The use of daratumumab in multiple myeloma: Developing novel immunotherapy strategies to prolong survival
Multiple myeloma (MM) is a type of clonal neoplasm with substantial morbidity and mortality. With the development of better therapies, MM has transformed from untreatable to still incurable but treatable.1 At a recent webinar organized by the Hong Kong Society of Haematology, Professor María-Victoria Mateos, a consultant physician and Associate Professor at the University Hospital of Salamanca-IBSAL, Salamanca, Spain emphasized the emerging role of the monoclonal antibody (mAb), daratumumab, for the management of MM.†
The lack of ideal target antigens for mAb immunotherapy in MM treatment
Immunotherapy is a type of treatment that stimulates or restores a patient’s immune system to help fight the diseases. mAb therapy is one such treatment that activates the immune system by having mAbs attached to the antigens on cancer cells. By marking these cancer cells for the immune system to destroy, mAb therapy provides a targeted therapeutic option that can reduce off-target side effects.2 For MM, Prof. Mateos highlighted: “There have been many mAb therapies targeting different antigens on the surface MM plasma cell and bone marrow microenvironment which have been discovered, however, the efficacy evaluated for the mAbs as monotherapy was modest, indicating that these targets are not ideal for the treatment of MM patients.”3-5
Daratumumab as the first FDA approved CD38-targeting mAb single agent for MM
Where many different antigens are not ideal targets for MM treatment, CD38 was the first target that resulted in high efficacy. Daratumumab is the first CD38-targeting mAb approved as a single agent for MM.6 Through direct on-tumor actions such as complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), and antibody-dependent cellular phagocytosis (ADCP), daratumumab exhibits anti-myeloma activity which leads to tumor cell death. The inhibition of ectoenzymatic function and direct induction of apoptosis may also contribute to the efficacy of daratumumab in killing the MM cells. Moreover, daratumumab improves host-anti-tumor immunity by eliminating the regulatory T cells, regulatory B cells and myeloid-derived suppressor cells.6 Prof. Mateos further commented “These mechanisms of action are responsible for the rapid response which is shown when daratumumab is used to treat MM patients”.7
Addition of daratumumab in current SOC is associated with survival benefit in new SOC transplant-ineligible NDMM patients
The current standard of care (SOC) treatments for non-transplant newly diagnosed MM (NDMM) patients consist of PIs such as bortezomib-melphalan-prednisone (VMP), immunomodulatory drugs such as lenalidomide-dexamethasone (Rd) and the combination PIs and IMiDs such as modified lenalidomide‐bortezomib‐dexamethasone (VRD/lite).8–11 “Towards the future,” Prof. Mateos commented, “daratumumab is being added to all these platforms to generate a new SOC for management of this population.”12,13
In the randomized phase 3 ALCYONE study, 706 transplant-ineligible NDMM patients are randomized into receiving either SOC with VMP for 9 cycles in the control arm or the addition of daratumumab to SOC (D-VMP) for the first 9 cycles in the experimental arm. Patients in the experimental arm continued to receive daratumumab as monotherapy once per month after the first 9 cycles. The primary endpoint was progression-free survival (PFS) and the secondary endpoint included overall survival (OS), safety, minimal residual disease rate (MRD), and overall response rate (ORR).7
The updated efficacy results reported at the American Society of Hematology (ASH) 2019 meeting showed that D-VMP resulted in a significant benefit in PFS: After a median follow-up of 40.1 months, the median PFS with D-VMP vs. VMP was at 36.4 vs. 19.3 months [hazard ratio (HR)=0.42; 95% CI: 0.34-0.51, p<0.0001] (Figure 1A). When used after one line of therapy, the PFS was not reached with D-VMP vs. 42.3 months with VMP (HR=0.55; 95% CI: 0.43-0.71, p<0.0001). The estimated 36-month OS rate with D-VMP and VMP were at 78% and 68%, respectively, with a significant benefit for OS observed for D-VMP when compared to VMP (HR=0.60; 95% CI: 0.46-0.80, p=0.0003). At 42 months, the estimated OS with D-VMP and VMP were at 75% and 62%, respectively, demonstrating that the addition of daratumumab prolonged survival for transplant-ineligible NDMM patients (Figure 1B).7
The benefit of D-VMP was also demonstrated with an improved ORR and higher proportion of patients that were MRD-negative. In both the primary and updated analysis, 91% of patients receiving D-VMP achieved at least a partial response. Prof. Mateos commented “This put in context means that almost every NDMM patient not eligible for transplant and treated with D-VMP is going to achieve at least a partial response.”7
Approximately 33% of D-VMP treated patients were MRD-negative with 14% sustained MRD-negativity after 12 months. This MRD status has been associated with significant benefit in PFS and OS when compared to VMP treated patients where only approximately 7% VMP treated patients achieved MRD-negative after treatment. Prof. Mateos explained, “From my point of view, [MRD-negativity] will be the new objective that we will have in plan for every MM patient - to reach sustained MRD negativity.”7
The safety profile and tolerability were not affected with the addition of daratumumab. Hematologic and nonhematological events were comparable in both arms. Upper respiratory tract infection and pneumonia were the only adverse events reported more frequently in the D-VMP arm than VMP arm. The incidences of discontinuation and deaths were very low and comparable in both arms.7
Other PIs did not show significant improvement in PFS (in frontline transplant-ineligible patients)
While other PIs such as carfilzomib have also been studied for the treatment of MM patients, the efficacy results showed that these PIs are less favorable as a combination therapy. In the phase 3 ENDURANCE study, 1,087 NDMM patients were randomized into receiving either carfilzomib-Rd (KRd) for 9 cycles or bortezomib-Rd (VRd) for 12 cycles followed by maintenance with lenalidomide. Results presented at the American Society of Clinical Oncology (ASCO) meeting 2020 showed that the use of KRd (34.4 months) did not prolong PFS when compared to VRd (34.6 months). The three-year OS was also similar between VRd and KRd at 84% and 86%, respectively. Prof. Mateos thereby concluded that “this study thus did not confirm the superiority of carfilzomib to bortezomib [SOC].”14
The role of daratumumab in the relapsed/refractory setting
For patients previously treated with bortezomib-based combination and possibly exposed to lenalidomide but not progressed under lenalidomide therapy, the 2017 European Society for Medical Oncology (ESMO) guidelines recommend a triplet combination base of Rd (D-Rd, KRd, ixazomib-Rd or elotuzumab-Rd).15 In the randomized, open-label, phase 3 POLLUX study, the efficacy of D-Rd combination was evaluated and the results were presented in the ASH 2019 meeting.16
In patients receiving D-Rd, the median PFS was 45.0 months and a 57% reduction in the risk of progression or death was observed. In patients with 1 prior line of therapy, the median PFS was notably longer at 53.3 months when treated with D-Rd (Figure 2).16 D-Rd was also shown to be effective in patients who were refractory to bortezomib with a median PFS of 34.3 months. D-Rd was able to improve PFS outcome in patients with high and standard cytogenetic risk.16 Prof. Mateos further highlighted that “daratumumab increased the median PFS of the patients with standard and high cytogenetic risk significantly.”
Patients treated with D-Rd also achieved higher ORRs and deeper responses when compared to Rd with no new safety concerns identified under a longer follow-up period. This trial also demonstrated an improvement in the rate of MRD-negativity and was associated with sustained MRD-negativity with the addition of daratumumab.16 These updated results continue to support the use of daratumumab combination therapies in patients with relapsed/refractory multiple myeloma (RRMM) after 1 prior line of therapy.
For patients treated with bortezomib-based combinations followed by treatment-free interval and are exposed to lenalidomide and/or progressing under lenalidomide therapy, D-Vd is the recommended daratumumab combination by ESMO.15 In the CASTOR study, the PFS benefit was significant for D-Vd when compared to Vd with a median PFS of 16.7 vs. 7.1 months, respectively (HR=0.31; 95% CI: 0.24-0.39, p<0.0001).17
The benefit was further emphasized in patients with 1 prior line of therapy when treated with D-Vd vs. Vd with a median PFS of 27.0 vs. 7.9 months, respectively (HR=0.21; 95% CI: 0.15-0.31) (Figure 3). In patients who were refractory to lenalidomide, the median PFS for D-Vd was 7.8 vs. 4.9 months in the control arm. PFS benefits with D-Vd were also seen in both standard and high cytogenetic risk groups.17
D-Vd not only induced deeper and more durable responses, but also improved the MRD-negativity rates. The addition of daratumumab to Vd did not impact hematological toxicity with the exception of thrombocytopenia, which was mildly higher for D-Vd versus Vd. The most frequent adverse events were upper respiratory tract infection and pneumonia that was consistent with previous studies mentioned.17 Thus, these updated results continue to support the use of daratumumab combination therapies in patients with RRMM after 1 prior line of therapy.17
The addition of daratumumab to SOC is a novel treatment which demonstrated superior efficacy in the transplant-ineligible NDMM patients. Also, daratumumab has demonstrated tolerability and efficacy in treating RRMM patients when combined with Rd and Vd. The proven efficacy of daratumumab-based combinations in different groups of patients also provides the flexibility for the use of daratumumab in treating RRMM patients with various prior treatment histories who have been exposed to different PIs or IMiDs. Therefore, the addition of daratumumab as an immunotherapy should be considered as the new SOC for the management of MM.
†This article is sponsored by Janssen, a division of Johnson & Johnson (HK) Ltd
This is an independent editorial article, published and distributed through unrestricted educational support from the pharmaceutical community, for the purpose of continuing medical education only. The views expressed in this publication reflect the experience and/or opinion of the author(s) and are not necessarily those of editors, publisher and sponsor(s). Because of rapid advances in medicine, independent verification of clinical diagnoses, medical suitability and dosage should be made before treatment prescription. The appearance of advertisement, if any, has no influence on editorial content or presentation and does not imply the endorsement of products by the publication, or its authors and editors.
- Cowan AJ, et al. Global burden of multiple myeloma: A systematic analysis for the global burden of disease study 2016. JAMA Oncol. 2018;4(9):1221-1227.
- The American Cancer Society. Monoclonal Antobodies and Their Side Effects. https://www.cancer.org/treatment/treatments-and-side-effects/treatment-types/immunotherapy/monoclonal-antibodies.html. Accessed July 21, 2020.
- Chanan-Khan A, et al. Efficacy Analysis From Phase I Study of Lorvotuzumab Mertansine (IMGN901), Used as Monotherapy, In Patients with Heavily Pre-Treated CD56-Positive Multiple Myeloma - A Preliminary Efficacy Analysis. Blood. 2010;116(21):1962-1962.
- Jagannath S, et al. BT062, An Antibody-Drug Conjugate Directed Against CD138, Shows Clinical Activity in Patients with Relapsed or Relapsed/Refractory Multiple Myeloma. Blood. 2011;118(21):305-305.
- von Tresckow B, et al. A Phase II Clinical Trial of the Anti-EGFR Antibody Cetuximab in Patients with Refractory or Relapsed Multiple Myeloma: Final Results,. Blood. 2011;118(21):3965-3965.
- van de Donk NWCJ et al. CD38 antibodies in multiple myeloma: mechanisms of action and modes of resistance. Front Immunol. 2018;9:2134.
- Mateos M-V, et al. Daratumumab Plus Bortezomib, Melphalan, and Prednisone Versus Bortezomib, Melphalan, and Prednisone in Patients with Transplant-Ineligible Newly Diagnosed Multiple Myeloma: Overall Survival in Alcyone. Blood. 2019;134(Supplement_1):859-859.
- San Miguel JF, et al. Persistent overall survival benefit and no increased risk of second malignancies with bortezomib-melphalan-prednisone versus melphalan-prednisone in patients with previously untreated multiple myeloma. J Clin Oncol. 2013;31(4):448-455.
- Benboubker L, et al. Lenalidomide and dexamethasone in transplant-ineligible patients with myeloma. N Engl J Med. 2014;371(10):906-917.
- Durie BGM, et al. Bortezomib with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma without intent for immediate autologous stem-cell transplant (SWOG S0777): a randomised, open-label, phase 3 trial. Lancet. 2017;389(10068):519-527.
- O’Donnell EK, et al. A phase 2 study of modified lenalidomide, bortezomib and dexamethasone in transplant-ineligible multiple myeloma. Br J Haematol. 2018;182(2):222-230.
- Mateos M-V, et al. Daratumumab plus Bortezomib, Melphalan, and Prednisone for Untreated Myeloma. N Engl J Med. 2018;378(6):518-528.
- Facon T, et al. Daratumumab plus Lenalidomide and Dexamethasone for Untreated Myeloma. N Engl J Med. 2019;380(22):2104-2115.
- Kumar S, et al. Carfilzomib, lenalidomide, and dexamethasone (KRd) versus bortezomib, lenalidomide, and dexamethasone (VRd) for initial therapy of newly diagnosed multiple myeloma (NDMM): Results of ENDURANCE (E1A11) phase III trial. JCO. 2020;38(18_suppl):LBA3-LBA3.
- Moreau P, et al. Multiple myeloma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2017;28 Suppl 4:iv52-iv61.
- Kaufman JL, et al. Four-Year Follow-up of the Phase 3 Pollux Study of Daratumumab Plus Lenalidomide and Dexamethasone (D-Rd) Versus Lenalidomide and Dexamethasone (Rd) Alone in Relapsed or Refractory Multiple Myeloma (RRMM). Presented At The 61st American Society Of Hematology (ASH) Annual Meeting & Exposition; December 7-10, 2019; Orlando, Florida. Poster 1866.
- Mateos M-V, et al. Efficacy and Safety of Daratumumab, Bortezomib, and Dexamethasone (D-Vd) Versus Bortezomib and Dexamethasone (Vd) in First Relapse Patients: Two-Year Update of Castor. Blood. 2018;132(Supplement 1):3270-3270.
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