Evolution of frontline treatment for multiple myeloma: clinical investigation of quadruplets containing carfilzomib and anti-CD38 monoclonal antibodies

Abstract

Although survival rates for patients with newly diagnosed multiple myeloma (NDMM) have improved over recent decades, multiple myeloma (MM) remains without a cure for most. There is increasing consensus that achievement of deep remissions, especially minimal residual disease negativity (MRD −), in frontline treatment is crucial and translates into improved survival. The standard of care (SOC) for NDMM consists at minimum of a triplet regimen of therapies, with or without an autologous stem cell transplant, or a doublet regimen for certain ineligible, particularly frail patients who may have specific limitations. Recently, anti-CD38 monoclonal antibodies (mAbs), such as daratumumab (Dara) or isatuximab (Isa), have been integrated into frontline SOC regimens. Seeking to further deepen and prolong responses, several clinical trials have commenced investigating the addition of anti-CD38 mAbs to carfilzomib, lenalidomide, and dexamethasone (KRd). These quadruplet regimens (Isa/Dara-KRd) are being evaluated in the context of evolving treatment considerations for the heterogeneous population of patients with NDMM. In clinical trials, the addition of Isa/Dara to KRd achieved high rates of deep responses and MRD − . Favorable outcomes were observed in patients with NDMM independent of age, transplant eligibility, and cytogenetic risk, while these treatments did not result in unexpected or emergent safety risks. The efficacy observed with intensified, yet well-tolerated therapy may offer further development of risk- and response-adapted therapy for individualized patient needs. This review summarizes the clinical outcomes of quadruplet-based therapy with Isa/Dara-KRd in NDMM.

Supplementary Information

The online version contains supplementary material available at 10.1007/s00277-024-06143-7.

Introduction

Multiple myeloma (MM) is a malignant plasma cell disorder that accounts for 1% of all cancers and approximately 10% of all hematologic malignancies [1]. Globally, there were approximately 188,000 new cases and 121,000 deaths from MM in 2022, comprising 0.9% of new cancer cases and 1.2% of deaths [2]. Survival rates for newly diagnosed MM (NDMM) have improved over recent decades primarily because of the evolution of available treatment regimens [3–5]. Nonetheless, MM remains an uncured disease for the majority of patients, and attrition rates after frontline treatment and each subsequent line of therapy remain high, underscoring the importance of advancing more effective upfront treatment approaches that may translate into long-term remission and survival [6, 7]. The growing body of data correlating depth of response with duration of remission has led to a paradigm of upfront dose intensification in NDMM for many patients. This is evidenced by the widespread transition from doublet to triplet therapy and, more recently, even to quadruplet therapy as induction [3, 7–9].

The established standard-of-care (SOC) treatment approach in NDMM combines a proteasome inhibitor with immunomodulatory drugs plus steroid as a triplet regimen with or without an autologous stem cell transplant (ASCT) and now increasingly extended to a quadruplet regimen incorporating anti-CD38 monoclonal antibodies (mAbs) [4, 10–12]. The triplets bortezomib/lenalidomide/dexamethasone (VRd) and bortezomib/thalidomide/dexamethasone (VTd) are well-established SOC regimens that have achieved overall response rates (ORR) between 81%–98% and median progression-free survival (PFS) rates of 36–50 months as first-line therapy for MM [12–16]. The addition of anti-CD38 mAbs daratumumab (Dara) or isatuximab (Isa) to these backbone regimens has sought to further deepen and prolong responses to frontline treatment [4, 11].

The rationale for studying anti-CD38 mAbs in combination with existing SOCs in NDMM is supported by outcomes observed in relapsed/refractory MM (RRMM), where their addition to previously established doublet regimens increased anti-myeloma efficacy with improved survival rates while maintaining acceptable safety profiles [17–22]. Adding anti-CD38 mAbs to existing SOC therapies in patients with NDMM has also translated into higher rates of deep responses including complete remission and minimal residual disease negativity (MRD–) [11]. Pursuant to the paradigm of using the most effective treatments up front, Dara-VTd and Dara-VRd for transplant-eligible patients [23–27] and Dara/lenalidomide/dexamethasone (Dara-Rd) for transplant-ineligible patients [28] have emerged as attractive iterations from the previously established underlying SOC therapies.

Carfilzomib, a second-generation proteasome inhibitor, has been extensively studied and routinely used in the treatment of MM [29]. Carfilzomib is approved for the treatment of adult patients with RRMM who have received ≥ 1 prior line of therapy in combination with lenalidomide, Dara, Isa, and/or dexamethasone or as monotherapy [17, 30–32]. In the RRMM treatment setting, carfilzomib and dexamethasone (Kd) showed superiority, with significantly improved PFS, overall survival (OS), and lower rates of peripheral neuropathy versus the first-generation proteasome inhibitor, bortezomib, and dexamethasone [17, 19, 30]. As with other trials building upon established doublets, the addition of anti-CD38 mAbs to Kd increased the efficacy further in phase 3 clinical trials [17, 19, 30]. In NDMM, carfilzomib has also been studied extensively in combination with immunomodulatory drugs and dexamethasone [33, 34], and there has been widespread recognition of favorable efficacy with carfilzomib/lenalidomide/dexamethasone (KRd) therapy in both transplant-eligible and transplant-ineligible patients [12, 35–39].

KRd represents an attractive backbone for investigational quadruplet therapies inclusive of anti-CD38 mAbs for frontline treatment, especially where the objective is treatment intensification to rapidly achieve deep and durable remissions with the aim of a prolonged exposure to proteasome inhibition. As such, an array of clinical trials have been initiated, and a growing body of evidence is elucidating the efficacy and tolerability of KRd-based quadruplet regimens with the anti-CD38 mAbs daratumumab or isatuximab in NDMM [33]. This review discusses the available results of concluded and ongoing clinical trials investigating Dara-KRd or Isa-KRd in the frontline setting in the context of the evolving considerations in the treatment of patients with NDMM.

Methods

Clinical trial evidence was obtained via a search of PubMed and relevant conference websites for articles or abstracts based on Isa-KRd or Dara-KRd for the treatment of NDMM. The PubMed search for relevant articles was conducted between January 2017 and June 2024 based on the title and the abstract of the article. Search terms were (((isatuximab OR daratumumab OR anti CD38 monoclonal antibody) AND carfilzomib AND lenalidomide AND dexamethasone) OR (Isa-KRd) OR (Dara-KRd) OR (IKRd) OR (DKRd)) AND ((newly diagnosed multiple myeloma) OR ((frontline OR front line) multiple myeloma) OR (newly diagnosed MM)). Clinical studies in which patients with NDMM were treated with Isa-KRd or Dara-KRd were selected as relevant. Reviews, case reports, retrospective studies, and preclinical studies were not considered. Additionally, articles not reporting on patients with NDMM were excluded. A total of 40 articles were identified overall, and 11 were relevant (Fig. 1a).

Fig. 1.

Identification of relevant manuscripts (a) and congress abstracts (b). KRd, carfilzomib, lenalidomide, and dexamethasone

A similar approach was used to screen abstracts from congresses. Congresses included meetings of the American Society of Hematology, European Hematology Association, European Society for Medical Oncology, American Society of Clinical Oncology, International Myeloma Society, Lymphoma, Leukemia & Myeloma Congress, Society of Hematologic Oncology, and Congress on Controversies in Multiple Myeloma. A total of 48 abstracts were identified, 26 of which were deemed relevant (Fig. 1b). A summary of clinical trials and study design is provided in Table 1.

Table 1.

Isa/Dara-KRd drug combination studies in patients with NDMM

Study	Study design/ status	Primary endpoint	N	Patient population	HRCAs, n (%)	Treatment
Isa-KRd
IsKia[40] (NCT04483739)	Phase 3 Active, not recruiting	Rate of MRD– (10–5) by NGS after consolidation	302 (enrolled): • Isa-KRd: 151 • KRd: 151	Transplant-eligible Median age, y: • Isa-KRd: 61 • KRd: 60	• Isa-KRd: 18% • KRd: 19% Double hit: • Isa-KRd: 9% • KRd: 8% HRCA definition: t(4;14), t(14;16) and/or del(17p) Double hit including gain/amp(1q)	K dose 20/56 mg/m2 QW on days 1, 8, 15a; (Isa-)KRd induction for 4 cycles; HD melphalan and ASCT; (Isa-)KRd consolidation for 4 cycles and light consolidation for 12 cycles
GMMG-CONCEPT[41] (NCT03104842)	Phase 2 Active, not recruiting	MRD– (10–5) by NGF after consolidation	153 enrolled in first cohortb ITT population: •Transplant-eligible: 99 • Transplant-ineligible: 26	High-risk Transplant-eligible or transplant-ineligible Median (range) age, y: 62 (35–87) • Transplant-eligible: 58 (35–73) • Transplant-ineligible: 74 (64–87)	153 (100) 1 HRCA: 77 (61.6)  ≥ 2 HRCAs: 38 (30.4) HRCA definition: ISS stage II or III plus, ≥ 1 of del(17p), t(4;14), t(14;16) and/or > 3 copies 1q21	K dose 20/36 mg/m2 BW on days 1–2, 8–9, 15–16 (56 mg/m2 QW on days 1, 8, 15 following protocol amendment); Isa-KRd induction for 6 cycles; HDT and ASCT for transplant-eligible patients or 2 additional cycles for transplant-ineligible patients; Isa-KRd consolidation for 4 cycles; Isa-KR maintenance for 26 cycles
SKylaRk[42] (NCT04430894)	Phase 2 Active, not recruiting	Rate of ≥ CR after 4 cycles of Isa-KRd per IMWG response criteria	50 (enrolled)	Transplant-eligible Median (range) age, y: 59 (40–70)	23 (46) HRCA definition: del(17p), gain/amp 1q, and t(4;14), t(14;16), t(14;20)	K dose 20/56 mg/m2 QW on days 1, 8, 15a (Isa-KRd for up to 8 cycles induction); R maintenance for standard-risk, Isa-KR maintenance for high-risk with K dose 56 mg/m2 days 1, 15
Dara-KRd
MASTER[43] (NCT03224507)	Phase 2 Completed	MRD– (< 10–5) at any point during therapy; centrally assessed	123	Transplant-eligible (no age limit) Median (range) age, y: 61 (55–68); 20% ≥ 70	70 (57) • 0 HRCA: 53 (43) • 1 HRCA: 46 (37) • ≥ 2 HRCAs: 24 (20) HRCA definition: gain/amp 1q, t(4;14), t(14;16), t(14;20) or del(17p)	K dose 20/56 mg/m2 QW on day 1, 8, 15a; Dara-KRd induction for 4 cycles; HD melphalan and ASCT; Dara-KRd consolidation for 8 cycles; R maintenance if no sustained MRD–c
LCI-HEM-MYE-KRDD-001[44–46] (NCT04113018)	Phase 2 Active, not recruiting	≥ CR rate after 8 cycles of Dara-KRd induction therapy	39	Transplant-eligible (prior ASCT if MRD positive post-induction) Median age, years (range): 62 (34–78)	15 (39), including gain 1q21 HRCA definition: del(17p), t(4;14) and/or t(14;16)	K dose 20/56 mg/m2 QW on days 1, 8, 15a; Dara-KRd induction for 8 cycles; MRD-adapted KRd consolidation ± ASCT and R maintenance
IFM 2018–04[47] (NCT03606577)	Phase 2 Active, not recruiting	Proportion of patients receiving second ASCT	50	High-risk Transplant-eligible (tandem ASCT) Median (range) age, y: 57 (38–65)	50 (100) HRCA definition: del17p, t(4;14) and/or t(14;16)	K dose 20/36 mg/m2 BW on days 1–2, 8–9, 15–16d; Dara-KRd induction for 6 cycles; HD melphalan and ASCT; Dara-KRd consolidation for 4 cycles; second ASCT; Dara-R maintenance for 2 years
GEM2017FIT[48] (NCT03742297)	Phase 3 Active, not recruiting	MRD– (10–5) at end of induction by NGF	462 • VMP-Rd: 154 • Dara-KRd: 153 • KRd: 154	Transplant-ineligible Median age, y: 72	NA	K dose 36/56 mg/m2 BW during C1–C2, QW on C3 + ; VMP-Rd, KRd, or Dara-KRd induction for 18 cycles; Dara-Rd consolidation for 4 cycles for VMP-Rd and KRd; Dara-R maintenance for MRD-positive patients
MANHATTAN[49] (NCT03290950)	Phase 2 Active, not recruiting	MRD– rate (10–5) after up to 8 cycles by MFC	41	Transplant-ineligible Median (range) age, y: 59 (30–70)	20 (49) HRCA definition: ≥ 1 of 1q + , t(4;14), t(14;16), t(14;20), and/or del(17p)	K dose 20/56 mg/m2 QW on days 1, 8, 15a; 8 cycles Dara-KRd; after completion of 8 cycles, the clinical trial therapy was completed
UC-IRB17-1097[50] (NCT03500445)	Phase 2 Completed	Rate of sCR and/or MRD– (< 10–5) by NGS at end of cycle 8	42	Transplant-eligible or transplant-ineligible Median (range) age, y: 58 (39–79)	• 1 HRCA: 24 (57) • ≥ 2 HRCAs: 10 (24) HRCA definition: t(4;14), t(14;16), t(14;20),1q gain/amp, del(17p)	K dose 20/36 mg/m2 BW on days 1–2, 8–9, 15–16 for C1–C8, 36 mg/m2 Q2W on days 1, 2, 15, 16 for C9–C24; 24 cycles total Dara-KRd
MMY1001[51] (NCT01998971)	Phase 1b Active, not recruiting	Safety and tolerability	22	Transplant-ineligible Median (range) age, y: 60 (34–74)	NA	K dose 20/70 mg/m2 QW on days 1, 8, 15e; 13 cycles Dara-KRd total

ASCT, autologous stem cell transplant; BW, biweekly; C, cycle; CR, complete response; d, dexamethasone; Dara, daratumumab; HD, high dose; HDT, high-dose therapy; HRCA, high-risk cytogenetic abnormalities; IMWG, International Myeloma Working Group; Isa, isatuximab; ISS, International Staging System; ITT, intention-to-treat; IV, intravenous; K, carfilzomib; MFC, multicolor flow cytometry; MRD, minimal residual disease; NA, not available; NDMM, newly diagnosed multiple myeloma; NGF, next-generation flow; NGS, next-generation sequencing; QW, weekly; Q2W, every 2 weeks; R, lenalidomide; sCR, stringent complete response; VMP, bortezomib, melphalan, and prednisone

^a20 mg/m² IV C1, day 1 only; 56 mg/m² IV days 1, 8,15

^b153 patients were enrolled in the first cohort (127 transplant-eligible in arm A, 26 transplant-ineligible in arm B). According to the trial design, the ITT population included 99 transplant-eligible and all 26 transplant-ineligible patients

^cSustained MRD– was defined as at least two consecutive assessments of MRD < 10^–5 at least 12 months apart

^d36 mg/m² IV on days 1–2, 8–9, 15–16 and after first transplant 56 mg/m² IV days 1,8, 15

^e20 mg/m² on C1 day 1, escalated to 70 mg/m² at C1 day 8 onward if deemed tolerable

The efficacy and safety outcomes of clinical trials in patients with NDMM receiving Isa/Dara-KRd followed by ASCT are summarized in Tables 2 and 3, respectively. Efficacy and safety outcomes of clinical trials in patients with NDMM receiving Isa/Dara-KRd without transplant are summarized in Tables 4 and 5, respectively. Additional details of the study designs for all relevant clinical trials are summarized in Supplementary Material.

Table 2.

Activity of Isa/Dara-KRd drug combination therapies in patients with NDMM receiving ASCT

Study	Median follow-up, mo	ORR, %	Best response, %	MRD–, %	MRD– by cytogenetics, %
					High risk	Standard risk	Median (95% CI) PFS, mo	PFS rate (95% CI), %	Median (95% CI) OS, mo	OS rate (95% CI), %
Isa-KRd
IsKia[40]	20 (IQR, 18–23)	NR	Isa-KRd: • ≥ VGPR: 94 • ≥ CR: 74 KRd: • ≥ VGPR: 94 • ≥ CR: 72 (post-consolidation)	• Isa-KRd: 77 (10–5), 67 (10–6) • KRd: 67 (10–5), 48 (10–6) • 10–5: OR 1.67; P = 0.049 • 10–6: OR 2.29; P < 0.001	1 HRCA: • Isa-KRd: 76 (10–5), 72 (10–6) • KRd: 58 (10–5)  ≥ 2 HRCAs: • Isa-KRd: 77 (10–5), 77 (10–6) • KRd: 53 (10–5)	• Isa-KRd: 79 (10–5), 67 (10–6) • KRd: 70 (10–5)	NR	1-y: • Isa-KRd: 95 • KRd: 95	NR	NR
GMMG-CONCEPTa[41]	44	95	• ≥ VGPR: 91 • ≥ CR: 73 (95% CI, 63–81) (post-consolidation)	68 (10–5) (95% CI, 0.589–1) post-consolidation 82 (10–5) at any time point 73/63 (≥ 6/ ≥ 12 mo sustained MRD–)	68 (10–5)	N/A	Not reached	• 1-y: 86 (81–93) • 2-y: 78 (71–86) • 3-y: 69 (61–78)	Not reached	• 1-y: 92 (87–97) • 2-y: 84 (78–91)
Dara-KRd
MASTER[43, 52]	42.2 (IQR, 34.5–46.0)	98 • 0 HRCA: 98 • 1 HRCA: 100 • ≥ 2 HRCAs: 96	≥ CR: 86 • 0 HRCA: 91 • 1 HRCA: 89 • ≥ 2 HRCAs: 71 (post-consolidation)	81 (10–5) (95% CI, 73–88) 71 (10–6) 84 (71% [95% CI, 62–79]) patients reached MRD-SURE with treatment cessation	(10–5) • 1 HRCA: 86 (95% CI, 73–95) • ≥ 2 HRCAs: 79 (95% CI, 58–93) (10–6) • 1 HRCA: 80 • ≥ 2 HRCAs: 63 1-y sustained MRD– • 1 HRCA: 73 • ≥ 2 HRCAs: 46	78 (10–5) 68 (10–6) 64 (1-y sustained MRD–)	NR	2-y: 87 • 0 HRCA: 91 • 1 HRCA: 97 • ≥ 2 HRCAs: 58 (P < 0.001) 3-y: • 0 HRCA: 88 (78–95) • 1 HRCA: 79 (67–88) • ≥ 2 HRCAs: 50 (30–70)	NR	2-y: 94 • 0 HRCA: 96 • 1 HRCA: 100 • ≥ 2 HRCAs: 76 (P = 0.003) 3-y: • 0 HRCA: 94 (88–98) • 1 HRCA: 92 (86–96) • ≥ 2 HRCAs: 75 (63–85)
LCI-HEM-MYE-KRDD-001[44–46]	26 (95% CI, 17–27)	95	≥ VGPR: 36  ≥ CR: 56 (90% CI, 42–79) sCR: 44 (post-induction)	62 (10–5) 41 (10–6)	NR	NR	Not reached	2-y: 85 (72–99)	NR	NR
IFM 2018–04[47, 53]	33	Per-protocol population: 95 (end of induction)	Per-protocol population: VGPR; 60 CR/sCR: 31 (end of induction) CR/sCR: 48 (before consolidation) 70 (end of early consolidation) 81 (before maintenance)	Per-protocol population: 53 (10–5); 43 (10–6) (after induction) 97 (10–5); 94 (10–6) (before maintenance) Intention-to-treat population: 64 (10–5); 62 (10–6) (before maintenance)	Per-protocol population: 97 (10–5); 94 (10–6) (before maintenance)	N/A	Not reached	• 2-y: 87 (78–87) • 30-mo: 80 (68–94)	NR	• 2-y: 94 (87–100) • 30-mo: 91 (82–100)

ASCT, autologous stem cell transplant; CR, complete response; d, dexamethasone; Dara, daratumumab; HRCA, high-risk cytogenetic abnormalities; IQR, interquartile range; Isa, isatuximab; K, carfilzomib; MRD, minimal residual disease; MRD-SURE, minimal residual disease surveillance; N/A, not applicable; NDMM, newly diagnosed multiple myeloma; NR, not reported; OR, odds ratio; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; R, lenalidomide; sCR, stringent complete response; VGPR, very good partial response

^a99 patients were transplant eligible

Table 3.

Safety of Isa/Dara-KRd drug combination therapies in NDMM patients receiving ASCT

Study	AEs, n (%)	Common AEs, any grade	Grade ≥ 3 AEs, n (%)	Common grade 3–4 AEs	Serious AE, n (%)	Discontinuation due to AE, n	Cardiac toxicity: grade ≥ 3 AEs, n (%)a	Deaths during trial, n
Isa-KRd
IsKia[40]	• Hematologic: 55% Isa-KRd, 43% KRd • Non-hematologic: 90% Isa-KRd, 85% KRd	NR	• Hematologic: 40% Isa-KRd, 30% KRd • Non-hematologic: 41% Isa-KRd, 37% KRd	Hematologic: • Isa-KRd: neutropenia (37%), thrombocytopenia (15%) • KRd: neutropenia (22%), thrombocytopenia (17%) Non-hematologic: • Isa-KRd: infections (16%), gastrointestinal (7%), vascular (2%), cardiac events (1%) • KRd: infections (12%), vascular (7%), gastrointestinal (5%), cardiac events (4%)	NR	• Isa-KRd: 6% • KRd: 5%	NR	• Related: Isa-KRd, 4 (COVID, 2; pneumonia, 1; pulmonary embolism, 1); KRd (septic shock), 1 • Emergent: 0
GMMG-CONCEPTb[41]	91 (94)	• Hematologic: neutropenia (41%), thrombocytopenia (28%), leukopenia (26%), anemia (14%) • Non-hematologic: infections (61%), neuropathy (35%), infusion-related reaction (27%), gastrointestinal (20%), hypertension (14%), cardiac (11%)	76 (78)	• Hematologic: neutropenia (39%), thrombocytopenia (27%), leukopenia (25%), anemia (14%) • Non-hematologic: infections (28%), hypertension (10%), gastrointestinal (9%), renal (6%), neuropathy (2%), cardiac (2%), infusion-related reaction (1%)	NR	3	Cardiac events: 2 (2)	Related/ emergent: 5
Dara-KRd
MASTER[43]	123 (100)	• Hematologic: neutropenia (42%), lymphopenia (28%), anemia (22%), thrombocytopenia (18%) • Non-hematologic: fatigue (56%), bone pain (56%), maculopapular rash (41%), infusion-related reactions (28%), hypertension (26%)	94 (76)	• Hematologic: neutropenia (35%), lymphopenia (23%), anemia (11%), leukopenia (10%) • Non-hematologic: fatigue (9%), bone pain (6%), maculopapular rash (4%), hypertension (11%), thromboembolic events (4%), lung infection (4%)	22 (18)	• 2 (for K) • 2 (for R)	0 (1 patient grade 1–2)	• Related: 0 • Emergent: 3
LCI-HEM-MYE-KRDD-001[44–46]	39 (100)	• Infections (51%) • Treatment-related: diarrhea (39%), fatigue (36%), neutropenia (28%), constipation (26%), thromboembolic events (8%)	31 (80)	Treatment-related: neutropenia (21%), hypophosphatemia (13%)	14 (36)	NR	NR	• Related: 1 • Emergent: 0
IFM 2018–04[47]	NR	During induction: • Hematologic: neutropenia (36%), anemia (26%), thrombocytopenia (26%) • Non-hematologic: infections (42%), fatigue (26%), diarrhea (26%), nausea (26%) During consolidation: • Hematologic: neutropenia (21%), thrombocytopenia (19%), anemia (7%) • Non-hematologic: infections (35%), diarrhea (21%), fatigue (19%)	NR	During induction: • Hematologic: neutropenia (32%), anemia (18%), thrombocytopenia (14%) • Non-hematologic: nausea (4%), infections (4%), psychiatric (4%), diarrhea (2%) During consolidation: • Hematologic: neutropenia (14%), thrombocytopenia (9%) • Non-hematologic: infections (5%), nausea (2%)	NR	4	NR	• Related: 2 • Emergent: 7

AE, adverse event; ASCT, autologous stem cell transplant; d, dexamethasone; Dara, daratumumab; Isa, isatuximab; K, carfilzomib; NDMM, newly diagnosed multiple myeloma; NR, not reported; R, lenalidomide

^aDefinitions of preferred terms for cardiac toxicity listed in supplement as available

^b99 patients were transplant eligible

Table 4.

Activity of Isa/Dara-KRd in patients with NDMM not receiving ASCT

Study	Median follow-up, mo	ORR, %	Best response, %	MRD–, %	MRD– by cytogenetics, %		Median (95% CI) PFS, mo	PFS rate (95% CI), %	Median (95% CI) OS, mo	OS rate (95% CI), %
					High risk	Standard risk
Isa-KRd
GMMG-CONCEPTa[41]	33	89 (post-consolidation)	• ≥ VGPR: 89 • ≥ CR: 58	54 (10–5) 69 (10–5) at any time point 54/46 (≥ 6/ ≥ 12 mo sustained MRD–)	54 (10–5)	N/A	Not reached	• 1-y: 75 (60–95) • 2-y: 63 (46–85) • 3-y: 58 (42–82)	Not reached	• 1-y: 84 (70–100) • 2-y: 71 (55–92)
SKylaRkb[[42,54]]	26	100	C8: • ≥ VGPR: 98 • ≥ CR: 65 (post-consolidation)	C8: 72 (10–5) 19 (10–6)	NR	NR	NR	• 1-y: 98 (86–100) • 2-y: 91 (83–100)	NR	• 1-y: 98 (86–100) • 2-y: 96 (90–100)
Dara-KRd
GEM2017FIT[48]	33	VMP-Rd: 87 (P < 0.0001) Dara-KRd: 89 (P < 0.0001) KRd: 89 (P < 0.0001) (end of induction)	≥ CR: • VMP-Rd: 40 (P < 0.0001) • Dara-KRd: 61 (P < 0.0001) • KRd: 59 (P < 0.0001)	(10–5) • VMP-Rd: 32 (P < 0.0001) • Dara-KRd: 79 (P < 0.0001) • KRd: 69 (P < 0.0001) (10–6) • VMP-Rd: 24 (P < 0.0001) • Dara-KRd: 75 (P < 0.0001) • KRd: 59 (P < 0.0001)	NR	NR	NR	18 mo: • VMP-Rd: 79 • Dara-KRd: 87 • KRd: 87	NR	18 mo: • VMP-Rd: 91 • Dara-KRd: 90 • KRd: 95
MANHATTAN[49]	20.3 (95% CI, 19–22)	100 (end of C8)	• ≥ VGPR: 95 • ≥ CR: 95	71 (54–83) (10–5) 88 (1-y sustained MRD–)c	OR, 1.7 (95% CI, 0.36–8.6); P = 0.50 vs standard risk	N/A	NR	1-y: 98 (93–100)	NR	1-y: 100
UC-IRB17-1097[50]	27	95 (end of C8 induction) sCR and/or MRD–: 75 (95% CI, 61–89)	• ≥ VGPR: 95 • sCR: 68	59 (10–5) 35 (10–6) Best MRD– 65 (10–5), 53 (10–6) 40 (1-y sustained MRD–)d	NR	NR	NR	3-y: 85 • 0 HRCA: 100 • 1 HRCA: 92 • ≥ 2 HRCAs: 60	NR	3-y: 95
MMY1001[51]	23.3 (6.9–27.7)	100 (end of C13)	• ≥ VGPR: 86 • ≥ CR: 67	75 (10–5) (for 6 of 8 patients who achieved ≥ CR)	NR	NR	Not reached	1-y: 95 (71–99)	NR	NR

ASCT, autologous stem cell transplant; C, cycle; CR, complete response; d, dexamethasone; Dara, daratumumab; HRCA, high-risk cytogenetic abnormalities; Isa, isatuximab; ITT, intention-to-treat; K, carfilzomib; MRD, minimal residual disease; N/A, not applicable; NDMM, newly diagnosed multiple myeloma; NR, not reported; OR, odds ratio; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; R, lenalidomide; sCR, stringent complete response; SCT, stem cell transplant; VGPR, very good partial response; VMP, bortezomib, melphalan, and prednisone

^a26 patients were transplant ineligible

^bThe SKylaRk trial included transplant-eligible patients, but SCT was deferred in most patients (89%; 40/45 patients who were evaluable after induction and consolidation). A total of 36 patients completed C8 of therapy and were evaluable for MRD measurement. PFS and OS were evaluated in the ITT population (N = 50)

^cPatients who were assessed for MRD at 1-y follow-up

^dMRD < 10^–5 on two or more instances ≥ 1 y apart. The denominator includes patients with trackable MRD and ≥ 1 y of MRD follow-up if they had at least one MRD negative result

Table 5.

Safety of Isa/Dara-KRd in patients with NDMM not receiving ASCT

Study	AEs, n (%)	Common AEs, any grade	Grade ≥ 3 AEs, n (%)	Common grade 3–4 AEs	Serious AE, n (%)	Discontinuation due to AE, n	Cardiac toxicity: grade ≥ 3 AEs, n (%)a	Deaths during trial, n
Isa-KRd
GMMG-CONCEPTb[41]	22 (88)	• Hematologic: neutropenia (28%), thrombocytopenia (20%), anemia (20%), leukopenia (4%) • Non-hematologic: infections (48%), gastrointestinal (28%), cardiac (20%), neuropathy (16%), infusion-related reaction (16%), hypertension (16%), renal (16%)	18 (72)	• Hematologic: neutropenia (28%), thrombocytopenia (16%), anemia (12%), leukopenia (4%) • Non-hematologic: infections (28%), cardiac (20%), hypertension (8%), renal (8%), neuropathy (4%), gastrointestinal (4%)	NR	3	5 (20)	Related/emergent: 2
SKylaRkc[42]	NR	Grade 1–2 infusion-related reactions (20%), grade 1–2 hypertension (14%)	NR	Neutropenia (26%), elevated alanine aminotransferase (12%), fatigue (6%), thrombocytopenia (6%), acute kidney injury (4%), anemia (4%), febrile neutropenia (4%), hypertension (2%)	NR	2	Grade 3 myocardial infarction: 1 (2)	• Related: 0 • Emergent: 2
Dara-KRd
GEM2017FIT[48]	NR	NR	NR	Neutropenia • VMP-Rd: 50% • Dara-KRd: 47% • KRd: 24% (P < 0.0001) Thrombocytopenia • VMP-Rd: 34% • Dara-KRd: 17% • KRd: 16% (P < 0.0001) Infections • VMP-Rd: 12% • Dara-KRd: 16% • KRd: 15%	NR	• VMP-Rd: 8 • Dara-KRd: 6 • KRd: 14	Including hypertension and cardiac failure: • VMP-Rd: 5% • Dara-KRd: 14% • KRd: 11% (P < 0.0001)	Related: • VMP-Rd: 6 • Dara-KRd: 12 • KRd: 5
MANHATTAN[49]	NR	• Hematologic: neutropenia (36%), anemia (11%), thrombocytopenia (9%) • Non-hematologic: rash (45%), constipation (43%), fatigue (43%), insomnia (43%), nausea (43%), diarrhea (41%), hypertension (9%)	NR	• Hematologic: neutropenia (27%) • Non-hematologic: rash (9%), lung infection (7%)	8 (18)	0	1 (2)	Related/emergent: 0
UC-IRB17-1097[50]	NR	• Hematologic: lymphopenia (69%), thrombocytopenia (64%), anemia (59%), neutropenia (26%) • Non-hematologic: fatigue (88%), hyperglycemia (76%), diarrhea (71%), upper respiratory infectionsd (67%), lower extremity edema (67%), hypertension (57%)	NR	• Hematologic: lymphopenia (36%), thrombocytopenia (26%), neutropenia (21%), anemia (2%) • Non-hematologic: hypertension (17%), hypokalemia (10%), liver enzyme elevations (10%), hyperglycemia (7%), upper respiratory infections§ (7%)	NR	1	2, grade 3: atrial fibrillation, heart failure	Related/emergent: 0
MMY1001[51]	NR	• Hematologic: lymphopenia (64%), anemia (46%), thrombocytopenia (41%), neutropenia (36%), leukopenia (36%) • Non-hematologic: diarrhea (68%), cough (59%), upper respiratory infections (55%)	NR	• Hematologic: lymphopenia (59%), neutropenia (18%), anemia (9%), leukopenia (5%) • Non-hematologic: diarrhea (18%), insomnia (9%), increased alanine aminotransferase (9%)	10 (46)	1	1 (5) transient cardiac failure	Related/emergent: 0

AE, adverse event; ASCT, autologous stem cell transplant; d, dexamethasone; Dara, daratumumab; Isa, isatuximab; K, carfilzomib; NDMM, newly diagnosed multiple myeloma; NR, not reported; R, lenalidomide; SCT, stem cell transplant; VMP, bortezomib, melphalan, and prednisone

^aDefinitions of preferred terms for cardiac toxicity listed in supplement as available

^b26 patients were transplant ineligible

^cThe SKylaRk trial included transplant-eligible patients, but SCT was deferred in most patients (89%)

^dIncludes 16 patients (38%) with COVID-19 infection (1 was a grade 3 event)

Considerations in the Advancement of Frontline MM Treatment

MRD– as a treatment goal

There is expanding evidence that depth of response to treatment is prognostic of duration of response and MM disease remission, which along with improved abilities to detect deeper responses, has led to the emerging paradigm of increased dose density and therapeutic intensity in the frontline [8, 9, 24, 55]. Until recently, studies commonly assessed ORR to measure treatment response, but this has been found to be a less sensitive prognostic indicator of survival outcomes and less discriminating between therapeutic options than deeper measures of response, especially as recently introduced regimens achieve ORRs approaching 100% in clinical trials [13, 14, 16]. Achievement of MRD– status has been found to be the strongest predictor of survival outcomes, with deeper MRD– translating into longer PFS and OS [8, 9, 56, 57]. Considering recently conducted meta-analyses of MRD and survival outcomes in MM clinical trials [9, 56, 58]. an Oncologic Drugs Advisory Committee convened by the US Food and Drugs Administration voted unanimously that the evidence supports the use of MRD as an early endpoint in MM trials for accelerated approvals of new MM therapies [59].

In clinical trials, treatment with Isa/Dara-KRd has induced deep responses in patients with NDMM, including high rates of MRD–, with consistent efficacy in both transplant-eligible and transplant-ineligible NDMM. In patients who also received ASCT, MRD– rates post-consolidation ranged between 68 and 81% at 10^–5 (< 1 myeloma cell in 100 000 cells) and between 67 and 71% at 10^–6 (< 1 in 1,000,000) in entire trial populations without regard to baseline prognostic factors, such as disease staging or cytogenetic risk (Table 2) [40, 41, 43, 47]. In the phase 3 IsKia trial in patients with transplant-eligible NDMM, MRD– was superior for Isa-KRd versus KRd at 77% versus 67% at 10^–5 (P = 0.049) and 67% versus 48% at 10^–6 (P < 0.001) [40]. In the phase 2 MASTER trial, the use of Dara-KRd induction with ASCT and MRD-directed Dara-KRd consolidation and/or referral to treatment-free surveillance provided promising MRD– outcomes of 81% at 10^–5 and 71% at 10^–6 [43]. Likewise, two trials in high-risk NDMM patients receiving transplant reported impressive post-consolidation MRD– (10^–5) rates of 68% in CONCEPT (Isa-KRd) and > 90% in the per-protocol population in IFM2018-04 (Dara-KRd), which increased to 97% following the addition of a second ASCT in the latter [41, 47].

The high rates of MRD– observed with Isa/Dara-KRd and ASCT in NDMM compare favorably with those observed in other trials of experimental quadruplet regimens, such as Dara-VTd [23] or Dara-VRd [26, 27]. The addition of Dara to the underlying triplets yielded higher rates of MRD– that translated into longer PFS for patients. For example, in the PERSEUS trial, the MRD– rate (10^–5) post-consolidation was 57.5% with Dara-VRd, translating to an estimated 4-year PFS rate of 84% [27]. Although there is a relatively short follow-up in several of the KRd-based trials in transplant-eligible NDMM so far, it is anticipated that the impressive MRD– rates achieved by Isa/Dara-KRd after consolidation may also increase over the course of longer maintenance and follow-up and could translate into extended survival outcome [8, 9, 58]. The 1- to 3-year estimated PFS and OS rates with Isa/Dara-KRd with ASCT in clinical trials reported to date are promising (Table 2), especially considering their inclusion of many patients with a higher baseline risk for relapse.

In the absence of transplant, treatment with Isa/Dara-KRd in clinical trials resulted in MRD– rates ranging from 54 to 79% at 10^–5 and 19% to 75% at 10^–6 (Table 4) [41, 42, 48–51]. In the phase 3 GEM2017FIT trial, post-induction MRD– rates for elderly, fit, transplant-ineligible patients with NDMM treated with Dara-KRd were superior to KRd alone and to bortezomib/melphalan/prednisone (VMP)–lenalidomide/dexamethasone (Rd), with rates of 79% for Dara-KRd versus 69% for KRd (P < 0.0001) versus 32% for VMP-Rd (P < 0.0001) at 10^–5, and 75% versus 59% versus 24%, respectively, at 10^–6 (P < 0.0001) [48]. The phase 2 MANHATTAN trial that included both transplant-ineligible and transplant-deferring patients, independent of age, reported a similar MRD– rate of 71% at 10^–5 following 8 cycles of induction with Dara-KRd [49]. The LCI-HEM-MYE-KRDD-001 trial also showed high rates of MRD– (62% at 10^–5; 41% at 10^–6) after the same duration with Dara-KRd without transplant [44–46]; these responses were generally consistent in the MMY1001 (75% at 10^–5) and UC-IRB17-1097 (59% at 10^–5) studies, different dosing schedules notwithstanding [50, 51]. Even transplant-ineligible high-risk patients achieved a robust MRD– rate of 54% (10^–5) in the GMMG-CONCEPT trial with Isa-KRd [41].

In transplant-ineligible frail patients, the most rigorous SOCs that are well established are triplet regimens [60]. The phase 3 MAIA trial of Dara-Rd versus Rd for transplant-ineligible patients reported improved PFS with Dara-Rd (median, 61.9 months) [60], with an MRD– rate of 32% at 10^–5 as best response, which is not markedly greater than MRD– rates that have been observed with VRd/VTd in clinical trials and real-world practice [14, 28, 61]. Investigations into the use of VRd plus anti-CD38 quadruplet regimens without transplant for selected patients were recently published [62, 63]. Although data from the phase 3 trial of Dara-VRd (CEPHEUS) are yet to be reported, the phase 3 IMROZ study presented an MRD– rate of 58% at 10^–5 as best response at any time with Isa-VRd in patients with transplant-ineligible NDMM [63, 64]. As evidenced by the studies summarized in this review, Isa/Dara-KRd may improve upon deep response rates including MRD– while remaining tolerable in transplant-ineligible and transplant deferring patients (Tables 4 and 5) [41, 42, 44–46, 48–51], possibly portending further prolongation of remissions, although longer follow-up is required.

Patients with high-risk MM

An area of focus for treatment intensification, such as quadruplet therapies, has been high-risk patients with NDMM, a difficult-to-treat subset of patients representing 20% to 40% of the MM population [65]. This patient group represents a particularly urgent unmet need, as patients with high-risk chromosomal abnormalities (HRCA) have an overall higher risk of earlier relapse and shorter OS. Transplant-eligible patients with high-risk NDMM who are treated with SOC exhibit OS of < 3 years, and for those with ultra-high-risk disease (≥ 2 HRCAs), expected survival is < 2 years. In high-risk patients who cannot receive transplant, OS < 2 years may be expected [65, 66]. However, achieving MRD– has been found to be associated with better outcomes in MM patients with high-risk cytogenetics; 3-year PFS and OS rates are > 90% in patients with undetectable MRD with no significant difference between standard-risk (91%–96%) versus high-risk (97%–100%) patients [67].

As a potential backbone for the addition of anti-CD38 mAbs, KRd has shown benefit in both standard-risk and high-risk MM [35, 68, 69]. A phase 3 clinical trial of KRd versus VRd that evaluated a fixed number of cycles in patients with standard-risk NDMM and no intent for upfront ASCT did not demonstrate a difference in survival [70]. Although treatment with KRd was associated with a higher incidence of cardiac, pulmonary, or renal adverse events than VRd, the trial showed that KRd resulted in deeper responses to therapy and fewer occurrences of neurotoxicity, particularly peripheral neuropathy, compared to VRd, and may have overcome the impact of specific chromosomal abnormalities on OS [70, 71]. Additionally, the phase 2 FORTE trial observed a survival advantage of KRd plus ASCT regardless of risk status with impressive 1-year MRD– rates [35, 72]. Given these findings, addition of an anti-CD38 mAb to KRd has been hypothesized to benefit high-risk patients especially.

Evidence for this added benefit in high-risk patients with NDMM is supported by studies with Isa/Dara-KRd that resulted in deep responses including MRD–, regardless of risk status (eg, 0, 1, or ≥ 2 HRCA). In the MASTER trial that was specifically enriched for patients with HRCA (57% with ≥ 1 HRCA), Dara-KRd led to consistently high rates of post-consolidation MRD– at 10^–5 of 78%, 86%, and 79% in patients with 0, 1, and ≥ 2 HRCAs, respectively [73]. Deep responses translated to prolonged PFS and OS in patients with 0 or 1 HRCA despite most patients discontinuing therapy. The 3-year PFS rates were 88%, 79%, and 50% and 3-year OS rates were 94%, 92%, and 75% for patients with 0, 1, and ≥ 2 HRCAs, respectively, suggesting that there may be room for improvement in outcomes for patients with ultra-high-risk disease. Likewise, deep responses among high-risk patients were consistent in the IFM 2018–04 trial of Dara-KRd, which demonstrated a ≥ CR rate of 81% with pre-maintenance MRD– rates of 97% at 10^–5 and 94% at 10^–6 following tandem-ASCT and 30-month PFS and OS rates of 80% and 91%, respectively [47]. In the GMMG-CONCEPT trial, transplant-eligible high-risk patients with NDMM benefited from Isa-KRd and ASCT with ≥ CR rates of 73% and a MRD– rate of 68% at 10^–5 post-consolidation (82% MRD– as best response at any time), translating into a 1-year sustained MRD– in 63% of transplant-eligible patients. Median PFS and OS were not reached after 44 months of follow-up, and 2-year PFS and OS rates were 78% and 84%, respectively, across an entirely high-risk patient population [41]. Patients treated with Isa-KRd induction and consolidation in the IsKia trial achieved impressive and consistent post-consolidation MRD– at 10^–5 of 79%, 76%, and 77% in patients with 0, 1, and ≥ 2 HRCAs, respectively, with a 1-year PFS rate of 95% across all patients [40].

Isa/Dara-KRd has also resulted in deep responses and robust initial survival rates among patients with high-risk NDMM in the absence of upfront transplant. Patients deemed transplant-ineligible in the GMMG-CONCEPT trial for high-risk NDMM (≥ 1 HRCA) achieved a ≥ CR rate of 58%, post-consolidation (12 cycles total) MRD– of 54% at 10^–5 (69% as best response at any time), and a 46% 1-year sustained MRD– [41]. The previously mentioned MANHATTAN trial included 49% of patients with HRCAs, yet resulted in an MRD– rate of 71% at 10^–5 after 8 cycles of Dara-KRd and an 88% 1-year sustained MRD– rate [49]. Similarly, 72% of evaluable patients in the SKylaRk trial, which included 46% of patients with ≥ 1 HRCA, exhibited MRD– by the end of 8 cycles of Isa-KRd [42].

The reported efficacy with Isa/Dara-KRd in clinical trials discussed above appears favorable relative to the current SOCs and other emerging quadruplet regimens, especially among high-risk patients with NDMM. A subgroup analysis of high-risk patients in the CASSIOPEIA study reported ≥ CR rates of 37% and 60% MRD– at 10^–5 post-consolidation for patients receiving Dara-VTd and ASCT [74]. These were similar to outcomes from the Dara-VTd overall study population (≥ CR, 39%; MRD– at 10^–5, 64%) [23] but did not translate into the same reduction of risk of progression/death for high-risk patients (hazard ratio, 0.67 [95% CI, 0.35–1.30] versus intention-to-treat hazard ratio, 0.47 [95% CI, 0.33–0.67]) [23, 74]. In the phase 2 GRIFFIN trial, patients receiving Dara-VRd and ASCT with 0, 1, and ≥ 2 HRCAs achieved ≥ CR rates of 91%, 79%, and 62%, respectively; MRD– rates at 10^–5 of 76%, 56%, and 62%; and 2-year PFS rates of 97%, 94%, and 64% [75]. Similar results were seen for high-risk patients in the Dara-VRd arm of the PERSEUS trial, with a ≥ CR rate of 83% and MRD– of 68% at 10^–5, with no available data delineating the number of HRCAs among patients. Although mature survival data have not been reported, the PFS favorability of Dara-VRd versus VRd was somewhat attenuated for high-risk compared with standard-risk patients, with PFS hazard ratios 0.59 (95% CI, 0.36–0.99) and 0.35 (95% CI, 0.22–0.56), respectively [27].

As such, Isa/Dara-KRd may be an important treatment option, especially for patients with high-risk disease. The evidence suggests that a consistently high proportion of patients with ≥ 2 HRCAs are also able to achieve MRD– with Isa/Dara-KRd induction and consolidation; however, this population still harbors a worse prognosis and may benefit from sustained, intensified, and/or alternative therapy compared with patients with 0 or 1 HRCA.

The future role of transplant

Considering the deeper responses to frontline therapy that have been achieved with quadruplet regimens such as Isa/Dara-KRd, the need for upfront transplantation has been increasingly questioned, and many patients are now given the option of deferred transplant with upfront collection of stem cells [76]. Previously, the DETERMINATION and IFM 2009 studies showed that upfront ASCT may not necessarily translate into longer OS [13, 77], although many factors throughout treatment and subsequent to ASCT could have affected survival outcomes, including ASCT-associated risks of adverse events (AEs) and post-transplant mortality.

The ability of Isa/Dara-KRd to drive deep and sustained responses may afford patients the ability to forego or delay transplant, possibly preserving it for salvage therapy at first relapse. Dara-KRd without ASCT in the UC-IRB17-1097 study [50] (Table 3) resulted in rates of MRD–, 1-year sustained MRD–, CR, and ORR comparable to those observed in patients treated with KRd plus ASCT in the FORTE study [35]. The MANHATTAN trial enrolled transplant-ineligible and transplant-deferring patients. Of the 29 (71%) patients who achieved MRD– by the end of Dara-KRd therapy, only 5 elected to undergo ASCT within the following 9 months of follow-up, allowing most patients to further delay transplant [49]. These results are further supported by the SKylaRk trial with Isa-KRd, in which optional ASCT was deferred in most patients (89%, n = 40/45). After 8 cycles of Isa-KRd, transplant-deferred patients achieved an ORR of 100% with ≥ CR of 65% and resulted in MRD– at 10^–5 of 72% in MRD-evaluable patients [42].

Additional studies and longer follow-up are needed to determine whether there is a net benefit to deferred ASCT for transplant-eligible NDMM patients receiving quadruplet regimens. The ongoing randomized phase 3 trial MIDAS is directly testing the clinical benefits of upfront transplant versus deferral for MRD– patients and single transplant versus tandem transplant for MRD-positive patients following induction with Isa-KRd, evaluating postponement of frontline ASCT as a treatment goal [78]. Additionally, the phase 2 MASTER-2 study is also evaluating the benefits of upfront versus deferred ASCT and potential sequential therapy guided by MRD assessments following induction with Dara-VRd [79].

Response-adapted therapy

In addition to raising questions about the role of upfront ASCT in eligible patients, the introduction of highly effective quadruplet regimens has raised considerations about the potential for de-escalation of therapy following confirmation of a deep and sustained response, possibly sparing some patients unnecessary risks of toxicity and relieving selective pressures that could drive development of future treatment resistance. MRD is emerging as a tool that could guide therapy for some patients through intensification, de-intensification, and/or cessation, and understanding of how MRD may be used to guide treatment decision making is evolving [57, 80–82]. The MASTER study specifically investigated whether NDMM patients with confirmed MRD– could discontinue therapy and sustain durable remissions. With a median follow-up of 42 months, 71% of MRD-evaluable patients discontinued therapy after two consecutive MRD– assessments separated by one phase of therapy (either ASCT or four 4-week cycles of treatment) and began follow-up with observation only; 52% of patients remained off therapy with sustained MRD–, varying by baseline cytogenetic risk. Two-year MRD resurgence was low for patients with 0 and 1 HRCA (9% and 14%, respectively) and high for patients with ≥ 2 HRCAs (60%), with 3-year PFS rates of 88%, 85%, and 60% [43]. In contrast, the GMMG-CONCEPT trial for high-risk NDMM (patients with 1 HRCA, 62%; ≥ 2 HRCAs, 30%) evaluated an extended treatment schedule inclusive of Isa-KR maintenance. MRD– was sustained for ≥ 1 year in 63% of transplant-eligible patients and 46% of transplant-ineligible patients, translating to prolonged PFS among both patient groups, and that appeared to exceed 3 years even in patients with ≥ 2 HRCAs [41]. Treatment de-intensification or cessation could be a reasonable approach for standard-risk and some high-risk patients with NDMM following Isa/Dara-KRd treatment, although the ideal timepoint(s) for MRD assessment and duration of sustained MRD– to inform clinical decision-making merit further investigation [43, 78]. The totality of evidence suggests that ultra-high-risk patients may be more likely to have disease progression even if a high proportion may achieve MRD–[41, 43] and may therefore benefit from a more intensified, extended, and/or continuous treatment schedule[41, 83] or the addition of novel therapies [84].

Enhancing efficacy in selected elderly patients

Intensification of therapy may introduce risks of complications and AEs, particularly in older patients in whom MM more often occurs. The median age at diagnosis of MM is 69 years, and patients with MM in the real-world setting frequently present with comorbidities and conditions that create challenges to straightforward selection of therapy [85]. Historically, frail and elderly patients have been less likely to receive intensified therapies, such as triplet regimens, transplant, or doublet maintenance, compared with younger and more fit patients [85]. In 2015, the International Myeloma Working Group established a consensus frailty score for the prognosis of elderly/frail patients with MM [86]. Since then, several studies have used similar scoring systems and/or geriatric assessments to characterize the fitness or frailty of patients in efforts to select or characterize patients for whom novel therapies may be most appropriate with a more discriminating measure than age alone [85].

Consistent with previous trials of carfilzomib regimens [87–90], quadruplet therapies with Isa/Dara-KRd have also demonstrated clinical benefit in elderly patients. In the MASTER trial, for example, no upper age limit was imposed on patient enrollment as long as investigators deemed the patients fit for transplant, leading to the participation of 20% of patients ≥ 70 years of age [43]. Transplant-ineligible patients in GMMG-CONCEPT had a median age of 74 years [41]. The clinically meaningful results of both studies have already been discussed within this review. Initial trial results from GEM2017FIT, a phase 3 trial that enrolled elderly fit NDMM patients aged between 65 and 80 years [48], highlight the importance of frailty scores in determining optimally intensive therapies while preserving tolerability in appropriate patients, potentially including those of older age. In this trial, MRD– rates at 10^–5 were significantly higher with KRd (69%) and Dara-KRd (79%) compared with VMP-Rd (32%); 18-month estimates of PFS rates were 87% for KRd and Dara-KRd, respectively, versus 79% for VMP-Rd, accompanied by lower rates of grade 3 to 4 neutropenia and thrombocytopenia in the KRd and Dara-KRd arms and overall comparable rates of infection across all three arms [48]. Grade 3–4 cardiovascular AEs, including hypertension and cardiac failure, were more frequent in the KRd and Dara-KRd groups than with VMP-Rd (11% versus 14% versus 5%, respectively) [48]. Future analyses may help characterize patients with frailty-related factors, such as older age, comorbidities, or compromised daily functioning, for whom KRd-based quadruplet therapies may or may not be appropriate.

Safety

Whenever considering intensification of therapy to aggressively abrogate disease burden, it is imperative to consider the burden on the patient also. Across clinical trials adding anti-CD38 mAbs to KRd, there were no unexpected or emergent safety risks. Consistent with the known toxicity profiles of these treatments, patients experienced infusion site reactions, especially when the anti-CD38 mAb was infused intravenously. Hematologic AEs (including neutropenia, lymphopenia, anemia, thrombocytopenia, and leukopenia) and nonhematologic AEs (including fatigue, bone pain, rash, and upper respiratory tract infections) were consistent with the known safety profiles of each therapy. Importantly, the addition of anti-CD38 mAbs did not exacerbate or introduce new risks of cardiac toxicities (Tables 3 and 5) [40–43, 46–51]. Patients treated with KRd should be monitored for clinical signs or symptoms of cardiac failure or ischemia and dosing of carfilzomib withheld for grade ≥ 3 cardiac adverse events until recovery, with consideration of restarting at a lower dose based on benefit/risk assessment. In patients aged ≥ 75 years, a complete comprehensive medical assessment should be carried out before starting carfilzomib treatment and they should remain closely followed [32]. The most common adverse events occurring in at least 20% of patients treated with carfilzomib in the combination therapy trials that supported its indications for the treatment of RRMM included anemia, diarrhea, hypertension, fatigue, upper respiratory tract infection, thrombocytopenia, pyrexia, cough, dyspnea, and insomnia [32].

Future development with ongoing studies of anti-CD38 quadruplet therapy in NDMM

Many questions remain unanswered in the emerging era of quadruplet therapies for NDMM. Given the increasing recognition of MRD as a prognostic indicator of remission and survival, response-adapted therapy is a logical next step, where transplant could potentially be deferred and/or patients with acceptable risk factors may be spared overly rigorous regimens, whereas patients with difficult-to-treat MM may benefit from response-tailored intensification. Going forward, research and clinical practice employing novel therapies and combinations, including Isa/Dara-KRd, may question the longstanding myeloma paradigm that categorizes patients as transplant-eligible and -ineligible, which has historically disqualified older patients from intensified therapies. Tailoring therapy based on the goals of care, fitness of the patient, and each patient’s individual risk profile to provide the best optimal therapy independent of age is an increasingly realistic aspiration. In light of the encouraging results observed with upfront quadruplet combination therapy to date, several more studies have been initiated to evaluate the potential of KRd plus anti-CD38 in NDMM, including some focusing on the urgent needs for patients with high-risk MM [78, 91, 92], and protocols in which patients will or will not receive upfront ASCT [78, 91–95].

Conclusion

The addition of anti-CD38 mAb to KRd has shown promising results including high rates of MRD– that compare favorably to existing SOCs and emerging quadruplet regimens in various patient groups with NDMM. The efficacy observed with intensified yet well-tolerated regimens could potentially enable risk- and response-adapted treatment strategies. However, a lack of head-to-head trial data and open questions such as the optimal timepoint(s) for MRD– assessment and the potential role of quadruplet regimens as transplant-sparing upfront treatment strategies suggest the need for further investigation.

In summary, Isa/Dara-KRd are favorable and tolerable treatment options within the emerging SOC employing quadruplet regimens where appropriate for patients with NDMM.

Supplementary Information

Below is the link to the electronic supplementary material.

Author Contributions

F.E., I.M., R.N., and K.W. contributed to data collection and writing of the original draft. L.J.C. and O.L. contributed to data collection. All authors (L.J.C., F.G., O.L., M-V.M., P.M., C.T., F.E., I.M., R.N., K.W.) contributed to conceptualization of the review, review and edit of subsequent drafts, approved the final manuscript, and agreed to publication.

Funding

The study was sponsored and funded by Amgen Inc.

Data Availability

No datasets were generated or analysed during the current study.

Declarations

Ethics Approval

N/A.

Consent

N/A

Competing Interests

L.J.C. received research funding from Amgen, BMS, Caribou, Genentech, and Janssen; and honoraria from Adaptive Biotechnologies, Amgen, BMS, Janssen, and Pfizer. F.G. reports consulting fees from Amgen, BMS, Oncopeptides, Pfizer, and Roche; honoraria from AbbVie, Amgen, BMS, Janssen, Sanofi, and Takeda; and data safety monitoring or advisory board participation from AbbVie, Amgen, BMS, Janssen, Oncopeptides, Pfizer, Roche, Sanofi, and Takeda. O.L. acknowledges funding from Amgen, Celgene, FDA, Glenmark, IMF, Janssen, Karyopharm Therapeutics, 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 for scientific talks/participation in advisory boards for AbbVie, Adaptive, Amgen, Binding Site, BMS, Celgene, GSK, Janssen, Juno, and Pfizer; and serving on Independent Data Monitoring Committees (IDMCs) for international randomized trials by Janssen, Merck, Novartis, and Takeda. M-V.M. reports consulting fees from Amgen, GSK, Janssen, Seagen, and Takeda; honoraria and data safety monitoring or advisory board participation from AbbVie, Amgen, Celgene, GSK, Janssen, Oncopeptides, Pfizer, Regeneron, Roche, Sanofi, and Takeda. P.M. reports advisory board participation and honoraria from AbbVie, Amgen, BMS, Celgene, Janssen, Pfizer, Sanofi, and Takeda. C.T. received honoraria from and served in a consulting or advisory role for AbbVie, Amgen, Celgene, Janssen, and Takeda; and had travel, accommodations or other expenses paid or reimbursed by AbbVie, Amgen, Janssen, and Takeda. F.E., I.M., and R.N. are employees of Amgen. K.W. has served in a consulting or advisory role for Adaptive Biotechnologies, Amgen, BMS, Celgene, GSK, Janssen-Cilag, Karyopharm Therapeutics, Oncopeptides, Roche, Sanofi, and Takeda; received travel, accommodations, and/or expenses from Amgen, BMS, Celgene, GSK, Janssen-Cilag, and Takeda; honoraria from AbbVie, Adaptive Biotechnologies, Amgen, BMS, Celgene, GSK, Janssen-Cilag, Karyopharm Therapeutics, Novartis, Oncopeptides, Pfizer, Roche/Genentech, Sanofi, and Takeda; and research funding from Amgen, BMS, Celgene, GSK, Janssen-Cilag, and Sanofi.