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Triplet combination increases MRD negativity in multiple myeloma
A triplet combination composed of carfilzomib, lenalidomide and dexamethasone conferred high rates of minimal residual disease negativity in patients with newly diagnosed or high-risk smoldering multiple myeloma, according to study results.
Further, the achievement of minimal residual disease (MRD) negativity prolonged PFS in newly diagnosed patients, results showed.
Patients with newly diagnosed multiple myeloma achieved deep responses with carfilzomib (Kyprolis, Onyx Pharmaceuticals), lenalidomide (Revlimid, Celgene) and dexamethasone in previous analyses, according to study background.
“Treatment with [carfilzomib, lenalidomide and dexamethasone] was found to have a favorable peripheral neuropathy profile … which may allow for greater treatment adherence and an increased likelihood to reach negativity for MRD compared with use of other proteasome inhibitors,” Ola Landgren, MD, PhD, chief of myeloma service at Memorial Sloan Kettering Cancer Center, and colleagues wrote. “Given that many patients with newly diagnosed multiple myeloma who are treated with [carfilzomib, lenalidomide and dexamethasone] achieved the deepest level of responses recognized by current standardized criteria, there is a need to assess MRD.”
The analysis included 45 patients with newly diagnosed multiple myeloma (median age, 60 years; range, 40-88) and 12 patients with smoldering multiple myeloma (median age, 58 years; range, 48-65).
Patients received eight 28-day cycles of carfilzomib (20/36 mg/m2 on days 1, 2, 8, 9, 15 and 16), lenalidomide (25 mg on days 1-21) and dexamethasone (20 mg for cycles 1-4 and 10 mg for cycles 5-8 on days 1, 2, 8, 9, 15, 16, 22 and 23). Those who achieved at least stable disease then received 24 cycles of lenalidomide extended dosing.
Grade 3 or higher neuropathy served as the primary endpoint for patients with newly diagnosed multiple myeloma. Very good partial response rate or better served as the primary endpoint for patients with smoldering multiple myeloma. The researchers assessed MRD in both patient cohorts.
Median follow-up was 17.3 months for patients with newly diagnosed multiple myeloma and 15.9 months for smoldering multiple myeloma.
No patients with newly diagnosed multiple myeloma experienced grade 3 or 4 neuropathy; however, 33% of patients experienced grade 1 neuropathy and 9% experienced grade 2 neuropathy.
The most common any-grade adverse events among patients with high-risk smoldering multiple myeloma included lymphopenia (n = 12; 100%) and gastrointestinal disorders (n = 11; 92%).
All patients with smoldering multiple myeloma achieved a very good partial response or better.
Researchers detected MRD negativity in 11 of these patients (92%; 95% CI, 61%-100%) using multiparametric flow cytometry and nine patients (75%, 95% CI, 43%-94%) using next-generation sequencing.
Twenty-eight patients with newly diagnosed multiple myeloma achieved a near-complete response. All of these patients (100%; 95% CI, 88%-100%) achieved MRD negativity based on multiparametric flow cytometry, and 14 of 21 evaluable patients (67%; 95% CI, 43-85) achieved MRD negativity based on next-generation sequencing.
MRD negativity corresponded with higher 12-month PFS rates than MRD positivity among patients with newly diagnosed multiple myeloma by flow cytometry (100% vs. 79%; P < .001) and next-generation sequencing (100% vs. 95%; P = .02).
No patients with smoldering disease experience disease progression during the study and each have maintained their best response at the time of the data cutoff.
“Taken together, our results provide further evidence for the role of 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,” Landgren and colleagues concluded. “… In addition, the pilot study in high-risk smoldering multiple myeloma patients provides proof of principle to support future large-scale trials of tolerable regimens capable of achieving high rates of sustainable MRD-negative responses in this population.”
Pieter Sonneveld
MRD assessment may become an important tool in evaluating clinical trial results, Pieter Sonneveld, MD, PhD, senior staff hematologist at the Erasmus MC Cancer Institute in Rotterdam, the Netherlands, wrote in an accompanying editorial.
“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,” Sonneveld wrote. “New ways of response evaluation such as MRD and PET/CT negativity should be introduced for clinical trials and ultimately also in clinical practice. This is also important for long-term clinical strategies for patient treatment, since MRD negativity predicts for survival.” – by Cameron Kelsall
Disclosure: The researchers report no relevant financial disclosures. Sonneveld reports research funding from and advisory roles with Celgene, Janssen, Karyopharm, Novartis and Onyx/Amgen.
Perspective
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Suzanne Lentzsch
Shahzad Raza
In the current study, Korde and colleagues evaluated 45 patients with newly diagnosed multiple myeloma (NDMM) and 12 patients with high-risk smoldering multiple myeloma (SMM) and assessed the safety, efficacy and clinical response to CRd followed by maintenance lenalidomide. In addition, they performed minimal residual disease (MRD) testing using multiparametric flow cytometry (MFC) and next-generation sequencing (NGS) for both groups of patients.
All NDMM patients completed at least two cycles. Among patients with NDMM, complete response was reported in 56%. Eighty-nine percent of patients achieved at least a very good partial response and 98% achieved at least a partial response, suggesting that the combination of CRd is highly active in NDMM. Responses improved as patients continued to receive more cycles of CRd. The complete response and stringent complete response rate increased from 7% after two cycles to 43% after eight cycles. Eighty-four percent of patients who achieved at least a partial response (n = 37) maintained a partial response for at least 24 months, and 88% of patients who achieved a complete response or stringent complete response (n = 22) maintained a complete response for at least 24 months.
Among high-risk SMM patients, 50% achieved a very good partial response and 100% had partial response. However, over a median of six cycles (range, 2-20), all patients eventually achieved a complete response.
The PFS at 18 months for MRD-negative patients measured by both MFC and NGS was 100%. In contrast, the PFS at 18 months for MRD-positive patients measured by MFC was 63% compared with 84% when measured by NGS.
Taken together, the data by Korde and colleague show the high efficacy and safety of CRd. Unfortunately, the trial is limited by a short follow-up and small sample size. Further, the present study uses MFC assay with a sensitivity of 1x10-5, and reports a 98% MRD negativity in patients who have achieved at least a near-complete response. However, there were an additional 30% MRD-positive cases detected by NGS in patients with near-complete response, suggesting the need for standardized technique for MRD assessment. So the optimal MRD sample type (bone marrow aspirate vs. peripheral blood) or method (flow cytometry vs. molecular testing) are all unresolved questions in MRD testing. Further, patients with low-risk and SMM prior to progression into overt myeloma often do not achieve a complete response with therapy, but usually do very well regardless. Therefore, in the absence of a clear benefit of MRD as an endpoint of treatment, MRD testing should only be incorporated in large prospective clinical trials.
Reference:
Stewart AK, et al. N Engl J Med. 2015;doi:10.1056/NEJMoa1411321.Suzanne Lentzsch, MD, PhD
Columbia University Medical Center
Shahzad Raza, MD
Columbia University Medical Center