RVD + ASCT + Lenalidomide Maintenance Benefits Patients without High-Risk Cytogenetics and Results in Recovery of the Normal Plasma Cell Composition in Bone Marrow
Authors: Silvennoinen Raija , Anttila Pekka , Säily Marjaana , Lundan Tuija , Heiskanen Jouni , Siitonen Timo , Kakko Sakari , Putkonen Mervi , Ollikainen Hanna , Terävä Venla , Partanen Anu , Launonen Kirsi , Räsänen Anu , Sikiö Anu , Suominen Merja , Bazia Piotr , Kananen Kristiina , Lievonen Juha , Selander Tuomas , Västrik Imre , Pelliniemi Tarja-Terttu , Porkka Kimmo , Remes Kari , Jantunen Esa 
Published: October 2019

Abstract
Introduction
The majority of myeloma (MM) patients will relapse or progress in 2-3 years after initial treatment. To prolong remission time several regimens have been investigated for consolidation and maintenance. Minimal residual disease (MRD) has been considered to be a potentially novel primary endpoint in evaluating the efficacy of new therapies. The FMG-MM02 study (NCT01790737) was designed to explore the response to lenalidomide, bortezomib and dexamethasone (RVD) induction, followed by a single ASCT and lenalidomide (LEN) maintenance in newly diagnosed MM patients. The primary endpoint is immunophenotypic remission (IR) and will be compared with molecular remission as a secondary endpoint in sCR patients. Here we present the IR results, comparison with RQ-PCR, and short-term results of other secondary endpoints; improvement of responses during maintenance and PFS.
Patients and methods
Three RVD cycles consisted of LEN 25 mg/d po on days 1-14, bortezomib 1.3 mg/m2 sc on days 1,4,8,11 and dexamethasone 20 mg po on days 1-2, 4-5, 8-9 and 11-12, followed by MEL200 + ASCT. Three months later patients started LEN 10 mg/d on days 1-21 in 28-day cycles until progression or excess toxicity. Multiparameter flow cytometry (MFC) assays were performed in five Finnish university hospital laboratories. After gating with CD38/CD138/light scatter the expressions of CD45/CD19/CD56/CD27/CD28/CD81/CD117/intracytoplasmic Κ/λ were assessed in all samples at diagnosis and informative markers were used for MFC-MRD analysis. Fifty immunophenotypically abnormal plasma cell events was the lower limit for quantitation in MRD analysis and at least 0.5 x 106 total nucleated cells were needed to reach the sensitivity of 0.01%.
Results
Overall response rate (ORR) was 86% by intention-to-treat (ITT) after RVD induction. Three months after ASCT 47/80 (59%; ITT) patients had achieved ≥ VGPR and 29/80 (36%) were in IR. Nine patients were withdrawn early due to toxicity. Of the per protocol treated 71 patients 29 (41%) were in IR. After a minimum follow-up of 12 months after ASCT (9 months on maintenance) 38/80 (48%) patients were in at least VGPR and 24/80 (30%) in IR by ITT. Eighteen patients (23 %) have progressed and 4 patients (5 %) have died. From those patients who have continued maintenance 24/44 (55%) patients were in IR. The median follow-up is 22 (2-38) months. Four additional patients have achieved IR during the maintenance and 13 (22%) have upgraded their serological response. The proportion of MM cells among all plasma cells (PC) decreased from the median of 44% (3-100%) to 17% (9-28%) in MFC-positive patients during 9 months of maintenance.
The median number of total nucleated cells was 0.7 x 106 in MFC-MRD negative samples resulting in the median sensitivity of < 0.007% of all samples. Fifty percent (11/22) of the samples of sCR/MFC-MRD negative patients were also PCR-negative with the median sensitivity of < 0.0006%. The remaining 50% (11/22) of the samples were still PCR-positive with the median amount of 0.002%. The median PFS for all study patients has not been reached; estimated median PFS is 29 months (95% CI 25-32). Patients (n=24/80, 30%) with high-risk (HR) cytogenetic (del17p, t(4;14), t(14;16) and/or +1q) had significantly shorter PFS (21 months vs. median not reached), p=0.04. ORR of HR patients was 18/24 (75%) and 11/24 (46%) reached IR at least once before relapse. Patients with t(4;14) (n=8), had the worst outcome with the median PFS of only 9 (4-13) months compared to median not yet reached of all other patients or patients without t(4;14), p<0.001.
Conclusion
RVD + ASCT + short-term LEN maintenance resulted in 30% IR by ITT but in 55% IR for those who were able to continue protocol treatment. With 9 months of LEN maintenance serological responses improved more than immunophenotypic responses, but the constitution of PCs of MFC-MRD positive patients showed recovery. RVD + ASCT + LEN maintenance seems to benefit most patients without HR cytogenetics. This study confirms previous findings that PCR is one logarithm more sensitive than MFC in MRD assessment.

Disclosures
Silvennoinen: Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Lecture fee; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Other: Lecture fee. Säily:Celgene: Other: Educational grant for congress participation; Amgen: Other: Educational grant for congress participation. Siitonen:Celgene: Other: Lecture fee; Amgen: Other: Lecture fee. Räsänen:Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene, Amgen: Other: Educational grant for congress participation. Kananen:Celgene, Sanofi Genzyme: Other: Educational grant for congress participation; Amgen: Other: Lecture fee. Lievonen:Novartis: Consultancy; Celgene, Amgen: Honoraria; Takeda, Roche: Other: Educational grant for congress participation; Janssen, Celgene, Amgen, Novartis, Takeda, Roche: Other: Educational grant for congress participation. Pelliniemi:Novartis: Consultancy; Alexion, Novartis, Roche: Other: Lecture fee. Porkka:Celgene: Research Funding. Remes:Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees; Teva: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees.