Daratumumab, carfilzomib, lenalidomide, and dexamethasone with tandem transplant for high-risk newly diagnosed myeloma Free

High-risk (HR) cytogenetic abnormalities are associated with poor outcomes in patients with newly diagnosed multiple myeloma (NDMM).^1,2 Risk-adapted strategies are, therefore, needed for MM. Despite the incorporation of proteasome inhibitors, immunomodulatory drugs, and anti-CD38 monoclonal antibodies, survival improvement for patients with HR myeloma is uncertain.³ To date, triplet (bortezomib, lenalidomide, and dexamethasone [VRd]) or quadruplet (daratumumab, bortezomib, thalidomide, and dexamethasone [D-VTd]) induction plus transplant, followed by lenalidomide maintenance, is the standard of care for patients who are transplant eligible (TE) with NDMM (TE-NDMM).⁴ More recently, the triplet combination of carfilzomib, lenalidomide, and dexamethasone (KRd) plus transplant demonstrated high efficacy with a favorable safety profile for patients with TE-NDMM.^5,6 The addition of daratumumab to VTd, VRd, or KRd also resulted in deep response rates and high minimal residual disease (MRD) rates in patients with TE-NDMM.^6-9 In the past years, tandem transplant also resulted in a progression-free survival (PFS) and overall survival (OS) improvement over single transplant in patients with TE-NDMM.¹⁰ This context led to the design of the phase 2 study 2018-04 from the Intergroupe Francophone du Myelome (IFM), evaluating the feasibility and efficacy of D-KRd induction and consolidation plus tandem transplant in HR TE-NDMM. This trial was registered at www.clinicaltrials.gov as #NCT03606577.

This multicenter, single-arm, open-label, phase 2 study was conducted in 11 centers of the IFM from July 2019 to March 2021. Eligible patients were aged ≤65 years and had previously untreated symptomatic NDMM with measurable paraprotein in the serum (≥0.5 g/dL) or urine (>0.2 g/24 h). Key inclusion criteria were: TE, Eastern Cooperative Oncology Group performance status ≤2, adequate renal function, and presence of at least 1 HR cytogenetic abnormalities among del(17p), t(4;14), or t(14;16) determined by fluorescence in-situ hybridization analysis. The threshold for positivity for these abnormalities were 30%. Key exclusion criteria were: human immunodeficiency virus, hepatitis B virus and hepatitis C virus positivity, history of other malignancy (other than basal cell carcinoma and carcinoma of the cervix in situ), and grade ≥2 peripheral neuropathy (National Cancer Institute Common Toxicity Criteria Version 4.0). All patients provided written informed consent. The study was approved by the relevant national health authority agency and the French national ethics committee and was conducted in accordance with the International Conference on Harmonization of Good Clinical Practice guidelines and the principles of the Declaration of Helsinki.

Induction therapy comprised six 28-day cycles of IV daratumumab (16 mg/kg on days 1, 8, 15, and 22 for cycles 1 and 2 as well as on days 1 and 15 for cycles 3-6), IV carfilzomib (20/36 mg/m² on days 1-2, 8-9, and 15-16), oral lenalidomide (25 mg on days 1-21), and oral dexamethasone (20 mg on days 1-2, 8-9, 15-16, and 22-23). Stem cell harvest was planned after cycle 6 for all patients after high-dose cyclophosphamide (3 g/m²) plus granulocyte-colony stimulating factor (5 μg/kg according to local practice). The target yield was 5 × 10⁶ CD34⁺ cells per kg. Patients proceeded to transplant using melphalan 200 mg/m² as the conditioning regimen. One month after hematologic recovery, patients who did not progress proceeded to consolidation therapy including four 28-day D-KRd cycles with IV daratumumab (16 mg/kg on days 1 and 15), IV carfilzomib (56 mg/m² on days 1, 8, and 15), oral lenalidomide (15 mg on days 1-21 for cycle 7 and 25 mg on days 1-21 for cycles 8-10), and oral dexamethasone (40 mg on days 1, 8, 15, and 22). Patients subsequently received second transplant (melphalan 200 mg/m²) followed by 2 years of maintenance therapy with lenalidomide (10 mg on days 1-21, 28-day cycle) and daratumumab (16 mg/kg every 8 weeks). Unless contraindicated, all patients received anticoagulation for prevention of deep vein thrombosis with low molecular weight heparin, antiviral therapy for herpes zoster prevention, and antibiotic prophylaxis for bacterial infections until the completion of the program.

The primary objective was feasibility, with rate of patients who completed second transplant as primary end point. Secondary end points included response rates (overall response, partial response, very good partial response, complete response, and stringent complete response) and MRD at each step of the program, quality of stem cell harvest, PFS, OS, and safety. Myeloma response assessment was based on the modified International Myeloma Working Group uniform response criteria.¹¹ Complete response (CR) was defined as negative serum and urine immunofixation, absence of soft tissue plasmacytoma, normal calcium concentration, and <5% plasma cells in the bone marrow. Stringent CR (sCR) was defined with the above criteria plus a normal serum free light chain ratio. MRD was assessed by next-generation sequencing (NGS) as previously described.¹² All patients were followed until death or end of the study. Safety was monitored until 30 days after the last dose of study drug, except for secondary malignancies (monitored continuously during follow-up). Toxicities were graded according to the National Cancer Institute Common Toxicity Criteria of Adverse Events (version 4.03; Bethesda, MD).

The goal of this program was to validate the feasibility of tandem autologous stem cell transplantation (ASCT) in patients at HR in the context of D-KRd induction and consolidation aimed at improving the depth of response. We considered this program as feasible in patients at HR, provided that 70% of them are able to tolerate the tandem ASCT procedure. A sample size of 50 patients was required to estimate a feasibility rate of 70% within a 95% confidence interval (CI) of ±13% (95% CI, 57-83). Median follow-up duration was estimated using the reverse Kaplan-Meier method. PFS was calculated as the time from the start of treatment to the first documentation of progressive disease or death if the patient died due to any cause before progression. OS was calculated as the time from the start of treatment to death. The Kaplan-Meier method was used to estimate the survival distribution. All analyses were conducted using R (version 4.2.3).

Between July 2019 and March 2021, 50 eligible patients with symptomatic TE-NDMM were enrolled in 11 centers in France. Patients’ demographic and baseline disease characteristics are summarized in Table 1. The median age at study entrance was 57 years (range 38-65). Thirty-eight (76%) and 12 patients (24%) had stage II and III, respectively, according to the revised International Scoring System.¹³ Positron emission tomography-computed tomography (PET-CT) was performed at baseline in 43 patients, of whom 4 (9.3%) had extramedullary disease (EMD). Three patients (6%) presented with criteria for primary plasma cell leukemia (PCL) (>5% circulating plasma cells). Based on the inclusion criteria, all patients harbored an HR cytogenetic profile. Del(17p), t(4;14), and t(14;16) were found in 20 (40%), 26 (52%), and 10 patients (20%), respectively. The presence of gain 1q and del(1p32) were also analyzed and detected in 25 (50%) and 6 patients (12%), respectively. Thirty patients (60%) presented with at least 2 HR abnormalities. Overall, 46 patients (92%) completed induction (2 patients had progressive disease, and 2 patients discontinued due to adverse event [AE]), and 42 patients (84%) underwent ASCT 1 (4 patients had stem cell collection failure). Forty (80%) completed consolidation (1 patient withdrew consent, and 1 patient discontinued due to AE), and 36 (72%) completed second transplant (4 patients due to stem cell collection failure). With at least 70% of patients completing second transplant, the study met its primary end point. Overall, 14 patients discontinued before maintenance, due to unsufficient stem cell harvest (n = 8), disease progression (n = 5), or AE (n = 1). Thirty-six patients entered maintenance. Maintenance is still ongoing in 24 patients, and 6 patients have now completed maintenance. The flowchart is summarized in Figure 1.

Twenty-seven patients had a stem cell collection after cycle 6 of induction, with a median CD34⁺ cell yield of 6.1 × 10⁶ per kg (range, 0 to 16 × 10⁶). For 6 patients (of 27), stem cell harvest was unsufficient to proceed to tandem transplant. Therefore, study protocol was amended to collect stem cell after cycle 3 of induction. Twenty-one patients had a stem cell collection after cycle 3, with a median CD34⁺ cell yield of 8.3 × 10⁶ per kg (range, 4.1 × 10⁶ to 26 × 10⁶). For 2 patients (of 21), stem cell harvest was unsufficient to proceed to tandem transplant.

Response rates are summarized in Figure 2A. In the per protocol population, the overall response rate by the end of induction was 95% (n = 46), including 60% (n = 29) very good partial response and 31% (n = 15) CR/sCR. The CR/sCR rate was 48% before consolidation (n = 42), 70% by the end of early consolidation (n = 41), and 81% before maintenance (n = 36). MRD analysis (NGS, 10^–5 and 10^–6 threshold) was performed after induction (n = 39 [of 48]), after first transplant (n = 37 [of 42]), after consolidation (n = 32 [of 41]), and after second transplant (n = 33 [of 36]; Figure 2B). After induction, per protocol MRD negativity rates were 53% at 10^–5 and 43% at 10^–6. Before maintenance, per protocol MRD negativity rates were 97% at 10^–5 and 94% at 10^–6. In the intent-to-treat population (n = 50), MRD negativity rates were 64% at 10^–5 and 62% at 10^–6 before maintenance.

As of July 2023, the median follow-up from the start of therapy was 33 months. Nine patients had disease progression, including 2 patients who discontinuated the study due to stem cell collection failure (n = 1) or AE (n = 1). Two patients had disease progression during induction phase, and 5 patients had disease progression during maintenance. Among these 5 patients, 4 achieved MRD negativity (10^–6) before maintenance. Seven patients died; 5 patients due to myeloma progression and 2 patients due to AE. The median PFS and OS were not reached. The 30-month PFS was 80% (95% CI, 68-94), and the 30-month OS was 91% (95% CI, 82-100; Figure 3). The prognostic impact of baseline parameters, including cytogenetic subgroup (t(4;14), t(14;16), del(17p), gain(1q), del(1p), and >2 HR abnormalities), EMD, and revised International Scoring System, has been analyzed. None of these paramaeters was significantly associated with poorer PFS or response assessment (postinduction response and postinduction MRD). Among 3 patients with primary PCL, 1 had early disease progression during induction. The other 2 patients are still progression free and in the maintenance phase.

Two patients died due to D-KRd–related AEs: septic shock (n = 1, during induction) and JC virus–related progressive multifocal leukoencephalopathy (n = 1, during maintenance). Overall, 4 patients (8%) discontinued treatment permanently due to treatment-related toxicity: 2 patients during induction (tumor lysis syndrome and COVID-19 infection), 1 during consolidation (COVID-19 infection), and 1 patient during maintenance (JC virus infection). Dose reduction of carfilzomib, lenalidomide, or dexamethasone occured in 23 (46%), 37 (74%), and 17 patients (34%), respectively. AEs were reported for at least 10% of patients and are described in Table 2. During induction, neutropenia was the most frequent hematologic treatment-related AE, occurring in 18 patients (36%), mainly grade 3 or 4 (n = 16). For non-hematologic toxicity, most common AEs were infections (n = 21 [42%]), gastrointestinal symptoms (n = 24 [48%]), fatigue (n = 13 [26%]), and psychiatric issues (n = 10 [20%]), mostly grade 1 or 2. During consolidation, neutropenia was the most frequent hematologic treatment-related AE, occurring in 9 patients (21%), mainly grade 3 or 4 (n = 6). For nonhematologic toxicity, most common AEs were infections (n = 15 [35%]), gastrointestinal symptoms (n = 15 [35%]), fatigue (n = 8 [19%]), and psychiatric issues (n = 10 [20%]), mostly grade 1 or 2. Twenty-one patients (42%) developed COVID-19 infection, mostly grade 1 to 2, except for 3 patients (grade 3 COVID-19 infection). Overall, sensory peripheral neuropathy was reported in 7 (14%) and 3 patients (7%) during induction and consolidation, respectively, all grade 1 or 2. Five patients (10%) developed deep vein thrombosis, all cases during induction. One patient (2%) developed reversible grade 2 carfilzomib-related cardiac insufficiency.

Although HR cytogenetics are associated with poor survival in MM, very few prospective trials specifically addressed this difficult-to-treat population.^14,15 The definition of HR cytogenetics is rapidly evolving in MM. At the time of study design, HR cytogenetics were defined by the presence of at least 1 abnormality among del(17p), t(4;14), and t(14;16).¹³ More recently, the adverse prognosis value of other chromosome abnormalities, including del(1p32) or gain 1q, has been demonstrated.^1,2,16 In our study, two-third of patients presented with at least 2 HR among del(17p), t(4;14), t(14;16), del(1p32), or gain 1q, and only 8 patients (16%) had t(4;14) or t(14;16) as sole HR chromosome abnormality. EMD is also considered as an independent adverse prognostic marker in MM.^17,18 In this study, 4 patients presented with EMD, including 3 with criteria for primary PCL, in addition to HR cytogenetics. The primary objective of this phase 2 study was to evaluate the feasibility of a tandem transplant program with D-KRd as quadruplet induction (6 cycles) and consolidation (4 cycles) in patients with HR NDMM. In the IFM randomized study 99-04, nearly 25% of patients were not able to be randomized for second transplant.¹⁹ In this study, with extensive quadruplet therapy as induction and consolidation after transplant, we hypothesized a 30% rate of patients not able to complete second transplant. To improve tolerability, the study was designed with delayed second transplant after consolidation. The study met its primary end point with 36 patients (72%) who were able to complete the second transplant. The main cause of treatment discontinuation before second transplant was unsufficient stem cell collection for tandem transplant (n = 8), followed by AE (n = 3), disease progression (n = 2), and consent withdrawal (n = 1). D-KRd as induction and consolidation was tolerable, with no new safety signal observed in comparison with previous report with KRd with or without anti-CD38 plus transplant.^6,20,21 Most common grade 3 to 4 AEs were hematologic, including 32% and 14% grade 3 to 4 neutropenia and thrombocytopenia during induction, respectively. Most common nonhematologic toxicity were infections. Forty-two percent and 35% of patients had infections during induction and consolidation, respectively. Infections were mostly grade 1 or 2, with 4% and 5% grade 3 to 4 infections during induction and consolidation, respectively. Two patients died due to infection (septic shock and JC virus infection). Stem cell collection was unsufficient to perform single (n = 4) or second transplant (n = 4) in 8 patients, representing the most common reason for study discontinuation. Stem cell collection failure rate when performed after cycle 6 was unexpected and led to study amendment to collect stem cells after cycle 3. Previous report showed that stem cell mobilization after quadruplet induction (D-VTd, D-VRd, or D-KRd) did not impair the feasibility of single transplant.^9,22,23 In the GMMG CONCEPT trial (isatuximab KRd induction plus transplant), 6 patients (of 97) did not undergo transplant due to unsuccessful mobilization, and 7 patients received tandem transplant.¹⁴ In the context of KRd + anti-CD38 quadruplet induction with intent of tandem transplant, attention should be paid to stem cell mobilization, which should be preferentially planned before cycle 4. This phase 2 study demonstrated strong efficacy results, with 94% of patients achieving MRD negativity rates (NGS, 10^–6) before maintenance (per protocol analysis). Even if indirect comparison are questionable, these results compare favorably with MRD negativity rates obtained after D-VRd plus transplant (36% MRD negativity by NGS 10^–6 in Griffin) or after KRd plus transplant (62% MRD negativity by flow 10^–5 in FORTE).^6,8 The phase 3 randomized study PERSEUS recently demonstrated a PFS superiority of D-VRd over VRd plus transplant, a new standard of care in TE-NDMM.⁹ In the D-VRd arm (n = 355), the rate of patients achieving MRD negativity (NGS, 10^–6) was 65.1% in the D-VRd arm.⁹ In this study, deep responses translated into high rates of PFS and OS, with a 30-month PFS of 80% and 30-month OS of 91%. Efficacy results from this phase 2 study are in accordance with those obtained with isatuximab KRd plus tandem transplant in the GMMG CONCEPT trial, with a 3-year PFS of 68.9% in patients with HR TE-NDMM.¹⁴ In the OPTIMUM phase 2 trial, patients with HR cytogenetics (≥2 genetic risk markers t(4;14)/t(14;16)/t(14;20), del(1p), gain 1q, and del(17p) and/or SKY92 gene expression risk signature) received D-cyclophosphamide-VRd quintuplet induction followed by transplant, VRd consolidation, and D-lenalidomide maintenance.¹⁵ This intensive approach also resulted in a high PFS rate (30-month PFS, 77%). In the PERSEUS study, including 21.4% patients at HR, defined by the presence of t(4;14), t(14;16), or del(17p), the estimated PFS at 48 months was 84.3 in the D-VRd arm. In patients at HR, early relapse still occurs despite intensive therapy. In our study, 9 patients experienced disease progression, highlighting the need for innovative approaches (ie, CAR-T and T-cell engagers) in this population of patients with HR NDMM. Moreover, a longer follow-up is mandatory to better assess the duration of response in this population. In the context of patients with TE-NDMM, MRD negativity has been shown to partially abrogate the adverse prognosis impact of HR baseline cytognetic.^12,24 In this study, 4 out of 5 patients who progressed during maintenance achieved MRD negativity (NGS, 10^–6) after second transplant. The phase 3 trial MIDAS, exploring MRD-driven consolidation and maintenance (NCT04934475), will provide major information helping to decipher the respective impact of MRD and baseline cytogenetics on the outcome of patients with TE-NDMM.

In conclusion, D-KRd with tandem transplant is feasible in patients with HR TE-NDMM and resulted in high rates of MRD negativity and PFS. This approach (anti-CD38–KRd with tandem transplant) is currently evaluated in patients with positive MRD after induction in the phase 3 randomized trial MIDAS (NCT04934475).

The authors gratefully acknowledge the work performed by individual research teams at all participating study sites; they are also indebted to C. Louni, L. Biron, and M. Gautier for their administrative and material support. The authors also thank the following centers and investigators from the IFM that participated in this study: Nantes, Hôpital Hôtel Dieu (P. Moreau, N. Blin, P. Chevallier, J. Delaunay, V. Dubruille, T. Gastinne, T. Guillaume, S. Le Gouill, B. Mahé, C. Touzeau); Toulouse, IUC Oncopole (A. Perrot, B. Hebraud); Bordeaux Hôpital Haut Lévêque (C. Hulin, S. Dimicoli-Salazar, F. X. Gros, K. Bouabdallah); Lille, Hôpital Claude Huriez (T. Facon, S. Manier, M. O. Petillon); Dijon, Centre Hospitalier du Bocage (J. N. Bastie, I. Lafon, C. Favennec, P. Robert, N. Ahwij, A. Herbin, F. Larosa); Lyon, Centre Hospitalier de Lyon Sud (L. Karlin, F. Bouafia-Sauvy, D. Ghergus, E. Ferrant, C. Golfier, A. Lazareth, A. Maarek); Nancy, CHU Brabois (D. Ranta, P. Feugier, C. Jacquet, H. Jaddi, R. Ferry, S. Schulmann, R. Morizot); La Roche sur Yon, CHD les Oudairies (M. Tiab, B. Villemagne, K. Agbetsivi, N. Morineau, S. Vigouroux); Caen, CHU Côte de Nacre (M. Macro, S. Cheze, J. P. Vilque, A. C. Gac, S. Chantepie, M. Frenkiel); and Poitiers, CHU Poitiers (X. Leleu, C. Tomowiak, S. Guidez, T. Systchenko). Carfilzomib was provided by Amgen. Lenalidomide was provided by Bristol Myers Squibb. Daratumumab was provided by Janssen.

Pharmaceutical companies were not involved in protocol writing, data collection, analysis, interpretation, or manuscript writing.

Contribution: C.T., A.P., H.A.-L., and P.M. designed the study; H.A.-L., and J.C. performed NGS and genetic analysis; C.T., A.P., C.H., S.M., M.M., M.-L.C., L.K., M.E., C.J., M.T., and X.L. recruited patients; A.J., and L.P. analyzed data; and C.T. and P.M. wrote the paper.

Conflict-of-interest disclosure: C.T., A.P., P.M., J.C., C.H., S.M., L.K., and X.L. are on the advisory boards of and received honoraria from Janssen, Bristol Myers Squibb, and Amgen. The remaining authors declare no competing financial interests.

Correspondence: Cyrille Touzeau, Service d’Hématologie Clinique, Centre Hospitalier Universitaire, Place Alexis Ricordeau, 44093 Nantes, France; email: cyrille.touzeau@chu-nantes.fr.