In the JournalsPerspective

Early lenalidomide delays multiple myeloma progression

Sagar Lonial

Early treatment with lenalidomide for smoldering multiple myeloma appeared to delay progression to symptomatic multiple myeloma compared with observation alone, according to results of a randomized phase 3 trial published in Journal of Clinical Oncology.

“We decided to conduct this research after a 2013 trial by Mateos and colleagues of lenalidomide plus dexamethasone compared with observation alone for high-risk smoldering multiple myeloma. My colleagues and I wanted to address the same question, but with lenalidomide alone to remove the side effects of dexamethasone,” Sagar Lonial, MD, FACP, chair and professor in the department of hematology and medical oncology at Winship Cancer Institute of Emory University, and a HemOnc Today Editorial Board Member, told Healio. “It was also becoming clearer that not all patients with smoldering multiple myeloma were the same, and that for the highest-risk group, early intervention may make a big difference.”

Results of the phase 2 run-in trial, which included 44 patients treated with lenalidomide (Revlimid, Celgene) to assess safety, showed PFS rates of 98% at 1 year, 87% at 3 years and 78% at 5 years.

For the open-label, multicenter phase 3 trial, Lonial and colleagues enrolled 182 patients (median age, 64 years; range 31-86) with intermediate- or high-risk smoldering multiple myeloma.

Researchers randomly assigned patients to either 25 mg lenalidomide (n = 92) on days 1 to 21 of every 28-day cycle or observation (n = 90). Both therapy and observation continued until disease progression, toxicity or withdrawal for other reasons.

Patients assigned lenalidomide were required to use thrombosis prophylaxis, which could consist of a minimum of 325 mg aspirin daily, and were encouraged to mobilize stem cells after four to six cycles of therapy.

PFS served as the study’s primary endpoint, with disease progression requiring the development of end-organ damage attributable to multiple myeloma and biochemical progression, according to the researchers.

Median follow-up was 35 months.

Fifty percent of patients (95% CI, 39-61) in the lenalidomide group responded to therapy, whereas no responses occurred in the observation group.

Results showed significantly longer PFS in the lenalidomide group compared with the observation group (HR = 0.28; 95% CI, 0.12-0.62). PFS for the lenalidomide group was 98% at 1 year, 93% at 2 years and 91% at 3 years, compared with 89% at 1 year, 76% at 2 years and 66% at 3 years for the observation group.

Thirty-six patients (41%) in the lenalidomide group experienced grade 3 or grade 4 hematologic and nonhematologic adverse events, including 25 patients (28%) with nonhematologic events. Four deaths occurred in the observation group vs. two deaths in the lenalidomide group (HR for death = 0.46; 95% CI, 0.08-2.53). Forty-five patients in the lenalidomide group discontinued treatment, including 18 who stopped because of adverse events from treatment.

Three-year cumulative incidence of invasive secondary primary cancers was 5.2% in the lenalidomide group vs. 3.5% in the observation group.

“For patients who are in the highest risk category of smoldering multiple myeloma — those who meet the Mayo 20/2/20 criteria, which is the group that benefited most with a reduction in risk for progression to multiple myeloma of more than 90% at 3 years — early intervention does offer benefit,” Lonial told Healio. “The next question is, can more treatment offer additional benefit over simply lenalidomide or lenalidomide plus dexamethasone? We do not know the answer, but it is being tested in the current ECOG trial of lenalidomide plus dexamethasone vs. lenalidomide plus dexamethasone and daratumumab [Darzalex, Janssen Oncology].” – by Jennifer Southall

Reference:

Mateos MV, et al. N Engl J Med. 2013;doi:10.1056/NEJMoa1300439.

For more information:

Sagar Lonial, MD, can be reached at Winship Cancer Institute of Emory University, 1365 Clifton Road, Building C, Room 3000, Atlanta, GA 30322; email: sloni01@emory.edu.

Disclosures: NCI funded the study. Lonial reports consultant/advisory roles with AbbVie, Amgen, Bristol-Myers Squibb, Celgene, GlaxoSmithKline, Janssen Oncology, Juno Therapeutics, Merck, Novartis and Takeda; and research funding from Bristol-Myers Squibb, Celgene and Takeda. Please see the study for all other authors’ relevant financial disclosures.

Sagar Lonial

Early treatment with lenalidomide for smoldering multiple myeloma appeared to delay progression to symptomatic multiple myeloma compared with observation alone, according to results of a randomized phase 3 trial published in Journal of Clinical Oncology.

“We decided to conduct this research after a 2013 trial by Mateos and colleagues of lenalidomide plus dexamethasone compared with observation alone for high-risk smoldering multiple myeloma. My colleagues and I wanted to address the same question, but with lenalidomide alone to remove the side effects of dexamethasone,” Sagar Lonial, MD, FACP, chair and professor in the department of hematology and medical oncology at Winship Cancer Institute of Emory University, and a HemOnc Today Editorial Board Member, told Healio. “It was also becoming clearer that not all patients with smoldering multiple myeloma were the same, and that for the highest-risk group, early intervention may make a big difference.”

Results of the phase 2 run-in trial, which included 44 patients treated with lenalidomide (Revlimid, Celgene) to assess safety, showed PFS rates of 98% at 1 year, 87% at 3 years and 78% at 5 years.

For the open-label, multicenter phase 3 trial, Lonial and colleagues enrolled 182 patients (median age, 64 years; range 31-86) with intermediate- or high-risk smoldering multiple myeloma.

Researchers randomly assigned patients to either 25 mg lenalidomide (n = 92) on days 1 to 21 of every 28-day cycle or observation (n = 90). Both therapy and observation continued until disease progression, toxicity or withdrawal for other reasons.

Patients assigned lenalidomide were required to use thrombosis prophylaxis, which could consist of a minimum of 325 mg aspirin daily, and were encouraged to mobilize stem cells after four to six cycles of therapy.

PFS served as the study’s primary endpoint, with disease progression requiring the development of end-organ damage attributable to multiple myeloma and biochemical progression, according to the researchers.

Median follow-up was 35 months.

Fifty percent of patients (95% CI, 39-61) in the lenalidomide group responded to therapy, whereas no responses occurred in the observation group.

Results showed significantly longer PFS in the lenalidomide group compared with the observation group (HR = 0.28; 95% CI, 0.12-0.62). PFS for the lenalidomide group was 98% at 1 year, 93% at 2 years and 91% at 3 years, compared with 89% at 1 year, 76% at 2 years and 66% at 3 years for the observation group.

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Thirty-six patients (41%) in the lenalidomide group experienced grade 3 or grade 4 hematologic and nonhematologic adverse events, including 25 patients (28%) with nonhematologic events. Four deaths occurred in the observation group vs. two deaths in the lenalidomide group (HR for death = 0.46; 95% CI, 0.08-2.53). Forty-five patients in the lenalidomide group discontinued treatment, including 18 who stopped because of adverse events from treatment.

Three-year cumulative incidence of invasive secondary primary cancers was 5.2% in the lenalidomide group vs. 3.5% in the observation group.

“For patients who are in the highest risk category of smoldering multiple myeloma — those who meet the Mayo 20/2/20 criteria, which is the group that benefited most with a reduction in risk for progression to multiple myeloma of more than 90% at 3 years — early intervention does offer benefit,” Lonial told Healio. “The next question is, can more treatment offer additional benefit over simply lenalidomide or lenalidomide plus dexamethasone? We do not know the answer, but it is being tested in the current ECOG trial of lenalidomide plus dexamethasone vs. lenalidomide plus dexamethasone and daratumumab [Darzalex, Janssen Oncology].” – by Jennifer Southall

Reference:

Mateos MV, et al. N Engl J Med. 2013;doi:10.1056/NEJMoa1300439.

For more information:

Sagar Lonial, MD, can be reached at Winship Cancer Institute of Emory University, 1365 Clifton Road, Building C, Room 3000, Atlanta, GA 30322; email: sloni01@emory.edu.

Disclosures: NCI funded the study. Lonial reports consultant/advisory roles with AbbVie, Amgen, Bristol-Myers Squibb, Celgene, GlaxoSmithKline, Janssen Oncology, Juno Therapeutics, Merck, Novartis and Takeda; and research funding from Bristol-Myers Squibb, Celgene and Takeda. Please see the study for all other authors’ relevant financial disclosures.

    Perspective

    Marta Wronska, DO  
    Marta Wronska
    Marc J. Braunstein, MD, PhD 
    Marc J. Braunstein

    Smoldering multiple myeloma (SMM) is a heterogeneous disease in which patients have between 10% and 59% clonal bone marrow plasma cells without additional myeloma-defining criteria. Approximately one-third of patients are categorized as high risk for progression within 2 years. There is no standard of care for management and, outside of the context of a clinical trial, most patients typically are closely observed for signs of progression.

    Considering that incidence of high-risk SMM is relatively low, Lonial and colleagues should be commended for contributing the second and largest randomized study supporting the benefit of lenalidomide for delaying progression to symptomatic disease.

    Data from a prior randomized study of 119 patients led by Maria-Victoria Mateos, MD, PhD, showed an OS benefit with lenalidomide and dexamethasone induction for nine cycles, followed by lenalidomide maintenance until progression. The regimen reduced risk for death by 69% compared with observation.

    In the current study, Lonial and colleagues randomly assigned 182 patients with intermediate- or high-risk disease to single-agent lenalidomide or observation. At median follow up of 35 months, results showed a 72% reduction in risk for progression, with 3-year PFS rates of 91% with lenalidomide vs. 66% with observation.

    In both studies, grade 1 to grade 3 adverse events were higher in the experimental arm; however, there were no significant differences in treatment-related mortality or secondary malignancies.

    One of the critiques of these studies is how higher-risk SMM was defined. After revision of the diagnostic criteria for symptomatic multiple myeloma in 2014, in which patients with ultra-high-risk SMM were classified as symptomatic myeloma, various risk models have been proposed to classify high-risk SMM.

    The study by Mateos and colleagues included patients who would not be considered to have symptomatic disease. In the study by Lonial and colleagues, patients were defined by slightly differing Mayo 2008 and 2018 criteria for intermediate- or high-risk disease. Although subgroup analysis showed a benefit of lenalidomide across different criteria, interestingly, patients categorized as high risk by Mayo 2018 stratification — which includes a higher percentage of plasma cells or higher serum free light chains than the 2008 criteria — showed the most significant benefit of single-agent lenalidomide. This suggests that patients with higher-risk SMM have the most to gain from earlier intervention, which is both intuitive and practical in terms of weighing costs vs. benefit of treatment.

    Data from these studies clearly indicate that a watch-and-wait approach is no longer ideal for patients with high-risk SMM. However, the question remains whether lenalidomide alone or combined with dexamethasone is the optimal regimen to prevent progression of SMM.

    At the most recent ASH Annual Meeting and Exposition, several abstracts that focused on treatment for patients with high-risk SMM were presented. They included a phase 2 study by Bustoros and colleagues — which evaluated the combination of ixazomib (Ninlaro, Takeda), lenalidomide and dexamethasone — and an update of the phase 2 GEM-CESAR study, which evaluated carfilzomib (Kyprolis, Amgen) with lenalidomide and dexamethasone along with stem cell transplantation and maintenance therapy.

    As we await maturation of data from these studies, we have mounting evidence from two randomized studies that suggest the path to delaying progression of SMM begins with extinguishing plasma cell clones early in high-risk patients.

    References:

    Braunstein M. Treatment of smoldering myeloma delays disease progression, yet questions remain. Available at: www.targetedonc.com/news/treatment-of-smoldering-myeloma-delays-disease-progression-yet-questions-remain. Accessed Jan. 10, 2020.

    Bustoros M, et al. Abstract 580. Presented at: ASH Annual Meeting and Exposition; Dec. 7-10, 2019; Orlando.

    Cocito F, et al. Leuk Lymphoma. 2019;doi:10.1080/10428194.2019.1620948.

    Kyle RA, et al. Hematol Oncol Clin North Am. 2014;doi:10.1016/j.hoc.2014.06.005.

    Lakshman A, et al. Blood Cancer J. 2018;doi:10.1038/s41408-018-0077-4.

    Lonial S, et al. J Clin Oncol. 2019;doi:10.1200/JCO.19.01740.

    Mateos MV, et al. Lancet Oncol. 2016;doi:10.1016/S1470-2045(16)30124-3.

    Mateos M-V, et al. Abstract 781. Presented at: ASH Annual Meeting and Exposition; Dec. 7-10, 2019; Orlando.

    Rajkumar SV, et al. Lancet Oncol. 2014;doi:10.1016/S1470-2045(14)70442-5.

    Ravindran A, et al. Blood Cancer J. 2016;doi:10.1038/bcj.2016.100.

    Marta Wronska, DO
    NYU Winthrop Hospital
    NYU Langone Health

    Marc J. Braunstein, MD, PhD
    NYU Long Island School of Medicine
    NYU Perlmutter Cancer Center
    NYU Langone Health


    Disclosures: Braunstein reports research funding from Janssen, as well as scientific advisory board roles with Amgen, AstraZeneca, Celgene, Janssen, Karyopharm Therapeutics, Takeda and Verastem. Wronska reports no relevant financial disclosures.