Dataset Information

Treatment of patients with multiple myeloma progressing on frontline-therapy with lenalidomide.

ABSTRACT: Over the last years, there has been great progress in the treatment of multiple myeloma with many new agents and combinations having been approved and being now routinely incorporated into treatment strategies. As a result, patients are experiencing benefits in terms of survival and better tolerance. However, the multitude of treatment options also presents a challenge to select the best options tailored to the specific patient situation. Lenalidomide is increasingly being used as part of frontline therapy in newly diagnosed multiple myeloma. This agent is typically administered until disease progression. It is currently unclear, how to best manage patients, who relapse while receiving lenalidomide as part of their frontline treatment. We conducted a review to summarize the available evidence in this setting. Our summary shows that there are very few data from current trials testing new combinations based on carfilzomib, pomalidomide, or daratumumab that address this specific patient population. Our review is aimed to summarize the available evidence to assist treatment decision making and to raise awareness of this lack of data to encourage further analyses and the incorporation of sequencing questions in future trial designs.

SUBMITTER: Moreau P

PROVIDER: S-EPMC6426995 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Treatment of patients with multiple myeloma progressing on frontline-therapy with lenalidomide.

Moreau Philippe P Zamagni Elena E Mateos Maria-Victoria MV

Blood cancer journal 20190320 4

Over the last years, there has been great progress in the treatment of multiple myeloma with many new agents and combinations having been approved and being now routinely incorporated into treatment strategies. As a result, patients are experiencing benefits in terms of survival and better tolerance. However, the multitude of treatment options also presents a challenge to select the best options tailored to the specific patient situation. Lenalidomide is increasingly being used as part of frontl ...[more]

PMID: 30894516

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Project description:BACKGROUND:For patients with multiple myeloma (MM), each additional line of therapy (LOT) is associated with lower response rates, shorter treatment duration and treatment-free intervals, and increased rates of toxicities and comorbidities. Here, we examine frontline treatment patterns, and attrition rates by LOT among newly diagnosed MM (NDMM) patients in the United States who were eligible or ineligible for autologous stem cell transplant (ASCT). METHODS:Data were identified from three US patient-level databases collectively covering the period January 2000 to September 2018. Patients had an index diagnosis of MM on or after January 1, 2007, medical and prescription insurance coverage at diagnosis, a 1-year look-back period prior to the index diagnosis, no prior malignancies in the 1-year period before index diagnosis, and had received ?1 LOT. RESULTS:Among patients who did not receive ASCT (non-transplant; n =?22,062), 12,557 (57%) received only 1 LOT and 9505 (43%) received >?1 LOT. Patients receiving only 1 LOT were significantly older, had higher mean Charlson Comorbidity Index (CCI) scores, and higher incidences of comorbidities. Among the 2763 patients receiving ASCT, 2184 received >?1 LOT, and 579 (21%) received only 1 LOT (ie, ASCT was the last treatment). 1682 (61%) patients received induction therapy as frontline treatment, of whom 187 (11%) also received consolidation therapy. The latter group was younger than those who received only induction therapy, had lower mean CCI scores, and comparable or lower incidences of selected comorbidities. The most common frontline therapy for non-transplant and transplant-eligible patients was bortezomib/dexamethasone and bortezomib/lenalidomide/dexamethasone, respectively. Attrition rates across all LOTs were high for non-transplant patients (range, 43-57%) and transplant patients (range, 21-37%). Treatment duration decreased by LOT for non-transplant patients and was consistent across LOTs for transplant patients. CONCLUSIONS:In this analysis, a substantial proportion of patients with NDMM who received frontline therapy did not appear to receive a subsequent LOT. These high attrition rates underscore the need to use the most optimal treatment regimens upfront rather than reserving them for later LOTs in which the clinical benefit may decrease.

Project description:Lenalidomide (Len) plus dexamethasone (Dex) is approved for the treatment of relapsed or refractory multiple myeloma (RRMM). It is possible that single-agent Len may be effective as prolonged treatment regimen in RRMM once patients demonstrate an initial response to Len+Dex induction. Patients with RRMM who responded to first-line Len+Dex in an observational study (NCT01430546) received up to 24 cycles of either Len (25 mg/day) or Len+Dex (25 mg/day and 40 mg/week) as prolonged treatment in a subsequent phase 2 clinical trial (NCT01450215). In the observational study (N = 133), median time to response was 1.7 (range 0.6-9.6) months. A complete response to all treatments received in both studies was observed in 11% of patients; very good partial response and partial response rates were 31% and 38%, respectively. Corresponding response rates in the subgroup of patients who did not enter the phase 2 trial (n = 71) were 3%, 18%, and 39%, respectively. Rates of disease progression at 2 years in the phase 2 trial were 47% versus 31% for Len versus Len+Dex (P = 0.14). After 36 months median follow-up in surviving patients, median time to progression was not reached with Len+Dex and was 24.9 months (95% confidence interval 12.5-not calculable, P < 0.001) with Len. Three-year OS among the total observational study population was 61% (95% CI, 52-69%). The corresponding rate among patients who entered the phase 2 clinical trial was 73% (95% CI, 60-83%) and was significantly lower among those patients who achieved ?PR but did not proceed into the phase 2 trial (55%; P = 0.01). In the phase 2 trial, OS was 73% in both treatment arms (P = 0.70). Neutropenia and thrombocytopenia were more common with prolonged (phase 2 trial) versus short-term (observational study) Len administration but remained manageable. Prolonged treatment with Len with or without Dex provides sustained, clinically relevant responses and demonstrates an acceptable safety profile.

Project description:ImportanceCarfilzomib-lenalidomide-dexamethasone therapy yields deep responses in patients with newly diagnosed multiple myeloma (NDMM). It is important to gain an understanding of this combination's tolerability and impact on minimal residual disease (MRD) negativity because this end point has been associated with improved survival.ObjectiveTo assess the safety and efficacy of carfilzomib-lenalidomide-dexamethasone therapy in NDMM and high-risk smoldering multiple myeloma (SMM).Design, setting, and participantsClinical and correlative pilot study at the National Institutes of Health Clinical Center. Patients with NDMM or high-risk SMM were enrolled between July 11, 2011, and October 9, 2013. Median follow-up was 17.3 (NDMM) and 15.9 months (SMM).InterventionsEight 28-day cycles were composed of carfilzomib 20/36 mg/m2 on days 1, 2, 8, 9, 15, and 16; lenalidomide 25 mg on days 1 through 21; and dexamethasone 20/10 mg (cycles 1-4/5-8) on days 1, 2, 8, 9, 15, 16, 22, and 23. Patients who achieved at least stable disease subsequently received 24 cycles of lenalidomide extended dosing.Main outcomes and measuresPrimary end points were neuropathy of grade 3 or greater (NDMM) and at least very good partial response rates (SMM). Minimal residual disease was also assessed.ResultsOf 45 patients with NDMM, none had neuropathy of grade 3 or greater. Of 12 patients with high-risk SMM, the most common of any-grade adverse events were lymphopenia (12 [100%]) and gastrointestinal disorders (11 [92%]). All patients with SMM achieved at least a very good partial response during the study period. Among the 28 patients with NDMM and the 12 with SMM achieving at least a near-complete response, MRD negativity was found in 28 of 28 (100% [95% CI, 88%-100%]), 11 of 12 (92% [95% CI, 62%-100%]) (multiparametric flow cytometry), 14 of 21 (67% [95% CI, 43%-85%]), and 9 of 12 (75% [95% CI, 43%-94%]) (next-generation sequencing), respectively. In patients with NDMM, 12-month progression-free survival for MRD-negative vs MRD-positive status by flow cytometry and next-generation sequencing was 100% vs 79% (95% CI, 47%-94%; P < .001) and 100% vs 95% (95% CI, 75%-99%; P = .02), respectively.Conclusions and relevanceCarfilzomib-lenalidomide-dexamethasone therapy is tolerable and demonstrates high rates of MRD negativity in NDMM, translating into longer progression-free survival in patients achieving MRD negativity. Carfilzomib-lenalidomide-dexamethasone therapy also demonstrates efficacy in high-risk SMM.

Dataset Information

Treatment of patients with multiple myeloma progressing on frontline-therapy with lenalidomide.

Publications

Treatment of patients with multiple myeloma progressing on frontline-therapy with lenalidomide.

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