Outcomes in multiple myeloma (MM) have improved dramatically in the last two decades with the advent of novel therapies including immunomodulatory agents (IMiDs), proteasome inhibitors and monoclonal antibodies. In recent years, immunotherapy for the treatment of MM has advanced rapidly, with the approval of new targeted agents and monoclonal antibodies directed against myeloma cell-surface antigens, as well as maturing data from late stage trials of chimeric antigen receptor CAR T cells. Therapies that engage the immune system to treat myeloma offer significant clinical benefits with durable responses and manageable toxicity profiles, however, the appropriate use of these immunotherapy agents can present unique challenges for practicing physicians. Therefore, the Society for Immunotherapy of Cancer convened an expert panel, which met to consider the current role of approved and emerging immunotherapy agents in MM and provide guidance to the oncology community by developing consensus recommendations. As immunotherapy evolves as a therapeutic option for the treatment of MM, these guidelines will be updated.
- guidelines as topic
- hematological neoplasms
- receptors, chimeric antigen
- antineoplastic protocols
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- guidelines as topic
- hematological neoplasms
- receptors, chimeric antigen
- antineoplastic protocols
Multiple myeloma (MM) is the second most commonly diagnosed hematological malignancy, with nearly 160 000 new cases worldwide in 2018.1 Before the 21st century, most patients with MM died within a few years after diagnosis, yet outcomes have improved dramatically during the past two decades. Novel therapies including immunomodulatory agents (IMiDs), proteasome inhibitors (PIs) and monoclonal antibodies (mAbs) have been incorporated into standard treatment approaches, which had previously been limited to stem cell transplants, alkylating agents and steroids.2–6 Additionally, advances in risk stratification based on cytogenetics7 8 as well as the ability to detect minimal residual disease (MRD) with a high degree of sensitivity using multicolor flow cytometry (MFC) or next-generation sequencing (NGS) technologies9 may further enhance the selection of treatment strategies both at initial diagnosis and relapse. Despite these breakthroughs, however, MM remains largely incurable, with the vast majority of patients experiencing relapse at some point.
Advances in understanding of the basic mechanisms of immune evasion and suppression in MM has led to new therapies with demonstrated benefits for patients. In 2015, the US Food and Drug Administration (FDA) approved two mAbs for the treatment of MM, daratumumab (dara) and elotuzumab,10 11 blazing a trail for the development of numerous other immunotherapies in this disease setting, including chimeric antigen receptor (CAR) T cells,12–15 antibody-drug conjugates (ADCs),16–18 bispecific T-cell engagers (BiTEs)19–21 and cancer vaccines.22 23 As the world’s leading non-profit member-driven organization dedicated to advancing cancer immunotherapy, the Society for Immunotherapy of Cancer (SITC) develops Cancer Immunotherapy Guidelines for a variety of disease states. Previously, SITC published the first-ever consensus statement for the use of immunotherapy to treat hematological malignancies in 2016.24
Immunotherapy is currently playing a pivotal role in MM treatment, necessitating clinical practice guidelines with detailed recommendations specific to these important, practice-changing modalities. Recognizing the rapid pace of advancement of the field, and a need to update the previously published consensus statement with practical guidance on how to incorporate the ever-growing number of immunotherapeutic agents that have been approved or are in the final stages of clinical development into the treatment of MM, SITC convened an expert panel encompassing perspectives from hematology, medical oncology, hematopathology, nursing and patient advocacy to provide evidence-based recommendations for the oncology community. This panel met to consider issues related to patient selection, dosing and monitoring, toxicity management and quality of life (QoL), with the goal of preparing a consensus statement on clinical use of immunotherapy for patients with MM.
In recognition of the rapid pace of advancement of the immunotherapy field, this consensus statement will discuss emerging therapies that have not yet, at the time of publication, received United States Food and Drug Administration (FDA) approval. As such, the manuscript is divided into two sections, based on FDA approval status at time of publication. Because recommendations concerning the use of IMiDs were published in the 2016 consensus statement on hematological malignancies,24 those agents are not extensively discussed in these guidelines, except as components of combination regimens with antibody therapies. Additionally, although allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an important therapeutic option in the management of MM, other groups have published consensus recommendations regarding its use25 and therefore a discussion of the approach was beyond the scope of these guidelines. As with any consensus statement, the recommendations contained within this paper are intended to provide guidance and are not a substitute for the professional judgment of individual physicians treating individual patients.
Materials and methods
SITC Multiple Myeloma Immunotherapy Guideline Expert Panel
The SITC Multiple Myeloma Immunotherapy Guideline Expert Panel consisted of 19 participants, including 17 medical oncologists, 1 nurse practitioner and 1 patient advocate. One Hundred percent of clinical expert panel members reported previous experience/knowledge regarding the use of immuno-oncology therapy for the treatment of patients with MM. The panel communicated regularly via email and teleconference in addition to completing online surveys (see online supplementary file 1), addressing clinical topics concerning the use of cancer immunotherapy for the treatment of patients with MM, which helped form the basis for consensus recommendations.
Consensus statement policy
The Institute of Medicine’s (IOM) Standards for Developing Trustworthy Clinical Practice Guidelines were used as a model to develop the consensus recommendations in this manuscript. IOM standards dictate that guideline development is led by a multidisciplinary team using a transparent process where both funding sources and conflicts of interest are readily reported. Recommendations are based on literature evidence, where possible, and clinical experience, where appropriate.26 For transparency, a draft of this consensus statement was made publicly available for comment after journal submission. All comments were considered for inclusion into the final manuscript. This consensus statement is intended to provide guidance and is not a substitute for the professional judgment of individual treating physicians.
Evidence and consensus ratings
Consensus recommendations were derived from evidence within the published literature along with responses to a clinical questionnaire that addressed current practices in the use or recommendation for use of immunotherapy agents (online supplementary file 1). SITC Cancer Immunotherapy Guidelines provide recommendations based on peer-reviewed literature and consensus within the expert panel. Consensus was defined as ≥75% agreement among expert panel members.
Conflicts of interest policy
As per SITC policy, expert panel members managed potential competing interests through disclosure of all financial relationships that might result in actual, potential or perceived conflicts of interest. No commercial funding was provided to support the expert panel, literature review, or the preparation of this manuscript.
Literature review process
The MEDLINE database was used to search the scientific literature for current therapies related to MM and immunotherapy in humans and encompassed articles published from 2012 to 2019, including clinical trials, meta-analyses, practice guidelines and research in humans. The search terms included ‘multiple myeloma’ AND ‘immunotherapy’, ‘daratumumab’, ‘elotuzumab’, ‘isatuximab’, ‘CAR T cell therapy’, ‘bispecific antibody’, ‘antibody-drug conjugate’ and ‘quality of life.’ Articles were screened by expert panel members to include only papers with clinically accurate and relevant information and to remove duplicate articles from independent searches, resulting in a final citation list cataloged using EndNote X9. The citation list was supplemented with additional articles identified by the panel, as appropriate and necessary for a comprehensive literature review.
The integration of effective mAbs into the treatment of patients with MM has been in clinical development for >10 years.27 The anti-CD38 therapy dara is the first immunotherapeutic mAb to be clinically tested and to elicit durable responses as a single agent. This reported efficacy, in addition to its proven safety record and enhanced clinical benefit in combination with other antimyeloma therapies, has led to several FDA approvals for dara in treating patients with MM. Such evidence, also demonstrating a lack of overlapping toxicity, deep clinical response rates and long durations of response, places dara in a crucial position for the treatment of patients with MM in both the first-line and the relapsed/refractory setting.
The phase III POLLUX study investigated dara plus lenalidomide and dexamethasone (D-Rd) versus Rd alone in relapsed or refractory multiple myeloma (RRMM). The dara regimen reduced the risk of disease progression or death by 63% and significantly increased overall response rate (ORR) in patients with RRMM compared with Rd alone (93% vs 76%; p<0.001). Furthermore, when combined with standard-of-care regimens across multiple phase III studies including POLLUX and CASTOR (bortezomib+dexamethasone±dara), the addition of dara led to ≥50% reductions in the risk of progression or death, doubled complete response (CR) rates and tripled MRD-negative rates at the 10-5 sensitivity threshold in patients with RRMM.28–30 A 4-year follow-up analysis of POLLUX examined 569 randomized patients (D-Rd, n=286; Rd, n=283). At a median follow-up of 51.3 months, D-Rd significantly prolonged progression-free survival (PFS) versus Rd (median 45.8 vs 17.5 months; HR 0.43; 95% CI 0.35 to 0.54; p<0.0001).31 A PFS benefit for D-Rd versus Rd was also observed regardless of cytogenetic risk status. In the phase III CASTOR trial evaluating dara in combination with bortezomib and dexamethasone (D-Vd) compared with Vd alone, the 12-month rate of PFS was 60.7% in the dara group vs 26.9% in the control group. Additionally, the ORR was higher in the dara group than the control group (82.9% vs 63.2%).32
The open-label, multicenter phase Ib EQUULEUS study (NCT01998971) evaluated dara in combination with various backbone regimens in patients with newly diagnosed MM as well as patients who had received prior therapy. In the dara plus pomalidomide and dexamethasone (D-Pd) treatment arm (n=103), only patients who had previous treatment were included (median number of prior therapies=4, range=1–13), all of whom had previous lenalidomide therapy. The ORR was 60% (95% CI 50.1 to 69.7) with 17 patients achieving CR or better and 5 (29%) of those patients achieving MRD negativity at the 10-5 threshold. Median PFS was 8.8 months (95% CI 4.6 to 15.4), and the 12-month PFS rate was 42% (95% CI 31.5 to 51.9). In exploratory analysis, PFS and ORRs were similar across patients with standard or high cytogenetic risk.33 Based on data from the EQUULEUS study, the FDA approved D-Pd for the treatment of patients with MM who have received at least two prior therapies including lenalidomide and a PI in 2017.
Significant PFS benefit was demonstrated for the addition of dara to carfilzomib and dexamethasone (KdD) for the treatment of patients with RRMM with measurable disease who had received one to three prior lines of therapy in the randomized, open-label, phase III CANDOR study (NCT03158688). After a median follow-up of 16.9 months and 16.3 months for the KdD and Kd arms, median PFS was not reached for the KdD arm vs 15.8 months for the control arm (HR 0.63; 95% CI 0.46 to 0.85; p=0.0014). The ORR was 84.3% vs 74.7% (p=0.0040), for KdD versus control, respectively, and the rate of CR or better was 28.5% vs 10.4% with an MRD-negative CR rate at 12 months of 12.5% for KdD vs 1.3% for Kd (p<0.0001).34
In an ongoing phase II, randomized study, the GRIFFIN trial (NCT02874742) compared the combination of dara, bortezomib, lenalidomide and dexamethasone (D-VRd) with VRD in 207 patients with newly diagnosed myeloma eligible for autologous HSCT. Patients received four induction cycles of D-VRd (or VRD) every 21 days followed by stem cell mobilization, high-dose therapy, and HSCT; two consolidation cycles of D-VRd (or VRD); and maintenance therapy with dara and lenalidomide (or lenalidomide alone) for 24 months.35 At primary end point analysis, by the end of consolidation (cycle 6), the study met its prespecified one-sided alpha of 0.1 with a stringent complete response (sCR) rate of 42.4% for patients receiving D-VRd vs 32% in the VRD arm. Responses have continued to deepen throughout maintenance—rates of sCR improved for D-RVd versus RVd (62.6% vs 45.4%; p=0.0177), as did rates of MRD negativity at the 10−5 threshold (51.0% vs 20.4%; p<0.0001).36 Overall, the regimen with dara (D-VRd) was found to be safe and more effective than VRd alone, with an increase in any-grade infection rates of 91% vs 62%, largely due to grade 1/2 upper respiratory tract infections. Stem cell yield was adequate in both arms. At a median follow-up of 22.1 months, the 24-month PFS rate was 95.8% vs 89.8%, favoring the D-VRd combination.37 Survival data have not yet matured at the time of this publication. A phase III study (PERSEUS) is ongoing to evaluate VRD versus D-VRD.38
Data from the phase III CASSIOPEIA trial39 of 1085 patients showed that incorporating dara into a regimen of bortezomib, thalidomide and dexamethasone (D-VTd) led to a 34% reduction in disease progression risk compared with the standard triplet therapy (VTd). The trial was divided into two parts, an induction and consolidation phase followed by maintenance treatment with dara or observation. In the induction phase, the addition of dara was associated with a 53% reduction in the risk of progression or death. At day 100 after transplantation, CR or better was observed in 39% of the patients in the dara-treatment group, with 64% achieving MRD-negativity, vs 26% and 44%, respectively, for those treated with VTd alone.40 With a median follow-up of 18.8 months, the estimated 18-month PFS rate was 93% D-VTd vs 85% VTd (HR 0.47; 95% CI 0.33 to 0.67; p<0.0001). Based on data from CASSIOPEIA, in September, 2019, the FDA approved D-VTd in newly diagnosed transplant-eligible patients.
The MAIA trial (NCT02252172) investigated the clinical benefit of adding dara to lenalidomide and dexamethasone (D-Rd) as part of a phase III, randomized trial in patients with transplant-ineligible untreated MM. The primary endpoint examined was PFS. At median follow-up of 28.0 months, of the 737 randomized patients, disease progression or death occurred in 26.4% of patients in the dara group and 38.8% in the control group. The estimated percentage of patients who were alive without disease progression at 30 months was 70.6% (95% CI 65.0 to 75.4) and 55.6% (95% CI 49.5 to 61.3) in the dara and control groups, respectively (HR 0.56; 95% CI 0.43 to 0.73; p<0.001). The rates of CR or better were 47.6% and 24.9% in the dara and control groups (p<0.001), respectively. A total of 24.2% vs 7.3% of patients in the dara and control groups, respectively, reported results below the threshold for MRD (one tumor cell per 105 total bone marrow cells) (p<0.001).41 Results from this study further support the use of dara in combination with standard therapies in first-line treatment of patients with MM.
The ALCYONE trial (NCT02195479) assessed the addition of dara to the combination of bortezomib, melphalan and prednisone (D-VMP) in patients with treatment-naïve MM who are ineligible for HSCT in a phase III, randomized study.7 In this study, 706 patients received nine cycles of VMP either alone or with dara until disease progression. The primary endpoint was PFS. At a median follow-up of 40.8 months, the median PFS was 36.4 months with D-VMP vs 19.3 months in the control group (HR for disease progression or death 0.55; 95% CI 0.43 to 0.71; p<0.0001). The estimated 36-month overall survival (OS) rate was 78% with D-VMP vs 68% with VMP, with a significant benefit for OS observed for D-VMP versus VMP alone (HR 0.60; 95% CI 0.46 to 0.80; p=0.0003).42
Other combination trials
An ongoing phase II trial (NCT03012880) is investigating the addition of dara to the triplet induction therapy of ixazomib, lenalidomide, and dexamethasone (IRd) to determine if the quadruplet regimen elicits enhanced efficacy with a feasible schedule. Patients with previously untreated MM were enrolled irrespective of their transplant eligibility and CR rate was the primary endpoint. Treatment consisted of ixazomib 4 mg (days 1, 8, 15), lenalidomide 25 mg (days 1–21), dexamethasone 40 mg weekly and dara 16 mg/kg weekly for two cycles, every other week during cycles 3–6, and then every 4 weeks thereafter. As of the final assessment, all patients were alive and progression-free with a median follow-up of 5.2 months (median five cycles, range 2–13). One patient discontinued for alternate therapy. Responses proved rapid with a 90% partial response (PR) or better (32% very good partial response (VGPR)) after two cycles, and 100% PR or better (50% VGPR) for 32 patients who completed four cycles. The overall best confirmed response rate among the 38 analyzed patients was 95%, including 11% CR and 47% VGPR.43
Dara is FDA-approved and the panel recommends its use in the following settings:
In combination with lenalidomide and dexamethasone (D-Rd)in newly diagnosed patients who are ineligible for autologous stem cell transplant and in patients with RRMM who have received at least one prior therapy.
In combination with bortezomib, melphalan, and prednisone (D-VMP) in newly diagnosed patients who are ineligible for autologous stem cell transplant.
In combination with bortezomib, thalidomide, and dexamethasone (D-VTD) in newly diagnosed patients who are eligible for autologous stem cell transplant.
In combination with bortezomib and dexamethasone (D-Vd) in patients who have received at least one prior therapy.
In combination with pomalidomide and dexamethasone (D-Pd)in patients who have received at least two prior therapies including lenalidomide and a PI.
As monotherapy, in patients who have received at least three prior lines of therapy including a PI and an IMiD or who are double-refractory to a PI and an IMiD.
Other combinations in newly diagnosed patients:
Based on emerging data (e.g. from the Griffin trial37), the panel was comfortable recommending D-VRd as one possible induction regimen option in newly diagnosed patients who are eligible for autologous stem cell transplant.
A consensus could not be reached regarding the use of dara in combination with carfilzomib, lenalidomide and dexamethasone (D-KRd) in newly diagnosed patients who are eligible for autologous stem cell transplant.
Other combinations in RRMM:
KdD is recommended for patients with RRMM in the USA that are refractory to immunomodulatory drugs and bortezomib, based on emerging data from the CANDOR trial.34
Cytogenetic risk status
In both the CASTOR and POLLUX trials, dara combinations improved PFS regardless of the cytogenetic risk status.28 30 The antibody combination regimens seem to offer more benefit to the high-risk patients relative to the doublet-based regimens in RRMM in these studies.29 In the phase III MAIA trial of newly diagnosed patients, the benefit of adding dara was more pronounced in the standard risk patients than the high-risk patients.41 However, no tests for interaction between cytogenetic risk and PFS were reported. Additionally, the subgroups with high-risk cytogenetics are relatively small (92 patients in MAIA, 168 patients in CASSIOPEIA), and power for comparison of PFS within these groups is not reported. At this juncture, the data remain inconclusive on benefit from the addition of dara in the newly diagnosed induction setting for patients with high-risk disease.
Until further phase III data become available, a consensus could not be reached to recommend that dara is the definitive choice for patients with high-risk cytogenetics, particularly in the frontline setting.
Dosing and administration
The dara package insert advises standard treatment with steroids, acetaminophen and antihistamines 1–3 hours prior to infusion to manage infusion-related reactions (IRRs).10 Across trials, the vast majority of IRRs occurred during the first dose.32 44 Additionally, a multicenter, open-label early access treatment protocol study found that IRR rate was one-third lower in patients who received 10 mg of the leukotriene receptor antagonist montelukast 30 min prior to dara dosing.45
Standard premedications as suggested below may be used to mitigate IRRs:
Dexamethasone, 20 mg intravenous (IV) (for dara monotherapy methylprednisolone, 100 mg is preferred).
Acetaminophen, 650–1000 mg oral.
Diphenhydramine, 25–50 mg oral or intravenous.
Montelukast, 10 mg, orally dissolving tablet (ODT) preferred, prior to first infusion.
After cycle 2, steroids may be omitted if the patient has tolerated dara without IRRs.
For patients with severe IRRs during dose or a history of respiratory comorbidities, oral corticosteroids (≤20 mg methylprednisolone or equivalent intermediate-acting or long-acting corticosteroid) should be administered per the prescribing label on each of the 2 days following dara infusions.
Short-acting and long-acting bronchodilators and inhaled corticosteroids may be considered for patients with a long history of chronic obstructive pulmonary disease (COPD).
The PAVO trial (MMY1004), an open-label dose-escalation phase Ib study, evaluated subcutaneous delivery of dara in patients with RRMM. Results suggested that dara can be administered safely in a short time (3–5 min) as a subcutaneous formulation with lower rates of IRRs, yet retaining efficacy.46 An ongoing phase III randomized multicenter study of subcutaneous versus administration of dara in patients with RRMM, the COLUMBA trial (NCT03277105), supports use of flat-dose 1800 mg dara subcutaneously. A total of 522 patients who had received a median of 4 prior lines of therapy including PIs and IMiDs were randomized to receive dara subcutaneously (n=263) or IV dara (n=259). The rates of all grade IRRs were 34.5% vs 12.7%, respectively and responses, median PFS and 6-month OS rates were comparable between both groups.47 Subcutaneous injection was non-inferior to IV dara across all body-weight subgroups, with subcutaneous being associated with lower rate of IRRs.48 Importantly, patients also reported improved experience with subcutaneous dara, based on shorter administration time.49 The phase II, open-label, multicenter PLEAIDES trial (NCT03412565) confirmed the safety profile of subcutaneous dara in combination with standard regimens such as VRd, Rd, or VMP in both the first-line and RR settings. Across groups, ORRs with subcutaneous dara- containing regimens were similar to those reported in IV dara trials (i.e. GRIFFIN for D-VRd, POLLUX for D-RD, ALCYONE for D-VMP). Importantly, the rate of IRRs across all cohorts receiving subcutaneous dara was 7.5% (15/199), with the majority (93.3%) being grade 1–2.50 Based on results from COLUMBA and PLEAIDES, the FDA approved subcutaneous dara on May 1, 2020.
The panel felt that the new subcutaneous formulation will provide a convenient option for patients.
Given that dara is only stable for 16 hours after reconstitution, the first dose of 16 mg/kg IV, with a median infusion time of 6–8 hours may result in drug remaining at the close of the infusion center that cannot be saved until the next day. Of note, stability data allow dara to be reconstituted in 4 mg/mL, thereby allowing volumes to be reduced.51
For infusion centers with limited hours of operation, the first dose of dara can be split as 8 mg/kg across 2 days, which has a median infusion time of approximately 4 hours on each day. Nearly all IRRs occur on the first dose.
For dose 4 and beyond, dara can be given safely over 90 min.52
Once subcutaneous dara is commercially available, the need to split dose will diminish.
Patients with severe renal insufficiency, defined as glomerular filtration rate <30, are typically excluded from clinical trials despite accounting for about 20% of patients with MM.53 However, anti-CD38 antibodies are not metabolized by the kidney, and there are case reports of patients being safely treated in the setting of severe renal insufficiency.54 55
Hepatitis B virus (HBV) reactivation carries significant risk of morbidity and mortality for patients receiving immune-modulatory and biological therapies. A large reservoir of individuals at risk for reactivation exists within the general population, including people currently infected and those with prior exposure.56 Both the American Society of Clinical Oncology (ASCO) and the American Gastrological Association guidelines recommend all patients with hematological malignancies receiving anticancer therapy should be screened for active or resolved HBV infection by blood tests for hepatitis B surface antigen (HepBsAg) and antibody to hepatitis B core antigen (HepBcAb).57 58 Two options exist for patients with evidence of prior exposure: serial monitoring for HBV DNA by PCR or initiation of prophylactic antivirals for patients deemed to be at high risk, such as those receiving biologics, high-dose chemotherapy or stem cell transplants.
Although patients with renal failure, patients with COPD and patients with plasma cell leukemia are commonly excluded from clinical trials, the panel felt that these populations may safely be treated with dara.
Before administering dara, patients should be tested for hepatitis B, given the potential risk of viral reactivation.
For patients with no known hepatitis B exposure history, serum tests should be performed for HepBcAb, HepBsAb, and HepBsAg. In cases with evidence of hepatitis B exposure, a PCR test for hepatitis B genomes is recommended. For patients with positive serum tests for HepBcAb, entacavir should be considered.
Prophylactic acyclovir should be administered to patients receiving dara.
Response evaluation, treatment duration
Because dara can render myeloma plasma cells CD38 negative by flow cytometry, treatment can hinder the ability to accurately ascertain MRD. Alternatives include evaluating for MRD by NGS or alternative anti-CD38 antibodies, such as vs38.59 60 Additionally, the Hydrashift 2/4 dara is an FDA-approved assay to mitigate antibody interference.61 Antibody interference testing is unnecessary for non-IgG kappa isotype patients, patients with detectable disease by free light chain (FLC) or Bence Jones protein (BJP), or patients with an M-spike >0.2 g/dL by serum protein electrophoresis (SPEP).62–64
Anti-CD38 antibodies such as dara interfere with blood bank testing by binding to CD38 on red blood cells (RBCs) and causing panagglutination on the indirect antiglobulin test.65 Because many patients with MM have received multiple transfusions in the context of treatment and may in fact have RBC alloantibodies, a false-positive result should not be assumed solely on the basis of dara exposure. The most common and widely validated method of interrupting anti-CD38 antibody binding to RBCs is to treat with the reducing agent dithiothreitol (DTT).66 Importantly, DTT has the potential to denature other clinically significant antigens including Kell and Yt.65
All approved dara-containing regimens have used dara until progression, which for patients reaching 7 months and beyond is once monthly. Based on pharmacokinetic data, it appears that if dara is to be given as maintenance therapy, a 4-week schedule is likely to maintain trough levels better than 8-week intervals. Trials are ongoing investigating dara as maintenance therapy after autologous stem cell transplant (NCT03901963 and NCT03346135).67 There is insufficient data to establish efficacy for retreatment with dara. However, a retrospective study of 34 patients with RRMM found that one third of patients refractory to both dara and pomalidomide responded when they were retreated with the combination.68
Response to dara should be monitored according to institutional protocols, most of which assay MM labs monthly. In patients with IgG kappa myeloma, serologic determination of CR can be confounded by the presence of dara.
In the presence of a measurable M-spike, dara will have a minimal effect on disease measurement. When patients reach undetectable levels, however, mass spectrometry or other antibody interference testing methods should be considered.
A consensus could not be reached to recommend retreatment with dara in patients relapsing on monthly dosing.
Patients on dara should receive seasonal influenza vaccines.
To manage infections following treatment, intravenous IgG (IVIG) should be administered according to established institutional criteria, which are not specific to dara.
Elotuzumab is a mAb targeting signaling lymphocytic activation molecule F7 (SLAMF7) that elicits its antitumor effect through both direct activation of natural killer (NK) cells and antibody-dependent cellular toxicity.69 Elotuzumab was first approved for MM on November 30, 2015.70 Although no studies have found benefit for elotuzumab monotherapy, either in the advanced71 or smoldering72 settings, it has demonstrated significant activity in combination with IMiDs and other agents in the relapsed and refractory setting.73 At the time of publication, elotuzumab has received FDA approval as combination therapy with lenalidomide and dexamethasone (E-Rd) for the treatment of adult patients with RRMM who have received one to three prior therapies or in combination with pomalidomide and dexamethasone (E-Pd) for adult patients who have received at least two prior therapies including lenalidomide and a PI.11
The ELOQUENT-2 trial (NCT01239797) was a phase III, randomized, open-label study that evaluated the efficacy and safety of E-Rd versus Rd alone in patients with MM who had received one to three prior lines of treatment and had documented disease progression after their most recent therapy. During the trial, 646 patients were randomized to E-Rd (n=321) or Rd (n=325), and in an extended 5-year follow-up, the longest median follow-up of any immuno-oncology agent in MM, 27% reduction in risk of progression or death was attained for E-Rd versus Rd (HR 0.73; 95% CI 0.60 to 0.87). The ORR was 79% (E-Rd) vs 66% (Rd).74 Approximately 32% of patients had del(17)p and 9% of patients had t(4;14), and the outcomes in high-risk patients were comparable with those of the patients at standard risk.75 The most common grade 3–4 adverse events (AEs) with E-Rd versus Rd were infections (35% vs 27%), neutropenia (26% vs 34%), anemia (17% vs 17%) and fatigue (10% vs 9%). Discontinuation of study regimens was mostly due to disease progression (55% vs 56% at the 5-year mark). Thus, E-Rd showed an overall sustained, durable improvement in PFS, reporting a 27% reduction in the risk of progression or death.74
Based on the results from ELOQUENT-2, ELOQUENT-3 (NCT02654132) was initiated as a phase II, randomized, open-label trial investigating the addition of elotuzumab to pomalidomide plus dexamethasone (E-Pd vs Pd). The combination of pomalidomide and dexamethasone has previously been shown to be effective in patients with MM refractory to lenalidomide and a PI.76 In ELOQUENT-3, a total of 117 patients were randomly assigned to receive either E-Pd (60 patients) or Pd alone (control; 57 patients) with the primary end point of investigator-assessed PFS.77 After a minimum follow-up period of 9.1 months, median PFS was 10.3 months in the E-Pd group vs 4.7 months in the control group (HR 0.54; 95% CI 0.34 to 0.86; p=0.008), and ORR was 53% vs 26%, respectively (OR 3.25; 95% CI 1.49 to 7.11). Benefit from E-Pd was also demonstrated in patients who had received at least four previous lines of therapy, with a median PFS of 10.3 months (95% CI 3.7 to not reached) in the E-Pd group and 4.3 months (95% CI 1.9 to 9.3) in the control group (HR 0.51; 95% CI 0.24 to 1.08). The safety of E-Pd was notable, with grade 3/4 neutropenia occurring in 13% in E-Pd vs 27% for PD and grade 3/4 infections occurring in 13% vs 22%. The main reason for discontinuation of the trial treatment was disease progression (43% of the treated patients in the E-Pd group and 56% of the treated patients in the control group).77
A phase II trial (NCT01478048) evaluated the addition of elotuzumab to the combination of bortezomib and dexamethasone (Vd) in patients with MM with documented disease progression after one to three prior lines of therapy. The 1-year PFS rate was 39% (95% CI 28% to 50%) with E-Vd vs 33% (95% CI 22% to 44%) with Vd, yielding a 28% reduction in the risk of progression or death with E-Vd compared with Vd. Follow-up analysis at the 2-year point revealed more striking differences between subgroups stratified by FcγRIIIa V genotype, with a median PFS of 22.3 months for patients in the E-Vd group who were homozygous for the high-affinity FcγRIIIa V (VV) allele (13 patients) compared with 9.8 months in patients in the E-Vd group homozygous for the low-affinity FcγRIIIa F (FF) allele (24 patients) and a sizeable improvement over patients in the Vd group homozygous for the V allele (8.2 months). A trend toward longer PFS with E-Vd was also observed across key subgroups, including in patients aged 65 years or older and in those who had received a prior PI or IMiD. Discontinuation in the overall population was mostly due to disease progression (57%). An increased rate of infections was observed for elotuzumab in combination with a PI: 67% vs 53% of all grade and 21% vs 13% of grade 3/4 for E-Vd versus Vd, respectively.78
Elotuzumab has also been studied in combination with thalidomide and low-dose dexamethasone in a phase II single-arm safety study in the relapsed/refractory setting, where minimal toxicity was observed with the triple regimen and efficacy data suggested potential clinical benefit in a highly pretreated population. In the trial, grade 3 or higher non-hematological AEs were reported in 63% of patients, most commonly asthenia (35%) and peripheral edema (25%), and six patients (15%) had an infusion reaction. The ORR was 38%, with median PFS 3.9 months and median OS 16.3 months.79 Another phase II trial (NCT03155100) evaluating the combination of elotuzumab, carfilzomib, pomalidomide and dexamethasone in RRMM is actively recruiting.
As of 2019, two phase III trials were exploring elotuzumab-containing regimens as a frontline option. ELOQUENT-1 (NCT01335399) is investigating the addition of E-Rd to treat newly diagnosed, non-transplant eligible MM.80 The phase III GMMG-HD6 trial (NCT02495922) is investigating the efficacy of elotuzumab in combination with VRd induction/consolidation and lenalidomide maintenance in transplant-eligible patients as frontline therapy.81 Additionally, SWOG S1211 (NCT01668719) is a phase I/II trial evaluating for the first time a four-drug E-VRd induction regimen in high-risk newly diagnosed MM. Phase I has been completed and of the eight patients enrolled, the most common AEs were fatigue (100%), peripheral sensory neuropathy (83%), edema (83%), lymphopenia (66%) and leukopenia (50%), with one dose-limiting toxicity (grade 4 lymphopenia) observed.82 E-Rd is also being evaluated in patients with high-risk smoldering multiple myeloma (SMM). In a phase II trial, of the 34 evaluable patients enrolled to both arms of the study, the clinical benefit rate was 97% with an ORR of 71%, including 9 very good VGPRs (26%) and 15 PRs (44%) and at the 1-year mark, no patients progressed to active disease during, or after, protocol therapy.83
No randomized studies have directly compared combination therapy with anti-CD38 antibodies (eg, dara and isatuximab) to elotuzumab-containing regimens. Given the temporary depletion of NK cells with anti-CD38 monoclonal antibodies, treatment with elotuzumab-containing (which may be dependent on NK cell function) regimens in the immediate next line of therapy has not been formally studied in prospective studies. The Monoclonal Antibodies in Multiple Myeloma: Outcomes after Therapy Failure study evaluated 275 patients with anti-CD38 refractory MM and found that the addition of elotuzumab had an ORR of 21% with median PFS 2.6 months and OS 8.3 months.84 A retrospective analysis of 50 heavily pretreated patients who received both elotuzumab and dara found that responses to elotuzumab decreased when given after dara, but responses to dara did not change regardless of the treatment sequence. No statistical difference was seen in ORR (78% for elotuzumab vs 89% for dara) for the initial antibody given, but a significant difference in ORR (61% for elotuzumab vs 88% for dara) was observed for the agent given second (p=0.04).85 Another retrospective study that analyzed 86 patients who had progressed on elotuzumab in combination with an immunomodulatory drug reported a 35.6% ORR on subsequent treatment with an anti-CD38 mAb (dara or isatuximab) with a median PFS of 4.6 months (95% CI 1.6 to 7.6) and median OS of 15.3 months (95% CI 8.2 to 22.4).86 A small retrospective analysis of 37 patients found significantly higher ORR and cumulative PFS for elotuzumab prior to dara (64.3% and 22.67%) compared with dara before elotuzumab ((34.8% and 10.5%).87 It is important to note, however, the clear selection biases in analysis of real-world patients treated with an agent without single agent activity.
E-Rd is approved in patients who have received one to three prior therapies.
E-Pd is approved in patients who have received at least two prior therapies.
Patients with high-risk cytogenetics may benefit from elotuzumab.
At present, there is no approved indication for the use of elotuzumab in the initial management of myeloma.
By consensus, elotuzumab-containing regimens may be considered for patients who have progressed on dara-containing regimens.
Elotuzumab should not be used as a single agent.
Prior treatment with elotuzumab is not a contraindication for treatment with anti-CD38 antibodies.
By consensus, elotuzumab-containing regimens are not recommended for patients with a rapidly growing disease burden.
Administration, dosing, and monitoring
In the ELOQUENT-2 trial, IRRs were reported in 33 patients (10%) in the elotuzumab arm, with mostly grade 1/2 IRRs and no grade 4 or 5 events. The majority of IRRs occurred during the first infusion.75 The prescribing information for elotuzumab recommends the premedication regimen developed during ELOQUENT-2: oral dexamethasone 28 mg 3–24 hours prior to each elotuzumab infusion and then an additional 8 mg administered intravenously 30–90 min before the infusion along with diphenhydramine (25–50 mg), ranitidine (50 mg) and acetaminophen (650–1000 mg).11 75 The prescribing information states that the infusion rate may be increased to 5 mL/min after four treatment cycles, however a phase II safety study found no increase in AEs with a faster infusion of elotuzumab administered over 1 hour from the third dose onward.88 ELOQUENT-2 and ELOQUENT-3 both gave elotuzumab at 10 mg/kg intravenous weekly for the first 8 weeks. However, in ELOQUENT-2, 10 mg/kg was continued every 2 weeks for cycles 3 and beyond whereas in ELOQUENT-3, elotuzumab was given 20 mg/kg intravenous every 4 weeks for cycle 3 and beyond.
Similar to other therapeutic antibodies, elotuzumab may interfere with protein electrophoresis or immunofixation measurements,89 causing false positives for M-spike results in the peripheral blood and potentially affecting the assessment of response according to the International Myeloma Working Group (IMWG) criteria. Unlike with dara, gel-shift approaches have not yet been developed to eliminate false positives for elotuzumab. Possible workaround options for the measurement of elotuzumab-induced M-spikes or imunofixation electrophoresis include the SLAMF790 or mass spectrometry-based approaches.62 63
In published trials, infusion-related reactions (IRRs) have been most prevalent with the first infusion.
The first dose of elotuzumab should start at 0.5 mL/min for the first 30 min, then 1 mL/min. The second dose should start at 3 mL/min for 30 min, then 4 mL/min and from the third dose on, the infusion can be given at 5 mL/min.
Per prescribing information, patients should be premedicated 45–90 min prior to infusion with dexamethasone 8 mg, an H1 and H2 blocker and acetaminophen (650–1000 mg orally).
For the most part, myeloma-specific immune responses should be measured with each cycle as per normal practice.
In patients with IgG kappa myeloma, determination of CR can be confounded by elotuzumab.
In the presence of a measurable M-spike, elotuzumab will have a minimal effect on disease measurement. When patients reach undetectable levels, however, mass spectrometry or other antibody-interference testing methods should be considered.
In the ELOQUENT-2 trial, serious AEs were reported in 65% and 57% of patients in the elotuzumab group and the control group, respectively75 and the incidence of serious AEs was 53% in the elotuzumab group and 55% in the control group, respectively during the ELOQUENT-3 study.77 The rates of anemia, neutropenia and thrombocytopenia were similar between the elotuzumab and control groups in both studies. In the ELOQUENT-2 trial, the incidence of grade 3 or 4 lymphocytopenia was significantly higher in the elotuzumab arm (77% vs 49%), however the rates were much lower and not significantly different between treatment arms during ELOQUENT-3 (8% vs 2%).75 77 Overall infection rates did not increase with the addition of elotuzumab in the ELOQUENT-2 or ELOQUENT-3 trials.75 77 However, increased incidence of herpes zoster infections was noted in the elotuzumab groups in both studies (4.1% vs 2.2% and 5% vs 2%).91
Although the ELOQUENT-2 and ELOQUENT-3 trials excluded patients in renal failure, a phase Ib study of E-Rd in 26 patients with MM and various levels of renal impairment did not observe any statistically significant differences in maximum observed serum concentration, nor areas under the concentration-time curves between the groups with severe renal impairment (creatinine clearance (CrCl) <30 mL/min) and end-stage renal disease (requiring dialysis) compared with patients with normal renal function (CrCl ≥90 mL/min).92 One case report described fatal renal failure in a man aged 61 years with IgG kappa MM who developed tumor lysis syndrome 1 week after elotuzumab treatment,93 but this has not been reported in any large clinical trials.
Although patients with renal impairment were excluded from clinical trials, the panel felt that elotuzumab may be used in patients with severe renal insufficiency (CrCL <30 mL/min).
A consensus could not be reached to recommend using elotuzumab in patients with hepatic impairment or plasma cell leukemia.
Antiviral prophylaxis is recommended for patients receiving elotuzumab.
To manage infections following treatment, IVIG should be administered according to established institutional criteria, which are not specific to elotuzumab.
At this time, no biomarkers of response or resistance to elotuzumab are known.
Isatuximab is a mAb that targets a distinct epitope on the plasma cell surface marker CD38, which promotes tumor cell killing through classic Fc-dependent immune-effector mechanisms, antibody-dependent cellular cytotoxicity, complement-dependent cellular cytotoxicity, and antibody-dependent cellular phagocytosis.94 Similar to dara, isatuximab has been shown to exhibit immunomodulatory effects in preclinical models through reducing the numbers of regulatory T cells (Tregs) as well as decreasing immune inhibitory cytokine production, including interleukin (IL)-10. Unlike dara, isatuximab was selected based on its ability to directly trigger MM cell death in the absence of cross-linking agents and independently of effector cells . In 2020, isatuximab was approved by the FDA in combination with pomalidomide and dexamethasone (I-Pd) for adult patients with MM who have received at least two prior therapies including lenalidomide and a PI based on results from the multicenter, multinational, randomized, open-label, two-arm, phase III ICARIA-MM study.
Isatuximab is currently being evaluated in multiple ongoing phase III clinical trials in combination with current standard treatments for people with both RRMM and treatment-naïve MM. In the relapsed refractory setting, based on promising results from a phase Ib study where isatuximab combined with carfilzomib led to an ORR of 61% and a clinical benefit rate of 86%, the ongoing IKEMA study (NCT03275285) recruited 302 participants with RRMM to assess the clinical benefit of isatuximab combined with carfilzomib and dexamethasone (I-Kd) versus Kd alone.95 In 2019, initial positive results from the randomized phase III ICARIA-MM (NCT02990338) trial96 were presented at the ASCO Annual Meeting and the European Society of Hematology Annual Meeting, reporting benefits for I-Pd in RRMM. The trial found that I-Pd prolonged PFS by 5 months compared with Pd alone (HR 0.596; 11.53 vs 6.47 months; 95% CI 0.44 to 0.81, p=0.001) and ORR was also significantly greater with I-Pd compared with Pd (60% vs 35%; p<0.0001), similar to the results observed in the phase Ib study that preceded this trial.97 The triplet regimen also demonstrated a significantly higher VGPR rate and a longer duration of response compared with Pd (31.8% vs 8.5%; p<0.0001 and median 13.27 vs 11.07 months, respectively). Among patients who achieved a response, I-Pd demonstrated faster median time to first response compared with Pd alone (35 vs 58 days). Moreover, time to next treatment was longer with I-Pd compared with Pd alone (HR 0.538; median not reached vs 9.1 months).98 These results were the basis for FDA approval of I-Pd for RRMM in 2020.
In patients with newly diagnosed MM, isatuximab is being evaluated in combination with the standard of care triplet regimen of VRd in multiple ongoing trials. The phase III IMROZ trial (NCT03319667)99 randomized 475 patients with newly diagnosed MM to receive either induction treatment with 4×6 week cycles with IV isatuximab+subcutaneous bortezomib+oral lenalidomide+IV or oral dexamethasone followed by continuous treatment with 4-week cycles with IV isatuximab+oral lenalidomide+IV or oral dexamethasone, or a control regimen of induction with VRd followed by continuous treatment with Rd. The primary outcome measure will be PFS and the estimated primary completion date is in December 2022. Another study evaluating the effect of isatuximab in combination with RVd induction therapy, GMMG HD7 (NCT03617731), had recruited 662 patients with newly diagnosed MM in 2019, and the trial will evaluate MRD negativity as well as PFS as primary outcome measures.
I-Pd is approved and recommended by the panel for patients with RRMM who have received more than two prior lines of therapy.
Although patients with renal failure, patients with COPD and patients with plasma cell leukemia were excluded from initial clinical trials, these populations may safely be treated with isatuximab.
Administration and dosing
In the phase Ib study of I-Rd, IRRs were observed in 83% of patients receiving isatuximab at an infusion rate of 250 mg/hour, prompting the adoption of a 175 mg/hour rate. The median durations for the first infusions were 3.7 and 3.1 hours, with shorter times for the second doses.100 Across multiple trials, IRRs most commonly occurred during the first doses of isatuximab, and were substantially less frequent on subsequent infusions.95 97 100
In accordance with published protocols, isatuximab should be started at 175 mg/hour initial infusion rate with a duration range of 2–7 hours.
Standard premedications are recommended up to 60 min prior to infusion to mitigate IRRs. Recommendations should be guided by label once approved by regulatory agencies. A suggested example is as follows:
Dexamethasone 40 mg IV or methylprednisolone 100 mg IV.
Diphenhydramine 50 mg IV or equivalent.
Ranitidine 50 mg intravenous or equivalent.
Acetaminophen 650–1000 mg oral administration.
In patients with respiratory disease (eg, asthma or reduced forced expiratory volume in 1 s), consider adding an adrenergic bronchodilator (albuterol inhaler/nebulizer) as premedication.
Prior exposure to mAb therapies
No large, randomized studies have evaluated whether prior exposure to mAbs alters efficacy of subsequent lines of therapy directed against the same antigen in MM. Dara has been demonstrated to reduce CD38 expression on MM cells within hours of the first infusion in clinical trials, yet some patients with reduced CD38 expression achieved deep and durable responses with treatment.101 A case report has been published describing two partial remissions in two relapsed patients after retreatment with dara, and plasma cells from those patients did not display decreased CD38 expression.102 More studies will need to be done to determine if retargeting CD38 is a viable option.
No consensus could be reached on using isatuximab in patients who had progressed on a dara-containing regimen.
Antibody interference in serum protein electrophoresis
Similar to dara, isatuximab may interfere with immunofixation results and appear as IgG kappa. Mass spectrometry, NGS or gel-shift approaches can help resolve antibody interference on SPEP. Antibody interference testing is unnecessary for non-IgG kappa isotype patients, patients with detectable disease by FLC or BJP or patients with an M-spike >0.2 g/dL by SPEP.62–64 89
For most patients, the panel recommends antibody interference testing by mass spectrometry for patients treated with isatuximab.
The European Society of Clinical Microbiology and Infectious Disease Study Group for Infections in Compromised Hosts concluded that, based on available evidence, CD38-targeting therapies likely do not substantially increase patients’ risk for bacterial infections.103 Results from trials with dara suggest that patients on combination regimens may be at elevated risk for varicella zoster virus infection and cytomegalovirus (CMV) reactivation.103–105
Patients should receive seasonal influenza vaccines while on isatuximab.
To manage infections following treatment, IVIG should be administered according to established institutional criteria, which are not specific to isatuximab.
Several promising new immunotherapy modalities are currently being evaluated in clinical trials for newly diagnosed as well as RRMM. Strategies include mAbs, CAR T cells, bispecific engagers of T cells, ADCs and cancer vaccines. Although the products described in subsequent sections have yet to be approved by the FDA at the time of publication, it is important for the oncology community to be familiar with emerging therapies, for possible consideration of referring their patients to an appropriate clinical trial or incorporating these new treatments into clinical practice, when they become available. Even though immune checkpoint inhibitors are FDA-approved for other disease settings and have been studied both as monotherapy and in combination with IMiDs for MM, safety signals observed in early trials and lack of clear clinical benefit motivated the panel to refer readers elsewhere for discussion of those agents.106 Given the rapid pace of the field, therapies other than those described in this manuscript may advance through clinical trials soon after publication, and inclusion or absence of a specific agent herein should not be interpreted as an endorsement.
Emerging therapies targeting BCMA
Both CD38 (the antigen targeted by dara and isatuximab) and SLAMF7 (elotuzumab) are expressed in healthy tissues including hematopoietic lineages and immune effector cells.107 108 B cell maturation antigen (BCMA), by contrast, is a surface marker with highly restricted expression that is very frequently upregulated in MM cells. In healthy tissues, BCMA is only found on late memory B cells committed to plasma cell differentiation, where it is required for the survival of long-lived plasma cells.109 110 In MM, BCMA is associated with the proliferation and survival of cancer cells, and it is associated with the induction of an immunosuppressive bone marrow microenvironment.111 112 Membrane BCMA is cleaved by the enzyme gamma secretase,113 114 leading to the formation of a soluble form (sBCMA), and elevated levels of sBCMA in patient serum have been correlated with disease status and poor prognosis.111 The administration of an oral gamma secretase inhibitor to patients can significantly increase BCMA density on the surface of malignant plasma cells and reduce sBCMA levels.114
CAR T cells
Escalating pipelines of BCMA-targeting CAR T therapies for MM have posted encouraging results. In late 2019, >40 trials investigating BCMA-targeting CAR T cells were actively recruiting patients, with the majority in phase I or phase I/II. Agents further along the path toward FDA approval are bb2121 (idecabtage vicleucel),12 115 a second-generation CAR containing a 4-1BB costimulatory motif, which received Breakthrough Therapy designation in 2017,116 and JNJ-68284528 (also called JNJ-4528, formerly LCAR-B38M), which binds to two distinct epitopes on BCMA,117 118 and has also been granted Breakthrough Therapy designation in addition to PRIME designation by the European Medicines Agency (EMA). Additionally, under investigation are cell-based therapies using NK cells119 as well as TCR-engineered T cells, such as the enhanced affinity NY-ESO-1 TCR.120
A phase I trial investigated the novel CAR T cell therapy, bb2121, in patients with heavily pretreated RRMM. For the first 33 consecutive patients who received a bb2121 infusion at the cut-off date of 6.2 months after last infusion, the ORR was 85% (95% CI 68.1 to 94.9), with 45% of patients having a CR (9%) or stringent CR (sCR 36%), respectively. Of the 15 patients with a CR, 6 relapsed. The median PFS was 11.8 months (95% CI 6.2 to 17.8). All 16 patients who had a response (PR or better) and who could be evaluated for MRD achieved MRD-negative status (≤10−4 nucleated cells). Successful expansion of CAR T cells was associated with responses, during which expanded cells persisted up to 1 year after the infusion. Interestingly, response rates of 74% or higher were observed among patients with progressive disease during their most recent line of therapy, those who had received dara as part of their most recent line, those who did not receive bridging therapy and those who had extramedullary disease (plasmacytomas) at baseline.12 Hematological toxic effects were the most common AEs of grade 3 or higher, including neutropenia (85% of patients), leukopenia (58%), anemia (45%) and thrombocytopenia (45%). Twenty-five patients (76%) experienced cytokine release syndrome (CRS) (grade 1–2 in 70% and grade 3 in 6% of patients). Neurological toxic effects occurred in 14 patients (42%) and were of grade 1–2 in 39% of patients. One patient (3%) had a reversible grade 4 neurological toxic effect.12
At the time of writing, several phase II trials are evaluating bb2121 in the RRMM setting, including KarMMa and KarMMa-2 (NCT03361748 and NCT03601078). The KarMMa-1 trial has completed recruitment for patients who have received at least three prior lines of therapy, whereas the KarMMa-2 study is enrolling multiple cohorts including subjects with ≥3 prior antimyeloma treatment regimens, subjects with one prior antimyeloma therapy including autologous stem cell transplantation (ASCT) and with early relapse, subjects with one prior antimyeloma therapy not including ASCT and with early relapse, and subjects with inadequate response to ASCT during their initial antimyeloma therapy. Additionally, a multicenter, randomized, open-label, phase III study comparing the efficacy and safety of bb2121 vs standard triplet regimens in subjects with RRMM treated with two to four prior lines of therapy, the KarMMa-3 trial (NCT03651128), is ongoing. KarMMa-4, which is a phase I study with bb2121 to be given after four cycles of induction chemotherapy in newly diagnosed, high-risk MM, has started recruiting (NCT04196491).
The EVOLVE study is a phase I/II trial evaluating the safety and efficacy of JCARH125, a fully human CAR, in patients with RRMM (NCT0343001). In late 2019, 44 patients with highly refractory disease (median of nine prior therapies, 64% with high-risk cytogenetics) had received various doses of JCARH125. Overall, an ORR of 82% was achieved, with CR/sCR reported in 27% and VGPR or better in 48% of patients with limited follow-up. At the lowest dose of 50×106 total CAR T cells, the CR/sCR reported was 43%, with a trend of deepening responses over time. CRS was observed in 80% of patients, with 9% having a grade ≥3 AE. Neurotoxicity occurred in 18% of patients, with 7% reported to be grade ≥3. The product received FDA orphan drug status in 2017.121
Another CAR T therapy in development is JNJ-4528 (identified as LCAR-B38M in China), which targets two distinct epitopes of BCMA. In early results from the LEGEND-2 phase I/II open study (NCT03090659) of 57 Chinese patients with RRMM treated with LCAR-B38M, the ORR was 88% and the CR rate was 68%. CRS was seen in 90% of patients, with 7% having grade 3 CRS. Only one patient developed neurotoxicity.117 At data cut-off, the OS rate at 18 months was 68% (range 54%–79%) with median duration of response (mDOR) 22 months (range 13–29). At 18 months, the rate of PFS was 50% (range 36–63) for all treated patients and 71% (range 52–84) for MRD-negative patients with CR. The median PFS for all treated patients was 20 months (range 10–28) and 28 months (range 20–31) for MRD-negative patients with CR. It is important to note that many therapies available in the USA are not routinely available in China, and these patients were significantly less heavily pretreated then the patients on US trials.122 The phase Ib/II CARTITUDE-1 study (NCT03548207) is evaluating JNJ-4528 in the USA and Europe, concomitantly with the ongoing phase II CARTIFAN-1 trial (NCT03758417) in China.123 As of June 24, 2019, 25 patients had been infused with JNJ-4528 in the phase Ib portion of the study. In an update presented December 2019 at the American Society of Hematology annual meeting, 21 patients were evaluable for response with a median follow-up of 3 months (range 1–10). Reduction in tumor burden was observed for all patients with ORR of 91% including 4 sCRs, 2 CRs, 7 VGPRs and 6 PRs. Of the 15 patients with evaluable bone marrow samples, 10 were MRD-negative at the 10−5 sensitivity level.124
P-BCMA-101, a novel BCMA-targeting CAR T produced using the non-viral transposase-transposon piggyBac DNA Modification System,125 has entered phase II testing. In a phase I trial with 11 patients, encouraging safety data was reported with only 1 case of suspected CRS that was minimal and short-lived. PR or better was obtained in 7 out of 10 patients. The manufacturing technology results in CAR T cell products with a high percentage of self-renewing, long-lived stem cell memory T cells due to the introduction of a selection gene along with the CAR. Second, the use of the protein Centyrin binder instead of a traditional antibody-based binder may yield a potentially less immunogenic product. Additionally, the small size of the Centyrin binder has allowed P-BCMA-101 cells to be engineered with a ‘safety switch’ gene to allow the cells to be eliminated if desired. The product received FDA RMAT designation in 2018 and orphan drug status in 2019.126
Early promise has also been demonstrated through the combination of BCMA CAR T cells and an oral gamma secretase inhibitor (GSI; JSMD194) designed to increase surface density of the BCMA target. Among the eight patients reported to date on this phase I trial (NCT03502577), a median 20-fold increase in BCMA surface density was observed following three doses of the oral GSI, and although the data are not mature, an ORR of 100% was noted among evaluable patients, including those treated at the lowest BCMA CAR T-cell dose (50×106).127
In the future, combination treatments using CAR T cells directed against BCMA as well as additional antigens may be needed to further improve clinical outcomes. A SLAMF7-targeting CAR, derived from elotuzumab, has been developed, and T cells transduced with the construct display anti-myeloma activity in vitro and in mouse models.128 GPRC5D has been shown to be a potentially important target for the immunotherapy of MM, and GPRC5D-targeted CAR T cells demonstrate preclinical myeloma-directed activity in vitro and in vivo, including in a BCMA antigen-escape model.129 Additionally, even though abnormal plasma cells in MM generally do not express CD19,130 a very small proportion of cancer stem cells may retain the marker,131 opening the door to treatment with existing anti-CD19 CAR T therapies, such as tisagenleceucel. In a study of 10 patients with RRMM who received high-dose melphalan and autologous stem cell transplant followed by infusion of CTL019 CAR T cells, 2 achieved longer PFS after HSCT+CTL019 compared with prior HSCT (479 vs 181 days and 249 vs 127 days). Durable response in this study was associated with the induction of T cells against SOX2, a stem-cell antigen.132 A study of 21 patients with RRMM who received infusions of CD19-targeting and BCMA-targeting CAR T cells reported 20 ORs (95%), including 9 sCRs (43%), 3 CRs (14%), 5 VGPRs (24%) and 3 PRs (14%).133 Another trial observed high initial response rates after administering a combination of CAR T-BCMA and CTL119 (an investigational product with a humanized CD19-targeting CAR) as consolidation therapy to 10 patients responding to third-line therapy, 4 of whom had high-risk cytogenetics. Absence of circulating B cells was observed in five patients, including two who had ongoing responses at 4 months and 1 year, hinting at the desirable long-term persistence of CAR T cells.134
The most frequent setting for clinical trials (and the setting where the reported clinical results are the most mature) are in the multiply relapsed/refractory space, especially for trials in the USA. For inclusion in the phase II KarMMa-1 trial of the BCMA-directed CAR T-cell therapy bb2121, for example, patients must have received three prior regimens including an IMiD, PI and an anti-CD38 antibody, and have been refractory to the last regimen. Because of the clinical setting, many patients treated with CAR T cells have had MM with extensive prior therapy.12 14 115 117 135–137 To date, there is no data demonstrating differences in safety or efficacy based on cytogenetics. As safety and efficacy is becoming apparent, more advanced products are beginning to be explored clinically in earlier lines, such as one to three prior therapies, and in the upfront setting for high-risk patient populations.
Heavy pretreatment, including prior allogeneic transplant or other BCMA-targeting therapies, does not necessarily preclude patients from CAR T treatment. Safety and possible efficacy was reported in a study by investigators from the Fred Hutchinson Cancer Research Center using a vector identical to JCARH125 with unique manufacturing. In this study, seven patients with a median of eight prior therapies, including autologous HSCT in 71% and allo-HSCT in 43% of subjects were treated, none of whom developed graft-versus-host disease (GVHD).137 In the phase I trial of bb2121, the median number of previous regimens was seven in the dose-escalation cohort and eight in the expansion cohort, and manufacturing was successful for 100% of patients.12 Regardless of prior therapies, an adequate number of lymphocytes can usually be collected, and CAR T cells have been successfully manufactured to the prespecified dose for most patients on most trials.12 14 115 117 135–138 However, the impact of previous chemotherapy on the quality of CAR T cells is not yet known. While more study is required to understand the benefit of repeat dosing at relapse with the same CAR T-cell product, there have been reports in the acute lymphoblastic leukemia (ALL) setting of clinical efficacy of retreatment in the presence of preserved antigen expression with an intensified lymphodepletion regimen.139 For MM, responses have also been reported in relapsed patients treated with anti-BCMA CAR T cells, even after prior treatment with different BCMA-targeting products, including CAR T cells.137
Performance status may be an important consideration in recommending patients for trial enrollment. A study evaluating JCAR017, an anti-CD19 CAR T, in relapsed/refractory non-Hodgkin’s lymphoma observed worse outcomes in patients with impaired performance status, defined as grade 2 on the Eastern Cooperative Oncology Group (ECOG) scale. The overall mDOR was 5.0 months, whereas the subset of patients scored ECOG 0–1 had an mDOR of 9.2 months. Similarly, the 6-month OS was 75% for all patients, and 88% for the ECOG 0–1 group.140
The decision of suitability for CAR T cell therapy is often based on the potential for toxicity. Thus, baseline bone marrow function, cardiopulmonary, hepatic and renal function as well as performance status and organ status with respect to ability to tolerate CRS should be evaluated and toxicities should be considered, especially prolonged cytopenias.
Registration trial results and FDA labels should guide disease-specific characteristics such as number of prior antimyeloma therapies.
For patients earlier in their disease course, the presence of high-risk disease is an unmet medical need, and may shift the benefit/risk calculation in support of enrollment on cellular therapy trials.
Heavily pretreated patients, including those who have undergone allo-HSCT may be considered for CAR T cell therapy.
No data have been reported indicating that prior bispecific antibody or ADC therapy impacts the potential efficacy of future CAR T cell therapy or vice versa, and the panel agreed that there is not enough data to report on a consensus. Future trials should seek to address this question.
Myeloma disease progression kinetics and likelihood of control should be weighed against the manufacturing time when considering patient eligibility for collection and likelihood to be clinically stable for CAR T cell administration.
Administration, dosing and monitoring
CAR T cell therapy involves extensive collaboration across the healthcare team. At the present time patients should be referred to centers of experience for CAR T cell therapies. This may change as the community gains more experience with this therapeutic modality.141 Prior to infusion, lymphodepletion is integral to CAR T cell treatment,