Abstract

CD38 antibodies were first evaluated in extensively pretreated patients with multiple myeloma (MM). Currently, there are 3 CD38 antibody–based regimens approved for the treatment of both transplant-eligible (daratumumab plus bortezomib-thalidomide-dexamethasone [D-VTd]) and transplant-ineligible (daratumumab plus lenalidomide-dexamethasone [D-Rd] or daratumumab plus bortezomib-melphalan-prednisone [D-VMP]) patients with newly diagnosed MM (NDMM). The phase 3 studies that evaluated these regimens uniformly showed that the addition of daratumumab to backbone regimens improved the depth of response, which translated into improved progression-free survival and also overall survival in 2 of the studies. Importantly, elderly patients age 75 years or older benefit from these regimens, indicating that these regimens have an acceptable safety profile. Although the number of patients with high-risk cytogenetics was relatively small, these patients also experienced benefit from the addition of daratumumab to standard-of-care regimens, but poor risk conferred by the cytogenetic aberrations is not completely abrogated. Altogether, daratumumab-based regimens have high anti-MM activity and a favorable toxicity profile and therefore represent new standards of care for patients with NDMM.

Learning Objectives

  • Review the evidence for the use of CD38 monoclonal antibodies in patients with NDMM

  • Understand the benefit of CD38 antibody-based therapy in several subsets of patients, including elderly patients and patients with high-risk disease

Clinical case

A 75-year-old man presented with bone disease and anemia and was diagnosed with multiple myeloma (MM) in 2017. Additional staging revealed International Staging System (ISS) stage II disease without poor-risk cytogenetic features. He also suffered from diabetes mellitus and grade 2 diabetic neuropathy. He walked 4 to 8 km with his dog every day and had no limitations in (instrumental) activities of daily living. At that time, he came to the office to discuss his first-line treatment options.

Introduction

The treatment landscape of MM is rapidly changing with the incorporation of CD38 antibodies in first-line regimens. Daratumumab is a first-in-class, fully human, CD38-targeting antibody that showed marked activity and a favorable toxicity profile when it was first evaluated as a single agent in heavily pretreated MM patients. This resulted in the evaluation of CD38 antibodies in early relapsed MM and subsequently in newly diagnosed (ND) disease. There are currently 3 CD38 antibody-based regimens approved by the US Food and Drug Administration and European Medicines Agency for the treatment of NDMM: 2 for transplant-ineligible patients (daratumumab plus bortezomib-melphalan-prednisone [D-VMP] and daratumumab plus lenalidomide-dexamethasone [D-Rd]), and 1 for transplant-eligible patients (daratumumab plus bortezomib-thalidomide-dexamethasone [D-VTd]). We will review the efficacy of these CD38 antibody–based combination regimens and then describe the value of CD38 antibody–based combination therapy in specific MM subgroups, with a focus on elderly patients and those with high-risk cytogenetic aberrations.

CD38 antibody–based therapy for transplant-ineligible patients

Established treatment options for transplant-ineligible NDMM patients include combination therapies such as lenalidomide-dexamethasone (Rd), bortezomib-melphalan-prednisone (VMP), and bortezomib-lenalidomide-dexamethasone (VRd). In addition, daratumumab-containing regimens are being used more often on the basis of the results from 2 randomized phase 3 trials. The ALCYONE study evaluated VMP with or without daratumumab in transplant-ineligible NDMM patients (median age, 71 years).1,2  Patients treated with daratumumab achieved a deeper response and had improved progression-free survival (PFS) compared with patients who were treated with VMP alone. With longer follow-up, the addition of daratumumab to VMP also resulted in an overall survival (OS) benefit. However, it should be acknowledged that only 10% of the patients who developed disease progression in the VMP arm were treated with a daratumumab-based relapse regimen, which would negatively impact OS in the VMP arm.1 

In a comparable patient population, the MAIA study (median age, 73 years) showed that adding daratumumab to continuous Rd improved the depth of response, PFS, and also PFS2 (defined as the time from random assignment to progression on the next line of therapy or death).3,4  At a median follow-up of 36.4 months, there was no difference in OS between treatment arms, and follow-up for long-term survival is ongoing.3,4  Importantly, faster and sustained improvement in health-related quality of life was observed in patients treated with daratumumab plus Rd compared with Rd alone.5 

CD38 antibody–based therapy for transplant-eligible patients

The CASSIOPEIA study demonstrated that addition of daratumumab to bortezomib-thalidomide-dexamethasone (VTd, a standard-of-care induction regimen in Europe) before (induction) and after transplantation (consolidation) improved the depth of response, PFS, and although follow-up is still short, also OS.6  In that study, 100 days after transplantation, there was a second random assignment to either observation or daratumumab maintenance (every 8 weeks until disease progression or for a maximum of 2 years).6  Results from the second random assignment for maintenance therapy are not yet available. Several other phase 3 trials are also evaluating the value of daratumumab as maintenance therapy after auto-SCT, including the AURIGA and DRAMMATIC studies, which are evaluating maintenance with daratumumab plus lenalidomide vs lenalidomide alone in NDMM patients after auto-SCT.

Management aspects

Daratumumab-based regimens are generally well tolerated. However, adding daratumumab to standard-of-care regimens increases the frequency of infections, especially respiratory infections, probably because of a higher frequency of neutropenia, as well as induction of hypogammaglobulinemia and depletion of natural killer cells. This highlights the importance of providing adequate supportive care, including growth factor support, prophylactic antibiotics, immunoglobulin replacement therapy, and vaccination.7  Furthermore, ∼30% to 40% of patients experience a generally mild infusion reaction, mostly during the first daratumumab infusion. A big step forward is the approval of the subcutaneous formulation of daratumumab, which reduces the time of administration to 3 to 5 minutes.8  CD38 antibodies also affect certain laboratory assays. CD38-targeting antibodies interfere with blood group compatibility testing because these antibodies also bind to CD38 molecules present on reagent or donor red blood cells.9  Several strategies are available to negate CD38 antibody interference with blood bank compatibility tests.9  Furthermore, CD38 antibodies can be detected as a small monoclonal band by serum protein electrophoresis and serum immune fixation electrophoresis, which may interfere with response evaluation in case the patient’s M-protein and the CD38 antibody have the same heavy- and light-chain isotype and co-migrate into the same region.9  The daratumumab-specific immune fixation electrophoresis reflex assay can be used to discriminate between residual M-protein and daratumumab.10 

Specific subgroups

Elderly patients

MM has a median age at presentation of ∼70 years, and elderly patients benefit less from novel agents, probably because of a reduced ability to tolerate the therapy, which then leads to treatment discontinuation. Subgroup analyses also show that patients age 75 years or older benefit from daratumumab-based regimens with improved response rates and better PFS (Table 1).1-3,11  The ALCYONE study also demonstrated improved OS in elderly patients who received daratumumab added to VMP, but this improvement did not reach statistical significance (Table 1).1  These studies also show that daratumumab-based therapy is well tolerated in elderly patients. However, the elderly population is very heterogeneous, and frailty assessment is needed to further define their frailty profile. Data on frailty are not currently available in the MAIA and ALCYONE studies.

Table 1.

Comparison of ALCYONE and MAIA studies

ALCYONE1,2,11 MAIA3,4,20 
All patientsAge <75 yAge ≥75 yAll patientsAge <75 yAge ≥75 y
D-VMPVMPD-VMPVMPD-VMPVMPD-RdRdD-RdRdD-RdRd
No. of patients 350 356 246 249 104 107 368 369 208 208 160 161 
Median follow-up, mo 40.1* 40.1* 40.1* 36.4 36.4 36.4 
PR or better (%) 90.9 73.9 92.3 75.5 87.5 70.1 93 82 95 82 90 81 
CR or sCR (%) 46 25 48 26 41 24 50 27 52 25 41 25 
MRD negativity (10−5) (%) 28 22 24 29 27.9 7.2 19.4 7.5 
PFS       
 HR 0.42 0.49 0.53 0.56 0.49 0.62 
 95% CI 0.34-0.51 0.36-0.68 0.32-0.85 0.44-0.71 0.35-0.69 0.44-0.87 
OS       
 HR 0.61 0.56 0.71 NR NR NR 
 95% CI 0.46-0.80 0.40-0.79 0.44-1.13    
Grade ≥3 (%)             
 Neutropenia 40 39 35 38 52 42 51 35 43 31 60 41 
 Infections 23 15 21 13 28 20 36 27 32 23 33 24 
Infusion-related reactions (all grade) (%) 27.7 NA 24 NA 36 NA 40.9 NA 44.9 NA 35.7 NA 
ALCYONE1,2,11 MAIA3,4,20 
All patientsAge <75 yAge ≥75 yAll patientsAge <75 yAge ≥75 y
D-VMPVMPD-VMPVMPD-VMPVMPD-RdRdD-RdRdD-RdRd
No. of patients 350 356 246 249 104 107 368 369 208 208 160 161 
Median follow-up, mo 40.1* 40.1* 40.1* 36.4 36.4 36.4 
PR or better (%) 90.9 73.9 92.3 75.5 87.5 70.1 93 82 95 82 90 81 
CR or sCR (%) 46 25 48 26 41 24 50 27 52 25 41 25 
MRD negativity (10−5) (%) 28 22 24 29 27.9 7.2 19.4 7.5 
PFS       
 HR 0.42 0.49 0.53 0.56 0.49 0.62 
 95% CI 0.34-0.51 0.36-0.68 0.32-0.85 0.44-0.71 0.35-0.69 0.44-0.87 
OS       
 HR 0.61 0.56 0.71 NR NR NR 
 95% CI 0.46-0.80 0.40-0.79 0.44-1.13    
Grade ≥3 (%)             
 Neutropenia 40 39 35 38 52 42 51 35 43 31 60 41 
 Infections 23 15 21 13 28 20 36 27 32 23 33 24 
Infusion-related reactions (all grade) (%) 27.7 NA 24 NA 36 NA 40.9 NA 44.9 NA 35.7 NA 

Patient population: NDMM, ineligible for transplant; Eastern Cooperative Oncology Group performance status, 0-2; creatinine clearance, ≥40 mL/min in ALCYONE and ≥30 mL/min in MAIA.

HR, hazard ratio; NA, not applicable; NR, not reported; PR, partial response; sCR, stringent complete response.

*

PFS and MRD data for the subgroups and toxicity data are based on the analysis with a follow-up of 16.5 months.2 

Response and toxicity data for the subgroups is based on the analysis with follow-up of 28.0 months.20 

Nevertheless, there is already preliminary evidence from a phase 2 study that daratumumab-based therapy is feasible in frail patients. The HOVON143 study showed that daratumumab combined with ixazomib and dexamethasone is effective in unfit and frail NDMM patients.12  Importantly, the Intergroupe Francophone du Myelome has a phase 3 study that is evaluating the efficacy and tolerability of subcutaneous daratumumab plus lenalidomide without dexamethasone vs lenalidomide plus dexamethasone in a frail NDMM patient population. A dexamethasone-free regimen will probably reduce the frequency of adverse events, such as infections, psychiatric adverse effects, and diabetes mellitus and thereby prevent treatment discontinuations, which have a major impact on survival.

High-risk disease

Interpreting the value of CD38 antibody–based therapy for patients with high-risk cytogenetic aberrations is challenging because of the relatively small numbers of patients with high-risk disease in the different studies (Table 2). However, a recent meta-analysis of randomized phase 3 trials showed that incorporating daratumumab into backbone regimens was associated with a significantly improved PFS among patients with high-risk disease (presence of del(17p), t(4;14) or t(14;16)) in both the ND and relapsed/refractory setting.13  PFS data for all individual phase 3 studies evaluating CD38 antibodies in NDMM and relapsed/refractory MM are provided in Table 2. Importantly, poor risk conferred by high-risk cytogenetic abnormalities is not completely abrogated by adding a CD38 antibody to backbone regimens (Table 2).1-3,6 

Table 2.

Impact of high-risk cytogenetic aberrations on PFS

Definition of high-risk cytogenetic profileStudies in patients with NDMMStudies in patients with RRMM
MAIA4 ALCYONE21 CASSIOPEIA6 POLLUX22 CASTOR23 CANDOR24 ICARIA25 IKEMA26 
t(4;14), t(14;16), or del(17p) by FISH or karyotype analysist(4;14), t(14;16), or del(17p) by FISH or karyotype analysisdel(17p) with cutoff 50% or t(4;14) with cutoff 30% by FISHt(4;14), t(14;16), or del(17p) by FISH or karyotype analysist(4;14), t(14;16), or del(17p) by FISH or karyotype analysisdel(17p), t(14;16) or t(4;14) by FISHdel(17p) with cutoff of 50%; t(14;16) with cutoff 30%; or t(4;14) with cutoff 30% by FISHdel(17p) with cutoff of 50%; t(14;16) with cutoff 30%; or t(4;14) with cutoff 30% by FISH
Cytogenetic risk categoryStandardHighStandardHighStandardHighStandardHighStandardHighStandardHighStandardHighStandardHigh
No. of patients 550 92 518 98 914 168 369 70 258 95 156 74 181 60 192 73 
Median follow-up, mo 36.4 36.4 27.8 27.8 18.8 18.8 44.3 44.3 50.2 50.2 16.9 16.9 11.6 11.6 20.7 20.7 
PFS                 
 HR 0.50 0.57 0.34 0.78 0.41 0.67 0.43 0.34 0.25 0.41 0.55 0.58 0.62 0.66 0.44 0.72 
 95% CI 0.38-0.65 0.32-1.04 0.26-0.45 0.49-1.26 0.26-0.62 0.35-1.30 0.32-0.57 0.16-0.72 0.18-0.35 0.21-0.83 0.31-0.97 0.30-1.12 0.42-0.93 0.33-1.28 0.27-0.73 0.36-1.45 
Definition of high-risk cytogenetic profileStudies in patients with NDMMStudies in patients with RRMM
MAIA4 ALCYONE21 CASSIOPEIA6 POLLUX22 CASTOR23 CANDOR24 ICARIA25 IKEMA26 
t(4;14), t(14;16), or del(17p) by FISH or karyotype analysist(4;14), t(14;16), or del(17p) by FISH or karyotype analysisdel(17p) with cutoff 50% or t(4;14) with cutoff 30% by FISHt(4;14), t(14;16), or del(17p) by FISH or karyotype analysist(4;14), t(14;16), or del(17p) by FISH or karyotype analysisdel(17p), t(14;16) or t(4;14) by FISHdel(17p) with cutoff of 50%; t(14;16) with cutoff 30%; or t(4;14) with cutoff 30% by FISHdel(17p) with cutoff of 50%; t(14;16) with cutoff 30%; or t(4;14) with cutoff 30% by FISH
Cytogenetic risk categoryStandardHighStandardHighStandardHighStandardHighStandardHighStandardHighStandardHighStandardHigh
No. of patients 550 92 518 98 914 168 369 70 258 95 156 74 181 60 192 73 
Median follow-up, mo 36.4 36.4 27.8 27.8 18.8 18.8 44.3 44.3 50.2 50.2 16.9 16.9 11.6 11.6 20.7 20.7 
PFS                 
 HR 0.50 0.57 0.34 0.78 0.41 0.67 0.43 0.34 0.25 0.41 0.55 0.58 0.62 0.66 0.44 0.72 
 95% CI 0.38-0.65 0.32-1.04 0.26-0.45 0.49-1.26 0.26-0.62 0.35-1.30 0.32-0.57 0.16-0.72 0.18-0.35 0.21-0.83 0.31-0.97 0.30-1.12 0.42-0.93 0.33-1.28 0.27-0.73 0.36-1.45 

FISH, fluorescence in situ hybridization; RRMM, relapsed/refractory multiple myeloma.

We will soon learn whether other regimens, such as daratumumab or isatuximab combined with VRd or carfilzomib-lenalidomide-dexamethasone (KRd) further improve the poor outcome conferred by high-risk cytogenetic aberrations. Alternatively, these patients may also benefit from new strategies that incorporate agents with novel mechanisms of action such as T-cell redirecting therapies. Daratumumab added to VMP/Rd/VTd also improved PFS in other subgroups with high-risk features, such as in patients with reduced renal function or ISS stage III disease.1-3,6 

First-line CD38-based treatment

Altogether, these studies indicate that the efficacy and safety of daratumumab in combination with standard-of-care regimens is now established in NDMM, and this supports the use of daratumumab-based regimens at diagnosis for both young and elderly patients. However, there are several open questions. First, in transplant-ineligible patients, D-Rd and D-VMP have not been compared head-to-head with VRd, which is commonly used in the United States and was also recently approved in Europe for transplant-ineligible patients. The SWOG S0777 study (median age, 63 years) showed an improved PFS and OS in patients treated with VRd compared with Rd.14  In that study, only 43% of the patients were age 65 years or older because both transplant-ineligible patients and younger patients who were not planned for immediate first-line transplantation could be enrolled.

Although comparisons between these trials should be made with caution because of major differences in age distribution, the median PFS with VRd was 34 months in patients age 65 years or older,14  whereas median PFS was 36.4 months with D-VMP, and PFS at 3 years was 68% with D-Rd. This indicates that, next to the new daratumumab-based regimens, VRd continues to represent an appropriate standard-of-care treatment whereby dose-adjusted VRd can be used in older patients to improve tolerance.15  Treatment choice is also dependent on the overall tolerability profile of the available therapeutic regimens. An advantage of the D-Rd regimen is the low rate of treatment-emergent neuropathy compared with the bortezomib-containing regimens.2,3,16  Other factors, including patient characteristics (eg, presence of comorbidities, frailty, and age), patient preferences, and reimbursement and availability issues, also have an impact on treatment selection. Importantly, bortezomib is given for a fixed period of time in the VRd regimen, whereas daratumumab is given until progression in the D-Rd and D-VMP regimens, which has important financial implications. Ongoing phase 3 trials are evaluating whether adding a CD38 antibody to the VRd regimen (daratumumab in the CEPHEUS trial and isatuximab in the IMROZ trial) results in additional survival benefit. Furthermore, less intensive 2-drug regimens such as Rd remain important options for frail patients.

Second, in many countries, VRd is the preferred regimen for transplant-eligible patients, and there are no studies comparing D-VTd with VRd before and after transplantation. The randomized phase 2 GRIFFIN study evaluates the value of the addition of daratumumab to VRd in transplant-eligible patients. Preliminary results show an improved depth of response including complete response and minimal residual disease (MRD) negativity with daratumumab added to VRd.17,18  At a median follow-up of 22.1 months, there was not yet a PFS or OS benefit for patients treated with daratumumab; follow-up for long-term survival is ongoing.17,18  Several studies are also evaluating carfilzomib, a second-generation proteasome inhibitor, plus lenalidomide-dexamethasone as a backbone for CD38 antibody–based combinations, aiming at further increasing the proportion of patients with sustained MRD negativity.

Furthermore, there are no trials comparing the strategy of first-line daratumumab vs CD38 antibody–based therapy at the time of first relapse. Although patients can receive a daratumumab-based regimen at the time of first relapse, we favor the use of CD38 antibodies for first-line therapy because in real-world clinical practice, only two-thirds of patients receive more than 1 line of therapy, which is more common in elderly patients.19  We also favor the use of the best drugs, including daratumumab, for first-line therapy to induce the deepest response possible, because clinical outcomes correlate with depth of response. Importantly, quality of life is best preserved during the first remission and gradually diminishes with each subsequent progression because of a cumulative burden of therapy and disease-related complications (eg, vertebral fractures). In addition, if results of a large daratumumab retreatment study are positive (NCT03871829), the design of the phase 3 studies in transplant-eligible patients allows for retreatment (eg, fixed duration of daratumumab in CASSIOPEIA, and stopping daratumumab in patients with sustained MRD negativity in PERSEUS).

Clinical case (continued)

We discussed with the patient the different treatment options inside and outside a clinical trial. Because the patient was an intermediate-fit 75-year-old man, our treatment goal was to induce a deep and durable response with a triplet or quadruplet regimen. Bortezomib-based regimens, including D-VMP and VRd, were not preferred options because bortezomib may aggravate the diabetic neuropathy. After counseling, he initiated treatment with D-Rd in the setting of a clinical trial, with aspirin as thrombosis prophylaxis and cotrimoxazol as antibacterial prophylaxis. After 6 months, dexamethasone was tapered and later stopped because of adverse events including insomnia. After 9 months, the dose of lenalidomide was eventually reduced from 25 mg to 10 mg because of fatigue. He achieved a complete response with no recurrence of disease up to this point, and daratumumab was continued according to schedule.

In conclusion, CD38 antibodies have transformed MM treatment with several phase 3 studies showing that both transplant-eligible and transplant-ineligible NDMM patients benefit from daratumumab-containing triplet or quadruplet regimens. Importantly, patients age 75 years or older also experience clinical benefit from adding daratumumab to VMP or Rd, which points to the favorable toxicity profile of this drug. Patients with high-risk cytogenetics also benefit from these new treatment strategies, but to a lesser extent than standard-risk patients, highlighting the need for the earlier incorporation of new drugs into their first-line treatment. Altogether, CD38 antibody–based combinations represent the new standard of care for NDMM patients, based on both high antitumor activity and an acceptable safety profile. The use of these regimens should, therefore, be considered as a first treatment option for both transplant-eligible and transplant-ineligible MM patients.

Conflict-of-interest disclosure

N.W.C.J.v.d.D. has received research support from Janssen Pharmaceuticals, Amgen, Celgene, Novartis, and Bristol Myers Squibb and serves on advisory boards for Janssen Pharmaceuticals, Amgen, Celgene, Bristol Myers Squibb, Takeda, Roche, Novartis, Bayer, and Servier. C.L.B.M.K. has nothing to disclose.

Off-label drug useNone disclosed.

Correspondence

N.W.C.J. van de Donk, Amsterdam University Medical Center, Vrije Universiteit Amsterdam, Department of Hematology, Cancer Center Amsterdam, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands; e-mail: n.vandedonk@amsterdamumc.nl.

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