Real‐World Outcomes of Newly Diagnosed Multiple Myeloma Patients Treated With Front‐Line Daratumumab Lenalidomide and Dexamethasone

The phase III MAIA trial evaluated daratumumab (dara), lenalidomide (len), and dexamethasone (dex) (DRd) versus Rd in newly diagnosed transplant ineligible multiple myeloma (MM) patients and demonstrated unprecedented survival outcomes for patients treated with DRd [1, 2]. In the MAIA trial, DRd treated patients received dara at 16 mg/kg IV until disease progression, len at 25 mg PO (or renally dosed) on days 1–21 for a maximum of 2 years, and dex at 40 mg weekly (or 20 mg if ≥ 75 years old) until disease progression or unacceptable toxicity. A post hoc analysis of the MAIA study revealed that patients treated with DRd for ≥ 18 months without modifications of DRd had superior overall response rates (ORR), progression free survival (PFS), and overall survival (OS) compared to those treated for < 18 months [3]. Little is known about the efficacy of DRd in real world (RW) practice and RW practice patterns including modifications of DRd treatment and subsequent treatment after progression on DRd. In this retrospective analysis, we aim to evaluate the RW efficacy and the clinical outcomes of NDMM patients treated with DRd across the tri-site Mayo Clinic Comprehensive Cancer Center (MCCC). We retrospectively analyzed the medical records of patients treated with DRd between January 2016 and July 2023 at the MCCC. Descriptive statistics were used to describe patient characteristics. Categorical variables were compared with Chi-square tests and continuous variables were compared with t-tests. Outcomes were estimated using the Kaplan–Meier method. IMWG criteria was used for response assessment [4]. Ultra high-risk myeloma was defined as per the new IMS/IMWG consensus recommendations [5]. Two hundred and two patients were included in the analysis, baseline characteristics are shown in Table 1. Starting len dose was 25 mg in 99 patients (49%), 15 mg in 51 patients (25.3%), ≤ 10 mg in 52 patients (25.7%), 20 patients received dara IV and 181 received dara SQ. Fifty-one (25.3%) patients received 1–2 cycles of a different regimen prior to DRd due to hospitalization (n = 5), renal insufficiency (defined as creatinine > 2 mg/dL and/or creatinine clearance < 40 mL/min; n = 12), poor performance status (n = 17), and other reason (n = 18). The ORR to DRd was 91% with 130 (64.3%) achieving ≥ VGPR and 32 (of 63 evaluable; 50.8%) achieving minimal residual disease negativity (MRD-) in the bone marrow at a sensitivity threshold of 10−5. Twenty-eight patients underwent autologous transplant (ASCT). The median number of DRd cycles for patients that underwent ASCT was 6 (2–38) compared to 18 (1–69) for patients that did not undergo ASCT. At a median follow-up time of 25 months, the median PFS of patients who did not undergo ASCT was 48 months, and 4-year OS rate was 52.2% (Figure 1A). Of the 28 patients that underwent ASCT, 26/28 received melphalan 200 mg/m2, and the median PFS was not reached (NR) and at 37 months of follow-up for patients that underwent ASCT, the PFS rate was 64.6%, and the OS rate was 74.7%. Twenty-seven patients received post-ASCT maintenance therapy; len (n = 12), dara (n = 1), len + dara (n = 11), other (n = 3). The median PFS was NR for patients who received len versus len + dara maintenance; PFS at 48 months was 55.6% for len and 76.2% for len + dara, p = 0.11. For patients that did not undergo ASCT, the median PFS for standard risk patients was 58 months, for high risk was 42 months and for ultra-high risk was 37 months, p = 0.47 (Figure 1B). For patients that did not undergo ASCT, the median PFS was 14 months for patients with extramedullary disease versus 48 months for those without extramedullary disease, p = 0.061. One hundred and thirty-five patients (66.8%) had modification of DRd. The median time from start of DRd to modification was 7 months (0–40 months). DRd modification included len dose stopped/dropped (S/D) (n = 35), dex dose S/D (n = 23), both len and dex S/D (n = 62), dara and/or dex S/D, len continued (n = 19). Reasons for DRd modification included len toxicity (tox) (n = 47), dex tox (n = 10), len and dex tox (n = 9), other reason that was not toxicity (n = 71). The median PFS for non-transplant patients with DRd modification was 58 months and was 14 months for patients who did not have DRd modification, p < 0.001 (Figure 1C). For patients who did not undergo ASCT and underwent DRd modification due to toxicity, their median PFS was 42.2 months compared to a median PFS of 58.1 months for patients who underwent DRd modification for reasons other than toxicity, p = 0.028 (Figure 1D). We did a 6-month landmark analysis for patients who underwent DRd modification versus not at 6 months and the median PFS rate for patients who underwent DRd modification was 51.2 months compared to 8.4 months for patients who did not undergo DRd modification, p < 0.001 (Figure 1E). Patients with DRd mod stayed on DRd 3× as long (16.0 months) compared to those without modification (6.3 months), p = 0.015. For patients who received 1–2 cycles of a different regimen prior to starting DRd (n = 51), their median PFS was 48 months (42-NR) compared to a median PFS of 47 months (42-NR) for patients who started 1st line therapy with DRD, p = 0.77. The median PFS for DRd treated patients that did not undergo ASCT with renal insufficiency was 37 months compared to 58 months for patients without renal insufficiency, p = 0.46 (Figure 1F). The median PFS for DRd treated that did not undergo ASCT and were ≥ 75 years of age was 42 months compared to 58 months for patients < 75 years of age, p = 0.16. The median PFS for DRd treated that did not undergo ASCT and were ≥ 80 years of age (n = 57) was 43 months compared to 58 months for patients < 80 years of age, p = 0.46 (Figure 1G). Forty-five patients relapsed after DRd treatment. The median follow-up time since relapse after DRd was 13 months and the most common subsequent therapies included other (n = 8; 5/8 received a bortezomib(V)-based regimen), DVd (n = 5), DRd, VPd, and carfilzomib-P-dex (KPd) in 4 patients each. ORR was 52%, PFS rate at 12 months with post-DRd treatment was 74% and OS rate at 12 months was 91% (Figure 1H). At the time of relapse from 1st line DRd, 41 patients were considered dara-refractory. Amongst patients that did not undergo ASCT, 23 have died due to MM-related causes including disease progression (n = 3), infection (n = 2), other (n = 18). The median age of patients that died was 82 years. In this RW analysis, survival outcomes appeared inferior with the use of DRd in NDMM patients compared to that reported in the MAIA trial. In the MAIA trial, the median PFS was about 62 months [2] and was 48 months (in patients that did not undergo ASCT) in our RW study. The 48-month OS rate was about 70% in the MAIA trial [2] and was 52% in our study. The median PFS for patients ≥ 80 years in MAIA was 52 months [2] compared to 43 months for the patients in our RW study and in our RW study, there was a numerically higher PFS for patients < 80 years of age (compared to ≥ 80 years) that did not reach statistical significance. Importantly, patients that had modification of DRd had superior PFS and stayed on DRd 3× longer than those without modification. These findings contrast data from the MAIA trial suggesting that treatment modification before 18 months (the median time to DRd modification in our study was 7 months) leads to inferior efficacy and survival outcomes [6]. Our data suggests that modifying DRd allows patients to stay on treatment longer which may translate superior survival outcomes and this is in line with other real world and clinical trial data showing that reduced dose intensity of MM therapy does not result in inferior survival outcomes [7, 8]. Patients in this RW analysis were older (median age of 75 vs. 73) and had more high-risk cytogenetics (32% vs. 15%), compared to patients on the MAIA trial and this may explain the inferior survival outcomes of patients in this RW analysis compared to MAIA. Limitations of our study include its retrospective design and the heterogeneous patient population which included patients that received 1–2 cycles of a different regimen prior to starting DRd as well as patients that underwent ASCT which includes a fitter patient population was that removed from the survival analyses and analyzed separately. Although there was heterogeneity in institutional practices for dosing of len and dex and treatment modifications, this analysis is reflective of the variability seen in real-world practice patterns, even across the tri-site MCCC. Another limitation of our study is the potential for survivorship bias in patients who underwent DRd modification. In effort to mitigate this, we performed a 6-month landmark analysis and found that patients who had modification of DRd still had superior PFS compared to patients who didn't have modification of DRd. Patients who had modification of DRd due to toxicity had inferior PFS compared to patients who had modification of DRd due to other reasons that were not related to toxicity and this may reflect a higher comorbidity burden in patients who required DRd modification due to toxicity such as renal insufficiency which has historically resulted in worse PFS outcomes in MM patients. While attrition rates have been going down over time, attrition rates after 1st line therapy remain high amongst patients ≥ 75 years of age and this may explain the lower OS in patients treated with DRd that did not undergo ASCT in this RW analysis [9, 10]. The majority of the patients that died in this study did not die of myeloma-related causes highlighting the long-term efficacy of DRd and the highly efficacious therapeutic options for MM in the modern era. Patients who progress on DRd can be effectively salvaged with currently available therapies. Regimens containing proteasome inhibitors are often used and lead to high response rates and durable disease control. As anti-CD38 monoclonal antibody-containing quadruplets and T-cell redirecting therapies make their way into the front-line treatment for transplant ineligible MM patients [11-13], DRd remains a viable treatment option for the treatment of newly diagnosed MM in RW practice. Ricardo D. Parrondo and Ricardo C. B. de Menezes designed the study. Ricardo D. Parrondo and Ricardo C. B. de Menezes wrote the manuscript. Hanna Sledge performed the statistical analysis. Ricardo C. B. de Menezes, Madhavi Nayyar, and Kanika Yadav collected the data. Ricardo D. Parrondo, Ricardo D.B. de Menezes, Leif Bergsagel, Rafael Fonseca, Prashant Kapoor, Morie A. Gertz, Angela Dispenzieri, Francis Buadi, Nadine Abdallah, Saurabh Chhabra, S. Vincent Rajkumar, Wilson I. Gonsalves, Joselle Cook, Shaji Kumar, Asher A. Chanan-Khan, Vivek Roy, and Sikander Ailawadhi analyzed the data for the study. All authors critically revised the manuscript and approved the final version. The study protocol and all amendments were reviewed and approved by the Institutional Review Board at Mayo Clinic Florida (IRB # 23-001194) as an IRB-exempt study. The study was conducted in accordance with the International Conference on Harmonisation Good Clinical Practice guidelines, the principles originating from the Declaration of Helsinki. Individual informed consent was obtained per institutional requirements and guidelines. Ricardo D. Parrondo serves on the advisory board for Sanofi Aventis, Johnson and Johnson, and Astra Zeneca and has received research funding from Bristol Myers Squibb Foundation and GlaxoSmithKline. Sikander Ailawadhi has provided consultancy for Celgene, Amgen, Janssen and Takeda, and has received research funding from Pharmacyclics, Cellectar and Janssen. Saurabh Chhabra has received honoraria from Sanofi, Ascentage Pharma, Sobi, Legend Biotech, BMS and research funding from Johnson and Johnson, Cynata Therapeutics, C4 Therapeutics, Abbvie, Ascentage Pharma, AstraZeneca, Cullinan Therapeutics. Asher A. Chanan-Khan has received research funding from Xencor Pharmacyclics, Merck, Janssen, Ascentage and Millennium. Prashant Kapoor received research funding from Takeda Pharmaceuticals, Celgene, and Amgen. Angela Dispenzieri received research funding from Celgene, Millennium Pharmaceuticals, Pfizer, and Janssen and received a travel grant from Pfizer. Morie A. Gertz served as a consultant for Millennium Pharmaceuticals and received honoraria from Celgene, Millennium Pharmaceuticals, Onyx Pharmaceuticals, Novartis, GlaxoSmithKline, Prothena, Ionis Pharmaceuticals, and Amgen. Leif Bergsagel served as consultant: Oncopeptidfes. Salarius, Radmetrix, Omeros, CellCentric, AbbVie, Pfizer. Rafael Fonseca performs consulting for: AbbVie, Adaptive, Amgen, Apple, BMS/Celgene, GSK, Janssen, Karyopharm, Pfizer, RA Capital, Regeneron, Sanofi. Scientific Advisory Board: Caris Life Sciences. Board of Directors: Antengene. Patent for FISH in MM ~$2000/year. Shaji Kumar Consulting or Advisory Role: Takeda, Janssen Oncology, Genentech/Rocher, Abbvie, BMS/Celgene, Pfizer, Regeneron, Sanofi, K36 Therapeutics; travel, accomodation and expenses: Abbvie, Pfizer; Research funding: Takeda, Abbvie, Novartis, Sanofi, Janssen Oncology, MedImmune, Roche/Genentech, CARsgen Therapeutics, Allogene Therapeutics, GSK, Regeneron, BMS/Celgene. The remaining authors declare no competing financial interests. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.