Key Points
Question
Can a measurable residual disease (MRD)-adapted study design employing elotuzumab with weekly carfilzomib, lenalidomide, and dexamethasone (Elo-KRd) without stem cell transplant lead to high rates of stringent complete response (sCR) and/or MRD-negativity in newly diagnosed patients with multiple myeloma?
Findings
In this nonrandomized phase 2 trial including 46 patients with newly diagnosed multiple myeloma, the rate of sCR and/or MRD negativity (10−5) after 8 cycles of Elo-KRd was 26 of 45 (58%), meeting the predefined statistical threshold for efficacy.
Meaning
An MRD-adapted design using Elo-KRd without transplant was associated with deep, durable responses and an expected safety profile; this therapeutic approach may decrease treatment exposure over time while maintaining deep responses.
This measurable residual disease–adapted study examines the association of treatment with elotuzumab with weekly carfilzomib, lenalidomide, and dexamethasone without stem cell transplant with rates of stringent complete response and measurable residual disease–negativity in patients with newly diagnosed multiple myeloma.
Abstract
Importance
Treatment of newly diagnosed multiple myeloma (NDMM) with a quadruplet regimen consisting of a monoclonal antibody, proteasome inhibitor, immunomodulatory imide, and corticosteroid has been associated with improved progression-free survival (PFS) compared with triplet regimens. The optimal quadruplet combination, and whether this obviates the need for frontline autologous stem cell transplant (ASCT), remains unknown. We evaluated elotuzumab and weekly carfilzomib, lenalidomide, and dexamethasone (Elo-KRd) without ASCT in NDMM.
Objective
To investigate the efficacy of Elo-KRd using a measurable residual disease (MRD)-adapted design in NDMM regardless of ASCT eligibility.
Design, Setting, and Participants
This multicenter, single-arm, phase 2 study enrolled patients between July 2017 and February 2021. Median follow-up was 29 months.
Interventions
Twelve to 24 cycles of Elo-KRd; consecutive MRD-negative results at 10−6 by next-generation sequencing (NGS) after cycles 8 (C8) and 12 determined the duration of Elo-KRd. This was followed by Elo-Rd (no carfilzomib) maintenance therapy until disease progression.
Main Outcomes and Measures
The primary end point was the rate of stringent complete response (sCR) and/or MRD-negativity (10−5) after C8 Elo-KRd. Secondary end points included safety, rate of response, MRD status, PFS, and overall survival (OS). As an exploratory analysis, MRD was assessed using liquid chromatography mass spectrometry (MS) on peripheral blood samples.
Results
Forty-six patients were enrolled (median age 62 years, 11 [24%] aged >70 years). Overall, 32 (70%) were White, 6 (13%) were Black, 3 (6%) were more than 1 race, and 5 (11%) were of unknown race. Thirty-three (72%) were men and 13 (28%) were women. High-risk cytogenetic abnormalities were present in 22 (48%) patients. The rate of sCR and/or MRD-negativity after C8 was 26 of 45 (58%), meeting the predefined statistical threshold for efficacy. Responses deepened over time, with the MRD-negativity (10−5) rate increasing to 70% and MS-negativity rate increasing to 65%; concordance between MRD by NGS and MS increased over time. The most common (>10%) grade 3 or 4 adverse events were lung and nonpulmonary infections (13% and 11%, respectively). There was 1 grade 5 myocardial infarction. The estimated 3-year PFS was 72% overall and 92% for patients with MRD-negativity (10−5) at C8.
Conclusions and Relevance
An MRD-adapted design using elotuzumab and weekly KRd without ASCT showed a high rate of sCR and/or MRD-negativity and durable responses. This approach provides support for further evaluation of MRD-guided deescalation of therapy to decrease treatment exposure while sustaining deep responses.
Trial Registration
ClinicalTrials.gov Identifier: NCT02969837
Introduction
Contemporary approaches to the treatment of newly diagnosed multiple myeloma (NDMM) using triplet induction therapy with and without frontline autologous stem cell transplantation (ASCT) have been associated with excellent outcomes, with upfront ASCT improving progression-free survival (PFS) but not overall survival (OS) over delayed ASCT.1,2 Nevertheless, most patients will experience progression and/or death regardless of the receipt of ASCT.
Replacing bortezomib-based induction therapy with carfilzomib, lenalidomide, and dexamethasone (KRd) have produced mixed results; cumulatively, the data suggest that extended KRd with or without transplant is highly effective in patients with NDMM.2,3,4,5,6,7
Quadruplet regimens consisting of a monoclonal antibody (mAb) added to a proteasome inhibitor (PI) and immunomodulatory imide (IMiD) framework have been associated with deeper responses and/or PFS compared with triplet regimens in randomized studies.8,9,10,11,12,13 However, the optimal combination of mAb (elotuzumab [Elo], daratumumab [Dara], or isatuximab), PI (bortezomib or carfilzomib), and IMiD (thalidomide or lenalidomide) remains unknown. More intensive up-front therapy may allow for shorter courses of therapy and the elimination of ASCT from the frontline treatment paradigm. An MRD-adapted treatment approach is rational because it may identify which patients can be administered shorter courses of intensive therapy without compromising efficacy.
In this phase 2 study, we used a next-generation sequencing (NGS) MRD-adapted design to study the safety and efficacy of Elo and weekly KRd (Elo-KRd) as extended therapy in patients with NDMM without immediate intent for ASCT.
Methods
Study Design and Participants
This was a multicenter, open-label, single-arm, phase 2 study. Patients were enrolled from 3 Multiple Myeloma Research Consortium (MMRC) sites in North America. Patients aged 18 years or older with NDMM requiring systemic therapy by International Myeloma Working Group (IMWG) criteria were eligible, regardless of ASCT eligibility. Complete eligibility criteria can be found in the trial protocol in Supplement 1. All patients provided written informed consent. The study was registered at ClinicalTrials.gov (NCT02969837) and was conducted in accordance with the US Food and Drug Administration, International Conference on Harmonization Guidelines for Good Clinical Practice, and the Declaration of Helsinki. The study protocol was approved by the institutional review boards of the participating institutions.
Treatment
Patients received between 12 and 24 cycles of Elo-KRd, with the duration of Elo-KRd treatment based on MRD results by the clonoSEQ NGS assay (Adaptive Biotechnologies), followed by Elo-Rd maintenance until progression (eFigure 1 in Supplement 2). The Elo was administered intravenously (IV), 10 mg/kg, on days 1, 8, 15, and 22 for cycles 1 to 2, days 1 and 15 for cycles 3 and beyond, and day 1 during maintenance (all 28-day cycles). Carfilzomib (K) was administered by IV on days 1, 8, and 15 of each cycle, 20 mg/m2 on cycle 1 day 1, then escalated to 70 mg/m2. Lenalidomide, 25 mg, was given orally on days 1 to 21 and dexamethasone, 40 mg (20 mg if aged ≥ 75 years), orally on a weekly basis.
All ASCT-eligible candidates could undergo stem cell mobilization and collection after cycle 4. Patients with consecutive MRD-negative assessments by NGS at a threshold of 10−6—or MRD-negativity at 10−5 if insufficient DNA input for 10−6 determination—after cycles 8 and 12 proceeded to Elo-Rd maintenance until disease progression. Patients who converted from MRD-positivity (10−6) to MRD-negativity (10−6) between cycles 8 and 12 received 6 additional cycles of Elo-KRd followed by Elo-Rd maintenance. Patients with MRD-positivity (10−6) after cycle 12 received 12 additional cycles of Elo-KRd followed by Elo-Rd maintenance. Participant MRD status by next-generation flow cytometry (NGF) (limit of detection [LoD] 2 × 10−6)14 was allowed a priori to guide decision-making per protocol for patients without a trackable clone by NGS.
Patients without disease progression who pursued ASCT off-protocol before reaching the primary end point were excluded from the primary end point analysis per study design.
Assessments
Landmark evaluations were performed after cycles 4, 8, 12, 18, and 24 and included bone marrow (BM) MRD evaluation by NGS using clonoSEQ (LoD 6.8 × 10−7 with input of 20 µg DNA), NGF when applicable, and peripheral blood evaluation by liquid chromatography mass spectrometry (MS, performed by Bristol Myers Squibb).15
Adverse events (AEs) were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.0), and were recorded from the day of signed consent through 30 days after the last dose of Elo-KRd or initiation of new therapy.
Study End Points
The primary end point of the study was the rate of sCR and/or MRD-negativity by NGS after 8 cycles, with MRD-negativity defined as per IMWG criteria with a minimum sensitivity of 10−5.16 Elo is an IgG κ mAb that cannot be easily distinguished from IgG κ paraprotein by serum protein immunofixation. Given that MRD by NGS may not be evaluable owing to untrackable clonal sequences, the sCR and/or MRD end point was chosen. Participant IMWG response and MRD status were also included separately as secondary end points.
Statistical Analysis
We estimated that 40 patients would be required to test the null hypothesis that the rate of sCR and/or MRD-negativity (10−5) after 8 cycles was 30% or less (as observed with KRd3) against the alternative that it was more than 30% using an exact 1-sided binomial test at the α = .10 significance level. This provided 85% power if the true sCR and/or MRD-negativity rate was 50%. Seventeen or more responders among 40 patients would be sufficient to reject the null hypothesis and conclude efficacy.
Efficacy analyses were performed based on an intent-to-treat (ITT) analysis, including MRD negativity rate per the international consensus on MRD reporting.17 Patients without disease progression who discontinued treatment prior to C8 for ASCT were not included in C8 response evaluations but were included in all other evaluations. Comparisons of categorical data were conducted with χ2 or Fisher exact tests. The Kaplan-Meier method was used for time-to-event end points including PFS and OS using GraphPad statistical software (version 7; GraphPad Software, Inc).
Results
Patient Characteristics
Forty-six patients entered the treatment phase between July 2017 and February 2021. The data cut off was October 31, 2021. The median age was 62 years, with 17 (37%) patients aged 65 years or older and 11 (24%) aged 70 years of older (Table 1). High-risk cytogenetic abnormalities by fluorescent in situ hybridization according to IMWG criteria were present in 22 (48%) patients, including 10 (22%) with del(17p), 16 (35%) with 1q copy number abnormalities (9% 1q amplification), and 8 (17%) with 2 or more high-risk abnormalities.
Table 1. Baseline Characteristics.
| Characteristic | No. (%) |
|---|---|
| Total No. of patients | 46 |
| Age, median (range), y | 62 (43-81) |
| >70 | 11 (24) |
| Sex | |
| Female | 13 (28) |
| Male | 33 (72) |
| Race | |
| Black | 6 (13) |
| More than 1 race | 3 (6) |
| White | 32 (70) |
| Unknown | 5 (11) |
| Ethnicity | |
| Hispanic | 2 (4) |
| Non-Hispanic | 38 (83) |
| Unknown | 6 (13) |
| ECOG performance status | |
| 0 | 21 (46) |
| 1 | 25 (54) |
| ISS stage | |
| I | 11 (24) |
| II | 23 (50) |
| III | 7 (15) |
| Unknown | 5 (11) |
| IgG κ monoclonal protein | 26 (57) |
| Cytogenetic risk by FISH | |
| Unknown | 1 (2) |
| Standard | 23 (50) |
| High | 22 (48) |
| t(4;14) | 3 (7) |
| t(14;16) | 0 (0) |
| t(14;20) | 0 (0) |
| del(17p) | 10 (22) |
| 1q Copy number abnormalities | 16 (35) |
| 1q Amplification | 4 (9) |
| ≥2 High-risk abnormalities | 8 (17) |
| Trackable MRD clone for NGS | 40 (87)a |
| Trackable mass spectrum | 26 (57) |
| No. of cycles of therapy, median (range) | 18 (2-38) |
| Proceeded to ASCT off protocol | 8 (17) |
| ≥VGPR (elective) | 6 (13) |
| PD (postprotocol) | 2 (4) |
Abbreviations: ASCT, autologous stem cell transplant; ECOG, Eastern Cooperative Oncology Group; FISH, fluorescence in situ hybridization; ISS, International Staging System; MRD, measurable residual disease; NGS, next-generation sequencing; PD, progressive disease; VGPR, very good partial response.
Two patients were censored before cycle 8 per protocol.
Of the 46 patients who entered the treatment phase, 45 (98%) were evaluable for response at the primary end point after 8 cycles owing to the prespecified censoring of 1 patient who received ASCT before C8 while in response (Figure 1). The median treatment duration was 18 cycles (range 2 to 38). In total, 6 (13%) patients in response proceeded to ASCT off protocol.
Figure 1. CONSORT Diagram for Enrolled Patients.
ASCT indicates autologous stem cell transplant; MRD, measurable residual disease by next-generation sequencing.
Effectiveness
After 8 cycles of Elo-KRd (n = 45), 26 of 45 (58%; 95% CI, 42% to 73%) patients reached the primary end point of sCR and/or MRD negativity, thereby meeting the predefined statistical threshold for efficacy. At the end of 8 cycles of Elo-KRd, 17 (38%) patients reached sCR, 21 (47%) CR or better, 38 (84%) achieved VGPR or better, and 39 (87%) PR or better. There was 1 (2%) early discontinuation owing to toxic effects after cycle 4 and 1 (2%) early death during cycle 2. Of the 4 patients who had disease progression before C8, all had 17p deletion and/or 1q amplification.
The rates of best response in the ITT population (n = 46) were 26 of 46 (57%) sCR, 32 of 46 (70%) achieved CR or better, 43 of 46 (93%) a VGPR or better, and 44 of 46 (96%) PR or better. A total of 33 of 46 (72%) patients attained sCR and/or MRD negativity. Stratified by IMWG risk status (1 patient had unknown cytogenetic results), the rate of CR or better as best response was 18 of 23 (78%) for standard-risk and 14 of 22 (64%) for patients with high-risk cytogenetics (P = .34). A swimmer plot summarizing all patient responses can be found in Figure 2.
Figure 2. Duration and Depth of Response to Therapy.
Swimmer lane plot showing duration and depth of response to therapy, by number of cycles and follow-up. ASCT indicates autologous stem cell transplant; CR, complete response; MRD, measurable residual disease; MS, mass spectrometry; PD, progressive disease; PR, partial response; sCR, stringent complete response; VGPR, very good partial response.
Measurable Residual Disease Status and Kinetics
A total of 40 (87%) patients had a trackable clone for MRD by NGS (including 1 patient censored before C8). By ITT, which also included any patient with disease progression before C8 as MRD positive (n = 41), 26 (63%) patients had MRD negativity (10−5) and 21 (51%) had MRD-negativity (10−6) after 8 cycles. As best response (n = 43), MRD negativity (10−5) was achieved in 30 (70%) and MRD negativity (10−6) in 26 (60%) patients. Consecutive MRD negativity (10−5) at cycles 8 and 12 was achieved in 19 of 43 (44%) patients. Four of 14 (29%) and 5 of 19 (26%) patients converted from MRD positive after C8 to MRD negative at a later time point at the 10−5 and 10−6 sensitivity thresholds, respectively. Sustained MRD-negativity (2 consecutive MRD-negative [10−5] results ≥1 year apart) occurred in 15 of 30 patients (50%) (Table 2) with 1 progression event occurring at 34 months. For patients with standard-risk cytogenetics, 16 of 23 (70%) had MRD-negativity (10−5) following C8 and 18 of 23 (78%) had MRD-negativity (10−5) as best response; for patients with high-risk cytogenetics, 10 of 22 (45%) and 12 of 22 (55%) had MRD negativity (10−5) following C8 and as best response, respectively.
Table 2. Overall Response and Measurable Residual Disease (MRD)-Negativity Rates.
| Response | No. (%) | |
|---|---|---|
| After 8 cycles | Best response | |
| Evaluable for response | 45 | 46 |
| ≥MR (CBR) | 39 (87) | 45 (98) |
| ≥PR | 39 (87) | 44 (96) |
| ≥VGPR | 38 (84) | 43 (93) |
| ≥CR | 21 (47) | 32 (70) |
| sCR | 17 (38) | 26 (57) |
| PD | 4 (9) | 1 (2) |
| Early discontinuation | 1 (2) | NA |
| Early death | 1 (2) | NA |
| MRD by NGS | ||
| MRD negative (10−5)a | 26/41 (63) | 30/43 (70) |
| MRD negative (10−6)a | 21/41 (51) | 26/43 (60) |
| sCR and/or MRD negative (10−5) by NGSa | 26/45 (58) | 33/46 (72) |
| MRD kinetics | ||
| Sustained MRD negative (10−5) by NGSb | NA | 15/30 (50) |
| Converted after cycle 8c | ||
| MRD positive (10−5) to MRD negative (10−5) | 4/14 (29) | NA |
| MRD positive (10−6) to MRD negative (10−6) | 5/19 (26) | NA |
Abbreviations: CBR, Clinical benefit rate; CR, complete response; MR, minor response; MRD, measurable residual disease; NA, not applicable; NGS, next-generation sequencing; PD, progressive disease; PR, partial response; sCR, stringent CR; VGPR, very good partial response.
Patients with no clone identities are excluded from denominator, except for patients with PD who are considered MRD-positive. Missing MRD result at a time point for those with a clone identified as MRD positive.
MRD <10−5 on 2 or more instances at least 1 year apart. Denominator includes patients with trackable MRD and at least 1 year of MRD follow-up.
Denominator includes patients still on protocol, with trackable MRD, and MRD positivity at the end of cycle 8.
Excluding patients who experienced disease progression or death prior to C8 using the landmark method,18 MRD-negativity (10−5) at C8 was associated with both superior PFS and OS compared with MRD positivity (10−5); among patients with MRD negativity (10−5) at C8, 1 experienced disease progression and all were alive at last follow-up (Figure 3). For patients who achieved MRD negativity (10−5) (n = 30), there was no statistically significant difference in PFS when stratifying by cytogenetic risk.
Figure 3. Progression-Free Survival (PFS) and Overall Survival (OS), by Cytogenetic Risk, and by Measurable Residual Disease (MRD) Status.
A, Overall PFS and OS by intent to treat (ITT) analysis; B, PFS stratified by cytogenetic risk. One patient had unknown cytogenetics. C, PFS; and D, OS stratified by MRD by next-generation sequencing (NGS) status at a sensitivity threshold of 10−5 after cycle 8. Patients who did not have a clone identification at baseline or who discontinued protocol therapy for any reason before cycle 8 were not included.
Mass Spectrometry Status and Kinetics
Mass spectrometry was assessed in the 26 (57%) patients with samples available. The MS-negativity rate was 31% after 8 cycles, with additional patients converting to MS negativity at a later time point resulting in an MS-negativity rate of 65% as best response. Limited sample size precluded determination of the association of MS status with PFS (eFigure 2 in Supplement 2).
There was 54% agreement between 24 paired MS and NGS samples at C8 (Cohen κ, 0.12; 95% CI, –0.21 to 0.45), with 2 cases NGS positive/MS negative and 9 cases NGS negative/MS positive (eFigure 3 in Supplement 2). Concordance increased substantially at later time points; there was 87% agreement between 23 paired samples at cycle 12 (Cohen κ, 0.74; 95% CI, 0.46 to 1.0) with 2 cases NGS positive/MS negative and 1 case NGS negative/MS positive. Beyond cycle 12, only 2 discordant cases remained, and both occurred in patients who have not had evidence of disease progression; 1 patient who had both sustained NGS negative/MS negative experienced disease progression.
Patient Disposition
Of the 46 enrolled patients, all 28 (61%) eligible to transition to Elo-Rd maintenance did so, including 20 (43%) after cycle 12, 2 (4%) after cycle 18, and 6 (13%) after cycle 24. All patients who transitioned to Elo-Rd after cycle 12 had MRD negativity (10−6) at both cycles 8 and 12 except for 1 patient who was MRD negative at 10−5 but MRD positive at 10−6. At the cutoff date, 6 (13%) patients continued Elo-KRd treatment. Twelve (26%) patients discontinued therapy before completing Elo-KRd per protocol; 6 owing to disease progression, 3 owing to elective ASCT without disease progression, 2 owing to adverse events before Elo-Rd maintenance phase, and 1 owing to early death (eTable 1 in Supplement 2).
After transitioning to Elo-Rd maintenance, a total of 9 (20%) patients (median duration of Elo-Rd treatment, 23 cycles) elected to withdraw from the study to pursue single-agent maintenance therapy. This included 6 (13%) patients who ultimately discontinued all antimyeloma therapy and are currently under MRD surveillance. None of these patients were censored for PFS and OS.
Progression-Free Survival and Overall Survival
At a median follow-up of 28.7 months (range, 1.4-50.1 months), there were 9 progression events and 8 deaths. Median PFS and OS have not been reached. The estimated 3-year PFS and OS rates were 72% and 78%, respectively (Figure 3). Patients with MRD negativity (10−5) at C8 had estimated 3-year PFS and OS rates of 92% and 100%, respectively. The 3-year PFS rates were 86% for patients with standard risk and 61% with high-risk disease, and the 3-year OS rates were 91% and 64%, respectively (Figure 3).
Safety and Tolerability
Dose reductions were carried out in 2% of patients for elotuzumab (n = 1), 46% for carfilzomib (n = 21), 37% for lenalidomide (n = 17), and 35% for dexamethasone (n = 16). Three (7%) patients discontinued treatment because of AEs, including 1 grade 5 AE (myocardial infarction) during cycle 2. Hematologic AEs (grades 3-4) included neutropenia (5 [11%]), thrombocytopenia (4 [9%]), lymphopenia (3 [7%]), and anemia (1 [2%]) (eTable 2 in Supplement 2). The most common nonhematologic AEs were fatigue (33 [72%], all grades 1-2), diarrhea (29 [63%], all grades 1-2), nonpulmonary infections (22 [48%], including 5 [11%] grades ≥3), dyspnea (20 [44%], including 1 [2%] grade ≥3), upper respiratory infections (19 [41%], all grades 1-2), and peripheral neuropathy (19 [41%], all grades 1-2) (eTable 2 in Supplement 2). Cardiac events occurred in 12 (26%) patients, including 4 (9%) grade 3 or higher events: 2 episodes of atrial fibrillation, 1 episode of left ventricular systolic dysfunction, and 1 grade 5 myocardial infarction. Hypertension occurred in 11 (24%; including 3 grades ≥3, [7%]) patients and thromboembolic events in 5 (11%; including 2 grades ≥3, [4%]). Six (13%) patients contracted SARS-CoV-2, one of whom had a prolonged hospitalization for severe infection but later resumed therapy.
Discussion
This MRD-adapted phase 2 study assessed the safety and efficacy of extended Elo and weekly KRd in the treatment of NDMM without ASCT. Eight cycles of Elo-KRd were associated with high rates of both sCR and MRD negativity by NGS for a combined sCR and/or MRD-negativity rate of 58% in a population enriched for high-risk cytogenetic abnormalities (48%), thereby meeting the primary end point. These results compare favorably with sCR rates for KRd, which varied from 6% in the phase 3 ENDURANCE trial (8 cycles KRd) to 42% in a nonrandomized phase 2 study (24 cycles), 44% in the KRd arm of the FORTE trial (12 cycles), and to 62% after 8 cycles.2,3,6,19
Half of the patients with MRD negativity (10−5) were able to sustain it for at least 1 year. Importantly, 5 (26%) patients with MRD positivity (10−6) after 8 cycles converted to MRD negativity (10−5) at a later time point to generate rates of MRD negativity of 70% (10−5) and 60% (10−6). This suggests that extended duration of therapy may deepen responses beyond 8 cycles, and that caution in using MRD status at early time points to determine employment and timing of ASCT is advised; longer durations of induction therapy may be needed for future studies.
Our findings suggest MS is useful as a complementary MRD assay, as shown in other studies.20,21 Patient MS status remained positive at early time points owing to immunoglobulin recycling that continues long after eradication of the culprit plasma cell clone in the BM. Concordance between MS in the peripheral blood and NGS in the BM increased over time, suggesting that NGS may be a better tool than MS for early assessment of MRD negativity.
In previous studies, the addition of Dara to VTd or VRd was associated with higher rates of sCR, MRD negativity, and superior PFS.8,9,13,22 In contrast, the addition of Elo to VRd was not associated with improved outcomes.23,24,25 The lack of benefit seen with Elo in combination with bortezomib and/or lenalidomide to respective control arms may reflect a lack of synergy and/or inferiority of the compound with anti-CD38 mAbs.
Studies have shown that Elo-KRd was associated with high rates of deep response comparable to Dara-KRd with or without ASCT.10,11,12 In the MANHATTAN trial, 8 cycles of Dara-KRd was associated with an MRD-negativity rate of 71% (10−5; flow cytometry); 29% received postprotocol ASCT.10 The MRD-adapted MASTER study of Dara-KRd and ASCT was enriched for patients with high-risk disease and protocolized treatment-free MRD surveillance after 2 consecutive MRD-negativity (10−5) results; the rates of MRD negativity were 80% (10−5) and 66% (10−6), and 71% entered MRD surveillance.11 In our cohort of 22 patients with high-risk disease, the MRD-negativity (10−5) rate was 55%; as evidenced by the similar PFS and OS between standard and high-risk disease, we also showed that MRD negativity may mitigate the negative effect of high-risk disease.2,4,26,27
The 3-year OS of 78% is not better than triplets with or without ASCT; however, half of the deaths (4/8) that occurred were from primary refractory disease in ultra high-risk MM, who are underrepesented in randomized studies. This serves as a clarion call to enhance treatment options for these patients.
Nine (20%) patients elected to proceed with lenalidomide maintenance alone after completion of at least 24 cycles on protocol. Of these, 6 (13%) discontinued therapy entirely after achieving sustained MRD negativity (10−6) and underwent MRD surveillance. Our results suggest that extended duration of therapy may work to continually suppress or eliminate myeloma clones, leading to high rates of sustained MRD negativity and subsequent therapy deescalation.
The safety of Elo-KRd was consistent with what is known about these agents individually and in combination. Three patients discontinued treatment owing to intolerance. The rate of grade 3 to 4 dyspnea was 2%. Significant cardiac events were rare; 1 patient died from a suspected (but not confirmed) myocardial infarction attributed to therapy. The rate of pulmonary infections (13% grade 3-4) was similar to what has been observed with mAbs in MM.28 High rates of grade 1 to 2 peripheral neuropathy were seen (41%), which was lower compared with Dara-VRd (63%, 7% grade 3-4).9,22 Lenalidomide may be responsible for a significant portion of the observed neuropathy in this and other cited studies.
Limitations
Limitations of this study include the nonrandomized design, small sample size, and the use of a nonstandard end point. Participants were predominantly male, who have worse prognosis.29 The lack of ASCT in this study could be viewed as a detriment to those with high-risk disease. Notably, of the 4 (9%) patients who had progression before C8, 3 had disease progression before C4 when ASCT might have normally been used. Slightly lower rates of early disease progression (5%) were seen in the MASTER trial, which included early ASCT. This nonrandomized MRD-adapted design cannot answer whether patients with MRD negativity or MRD positivity benefit from extending quadruplet therapy by 6 to 12 cycles compared with deescalation. Although not overburdensome, once-monthly infusions during Elo-Rd maintenance may lead to substantial cost and the role of mAbs as maintenance requires further evaluation.
This MRD-adapted study of Elo and weekly KRd without ASCT provides supporting evidence that MRD may be useful in guiding decision-making in MM. Measurable residual disease negativity allowed for deescalation of carfilzomib, thereby reducing patient’s infusion center visits, potential toxic effects, and cost without compromising efficacy in a population enriched with high-risk disease. A phase 3 randomized trial of Elo-KRd vs KRd with ASCT for newly diagnosed MM is ongoing (NCT03948035); if Elo-KRd proves superior, a randomized comparison of Elo vs anti-CD38 mAb based quadruplets would help determine the optimal combination of therapies in the frontline setting. Separately, a randomized study is needed to validate an MRD-adapted approach for deescalation of treatment based on BM and peripheral blood MRD assays.
Trial Protocol
eFigure 1. Elo-KRd Trial Schema
eFigure 2. Progression free survival (PFS) by mass spectrometry (MS) status
eFigure 3. Dis/Agreement Between Next-Generation Sequencing (NGS) and Mass Spectrometry (MS) Samples
eTable 1. Patient Disposition
eTable 2. Treatment-emergent Adverse Events during Elo-KRd
Data Sharing Statement
References:
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Trial Protocol
eFigure 1. Elo-KRd Trial Schema
eFigure 2. Progression free survival (PFS) by mass spectrometry (MS) status
eFigure 3. Dis/Agreement Between Next-Generation Sequencing (NGS) and Mass Spectrometry (MS) Samples
eTable 1. Patient Disposition
eTable 2. Treatment-emergent Adverse Events during Elo-KRd
Data Sharing Statement