In the past decade, use of immunotherapy has arisen as a novel adjunct to multiple myeloma therapy. Daratumumab is the first anti-CD38 monoclonal antibody to be approved by the U.S. Food and Drug Administration (FDA), in November 2015, for use in treating relapsed or refractory multiple myeloma.1 Since its initial approval, daratumumab has been studied in combination with other approved therapies—including immunomodulatory drugs, such as lenalidomide and pomalidomide, and proteasome inhibitors, such as bortezomib and carfilzomib. In addition, clinical trials have studied the use of daratumumab in earlier lines of therapy. One such trial is POLLUX, a pivotal phase III randomized, open-label, multicenter trial evaluating the combination of daratumumab with lenalidomide and dexamethasone (DRd) vs lenalidomide and dexamethasone (Rd) in the setting of relapsed or refractory multiple myeloma.
Key Findings From POLLUX Trial
In POLLUX, 569 patients with relapsed or refractory multiple myeloma, with a median of one prior line of therapy, were randomly assigned to DRd (n = 286) vs Rd (n = 283). The results at a median follow-up of 54.8 months showed a median duration of therapy of 34.3 vs 16.0 months and a median progression-free survival of 45.0 vs 17.5 months (P < .0001) for DRd vs Rd. Additional results from POLLUX showed superior minimal residual disease (MRD) negativity rates at 10-5 (33% vs 7%, P < .0001) and overall response rates (93% vs 76%, P < .0001) with DRd. The safety profile indicated increased toxicities with DRd, such as hematologic (grade 3 or 4 neutropenia), gastrointestinal (diarrhea), respiratory infection (pneumonia), and infusion reactions. As for cytogenetic risk stratification, at a median follow-up of 44.3months, DRd was shown to have superior progression-free survival, overall response rate, and MRD-negative rates for both standard- and high-risk patients. Similar findings were observed in an analysis according to age between 65 and 74 compared with at least 75.
The results of POLLUX led to FDA approval in July 2016 for the use of daratumumab with Rd in the relapsed or refractory multiple myeloma setting.2 The favorable safety and efficacy of DRd in older patients and in the setting of relapsed or refractory multiple myeloma as seen in POLLUX led to evaluation of its use in patients with newly diagnosed multiple myeloma, specifically the transplant-ineligible population, in the MAIA trial.
The authors concluded that front-line use of DRd in this patient population improved overall survival and progression-free survival without any unforeseen safety concerns….— Monique Hartley-Brown, MD, MMSc
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Comparison With MAIA Trial
The MAIA trial, a phase III, randomized, open-label, multicenter trial, evaluated DRd (n = 368) vs Rd (n = 369) in the front-line setting for transplant-ineligible patients with newly diagnosed multiple myeloma. The primary analysis at a median follow-up of 28.0 months showed significantly improved progression-free survival with DRd, supporting the June 2019 FDA approval of daratumumab with Rd in this setting. An interim analysis of overall survival, recently reported by Facon and colleagues,3 and summarized in this issue of The ASCO Post, has shown a significant benefit with DRd. (Details of the trial appear in the accompanying summary on page 24.)
The report by Facon et al also provides updated data showing superior progression-free survival, time to disease progression, and overall response rate (including complete response or better and MRD-negative status) with DRd at a median follow-up of 56.2 months. At the time of the analysis, median progression-free survival and time to disease progression were not reached in the DRd group and were significantly prolonged vs the Rd group. Furthermore, fewer patients in the DRd group required subsequent therapy (31%) compared with the Rd group (51%). Of note, fewer patients in the DRd group continued to a subsequent daratumumab-containing regimen (10% vs 21% at first relapse and 15% vs 46% at any subsequent relapse); this is not surprising, given the concern for daratumumab-exposed/refractory disease at disease progression in the DRd group. Fewer deaths were observed in the DRd group (32%) compared with the Rd group (42%) at the time of assessment. This suggests that disease control in the front-line setting with the use of triplet therapy is advantageous compared with doublet therapy. This also speaks to the safety and tolerability of DRd in the front-line setting for treatment of transplant-ineligible patients with newly diagnosed multiple myeloma.
Median overall survival was not reached (95% confidence interval [CI] = not reached to not reached) in the DRd group vs not reached (95% CI = 55.7 months to not reached) in the Rd group, representing a statistically significant difference showing an estimated 32% lower risk of death in the DRd group (hazard ratio (HR) = 0.68, 95% CI = 0.53–0.86, P = .0013). Subgroup analyses of overall survival stratified by International Staging System stages I, II, and III, and cytogenetics (standard- vs high-risk) all favored DRd. Other secondary endpoints favoring DRd included prolonged the duration of therapy (47.5 vs 22.6 months) and delay to the next line of therapy.
As in POLLUX, the most common toxicities in the MAIA trial were grade 3 or 4 neutropenia (54% vs 37%) and grade 3 or 4 infections (41% vs 29%; pneumonia in 19% vs 11%). Treatment-related deaths were comparable in the two groups (4% vs 3%). A notable observation was the increased incidence of secondary malignancies in the DRd group (20% vs 13%). The etiology for this is unclear, and it will be important to evaluate this further in the current climate of front-line use of daratumumab.
The toxicity findings of increased cytopenias and infections in the DRd group is not surprising. CD38 antigen receptors are found on red blood cells; the confounding indirect Coombs positive test findings may be due to this cross-reactivity. Other daratumumab-based combination trials have shown increased myelosuppression in the setting of daratumumab added to immunomodulatory drugs.
Also observed are the hypogammaglobulinemia effects of daratumumab-based regimens due to its targeting of CD38 and its antibody-dependent cellular cytotoxicity, antibody-dependent cellular phagocytosis, complement-dependent cytotoxicity, apoptosis, and immunomodulatory effects. Use of intravenous immunoglobulin to mitigate these hypogammaglobulinemia-causing effects has been shown to be effective in lowering the infection and pneumonia rates in patients treated with daratumumab.4,5
Several Questions Remain
The authors concluded that front-line use of DRd in this patient population improved overall survival and progression-free survival
without any unforeseen safety concerns, supporting the use of this regimen in the front-line setting of newly diagnosed multiple myeloma. The results of the MAIA trial prompted several trials evaluating the use of daratumumab in specific patient populations in the front-line setting. The MMY1001trial6 is evaluating daratumumab plus carfilzomib/dexamethasone, and the GRIFFIN trial7 is evaluating daratumumab, lenalidomide, bortezomib, and dexamethasone.
With the FDA approval of daratumumab in the front-line setting of newly diagnosed multiple myeloma arises several questions. How can patients who are daratumumab-exposed/refractory with relapsed or refractory multiple myeloma best be managed? How best can patients who will benefit most from daratumumab-based regimens upfront vs in relapse be identified? What is the role of other anti-CD38–targeted therapies in the setting of exposure to daratumumab? In the current climate of increasing use of quadruplet therapy and chimeric antigen receptor T-cell therapy, it is also important to assess how best to risk-stratify patients to determine the optimal timing to introduce daratumumab-based therapy.
Dr. Hartley-Brown works at the Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston.
DISCLOSURE: Dr. Hartley-Brown reported no conflicts of interest.
REFERENCES
1. Lonial S, Weiss BM, Usmani SZ, et al: Daratumumab monotherapy in patients with treatment-refractory multiple myeloma (SIRIUS): An open-label, randomised, phase 2 trial. Lancet. 387:1551-1560, 2016.
2. Offidani M, Corvatta L, Morè S, et al: Daratumumab for the management of newly diagnosed and relapsed/refractory multiple myeloma: Current and emerging treatments. Front Oncol 10:624661, 2021.
3. Facon T, Kumar SK, Plesner T, et al: Daratumumab, lenalidomide, and dexamethasone versus lenalidomide and dexamethasone alone in newly diagnosed multiple myeloma (MAIA): Overall survival results from a randomised, open-label, phase 3 trial. Lancet Oncol 22:1582-1596, 2021.
4. Hosokawa M, Kashiwagi H, Nakayama K, et al: Distinct effects of daratumumab on indirect and direct antiglobulin tests: A new method employing 0.01 mol/L dithiothreitol for negating the daratumumab interference with preserving K antigenicity (Osaka method). Transfusion 58:3003-3013, 2018.
5. Lancman G, Sastow D, Aslanova M, et al: Effect of intravenous immunoglobulin on infections in multiple myeloma patients receiving daratumumab. 2020 ASH Annual Meeting and Exposition. Abstract 1404. Presented December 5, 2020.
6. Andrzej JJ, Ajai C, Sagar L, et al: Daratumumab in combination with carfilzomib, lenalidomide, and dexamethasone in patients with newly diagnosed multiple myeloma (MMY1001): An open-label, phase 1b study. 2017 ASCO Annual Meeting. Abstract 8000.
7. Voorhees PM, Kaufman JL, Laubach J, et al: Daratumumab, lenalidomide, bortezomib, and dexamethasone for transplant-eligible newly diagnosed multiple myeloma: The GRIFFIN trial. Blood 136:936-945, 2020.
