Current and future role of carfilzomib‐based quadruplet combinations as therapy for newly diagnosed multiple myeloma

Abstract

The treatment of newly diagnosed multiple myeloma (NDMM) has advanced rapidly in recent years, with the standard of care (SOC) now including not only triplet combinations of proteasome inhibitors (PIs), immunomodulatory agents, and steroids but also quadruplet combinations that add the anti‐CD38 monoclonal antibodies isatuximab (Isa) or daratumumab (D) to a triplet backbone. In addition to the widely used bortezomib–lenalidomide–dexamethasone (VRd) combination, an alternative triplet option that can be considered is the combination of the second‐generation PI carfilzomib (K) with lenalidomide–dexamethasone (KRd). In patients with transplant‐eligible NDMM, US treatment guidelines have included the KRd triplet as a recommended regimen and the quadruplet combinations of either Isa‐KRd or D‐KRd as additional options. However, currently, KRd does not have regulatory approval for use in the NDMM population. This review describes the current evidence for using KRd as a backbone of therapy in frontline treatment regimens for patients with NDMM. In addition to multiple studies that have examined the KRd triplet in this population, several clinical trials have been investigating anti‐CD38‐KRd quadruplets. The data reported from these various trials are revealing deep and durable responses with Isa‐KRd and D‐KRd, including minimal residual disease negativity. Importantly, these benefits have also been demonstrated in high‐risk NDMM populations. KRd‐based combinations may represent a suitable alternative to VRd for some patients. This article discusses measures that may help to establish KRd‐based quadruplets as an additional SOC in this setting, including proper patient selection, steps to mitigate safety concerns, and the establishment of optimal dosing schedules.

INTRODUCTION

Multiple myeloma (MM) accounts for about 2% of all cancers and 10% of hematologic malignancies. ¹ In 2025, over 36,000 individuals will be diagnosed with MM in the United States. As patients with MM live longer with the advent and incorporation of novel therapies, it is important to use the most effective anti‐myeloma agents as early as possible to extend survival and improve quality of life. ² , ³ , ⁴ This is particularly true for newly diagnosed MM (NDMM), where the key pillars of treatment are steroids, proteasome inhibitors (PIs), immunomodulatory agents (IMiDs), and monoclonal antibodies (mAbs).

Treatment with the triplet combination of the PI bortezomib (V), an IMiD thalidomide (T) or lenalidomide (R), and dexamethasone (d) has been a standard of care (SOC) for frontline treatment of patients with transplant‐eligible (Te) NDMM. The combination of the anti‐CD38 mAb daratumumab (D) with bortezomib–thalidomide–dexamethasone was among the first quadruplet regimens approved for the treatment of Te NDMM. ⁵ , ⁶ With lenalidomide having largely replaced thalidomide to become the key IMiD in frontline treatment of NDMM, ⁷ , ⁸ , ⁹ , ¹⁰ , ¹¹ the SOC now includes bortezomib–lenalidomide–dexamethasone (VRd) as a triplet or as a backbone of therapy in quadruplet combinations that incorporate the anti‐CD38 mAbs isatuximab (Isa) or daratumumab.

Phase 3 studies of VRd with or without isatuximab ¹² or daratumumab ¹³ have demonstrated additional benefit to adding the anti‐CD38 mAb in Te NDMM. Quadruplet induction therapy is now a key recommendation across guidelines for Te NDMM, ¹⁴ , ¹⁵ and quadruplet use in NDMM treatment continues to rise. ¹⁶ In transplant‐ineligible (Ti) NDMM, triplet regimens have been the SOC. However, recent Phase 3 studies have also shown the benefit of quadruplets using VRd as a backbone of therapy, ¹⁷ , ¹⁸ , ¹⁹ and Isa‐VRd recently became the first such quadruplet to be approved for patients with Ti NDMM. ²⁰ , ²¹ , ²²

Alternative options that can be considered incorporate carfilzomib (K), a second‐generation PI, in upfront therapy for Te NDMM. The triplet KRd, with or without autologous stem cell transplant (ASCT), has been widely explored in clinical trials for frontline treatment. KRd‐based combinations may represent a suitable alternative to VRd for some patients, with several studies showing efficacy for the KRd triplet, ²³ , ²⁴ , ²⁵ , ²⁶ , ²⁷ , ²⁸ , ²⁹ , ³⁰ and more recently for quadruplets incorporating KRd as a backbone of therapy added to isatuximab (Isa‐KRd) or daratumumab (D‐KRd). ³¹ , ³² , ³³ , ³⁴ , ³⁵ , ³⁶ , ³⁷ , ³⁸ , ³⁹ , ⁴⁰ Although currently KRd does not have regulatory approval for patients with NDMM, the National Comprehensive Cancer Network® (NCCN®) guidelines in the United States have included KRd as a recommended regimen and either Isa‐KRd or D‐KRd as additional treatment options in Te NDMM. ¹⁵

This review will present the current evidence for using KRd and KRd‐based combinations as frontline treatment regimens for patients with NDMM. The article begins with a history of trials assessing the KRd triplet, before presenting all clinical trial evidence of quadruplets using anti‐CD38 mAbs and KRd in NDMM, and finally discussing factors that may influence the choice of VRd versus KRd backbones.

EFFICACY AND SAFETY OF THE KRD TRIPLET IN NDMM

Efficacy in single‐arm studies of KRd in patients with Te and Ti NDMM

Initial investigations explored the efficacy of KRd in both Te and Ti NDMM (Figure 1). These studies included a Phase 1/2 trial by the Multiple Myeloma Research Consortium (MMRC; n = 53) ²⁵ and a Phase 2 trial by the Intramural National Cancer Institute at the National Institutes of Health (NCI/NIH, Bethesda, MD; n = 45). ²⁷ , ²⁸ Phase 2 of the MMRC trial examined extended KRd for up to 24 cycles. The primary endpoint of near‐complete response or better (≥nCR) after four cycles was achieved in 38% of patients in the intention‐to‐treat (ITT) population. After a median follow‐up of 13 months, median progression‐free survival (mPFS) was not reached. ²⁵ In the NCI/NIH trial, patients received eight KRd cycles with optional stem cell collection. Specifically, after four KRd cycles, patients could have stem cells harvested for delayed transplant, and thereafter, patients received four additional KRd cycles, followed by 2 years of lenalidomide maintenance. ²⁸ Long‐term follow‐up (median 5.2 years) revealed mPFS of 67.3 months. ²⁷ After publication of the NCI/NIH trial in 2015, the NCCN® guidelines added KRd based on Category 2A evidence, making KRd available to NDMM patients in the United States. ¹⁵

Figure 1.

Timeline of key trial reports of carfilzomib, lenalidomide, and dexamethasone (KRd)‐based triplet and quadruplet regimens in patients with newly diagnosed multiple myeloma (NDMM). Frontline treatment with the KRd triplet has been studied in patients with NDMM in single‐arm ²⁵ , ²⁶ , ²⁷ , ²⁸ , ²⁹ and randomized ²⁴ , ⁴¹ trials. KRd is also being investigated as maintenance treatment in the Phase 3 ATLAS trial. ²³ The first readout for the Phase 3 COBRA trial of KRd versus bortezomib, lenalidomide, dexamethasone (VRd) is anticipated in mid‐2025. ⁴² Quadruplet regimens that add an anti‐CD38 monoclonal antibody to KRd as a backbone of therapy continue to be studied in patients with NDMM in several trials, ³¹ , ³² , ³³ , ³⁴ , ³⁵ , ³⁶ , ³⁷ , ³⁸ , ³⁹ , ⁴⁰ including the Phase 3 IsKia/EMN24 ³⁴ and MIDAS ³⁹ studies of isatuximab (Isa)‐KRd and the GEM2017FIT study of daratumumab (D)‐KRd. ³⁷ Abbreviations: C, cyclophosphamide; IFM, Intergroupe Francophone du Myélome; LCI, Levine Cancer Institute; MMRC, Multiple Myeloma Research Consortium; NCI/NIH, Intramural National Cancer Institute at the National Institutes of Health. ^aFirst randomization (induction and consolidation). ^bSecond randomization (maintenance). ^cMaintenance comparison only.

Efficacy in single‐arm studies of KRd in patients with Te NDMM only

Two other single‐arm, Phase 2 trials of KRd, by the MMRC (n = 76) ²⁶ and the Intergroupe Francophone du Myélome (IFM; n = 48), ²⁹ enrolled only patients with Te NDMM undergoing ASCT. In both trials, induction and consolidation each comprised four KRd cycles. ²⁶ , ²⁹ mPFS was not reached in the MMRC trial (median follow‐up: 56 months) ²⁶ and was 56.4 months in the IFM‐KRd study (median follow‐up: 60.5 months). ²⁹ In both trials, ≥60% of evaluable patients achieved the primary endpoint of stringent CR (sCR) after eight KRd induction/consolidation cycles. ²⁶ , ²⁹ In the MMRC study, in which patients also received 10 KRd maintenance cycles, the rate of at least very good partial response (≥VGPR) as overall best response was 91%, with 5‐year PFS of 72% (85% if minimal [measurable] residual disease negative [MRD−], measured by next‐generation sequencing [NGS] at a sensitivity threshold of 10^–5). ²⁶

Efficacy in studies comparing KRd with VRd in patients with NDMM

Based in part on the encouraging findings from the early trials, KRd was tested head‐to‐head in the Phase 3 randomized, multicenter ENDURANCE study against VRd in US patients who had either Ti NDMM or Te NDMM without intention for immediate ASCT (n = 1087). ENDURANCE excluded patients with high‐risk cytogenetics. Although the proportion of treated patients with ≥VGPR was significantly higher for KRd compared with VRd after 36 weeks of induction, treatment arms did not differ significantly for the primary endpoint of mPFS in the ITT population or for other key efficacy endpoints. ⁴¹ However, some design aspects of ENDURANCE may not have been optimal, including a relatively short follow‐up (median: 9 months) and an altered statistical design in which PFS only became a primary endpoint after a mid‐study increase in the number of patients targeted for enrollment. In addition, censoring bias may have occurred after some patients changed therapy before disease progression but were considered as remaining randomized to their originally assigned treatment. ⁴³ In a subanalysis, when therapy change was counted as an event, event‐free survival was significantly better for KRd compared with VRd. ⁴³

Outcomes from the Phase 3 COBRA trial (NCT03729804) will further help determine the benefit of KRd compared with VRd in the frontline setting. In COBRA, patients with Ti or transplant‐deferred Te NDMM (n = 250) are randomized to either 24 KRd cycles or the historical standard of 8 VRd cycles followed by 16 lenalidomide maintenance cycles. ⁴² The readout of MRD rate at 12 months, the first co‐primary endpoint, is anticipated in July 2025.

The benefit of KRd compared with VRd has been assessed in recent single‐center, retrospective, real‐world studies. A study conducted between 2015 and 2022 at the Memorial Sloan Kettering Cancer Center (MSKCC; NY, USA) compared KRd with VRd for patients with NDMM (n = 389) who received either early or deferred ASCT. Although mPFS was not reached in either arm, 5‐year PFS was significantly higher for KRd (67%) compared with VRd (56%; P = 0.027). Post‐induction CR or better (≥CR) and ≥VGPR rates were also significantly improved with KRd compared with VRd. ³⁰ However, in a study of patients with high‐risk Te NDMM (n = 121 [high risk defined as del(17p), t(4;14), t(14;16), or 1q21 gain/amplification]) who received triplet induction before ASCT between 2016 and 2018 at the MD Anderson Cancer Center (TX, USA), the mPFS difference between the KRd (38.2 months) and VRd (45.9 months) arms was not statistically significant (P = 0.25). ⁴⁴

Efficacy in randomized clinical trials of KRd in patients with Te NDMM

The results from the somewhat controversial ENDURANCE trial have contributed to KRd not being recommended as a first‐line treatment option in NDMM patients. ¹⁴ , ¹⁵ Nonetheless, the use of KRd in the treatment of NDMM has been supported by the findings of the abovementioned single‐arm studies, as well as randomized trials. Overall, deep and durable responses were reported with KRd in these studies, ²³ , ²⁴ , ²⁵ , ²⁶ , ²⁷ , ²⁸ , ²⁹ , ³⁰ and in some cases, mPFS was not reached with relatively long follow‐up (Table 1). ²⁴ , ²⁵ , ²⁶ , ³⁰

Table 1.

Data from studies of triplet therapy using KRd for patients with and without transplant.

Study name and treatment arm(s)	Study population (n)	Efficacy	Safetya
Clinical trials with KRd as induction/consolidation
Phase 1/2 MMRC (NCT01029054) 25 KRd with the option of transplantation	Te and Ti NDMM (n = 53)	mFU: 13 mo
		Response rates after ≥8 KRd cycles (n = 36): • sCR: 61% • ≥nCR: 78% • ≥VGPR: 92% MRD– (CR or suspected CR; MFCb; n = 22): 91% mPFS (n = 53): NR	Gr 3–4 TEAEs Hypophosphatemia: 25% Hyperglycemia: 23% Anemia: 21% Thrombocytopenia: 17% Neutropenia: 17% Deep‐vein thrombosis/pulmonary embolism: 9% Rash: 8% Elevated liver function test: 8%
Phase 2 NCI/NIH (NCT01402284) 27 , 28 KRd with R maintenance	Te or Ti NDMM (n = 45)	mFU 5.2 y: mPFS (ITT): 67.3 mo mFU 17.3  mo: ≥VGPR (ITT): 89% ≥CR (ITT): 56% MRD– (MFC; 10–5) • ≥nCR (n = 28): 100% • ≤VGPR (n = 15): 33% MRD– (NGSb) • ≥nCR (n = 21): 67% • ≤VGPR (n = 12): 0%	Gr 3–4 AEs c (mFU 17.3 mo) PN[PE]: no events Lymphopenia: Gr 3, 67%; Gr 4, 9% Thrombocytopenia: Gr 3, 20%; Gr 4, 4% Leukopenia: Gr 3, 16%; Gr 4, 4% Anemia: Gr 3, 27% Neutropenia: Gr 3, 24%; Gr 4, 9% Electrolytes/metabolism/nutritional: Gr 3, 36% Hepatobiliary: Gr 3, 11% Constitutional: Gr 3, 11% Skin: Gr 3, 11% Pulmonary: Gr3, 9%; Gr 4, 7% Vascular: Gr 3, 11%; Gr 4, 2% Infection: Gr 3, 13% Cardiac: Gr 3, 11%
Phase 2 (NCT01816971) 26 MMRC KRd induction (4 cycles), ASCT, KRd consolidation (4 cycles), KRd maintenance (10 cycles)	Te NDMM (n = 76)	mFU: 56 mo
		Response rates after 8 KRd cycles (n = 72): • sCR[PE]: 60% • ≥CR: 65% • ≥VGPR: 90% MRD– after 8 KRd cycles (NGS; mITT; 10–5): 52% mPFS: NR	Gr 3–4 TEAEs during KRd Neutropenia: 34% Lymphopenia: 32% Thrombocytopenia: 14% Anemia: 12% Infection: 22% Fatigue: 5% Diarrhea: 9% Hyperglycemia: 8% Rash: 5% Hypophosphatemia: 14% Hypertension: 5% Thromboembolic events: 7% PN: no Gr 3–4 cases
Phase 2 IFM KRd (NCT02405364) 29 KRd as induction/consolidation + ASCT	Te NDMM (n = 48 [at screening])	mFU: 60.5 mo
		sCR post‐consolidation (n = 42)[PE]: 62% ≥CR post‐consolidation (n = 42): 64% MRD– post‐consolidation (n = 42): • MFC (2 × 10–5): 93% • NGS (10–6): 63% mPFS: 56.4 mo	Gr 3–4 TEAEs (induction and consolidation) Lymphopenia: 65% Neutropenia: 35% Thrombocytopenia: 20% Infections: 22% PN: no Gr 3–4 cases
Phase 3 ENDURANCE (NCT01863550) 41 KRd versus VRd induction R (2 years or to PD)	NDMMd (n = 1087)	mFU: 9 mo
		KRd versus VRd mPFS (ITT)[PE]: 34.6 mo versus 34.4 mo (HR: 1.04; 95% CI, 0.83–1.31; P = 0.74) ≥VGPR (evaluable population): 74% versus 65% (P = 0.0015) ≥CR (evaluable population): 18% versus 15% (P = 0.13) MRD− (10–5; flow cytometry; evaluable population): 10% versus 7% (P = 0.079)	KRd versus VRd Gr ≥ 3 non‐hematologic TEAEs e Diarrhea: 4% versus 6% Fatigue: 6% versus 8% Lung infection: 8% versus 4% Hyperglycemia: 8% versus 6% PN: 1% versus 8% Dyspnea: 9% versus 3% Hypertension: 12% versus 7% Thromboembolic event: 6% versus 2% Gr ≥ 3 non‐hematologic TRAEs e Fatigue: 6% versus 6% Lung infection: 5% versus 2% Hyperglycemia: 6% versus 4% PN: <1% versus 8% Dyspnea: 7% versus 2%
Phase 2 FORTE (NCT02203643) 24 KRd + ASCT versus KCd + ASCT (induction‐consolidation)f	Te NDMM (n = 474)	mFU: 50.9 mo from first randomization
		KRd + ASCT versus KCd + ASCT: mPFS (ITT): NR versus 53 mo (HR: 0.54; 95% CI, 0.38–0.78; P = 0.0008) ≥VGPR post‐induction (ITT)[PE]: 70% versus 53% (OR: 2.14; 95% CI, 1.44–3.19; P = 0.0002) ≥VGPR pre‐maintenance (ITT): 89% versus 76% ≥CR pre‐maintenance (ITT): 54% versus 42% MRD– pre‐maintenance (10–5; MFC; ITT) 62% versus 43% (OR: 2.14; 95% CI, 1.36–3.35; P = 0.001)	KRd + ASCT versus KCd + ASCT (pre‐maintenance), Gr 3–4 TEAEs Neutropenia: 13% versus 11% Thrombocytopenia: 9% versus 4% Rash: 6% versus 1% Aminotransferase increase: 6% versus 0%
KR or R maintenance to PD	(n = 356)	mFU: 37.3 mo from second randomization
		KRd versus R: mPFS (ITT): NR in either arm ≥VGPR post‐maintenance (ITT): 99% versus 96% ≥CR post‐maintenance (ITT): 78% versus 75% MRD– post‐maintenance (10–5; MFC; ITT) 81% versus 79%	KRd versus R, Gr 3–4 TEAEs Neutropenia: 20% versus 23% Infections: 5% versus 7% Vascular events: 7% versus 1% Gastroenterological events: 5% versus 2%
Clinical trial with KRd as maintenance only
Phase 3 ATLAS (NCT02659293) 23 Any induction + ASCT + maintenance until PD with KRd (up to 36 cycles with MRD adaptation, then R alone) versus R alone	Te NDMM (n = 180)	mFU: 33.8 mo
		KRd versus R mPFS (ITT)[PE]: 59.1 mo versus 41.4 mo (HR: 0.51; 95% CI, 0.31–0.86; P = 0.012) ≥CR (ITT): 76% versus 71% MRD− after 6 cycles (NGS; n = 129): • 10–5: 52% versus 35% • 10–6: 39% versus 24%	KRd versus R, Gr 3–4 AEs c Neutropenia: 48% versus 60% Thrombocytopenia: 13% versus 7% Lymphopenia: 5% versus 2% Febrile neutropenia: 4% versus 6% Upper respiratory tract infection: 5% versus 3% Lower respiratory tract infection: 8% versus 1% Aminotransferase increase: 5% versus 0%
Retrospective studies
RWE 30 Single‐center study, United Statesg	NDMMh (n = 389 [KRd, n = 191; VRd, n = 198])	mFU: 58.8 mo
		KRd versus VRd mPFS[PE]: NR in either arm Post‐induction response rates: • ≥CR: 41% versus 25% (P < 0.01) • ≥VGPR: 86% versus 63% (P < 0.01) MRD− (flow cytometry; during or post‐induction; 10–5): 40% (n = 174) and 27% (n = 113) (P = 0.022)	KRd versus VRd, AEs c Pulmonary and cardiovascular AEs (Gr ≥ 2): 8% versus 5% Hypertension (Gr ≥ 2): 11% versus 4% Neuropathy (Gr 3): 0% versus 6%
RWE 44 Single‐center study, United Statesi	High‐riskj Te NDMM (n = 121 [KRd, n = 63; VRd, n = 58])	mFU: 34.4 mo
		KRd versus VRd mPFS[PE]: 38.2 mo versus 45.9 mo (P = 0.25) Post‐induction response rates: • CR: 24% versus 19% • VGPR: 49% versus 47% MRD− (NGF; post‐induction; 10–5): 18% (n = 60) and 13% (n = 56) (P = 0.022)	KRd versus VRd, TRAEs during induction PN (Gr 3): 0% versus 3%

Abbreviations: AE, adverse event; ASCT, autologous stem cell transplant; C, cyclophosphamide; CR, complete response; d, dexamethasone; FU, follow‐up; Gr, grade; HR, hazard ratio; ITT, intention‐to‐treat; K, carfilzomib; m, median; MFC, multiparameter flow cytometry; mITT, modified ITT; MMRC, Multiple Myeloma Research Consortium; mo, month; MRD–, minimal residual disease negativity; NCI/NIH, Intramural National Cancer Institute at the National Institutes of Health; nCR, near CR; NDMM, newly diagnosed multiple myeloma; NGF, next‐generation flow cytometry; NGS, next‐generation sequencing; NR, not reached; OR, odds ratio; PD, progressive disease; PE, primary endpoint; PFS, progression‐free survival; PN, peripheral neuropathy; R, lenalidomide; RWE, real‐world evidence; sCR, stringent CR; Te, transplant eligible; TEAE, treatment‐emergent AE; Ti, transplant ineligible; TRAE, treatment‐related AE; V, bortezomib; VGPR, very good partial response; y, year.

^a Incidence of Gr ≥ 3 PN and incidence of other Gr ≥ 3 events ≥5% in any arm.

^b Publication does not specify the MRD sensitivity threshold.

^c Publication does not specify whether the AEs were TEAEs or TRAEs.

^d Ti or Te without intention for immediate ASCT.

^e Grade 3 hematologic AEs were not reported.

^f A third treatment group received KRd without ASCT.

^g Memorial Sloan Kettering Cancer Center, NY.

^h Early or deferred ASCT.

ⁱ MD Anderson Cancer Center, TX.

^j High risk defined as del(17p), t(4;14), t(14;16), or 1q21 gain/amplification.

The randomized, Phase 2 FORTE trial (n = 474) examined KRd induction and consolidation in patients with Te NDMM. Patients who underwent ASCT received induction (4 cycles) and consolidation (4 cycles) with one of two carfilzomib‐based therapies, KRd or carfilzomib‐cyclophosphamide‐dexamethasone (KCd). Among patients who received ASCT, after a median follow‐up of 50.9 months, mPFS was not reached with KRd and was 53 months with KCd. The primary endpoint of ≥VGPR post‐induction in ITT patients was attained by 70% of KRd‐ compared with 53% of KCd‐treated patients (odds ratio [OR]: 2.14; P = 0.0002). When the rate of 1‐year sustained MRD− (multiparameter flow cytometry; 10⁻⁵ cutoff) was assessed in ITT patients, significant benefit was found in patients who received KRd plus ASCT (47%) compared with those who received KRd (12 cycles) without ASCT (35%) (OR: 1.69; P = 0.024). Efficacy benefits with KRd induction/consolidation extended to high‐risk patients. ²⁴

Data for KR as maintenance therapy have also emerged from the FORTE study, ²⁴ as well as an interim analysis of KRd maintenance in the Phase 3 ATLAS trial. ²³ After a second randomization post‐consolidation in FORTE (n = 306), KR demonstrated superior efficacy compared with lenalidomide alone (3‐year PFS [ITT]: 75% with KR vs. 65% with R; hazard ratio [HR]: 0.64; P = 0.023). This maintenance PFS benefit for KR compared with lenalidomide was consistent regardless of cytogenetic risk, with similar HR values among standard‐risk patients (HR: 0.56) and high‐risk patients (HR: 0.67; interaction P‐value: 0.70 [high risk defined as del(17p), t(4;14), t(14;16)]). ²⁴ Based partly on the FORTE maintenance data, an unplanned interim analysis was conducted for ATLAS, in which up to 36 KRd cycles are being compared with lenalidomide as maintenance in patients with Te NDMM who underwent ASCT (n = 180). Patients with MRD− after 6 KRd cycles de‐escalated to lenalidomide for the remainder of protocol‐directed maintenance. The interim ITT population analysis showed significant improvement in the primary endpoint of mPFS from starting maintenance with KRd (59.1 months) compared with lenalidomide (41.4 months; HR: 0.51; P = 0.012). ²³

Safety of KRd

Overall, in studies of the KRd triplet, the most common Grade ≥3 AEs, reported in ≥20% of patients, were hematologic events ²³ , ²⁴ , ²⁵ , ²⁶ , ²⁷ , ²⁸ , ²⁹ , ³⁰ and infections (Table 1). ²⁶ , ²⁹ KRd has been associated with higher incidences of cardiovascular events than VRd. When a composite of treatment‐related cardiac, pulmonary, and renal AEs was assessed in ENDURANCE, the incidence of Grade 3–5 events was significantly higher for KRd compared with VRd (16% vs. 5%; P < 0.0001). ⁴¹ Similarly, the MSKCC real‐world comparison of these triplet regimens reported significantly higher incidence of all‐grade pulmonary and cardiovascular AEs for KRd compared with VRd (21% vs. 9%; P < 0.01), and a numerically higher incidence of Grade ≥2 pulmonary and cardiovascular AEs (8% vs. 5%; P = 0.15). In that study, discontinuation rates due to AEs were lower with KRd than VRd. ³⁰ Of note, the previous practice of administering intravenous (IV) hydration with each carfilzomib dose has contributed to increased rates of congestive heart failure. Use of concurrent IV fluids is no longer advised except judiciously when high tumor lysis risk exists. Further measures that can help to minimize cardiovascular and pulmonary toxicity include baseline and repeat echocardiograms, low thresholds for checking B‐type natriuretic peptide, blood pressure control, and proper patient selection, with age over 75 years being a cardiovascular risk factor.

Peripheral neuropathy (PN) incidences are higher in patients treated with bortezomib‐containing regimens than with carfilzomib‐containing regimens. ⁴⁵ The NCI/NIH study of KRd evaluated Grade ≥3 neuropathy incidence as the primary endpoint. After a median follow‐up of 17.3 months, no Grade 3–4 PN events were reported. ²⁸ In the Phase 3 ENDURANCE study, incidences of PN as a Grade ≥3 treatment‐emergent adverse event (TEAE) were <1% for KRd and 8% for VRd. ⁴¹

Some populations might be more suited for either VRd or KRd because of their safety profiles. Modified dosing schedules for both carfilzomib and bortezomib are being adopted to improve tolerability and treatment burden (Figure 2).

Figure 2.

Choice of proteasome inhibitors (PIs) and dosing schedule can be tailored to fit the patient's needs and comorbidities. The main safety concerns for carfilzomib and bortezomib are cardiac toxicities and peripheral neuropathy, respectively. ⁴¹ , ⁴⁵ Modified dosing schedules for both carfilzomib and bortezomib are being adopted to improve tolerability and treatment burden. Abbreviations: BIW, biweekly (twice‐a‐week); QW, weekly.

Carfilzomib dosing in studies of KRd

The original Phase1/2 MMRC trial of KRd in NDMM established a schedule of twice‐a‐week carfilzomib dosing in the first 3 weeks of each 4‐week induction cycle; carfilzomib doses used in that study were 20, 27, or 36 mg/m². ²⁵ Twice‐a‐week administration of carfilzomib 36 mg/m² was subsequently adopted for induction in Phase 2 trials of KRd. ²⁴ , ²⁶ , ²⁸ , ²⁹ For the KRd triplet studies that included KRd consolidation steps, carfilzomib dosing during consolidation was the same as for induction. ²⁴ , ²⁶ , ²⁹

EFFICACY AND SAFETY OF ANTI‐CD38 BASED QUADRUPLETS WITH A KRD BACKBONE IN NDMM

Based on the established efficacy and safety of the KRd triplet, more recent NDMM trials have investigated the incorporation of KRd as a backbone of therapy in a quadruplet regimen together with an anti‐CD38 mAb. ³¹ , ³² , ³³ , ³⁴ , ³⁵ , ³⁶ , ³⁷ , ³⁸ , ³⁹ , ⁴⁰ There is increasing focus on depth of response, and in particular MRD−, which comprises the primary endpoint for many of these trials. Prognostic value of MRD– surpasses that of CR achievement, ⁴⁶ with the most favorable outcomes being associated with sustained MRD–. ⁴⁷ Furthermore, some of these trials feature a response‐adapted design, in which MRD status informs decisions at different treatment stages. ³¹ , ³² , ³⁷ , ³⁸ , ³⁹

Select trials of anti‐CD38 based quadruplets with a KRd backbone in patients with NDMM are summarized in Table 2. Two of these studies focused exclusively on patients with high‐risk disease. ³⁶ , ⁴⁰ Most of the trials have enrolled only patients with Te NDMM, including the Phase 3 IsKia/EMN24 and MIDAS trials of Isa‐KRd. ³⁴ , ³⁹ Two trials enrolled patients with NDMM regardless of transplant eligibility, ³³ , ³⁵ and another two enrolled predominantly patients with Te NDMM and a minority with Ti NDMM. ³¹ , ⁵⁰ The Phase 3 GEM2017FIT trial of D‐KRd enrolled only patients with Ti NDMM. ³⁷

Table 2.

Data from clinical trials of quadruplet therapy using a KRd backbone for NDMM.

Study name and treatment arm(s)	Study population	Efficacy	Safety (incidence of Gr ≥ 3 events ≥ 5% in any arm)
Isatuximab
Phase 3 IsKia/EMN24 (NCT04483739) 34 Isa‐KRd versus KRd	Te NDMM (n = 302)	mFU: 24 mo
		Isa‐KRd versus KRd MRD– post‐consolidation (NGS; ITT): • 10–5[PE]: 77% versus 67% (OR: 1.67; P = 0.049) • 10–6: 67% versus 48% (OR: 2.29; P < 0.001) MRD– post‐induction (NGS; ITT): • 10–5: 45% versus 26% (OR: 2.34; P < 0.001) • 10–6: 27% versus 14% (OR: 2.36; P = 0.004) ≥VGPR post‐consolidation: 94% in both arms ≥CR post‐consolidation: 74% versus 72% sCR post‐consolidation: 64% versus 67% mPFS: NR in either arm	Isa‐KRd versus KRd, Gr 3–4 TRAEs Neutropenia: 36% versus 22% Thrombocytopenia: 15% versus 17% Infections (excluding COVID‐19): 15% versus 11% Thromboembolism: 3% versus 6%
Phase 3 IFM 2020‐02 MIDAS (NCT04934475) 39 Isa‐KRd	Te NDMM (n = 791)	MRD– post‐induction (6 cycles; primarily NGS; ITT): • 10–5: 63% • 10–6: 47% ≥VGPR post‐induction (ITT): 92% nCR/CR post‐induction (ITT): 64%–66%	Gr 3–4 AEs a (post‐induction) Neutropenia: 25% Anemia: 7% Thrombocytopenia: 5% Infections: 7% Hepatobiliary disorders: 6%
Phase 2 GMMG‐CONCEPT (NCT03104842) 36 , 48 Isa‐KRd	High‐riskb NDMM (ITT: 99 Te patients aged ≤70 y; 26 Ti patients or aged over >70 y)	mFU (Te) 44 mo 36 : MRD− (10–5; NGF; n = 93) post‐consolidation[PE]: 68% ≥VGPR post‐consolidation (ITT): 91% ≥CR post‐consolidation (ITT): 73% mFU (Te) 54 mo 48 : mPFS: NR	Gr ≥ 3 AEs a (mFU [Te] 44 mo) 36 : Neutropenia: 39% Leukopenia: 25% Thrombocytopenia: 27% Anemia: 14% Infections (total): 28% Gastrointestinal: 9% Hypertension: 10% Renal: 6%
Phase 2 SKylaRk (NCT04430894) 38 Isa‐KRd	Te NDMM (n = 50)	mFU: 26 mo
		≥CR (ITT) • After 4 cycles[PE]: 32% • Post‐induction or consolidation: 58% ≥VGPR (ITT) • After 4 cycles: 78% • Post‐induction or consolidation: 86% MRD– after 4 cycles (NGS; n = 28 with ≥VGPR) • 10–5: 43% • 10–6: 18% MRD– after 8 cycles (NGS; n = 36) • 10–5: 72% • 10–6: 19% mPFS: NR	Gr 3–4 TRAEs Neutropenia: 26% Elevated ALT: 12% Fatigue: 6% Thrombocytopenia: 6%
Daratumumab
Phase 3 GEM2017FIT (NCT03742297) 37 D‐KRd versus KRd versus VMP‐Rd	Ti NDMM (elderly fit) (D‐KRd, n = 153; KRd, n = 154)	mFU: 33 mo
		D‐KRd versus KRd MRD− (NGF; 10–5) at end of induction (18 cycles; ITT): 61% versus 54% MRD− (NGF; 10–5) at end of induction (18 cycles; evaluable population) • All patients[PE]: 84% versus 75% • GAH < 20: 84% versus 73% • GAH ≥ 20: 83% versus 77% ≥CR at end of induction (18 cycles; ITT): 61% versus 58% ≥VGPR at end of induction (18 cycles; ITT): 86% versus 75% mPFS: NR for D‐KRd	D‐KRd versus KRd, Gr 3–4 AEs a Neutropenia: 47% versus 24% Anemia: 10% versus 5% Thrombocytopenia: 17% versus 16% Gastrointestinal symptomatology: 12% versus 7% Infections: 16% versus 15% Rash: 6% versus 12% Hypertension: 2% versus 5%
Phase 2 MANHATTAN (NCT03290950) 35 D‐KRd	NDMM (n = 41)	mFU: 20.3 mo
		MRD– after ≤8 cycles (10–5; MFC; ITT)[PE]: 71% ≥VGPR after ≤8 cycles (ITT): 95% mPFS: NR	Gr 3–4 AEs a Neutropenia: 27% Rash: 9% Lung infection: 7%
Phase 2 MASTER (NCT03224507) 32 , 49 D‐KRd	Te NDMM (n = 123)	mFU 42.2 mo 32 : MRD– at any time during treatment (NGS; ITT): • 10–5[PE]: 81% • 10–6: 71% mPFS: NR mFU 25.1 mo 49 : MRD– post‐induction (NGS; ITT): • 10–5: 38% • 10–6: 24% ≥CR (ITT) • Post‐induction (after 4 cycles): 36% • MRD‐directed consolidation: 86% ≥VGPR (ITT) • Post‐induction (after 4 cycles): 88% • MRD‐directed consolidation: 98%	Gr ≥ 3 TEAEs (mFU 42.2 mo) 32 Neutropenia: 35% Lymphopenia: 23% Anemia: 11% Thrombocytopenia: 10% Leukopenia: 10% Hypertension: 11% Fatigue: 9% Bone pain: 6%
Phase 2 IFM 2018‐04 (NCT03606577) 40 D‐KRd	High‐risk,c Te NDMM (n = 50)	mFU: 33 mo
		36 patients (72%) completed second transplant[PE] MRD– pre‐maintenance (NGS; ITT) • 10–5: 64% • 10–6: 62% mPFS: NR	Gr 3–4 TRAEs (induction/consolidation) Neutropenia: 39% Anemia: 12% Thrombocytopenia: 7% Infections: 6%
Phase 2 (NCT03500445) 33 MMRC D‐KRd	NDMMd (n = 42)	mFU: 27 mo
		sCR and/or MRD (<10−5; NGS) after 8 cycles (ITT)[PE]: 75% ≥CR after 8 cycles (ITT): 70% ≥VGPR after 8 cycles (ITT): 95% MRD– after 8 cycles (NGS; ITT) • 10–5: 59% • 10–6: 35% MRD– as best response (NGS; ITT) • 10–5: 65% • 10–6: 53% mPFS: NR	Gr ≥ 3 TEAEs Lymphopenia: 36% Thrombocytopenia: 26% Neutropenia: 21% Upper respiratory infections (including COVID‐19): 7% Hyperglycemia: 7% Hypertension: 17% Liver enzyme elevations: 10% Hypokalemia: 10%
Phase 2 (NCT04113018) 31 Single‐center study, United Statese D‐KRd	Te and Ti NDMM (n = 39)	mFU: 30.1 mo
		≥CR post‐induction[PE]: 54% ≥VGPR post‐induction: 92% MRD– post‐induction (NGS; ITT) • 10–5: 59% • 10–6: 41% MRD– post‐induction (NGF; ITT) • 10–5: 77% • 10–6: 31% mPFS: NR	Gr ≥ 3 TEAEs Neutropenia: 23% Hypophosphatemia: 23% Hypertension: 13% Syncope: 13% Hyperglycemia: 10% Platelet count decreased: 10%

Abbreviations: AE, adverse event; ALT, alanine aminotransferase; CR, complete response; d, dexamethasone; D, daratumumab; FU, follow‐up; GAH, Geriatric Assessment in Hematology; Gr, grade; HRCA, high‐risk chromosomal abnormality; Isa, isatuximab; ITT, intention‐to‐treat; K, carfilzomib; m, median; M, melphalan; MFC, multicolor flow cytometry; MMRC, Multiple Myeloma Research Consortium; mo, month; MRD–, minimal residual disease negativity; nCR, near‐CR; NDMM, newly diagnosed multiple myeloma; NGF, next‐generation flow cytometry; NGS, next‐generation sequencing; NR, not reached; OR, odds ratio; P, prednisone; PE, primary endpoint; PFS, progression‐free survival; R, lenalidomide; sCR, stringent CR; Te, transplant eligible; TEAE, treatment‐emergent AE; Ti, transplant ineligible; TRAE, treatment‐related AE; V, bortezomib; VGPR, very good partial response; y, year.

^a Publication does not specify whether the AEs were TEAEs or TRAEs.

^b Defined by mandatory International Staging System Stage II/III combined with del17p, t(4;14), t(14;16), or ≥4 (later amended to ≥3) 1q21 copies (amp 1q21) as HRCAs.

^c Presence of ≥1 high‐risk cytogenetic abnormalities among del(17p), t(4;14), or t(14;16).

^d Irrespective of eligibility for transplant.

^e Levine Cancer Institute, NC.

mPFS has not been reached yet in any of the trials for either Isa‐KRd or D‐KRd, including in two studies that now have median follow‐up periods of more than 4 years. ³⁷ , ⁴⁸ These various trials have reported deep and durable responses, including MRD− (Table 2). For many of the trials, follow‐up is ongoing. The Phase 2 ADVANCE trial of D‐KRd versus KRd in patients with Te NDMM (expected enrollment: n = 306) is also ongoing. ⁵¹

Efficacy in studies of anti‐CD38‐KRd quadruplets in Te NDMM

Isa‐KRd

IsKia/EMN24 is the first randomized Phase 3 trial with KRd as the backbone of an anti‐CD38‐based quadruplet in patients with Te NDMM. Patients aged <70 years were randomized (n = 302) to either Isa‐KRd or KRd. Patients in each treatment group received 4 induction cycles, followed by ASCT, 4 cycles of four‐drug consolidation, 12 light consolidation cycles, and optional lenalidomide maintenance. After a median follow‐up of 21 months, the primary endpoint of post‐consolidation MRD– (NGS; 10^–5 sensitivity) in ITT patients was met, with a significantly higher rate of 77% for Isa‐KRd compared with 67% for KRd (OR: 1.67; P = 0.049). The MRD– rate at 10^–6 sensitivity was also higher for Isa‐KRd compared with KRd (67% vs. 48%; OR: 2.29; P < 0.001). The MRD– benefit for Isa‐KRd compared with KRd was consistent regardless of cytogenetic risk, ⁵² at sensitivities of both 10^–5 (standard risk OR: 1.70; high risk OR: 2.30; interaction P‐value: 0.66 [high risk defined as del(17p), t(4;14), t(14;16)]) and 10^–6 (standard risk OR: 2.10; high risk OR: 4.95; interaction P‐value: 0.20). ³⁴ A preplanned analysis revealed that stem cell collection was feasible in the majority of IsKia/EMN24 patients, with no significant difference between treatment arms in numbers of stem cells collected; hematopoietic reconstitution succeeded in all transplanted patients. ⁵³

The ongoing Phase 3 IFM2020‐02 MIDAS trial of patients with Te NDMM features an MRD‐adapted consolidation and maintenance approach in which patients are grouped into four arms. In this study, which has the largest Isa‐KRd‐based trial population to date (n = 791), all patients receive six Isa‐KRd induction cycles. After induction, standard‐risk patients (MRD < 10^–5 [NGS]) are randomized 1:1 to consolidation with either six Isa‐KRd cycles (Arm A) or ASCT with two Isa‐KRd cycles (Arm B); Arms A and B then receive 3 years of lenalidomide maintenance. High‐risk patients (MRD > 10^–5 [NGS]) are randomized 1:1 to consolidation with either ASCT with two Isa‐KRd cycles (Arm C) or tandem ASCT (Arm D); Arms C and D then receive 3 years of maintenance with isatuximab and the cereblon E3 ligase modulatory drug iberdomide. The primary endpoint includes changes in the MRD– rate (NGS; 10^–6) from post‐induction baseline to end of consolidation, 1, 2, and 3 years. Post‐induction interim analysis revealed deep responses, including a ≥VGPR rate of 92% and high MRD− rates (63% at 10^–5 and 47% at 10^–6) in ITT patients after six Isa‐KRd cycles. ³⁹

The Phase 2 GMMG‐CONCEPT study enrolled an exclusively high‐risk population, defined as International Staging System Stage II or III plus one or more of the following: del(17p) in ≥10% of purified cells, t(4;14), t(14;16) and/or ≥4 (later amended to ≥3) copies of 1q21 (amp 1q21). The ITT population predominantly comprised patients with high‐risk Te NDMM (21% of patients with high‐risk Ti NDMM were also included). Patients with Te NDMM received six Isa‐KRd induction cycles, followed by high‐dose chemotherapy plus ASCT, four Isa‐KRd consolidation cycles, and up to 26 Isa‐KR maintenance cycles. Patients with Te NDMM (ITT: n = 99) achieved high response rates. Among evaluable patients with Te NDMM post‐induction, 65% achieved MRD− (10^–5; NGS), ⁵⁰ and this response continuously deepened over time. GMMG‐CONCEPT met its primary endpoint, with 68% of ITT patients with Te NDMM achieving MRD− (10^–5; NGS) post‐consolidation. ³⁶ When outcomes of the first GMMG‐CONCEPT cohort with a ≥4‐year follow‐up were assessed, Isa‐KRd maintained MRD− remissions in the majority of patients: 84% of patients with Te NDMM achieved MRD− on study, of whom 80% had ≥1‐year sustained MRD−. ⁴⁸ This longer term follow‐up also revealed that mPFS had not been reached in patients with Te NDMM 6 years after initiating treatment. ⁴⁸ The high‐risk patient population in GMMG‐CONCEPT reflected an unmet need, and the findings of this trial extended the established benefit of isatuximab to high‐risk NDMM. Furthermore, when a regimen is effective in a high‐risk population such as that enrolled in GMMG‐CONCEPT, the results may be considered translatable to the standard‐risk population. Since progression events occur at faster rates in high‐ versus standard‐risk patients, the results from a high‐risk population can represent a quicker readout for the entire population.

In the Phase 2 SKylaRk study, patients with Te NDMM (n = 50) received either upfront or deferred ASCT. The upfront ASCT arm received four Isa‐KRd induction cycles followed by ASCT and Isa‐KRd consolidation. The deferred ASCT arm received eight Isa‐KRd induction cycles. Maintenance comprised either Isa‐KR (patients who were high risk and/or were MRD‐positive) or lenalidomide (patients who were standard risk and/or were MRD‐negative). The primary endpoint of ≥CR after induction was achieved in 32% of patients, and response rates (≥CR and ≥VGPR) deepened over time. MRD− (NGS; 10^–5) was achieved in 62% of evaluable patients who achieved ≥VGPR after the first four Isa‐KRd induction cycles and deepened to 72% after eight cycles. ³⁸ In an analysis by cytogenetic risk of patients who deferred ASCT (median follow‐up: 35.9 months), 3‐year PFS was 80% in all patients, 90% in patients with no high‐risk chromosomal abnormalities (HRCAs; n = 20), 83% in those with 1 HRCA (n = 16), and not assessable in those with 2 HRCAs (n = 5). ⁵⁴

D‐KRd

In the Phase 2 MASTER study, patients with Te NDMM (n = 123) received 4 D‐KRd induction cycles, followed by ASCT and MRD‐adapted D‐KRd consolidation. Patients with two consecutive MRD– results (10^–5; NGS) entered treatment‐free observation (MRD surveillance [MRD‐SURE]); those who did not receive lenalidomide maintenance. In the ITT population, the MRD– rate (10^–5; NGS) was 38% post‐induction ⁴⁹ ; this increased to 81% for the primary endpoint of MRD– rate (10^–5; NGS) at any time in the study. ³² MRD‐adapted consolidation with D‐KRd was feasible in this all‐risk population, with 71% of patients reaching MRD‐SURE. ³² Among the patients who entered MRD‐SURE, the 24‐month cumulative incidence of progression since stopping therapy was 9% in patients with no HRCAs, 9% in those with 1 HRCA, and 47% in those with ≥2 HRCAs. ³²

In the Phase 2 IFM 2018‐04 study, D‐KRd and a tandem transplant were evaluated in a Te NDMM population (n = 50) that was high risk, defined as having del(17p), t(4;14), and/or t(14;16). Patients received six D‐KRd induction cycles, followed by first ASCT, 4 D‐KRd consolidation cycles, second ASCT, and 2 years of D‐R maintenance. The proportion of patients completing the second transplant (72%) was above the 70% feasibility threshold for tandem transplant that had been set to define primary endpoint achievement. Deep responses to D‐KRd induction were observed: in the ITT population, the pre‐maintenance MRD– rate (NGS) was 64% at 10^–5 sensitivity and 62% at 10^–6 sensitivity. ⁴⁰

In a single‐center Phase 2 study (NCT04113018) of 39 patients with Te or Ti NDMM at the Levine Cancer Institute (LCI; NC, USA), 8 D‐KRd induction cycles were followed by post‐induction treatment that was informed by ASCT eligibility and MRD status. The primary endpoint of ≥CR post‐induction was achieved by 54% of patients. Since this was lower than the predefined 70% threshold for ≥CR, the study was determined not to have met its primary endpoint (P = 0.375). Patients who were MRD– post‐induction received lenalidomide maintenance, with 78% achieving sustained MRD– for ≥12 cycles. Among those who were MRD‐positive post‐induction, Te patients (n = 8) underwent ASCT, after which 63% became MRD‐negative (10^–5; patients remaining MRD‐positive could receive up to 12 KRd consolidation cycles), and Ti patients (n = 4) received up to 12 KRd consolidation cycles, with none having converted to MRD– with 1 year of initiating consolidation. ³¹

Efficacy of D‐KRd in Ti NDMM: GEM2017FIT

GEM2017FIT is a Phase 3 Spanish trial that enrolled elderly fit patients with Ti NDMM. Fit patients were defined as having a Geriatric Assessment in Hematology (GAH) scale score ≤ 42 (scale: 0–94; lower scores indicate higher fitness). Patients were randomized into three groups, with induction consisting of either (i) D‐KRd (18 cycles), (ii) KRd (18 cycles), or (iii) bortezomib–melphalan–prednisone (VMP; 9 cycles) followed by Rd (9 cycles). The KRd and VMP‐Rd groups are to receive four D‐Rd consolidation cycles. Finally, MRD‐positive or MRD‐negative patients will receive maintenance therapy with D‐R or observation, respectively. Post‐induction results have been presented. In the ITT population, MRD− (next‐generation flow cytometry [NGF]; 10^–5) was achieved in 61% of D‐KRd‐ and 54% of KRd‐treated patients. MRD− (NGF; 10^–5) in the evaluable population, the primary endpoint of GEM2017FIT, was reported for 84% of D‐KRd‐ and 75% of KRd‐treated patients. Findings were similar for patients stratified by GAH scale score (<20 vs. ≥20). D‐KRd‐treated patients with GAH scale score ≥ 20 had lower 30‐month PFS (71%) compared with their fitter counterparts who had GAH scale score < 20 (88%). Sixty‐seven percent of D‐KRd‐ and 40% of KRd‐treated patients who discontinued because of toxicity or toxicity‐related death had a GAH scale score ≥ 20. These findings suggested that the D‐KRd quadruplet may be more suitable for fitter patients than for frailer elderly patients. ³⁷

Efficacy of D‐KRd in studies that enrolled patients with NDMM regardless of transplant eligibility

MANHATTAN was the first of the key Phase 2 studies of D‐KRd in NDMM to publish results. In this study, 41 patients with NDMM received up to eight D‐KRd induction cycles, in the absence of high‐dose chemotherapy and ASCT. This was followed by off‐study treatment, which consisted of SOC therapy with or without upfront ASCT, and maintenance therapy. The 71% MRD– rate (multiparameter flow cytometry; 10^–5; ITT) reported after ≤8 D‐KRd induction cycles exceeded the 40% rate that had been set for the study to achieve the primary endpoint. At the individual patient level, the clinical response deepened over time. ³⁵ The results from MANHATTAN led to the inclusion of D‐KRd in the NCCN® guidelines for NDMM in the United States. ¹⁵

An approach without transplant was evaluated in another Phase 2 study (NCT03500445), which enrolled 42 patients with NDMM, irrespective of transplant eligibility, at MMRC sites in the USA. Patients in this study received 24 D‐KRd cycles without ASCT. After eight cycles in the ITT population, the MRD– rates (NGS) were 59% at 10⁻⁵ and 35% at 10⁻⁶, and the primary endpoint of sCR and/or MRD– (10⁻⁵; NGS) was achieved in 75% of patients. Responses deepened with continued quadruplet therapy, with MRD– rates (NGS) increasing to 65% at 10^–5 and 53% at 10^–6. ³³

Safety of anti‐CD38‐KRd quadruplets

Anti‐CD38‐KRd quadruplets have been well tolerated; recurrent AEs have included hematologic and thromboembolic events as reported for KRd, as well as infections and hypertension (Table 2). The clinical trials of Isa‐KRd have reported manageable AEs, with safety profiles similar to previous reports, reinforcing the benefit‐risk profile of this combination. ³⁴ , ³⁶ , ³⁸ , ³⁹ Similarly, the addition of daratumumab to KRd has been reported to be well tolerated, with safety data being consistent with known safety profiles of the investigational products. ³¹ , ³² , ³³ , ³⁵ , ³⁷ , ⁴⁰ Among the studies of D‐KRd, IFM 2018‐04 reported one case of Grade 2 cardiac insufficiency that was deemed related to carfilzomib and was reversible, ⁴⁰ and the MMRC study reported one case of thrombotic microangiopathy that led to carfilzomib discontinuation. ³³

Carfilzomib dosing in anti‐CD38‐KRd quadruplets

Similar PFS has been observed with weekly and twice‐a‐week dosing of both carfilzomib ⁵⁵ and bortezomib. ⁵⁶ The efficacy and safety of weekly carfilzomib administered at 56 mg/m² have been established in a Phase 3 trial of patients with relapsed/refractory MM who received KRd, with weekly 56 mg/m² being non‐inferior to twice‐a‐week carfilzomib 27 mg/m², ⁵⁷ as well as a Phase 2 trial of patients with Te NDMM who received the carfilzomib–thalidomide–dexamethasone triplet. ⁵⁸ This carfilzomib regimen has been used in most of the trials of anti‐CD38‐KRd quadruplet combinations in NDMM (Figure 3). The induction step has included weekly carfilzomib at 56 mg/m² in all four of the Isa‐KRd trials, ³⁴ , ³⁸ , ³⁹ , ⁵⁰ as well as the MANHATTAN, MASTER and single‐center LCI Phase 2 trials of D‐KRd. ³¹ , ³² , ³⁵ With the exception of MANHATTAN, all of these trials included a consolidation step, which also specifies weekly carfilzomib at 56 mg/m². ³¹ , ³² , ³⁴ , ³⁸ , ³⁹ , ⁵⁰

Figure 3.

Carfilzomib dosing in key clinical trials of anti‐CD38 monoclonal antibody‐containing quadruplet regimens in patients with newly diagnosed multiple myeloma (NDMM). Clinical trials of anti‐CD38‐KRd quadruplet regimens in patients with NDMM are using a variety of carfilzomib dosing strategies. ³¹ , ³² , ³³ , ³⁴ , ³⁵ , ³⁷ , ³⁸ , ³⁹ , ⁴⁰ , ⁵⁰ Use of weekly carfilzomib at 56 mg/m² has been adopted for induction and/or consolidation in many of the studies. ³¹ , ³² , ³⁴ , ³⁵ , ³⁸ , ³⁹ , ⁴⁰ , ⁵⁰ Abbreviations: ASCT, autologous stem cell transplant; BIW, biweekly (twice‐a‐week); d, dexamethasone; D, daratumumab; Isa, isatuximab; K, carfilzomib; LCI, Levine Cancer Institute; MMRC, Multiple Myeloma Research Consortium; MRD, minimal residual disease; Q2W, every other week; QW, weekly; R, lenalidomide; Te, transplant eligible; Ti, transplant ineligible; wk, week. ^aDosing for induction was originally twice a week at 36 mg/m², but following a protocol amendment, was switched to weekly dosing at 56 mg/m². ^bNumber of consolidation cycles dependent on MRD– status. ^cTe patients who remained MRD‐positive post‐ASCT or Ti patients who were MRD‐positive post‐induction.

Three of the Isa‐KRd trials involved a switch from weekly to every‐other‐weekly dosing after consolidation. ³⁴ , ³⁸ , ⁵⁰ For light consolidation with KRd in IsKia/EMN24 and for maintenance with KR in SKylaRk, the every‐other‐weekly dose of carfilzomib remained at 56 mg/m². ³⁴ , ³⁸ For maintenance with KR in GMMG‐CONCEPT, the every‐other‐weekly carfilzomib dose was increased to 70 mg/m². ⁵⁰ Among D‐KRd trials, the GEM2017FIT, IFM 2018‐04, and MMRC studies started with twice‐a‐week carfilzomib at 36 mg/m². ³³ , ³⁷ , ⁴⁰ This was adjusted to twice‐a‐week carfilzomib 56 mg/m² for the remainder of induction (Cycles 3–18) in GEM2017FIT, ³⁷ weekly carfilzomib 56 mg/m² for consolidation in IFM 2018‐04, ⁴⁰ and twice‐a‐week carfilzomib 36 mg/m², every 2 weeks, for consolidation in the MMRC study. ³³

Stem cell mobilization

Up to 75% of mobilized CD34⁺ hematopoietic progenitor cells express CD38. Therefore, there are questions around whether exposure to anti‐CD38 mAbs may potentially impact stem cell mobilization and engraftment. ⁵⁹ Data from recent trials have demonstrated that stem cell collection is feasible in the majority of patients with NDMM treated with anti‐CD38 mAb‐KRd quadruplets (Figure 4), ³³ , ³⁵ , ⁴⁰ , ⁵³ , ⁶² , ⁶³ , ⁶⁴ although median stem cell yields may depend on the target CD34⁺ dose, total blood volumes processed during collection, and use of plerixafor or chemomobilization. Stem cell collection should be performed early during induction in responding patients, ideally after 3–4 cycles.

Figure 4.

Stem cell mobilization in transplant‐eligible (Te) newly diagnosed multiple myeloma (NDMM) trials. Clinical trials of anti‐CD38‐KRd quadruplet regimens in patients with NDMM have demonstrated that stem cell collection is feasible in the majority of patients treated with Isa‐KRd or D‐KRd. The Phase 3 IsKia/EMN24 study reported no significant difference between the Isa‐KRd and KRd arms in the number of stem cells collected. In most centers, infusion of at least 2.5 × 10⁶ CD34⁺ cells/kg of recipient body weight is considered sufficient for one autograft. ⁶⁰ , ⁶¹ CAD, cyclophosphamide, adriamycin, and dexamethasone; Cy, cyclophosphamide; d, dexamethasone; D, daratumumab; G‐CSF, granulocyte‐colony stimulating factor; IMWG, International Myeloma Working Group; Isa, isatuximab; IQR, interquartile range; K, carfilzomib; LCI, Levine Cancer Institute; MMRC, Multiple Myeloma Research Consortium; R, lenalidomide.

CONCLUSIONS

KRd has been established as a potent regimen, which in combination with anti‐CD38 mAbs has demonstrated efficacy benefit in multiple clinical trials in NDMM including in high‐risk patients. In Phase 3 trials, Isa‐KRd demonstrated some of the deepest responses to date in NDMM, including high rates of MRD−. In the IsKia/EMN24 ITT population post‐consolidation, the MRD− rate (10^–5) reached 77% after only eight Isa‐KRd cycles, with 67% of Isa‐KRd‐treated patients achieving an even deeper MRD response at 10^–6 sensitivity. Preliminary data from MIDAS have revealed achievement of MRD− (10^–5) in 63% of ITT patients post‐induction. The Phase 3 findings were consistent with Phase 2 trials of Isa‐KRd.

For D‐KRd, Phase 2 findings included an MRD− rate (10^–5) of 71% in the ITT for MANHATTAN after ≤8 cycles ³⁵ and a deepening response with ongoing treatment in the MMRC trial (NCT03500445). ³³ This is consistent with the Phase 3 data from GEM2017FIT in fit older patients that revealed an MRD− rate (10^–5) of 61% after 18 induction cycles in ITT patients. Furthermore, the MASTER trial demonstrated the successful implementation of an MRD‐guided consolidation strategy with D‐KRd, resulting in an MRD– rate (10^–5) in the ITT population at any time during treatment of 81% and an increase in the ≥VGPR rate from 88% post‐induction to 98% after MRD‐directed consolidation. ³²

These studies support KRd‐based quadruplets as an additional SOC in the NDMM setting, and the benefits conferred by ongoing treatment with carfilzomib must be weighed with patient preference, convenience, and toxicity. Compared with other recommended regimens such as Isa‐VRd and D‐VRd, patient groups that could experience the strongest clinical impact from anti‐CD38‐KRd quadruplets may include those at elevated risk of PN and patients with high‐risk cytogenetics. Importantly, in the exclusively high‐risk GMMG‐CONCEPT population, of those Isa‐KRd‐treated patients who attained MRD−, 80% subsequently achieved ≥1‐year sustained MRD−. ⁴⁸ Deepening responses were also reported with D‐KRd in the high‐risk IFM 2018‐04 population. ⁴⁰ These Phase 2 results have been supported by Phase 3 data, ³⁴ , ³⁹ including a post‐consolidation MRD– rate of 77% at 10^–6 sensitivity for Isa‐KRd in very high‐risk IsKia patients (≥2 HRCAs) compared with 27% for KRd (OR: 9.05; 95% confidence interval, 1.57–52.14). ³⁴

Although neither the KRd triplet nor anti‐CD38‐KRd quadruplets are recommended for NDMM in current European guidelines, ¹⁴ Isa‐KRd and D‐KRd were recently recommended for NDMM in the US NCCN® guidelines. ¹⁵ We anticipate similar developments in future European guidelines, particularly since many of the key trials enrolled European patients. The recommendations may lead to more frequent use of these combinations as frontline therapy for patients with NDMM, and their efficacy can be maximized by incorporating strategies to mitigate safety concerns, including the establishment of optimal dosing and administration schedules. More evidence on long‐term benefit across different populations will facilitate future decisions regarding the approval of these combinations in NDMM.

Although the recognition of KRd as a strong backbone of therapy in the frontline setting has taken some time due to conflicting results from some studies including ENDURANCE, the efficacy, safety, and tolerability of KRd‐based regimens have been demonstrated clearly in various studies. It is hoped that this evidence base will continue to strengthen, thus providing a valuable alternative option to physicians and patients in the future treatment of myeloma.

AUTHOR CONTRIBUTIONS

Ola Landgren: Writing—original draft; writing—review and editing. Noa Biran: Writing—original draft; writing—review and editing. Elizabeth K. O'Donnel: Writing—review and editing. Joseph Mikhael: Writing—original draft; writing—review and editing. Katja C. Weisel: Writing—review and editing. Annemiek Broijl: Writing—original draft; writing—review and editing. Saad Z. Usmani: Writing—review and editing. Philippe Moreau: Writing—original draft; writing—review and editing. Franseca M. Gay: Writing—review and editing. Roberto Mina: Writing—original draft; writing—review and editing. Paula Rodríguez‐Otero: Writing—original draft; writing—review and editing. Andrzej J. Jakubowiak: Writing—review and editing. Benjamin A. Derman: Writing—original draft; writing—review and editing.

CONFLICT OF INTEREST STATEMENT

O.L.: Funding from Amgen, Cannon Guzy Family Fund, Celgene, FDA, Glenmark, IMF, Janssen, Karyopharm, LLS, MMRF, Myeloma Solutions Fund, NCI/NIH, Paula and Rodger Riney Foundation, Perelman Family Foundation, Rising Tide Foundation, Seattle Genetics, Takeda, and Tow Foundation; honoraria from AbbVie, Adaptive, Amgen, Binding Site, Bristol Myers Squibb, Celgene, Cellectis, GSK, Janssen, Juno, and Pfizer; advisory board participation for AbbVie, Adaptive, Amgen, Binding Site, Bristol Myers Squibb, Celgene, Cellectis, GSK, Janssen, Juno, and Pfizer; independent data monitoring committee service for international randomized trials by Janssen, Merck, Novartis, and Takeda outside the submitted work.

N.B.: Research support from BMS, Celgene, Johnson and Johnson, Karyopharm, and Merck; advisory board participation for AbbVie, Amgen, BMS, Celgene, GSK, Johnson and Johnson, Karyopharm, Pfizer, Regeneron, and Sanofi; funding from BMS, Johnson and Johnson, and Sanofi; independent data monitoring committee service for international randomized trials by Johnson and Johnson.

E.K.O.: Consulting for, honoraria from, travel fees from, and advisory board participation for Sanofi.

J.M.: Consulting for Amgen, BMS, Janssen, Menarini, and Sanofi.

K.C.W.: Research grants from AbbVie, Amgen, BMS/Celgene, GSK, Janssen, and Sanofi (to the Institution); honoraria: AbbVie, Adaptive Biotech, Amgen, AstraZeneca, Beigene, BMS, Celgene, GSK, Janssen, Karyopharm, Menarini, Novartis, Oncopeptides, Pfizer, Roche, Sanofi, Stemline, and Takeda; advisory board participation for AbbVie, Adaptive Biotech, Amgen, Beigene, BMS, Celgene, GSK, Janssen, Karyopharm, Menarini, Novartis, Oncopeptides, Pfizer, Regeneron, Roche, Sanofi, and Takeda.

A.B.: Honoraria from and advisory board service for Amgen, Bristol Myers Squibb, Janssen, and Sanofi.

S.Z.U.: Research funding from Amgen, Array Biopharma, BMS, Celgene, GSK, Janssen, Merck, Pharmacyclics, Sanofi, Seattle Genetics, SkylineDX, and Takeda; consulting fees from AbbVie, Amgen, BMS, Celgene, EdoPharma, Genentech, Gilead, GSK, Janssen, Oncopeptides, Sanofi, Seattle Genetics, SecuraBio, SkylineDX, Takeda, and TeneoBio.

P.M.: Advisory board participation for and honoraria from AbbVie, Amgen, BMS, GSK, Janssen, Pfizer, Sanofi, and Takeda.

F.M.G.: Honoraria from AbbVie, Amgen, Bristol Myers Squibb/Celgene, GlaxoSmithKline, Janssen, Pfizer, Sanofi, and Takeda; advisory board service for AbbVie, Amgen, Bristol Myers Squibb/Celgene, Janssen, Oncopeptides, Pfizer, Roche, Sanofi, and Takeda.

R.M.: Honoraria from AbbVie, Amgen, Bristol Myers Squibb, Celgene, GSK, Janssen, Menarini, Pfizer, Sanofi, Stemline, and Takeda; advisory board participation for Amgen, Bristol Myers Squibb, GSK, Janssen, Pfizer, and Sanofi.

P.R.‐O.: Honoraria from, consulting for, or advisory board participation for AbbVie, Celgene‐BMS, GSK, H3Biomedicine, Janssen, Menarini, Pfizer, Roche, Sanofi, and Stemline. Steering committee member for Celgene‐BMS, Janssen, and Regeneron. Speaker's bureau for AbbVie, Celgene‐BMS, GSK, Janssen, and Sanofi. Travel grant from Pfizer.

A.J.J.: Honoraria and advisory board fees from AbbVie, Amgen, Bristol‐Myers Squibb/Celgene, GlaxoSmithKline, Gracell, Janssen, and Sanofi.

B.A.D.: Honoraria from Canopy, COTA, Janssen, and Sanofi; independent data monitoring committee service for international randomized trials by BMS; research funding from Amgen and GSK outside the submitted work.

FUNDING

Dr. Landgren is supported by the Sylvester Comprehensive Cancer Center National Cancer Institute Core Grant (P30 CA 240139) and the Riney Family Multiple Myeloma Research Program Fund, Tow Foundation, Myeloma Solutions Fund, and Cannon Guzy Family Fund.

DATA AVAILABILITY STATEMENT

Data sharing is not applicable to this article as no new data were created or analyzed in this study.