Quality of Life in Newly Diagnosed Patients with Multiple Myeloma Randomized to Either Krd or Ktd Induction Therapy Followed By Carfilzomib Maintenance or Control (AGMT MM 02 trial)
Authors: Ludwig Heinz , Melchardt Thomas , Andel Johannes , Gunsilius Eberhard , Sormann Siegfried , Hinke Axel , Hartmann Bernd L. , Podar Klaus , Willenbacher Wolfgang , Egle Alexander , Petzer Andreas , Zojer Niklas , Wöll Ewald , Ruckser Reinhard , Bozic Boris , Schmitt Clemens A. , Machherndl-Spandl Sigrid , Krauth Maria-Theresa , Schreder Martin , Agis Hermine , Tinchon Christoph , Fillitz Michael , Greil Richard 
Published: February 2021

Introduction
Carfilzomib-based induction therapy is highly effective in newly diagnosed pts with multiple myeloma (NDMM), but information on quality of life (QoL) during first line and maintenance therapy is not available. Here, we analyze patient-reported QoL in transplant-non eligible (TNE) NDMM pts randomized to either KTd or KRd induction therapy followed by second randomization to carfilzomib maintenance, or control.
Patients and Methods
At time of analysis, 101 TNE pts with NDMM had been enrolled, but QoL data documented for ≥ 2 cycles were available in 78 pts so far (median age: 75 years, ISS stage I: 26.6%, II: 35.4%, III: 38.0%, ECOG status 0: 51.9%, 1: 48.1%). Patients were randomized to either 9 cycles KTd or KRd, and subsequently (46 pts with ≥PR) to either carfilzomib maintenance therapy (d1 and 15) or to control for 12 months. Carfilzomib was administered twice weekly (27mg/m2) during cycles 1 and 2, and thereafter weekly at a dose of 56mg/m2. Thalidomide was given daily at 100mg (50mg in pts ≥75 years), lenalidomide at 25mg, d1-21 per 4 week cycle, and dexamethasone at 40 mg (20mg in pts ³75 years) once weekly.
QoL was assessed by the QoL questionnaire EORTC QLQ-C30. Assessments were done at baseline, and monthly thereafter for 21 months. A two-sided t-test was used for comparison with the general population. Wilcoxon signed-rank tests were applied to evaluate differences in QoL dimensions within the treatment groups. A clinically meaningful improvement has been defined as a change of ≥10 score points.
Results
Comparison with the general population : Mean scores for health-related global QoL (54.1±22.6) and physical functioning (61.2±25.0) were significantly lower in pts compared to those reported for the general population of similar age (67.2±20.6, p&lt;0.001, and 80.6±19.7, p&lt;0.001, respectively) (Nolte S et al., Eur. J. Cancer 2019).
Induction therapy: Health-related global QoL showed a clinically relevant improvement during carfilzomib-based induction therapy in both treatment groups (KRd: 54.5±19.9 to 65.0±20.2, p=0.10, KTd 53.6±24.8 to 68.2 ± 19.4, p=0.04), but a statistically significant increase in score points was noted in the KTd arm only. For physical functioning, a clinically relevant improvement was noted solely in pts on KRd, but the increase was not statistically significant (59.2 ± 22 to 73.2 ± 23.8, p=0.15), while during KTd no relevant changes were noted. Further clinically relevant improvements during induction therapy were observed for role functioning (KTd: 45 ± 39.3 to 61.6 ± 33.5, p=0.08, KRD: 51.5 ± 34.9 to 66.7 ± 30.1, p=0.29), emotional functioning (KTd: 61.2 ± 27.4 to 73.2 ± 20.5, p=0.04, KRd: 58.3 ± 23.2 to 73 ± 26.7, p=0.10), and pain with a statistically significant decrease in respective scores in both arms (KTd: 47.7 ± 37.4, to 24.2 ± 26.1, p=0.01, KRd: 54.8 ± 33.2 to 20.8 ± 21.5, p&lt;0.001)(Figure 1). Neuropathy, however, worsened clinically relevant and statistically significant in KTd treated pts (15.4 ± 24 to 27.8 ± 26.4, p=0.03), while during KRd treatment, no change was noted (22.2±30.8 to 22.2±28.0, p=0.66). Likewise, no changes were observed for nausea/vomiting, diarrhoea, constipation, fatigue, and cognitive function, while a clinically relevant improvement in social function was noted in pts during KRd induction (66.2±31.4 to 80.8±27.7, p=0.13).
Maintenance phase: Pts randomized to carfilzomib maintenance showed no clinically relevant change in health-related QoL score (70.3± 17 to 63.9±25.3), similar to the findings in the untreated controls, which showed a clinically not relevant improvement in scores (66.7.±21.0 to 75.9±18.8). The scores for physical functioning remained rather stable during the maintenance period and values at end of therapy or observation appeared similar between the carfilzomib (77.1±21.6) and the control group (83.7±25.4).
Conclusion
Health-related global QoL and physical functioning in our pts with TNE NDMM was significantly impaired at start of therapy compared to the general population. During carfilzomib-based induction TX, clinically meaningful improvements in health-related global QoL, physical (only in KTd), emotional, role, and social (only in KRd) functioning, and pain were achieved. Neuropathy worsened during KTd. Maintenance treatment with carfilzomib was well tolerated without a clinically relevant change during the treatment period or statistical significant difference to the untreated controls.

Disclosures
Ludwig: Seattle Genetics: Other: Advisory Boards; Sanofi: Other: Advisory Boards, Speakers Bureau; Bristol Myers: Other: Advisory Boards, Speakers Bureau; Janssen: Other: Advisory Boards, Speakers Bureau; Celgene: Speakers Bureau; Amgen: Other: Advisory Boards, Research Funding, Speakers Bureau; Takeda: Research Funding. Podar:Amgen, BMS-Celgene, Janssen, Roche: Consultancy, Honoraria, Research Funding. Willenbacher:Amgen, Janssen, Takeda, BMS-Celgene: Consultancy, Honoraria, Research Funding. Petzer:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite-Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Schreder:BMS-Celgene, Amgen: Consultancy. Agis:Janssen: Honoraria, Research Funding; Amgen: Honoraria; BMS: Honoraria; Celgene: Honoraria; Takeda: Honoraria. Greil:Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding; Daiichi Sankyo, Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding; MSD Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding; Astra zeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding; BMS/celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding.

OffLabel Disclosure:
Use of Carfilzomib in myeloma first-line treatment