R) regimen.

“With follow-up beyond 2 years, investigators can begin to think that the regimen delays progression to multiple myeloma, because untreated high-risk patients progress to multiple myeloma after a median duration of about 2 years. If patients remained in a negative minimum residual disease state for 5 years or beyond, the discussion could turn to the possibility that the regimen actually prevents progression to multiple myeloma,” Landgren said.

Landgren O, Mailankody S, Kwok M, et al. Correlative pilot study of carfilzomib, lenalidomide, and dexamethasone followed by lenalidomide extended dosing (CRd—R) in high risk smoldering multiple myeloma patients. Presented at: 55th ASH Annual Meeting; December 7-10, 2013; New Orleans, LA. Abstract 1939.

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