Multiple Myeloma Coverage from Every Angle
Editors:
Shaji K. Kumar, MD
Prashant Kapoor, MD, FACP
JNCCN Spotlights

(UPDATE) Daratumumab

Updated: Wednesday, April 12, 2023
Posted: Friday, July 19, 2019

Commentary by Multiple Myeloma Co-Site Editor for JNCCN 360

Shaji K. Kumar, MD

Professor of Medicine, Mayo Clinic, Rochester, Minnesota

The introduction of monoclonal antibodies represents one of the most important advances in medical therapeutics since the introduction of immunomodulatory drugs and proteasome inhibitors at the turn of the century. We have seen impressive clinical results in patients with multiple myeloma using CD38-targeted antibodies (daratumumab and isatuximab-irfc) alone and in combinations, as well as with elotuzumab (which targets SLAMF7) used in combination. Clinical trials over the past decade have helped determine the optimal place of anti-CD38 antibodies in the multiple myeloma treatment paradigm.

In a disease such as myeloma, which remains incurable with the current approaches, sequencing of therapies is an important aspect of long-term management, and there is significant emphasis on using the best treatment options at each stage, including relapse, of disease. Daratumumab has been studied in combination with virtually every other myeloma therapeutic, with many of the combinations having obtained regulatory approval for use in newly diagnosed and/or relapsed myeloma. In addition, data for daratumumab in combination with other immune therapies, such as bispecific T-cell engagers, are starting to emerge. Given the current data and ongoing trials, we anticipate this class of drugs will continue to have an important role in the overall management of myeloma for years to come.

 

Commentary by Multiple Myeloma Co-Site Editor for JNCCN 360

Prashant Kapoor, MD, FACP

Assistant Professor of Medicine and Oncology (Division of Hematology), Mayo Clinic, Rochester, Minnesota

Although CD38 was well known as a potentially “druggable” target on plasma cells for a long time, it was the introduction of daratumumab that served as an inflection point in the treatment paradigm of multiple myeloma, and we’ve witnessed progress in the field at an unrelenting pace ever since. However, many important questions about the use of monoclonal anti-CD38 antibodies remain unanswered, including their optimal duration of use, the feasibility of sequential rather than concurrent use with other therapies, the efficacy of rechallenge in the face of myeloma relapse, and the potential for targeting CD38 antigen with alternative novel approaches, such bispecific T-cell engagers and chimeric antigen receptor (CAR) T-cell therapy.

 

DISCLOSURES

Dr. Kumar has received clinical research support/data safety monitoring board from AbbVie, Allogene, Arcellx, Bristol Myers Squibb, Carsgen, GlaxoSmithKline, MedImmune, Oncopeptides, Roche Laboratories, and Takeda Pharmaceuticals North America and has served on a scientific advisory board or as a consultant or expert witness for AbbVie, BeiGene, Bluebird, Bristol Myers Squibb, Epizyme, GlaxoSmithKline, GLH Pharma, Oncopeptides, Pfizer, Regeneron Pharmaceuticals, Roche Laboratories, sanofi-aventis US, Secura, Takeda Pharmaceuticals North America, and Trillium.

Dr. Kapoor has served on a scientific advisory board or as a consultant or expert witness for BeiGene, Pharmacyclics, X4 Pharmaceuticals, Oncopeptides, Angitia Bio, GSK, AbbVie, and Sanofi and has received research funding from Amgen, Regeneron, Bristol Myers Squibb, Loxo Pharmaceuticals, Ichnos, Karyopharm, Sanofi, AbbVie, and GSK.

Clinical Trial Updates in Newly Diagnosed Multiple Myeloma

Although advances in the treatment of multiple myeloma have been made in recent years, newly diagnosed disease remains a management challenge. Since the daratumumab Spotlight was last updated in July 2019, several trials have further investigated the use of this anti-CD38 monoclonal antibody alone and in combination with other agents; the results have the potential to transform the treatment landscape in the newly diagnosed setting.

MAIA

In June 2019, the U.S. Food and Drug Administration (FDA) granted approval to daratumumab in combination with lenalidomide and dexamethasone (D-Rd) for patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplantation (ASCT).1 The approval was based on the prespecified interim analysis of the pivotal phase III MAIA trial, in which D-Rd seemed to significantly reduce the risk of disease progression or death by 44% versus Rd alone.2

In an updated analysis, with a median follow-up of 47.9 months, D-Rd prolonged the duration of progression-free survival (not reached vs. 34.0 months); however, overall survival data were not yet mature.3 After a median follow-up of 56.2 months, although the median duration of overall survival was not reached in either arm, the data demonstrating the survival advantage of combining daratumumab with lenalidomide and dexamethasone (ie, a 32% reduction in the risk of death) began to emerge4  

After a prolonged follow-up (median of 64.5 months), the median progression-free survival with D-Rd was found to be 61.9 months,5 and the median duration of overall survival was still not reached with D-Rd but was 65.5 months with Rd.

CASSIOPEIA

Based on data from part 1 of the phase III CASSIOPEIA trial, in September 2019, the FDA granted approval to daratumumab in combination with bortezomib, thalidomide, and dexamethasone (D-VTd) for adults with newly diagnosed multiple myeloma who are eligible for ASCT.6,7 An interim analysis from part 2 of the trial demonstrated a progression-free survival benefit with daratumumab maintenance therapy versus observation (not reached vs. 46.7 months), but surprisingly, the progression-free survival benefit of daratumumab maintenance therapy was confined to those who had not received daratumumab during induction.8,9

A measurable residual disease (MRD) analysis was conducted using data from both Parts 1 and 2 of the trial. After induction (9.2% vs. 5.4%) and consolidation (33.7% vs. 19.9%) therapies, the rate of MRD negativity was higher with D-VTd than with VTd alone.10 The rate of MRD negativity was found to significantly favor maintenance therapy with daratumumab over observation (58.6% vs. 47.1%). Overall, according to the investigators, patients who received induction therapy with D-VTd, ASCT, consolidation therapy with D-VTd, and maintenance therapy with daratumumab achieved the “highest and most durable” rates of MRD negativity.  

Ongoing research is focused on further defining the potential benefits of using an anti-CD38 monoclonal antibody as maintenance therapy. In particular, the phase III DRAMMATIC (ClinicalTrials.gov identifier NCT04071457) and AURIGA (NCT03901963) trials will compare maintenance therapy with daratumumab plus lenalidomide (DR) versus lenalidomide alone, with the latter study exclusively enrolling patients who showed evidence of detectable residual disease after ASCT.

ALCYONE

Data from the previously reported prespecified interim analysis of the phase III ALCYONE trial supported the May 2018 FDA approval of daratumumab in combination with bortezomib, melphalan, and prednisone (D-VMP) for patients with newly diagnosed multiple myeloma who are ineligible for ASCT.11,12 Based on the interim overall survival analysis, this combination demonstrated a significant benefit versus VMP alone (hazard ratio for death = 0.60).13

In an updated analysis, D-VMP appeared to continue to improve overall survival outcomes; a 37% reduction in the risk of death was seen with D-VMP versus VMP.14 The median duration of overall survival was 82.7 months with D-VMP and 53.6 months with VMP alone.

GRIFFIN

New data from the phase II GRIFFIN trial have demonstrated an improved stringent response rate (end of consolidation therapy: 42.4% vs. 32.0%) and depth of response with the addition of daratumumab to lenalidomide plus bortezomib and dexamethasone (D-RVd) versus RVd alone in patients with transplant-eligible newly diagnosed multiple myeloma.15 Based on the primary efficacy analysis, with a longer duration of follow-up, the stringent complete response rate further improved (62.6% vs. 45.4%), and responses continued to deepen.16

After 12 and 24 months of maintenance therapy with lenalidomide plus or minus daratumumab, the stringent complete response rates appeared to continue to favor treatment with D-RVd (12 months: 63.6%; 24 months: 66.0%) versus RVd (both 47.4%).17,18 No new safety concerns were observed at either timepoint.

At the conclusion of the predefined final analysis, a 55.0% reduction in the risk of disease progression or death was observed with D-RVd.19 The estimated 48-month progression-free survival rates were 87.2% and 70.0% with D-RVd and RVd, respectively. Additionally, after extended follow-up, no new safety concerns were reported.  

This regimen will be further evaluated in the phase III PERSEUS trial. Unlike GRIFFIN, it is powered to show a progression-free survival difference.

UK OPTIMUM/MUKnine

The phase II UK OPTIMUM/MUKnine trial aimed to determine the efficacy of induction therapy with daratumumab plus cyclophosphamide, lenalidomide, bortezomib, and dexamethasone (D-CRVd), bortezomib-augmented ASCT, and consolidation therapy with D-RVd (first) and D-RV (second) in patients with ultra–high-risk, newly diagnosed multiple myeloma or plasma cell leukemia. A total of 41% of patients were MRD-negative, 40% were MRD-positive, and 19% were not evaluable after induction therapy; these rates were 64%, 14%, and 22%, respectively, approximately 100 days after ASCT.20 The overall response rates were 94% after induction therapy and 83% after ASCT. [Editor’s Note: This was an intention-to-treat analysis, with 10% of patients not reaching the post-ASCT time point when the data were analyzed.]

Based on the final progression-free survival analysis, at 18 months, the UK OPTIMUM/MUKnine trial population demonstrated an improvement compared with a digital control arm comprising matched patients from the Myeloma XI/XI+ trial who had received induction therapy with cyclophosphamide, lenalidomide, and dexamethasone with or without carfilzomib, ASCT, and either maintenance therapy with lenalidomide or observation (81.7% vs. 65.9%).21 After all patients completed consolidation therapy, at a median follow-up of 40.0 months, the median duration of progression-free survival was not reached in the UK OPTIMUM/MUKnine population.22 The estimated 30-month progression-free survival rate was 77.0%; for context, this rate was 39.8% in the Myeloma XI trial. Over time, the investigators observed further separation between the UK OPTIMUM/MUKnine and Myeloma XI progression-free survival curves; this suggested there may be a sustained beneficial effect of ongoing consolidation therapy.

MASTER

The phase II MASTER trial was conducted to evaluate the safety and efficacy of induction therapy with daratumumab plus carfilzomib, lenalidomide, and dexamethasone (D-KRd); ASCT; and response-adapted, MRD-based consolidation therapy with the same quadruplet regimen in patients with newly diagnosed disease. After induction therapy and ASCT, 34% and 70% of patients achieved MRD negativity, respectively, at a sensitivity threshold of 10-5 cells; these rates were found to be 31% and 76% in an updated analysis.23,24

Based on the final primary endpoint analysis, with a median follow-up of 25.1 months, the MRD negativity rate was 80%.25 An extended follow-up analysis (median, 34.1 months) revealed an MRD negativity rate of 81%.26

MANHATTAN

Results from the phase II MANHATTAN trial further demonstrated the safety and antitumor activity of treatment with D-KRd in patients with newly diagnosed multiple myeloma.27 According to the investigators, MRD negativity in the bone marrow was achieved in 71% of the population at a sensitivity threshold of 10-5 cells. Serious treatment-related adverse events were observed in 18% of patients; no deaths were reported during the trial.

Other Trials in the Newly Diagnosed Setting

A phase II trial, which evaluated the weekly administration of D-KRd in the absence of autologous bone marrow transplantation, demonstrated an “unprecedented” MRD negativity rate of 83% in patients with newly diagnosed multiple myeloma.28 These results have prompted the initiation of the multicenter ADVANCE trial (NCT04268498), which will compare this regimen with the established standards of care.

Another phase II trial was conducted to investigate the safety and efficacy of daratumumab plus ixazomib, lenalidomide, and modified-dose dexamethasone. The investigators reported an overall best confirmed response rate of 95%, including 10% of patients with a stringent complete response, 5% with a complete response, and 23% with a near-complete response.29 Skin rash and hematologic toxicities were the most common reasons for dose adjustment.  

Clinical Trial Updates in Relapsed or Refractory Multiple Myeloma

Daratumumab has demonstrated favorable outcomes in patients with relapsed or refractory multiple myeloma. Several clinical trials are further exploring its use in different combinations, with the goal of expanding the potential benefits of treatment with this anti-CD38 monoclonal antibody to a broader population.

CANDOR

The results of the phase I MMY1001 trial highlighted the safety and antitumor activity of daratumumab plus carfilzomib and dexamethasone (DKd) in patients with relapsed or refractory multiple myeloma. Thus, the pivotal phase III CANDOR trial was initiated to compare this triplet regimen with Kd alone.30 In the primary analysis, the median duration of progression-free survival was not reached with DKd versus 15.8 months with Kd.31 The rates of adverse events of grade 3 or higher were 82.1% and 73.9%, respectively.

The results of the phase I MMY1001 trial highlighted the safety and antitumor activity of daratumumab plus carfilzomib

In August 2020, the FDA granted approval to DKd for the treatment of adults with relapsed or refractory multiple myeloma who have received one to three previous lines of therapy.32 This decision was based on the previously mentioned data, as well as those from the previously reported phase Ib EQUULEUS trial.

An updated analysis continued to demonstrate a progression-free survival benefit with DKd; the median duration was 28.6 months with DKd and 15.2 months with Kd.33 The treatment-emergent adverse-event profile was found to be consistent with that of the primary analysis.

POLLUX and CASTOR

In the previously reported primary analyses, the addition of daratumumab to bortezomib plus dexamethasone (DVd) in the CASTOR trial and to Rd in the POLLUX trial seemed to significantly improve progression-free survival outcomes in patients with relapsed or refractory multiple myeloma.34,35 An analysis of these phase III trials revealed higher rates of sustained MRD negativity with daratumumab-based combinations than with standard-of-care regimens; according to the investigators, this seemed to be associated with prolonged durations of progression-free survival.36

Based on the final overall survival analysis of the CASTOR trial, treatment with DVd prolonged the median duration of this endpoint versus Vd alone (49.6 vs. 38.5 months).37 A prolonged median duration of overall survival was also observed with D-Rd versus Rd alone (67.6 vs. 51.8 months) in the final overall survival analysis of the POLLUX trial.38 Taken together, these findings “demonstrate for the first time an overall survival benefit with daratumumab-containing regimens in relapsed or refractory multiple myeloma.”37

Phase I Trial of Daratumumab in Combination With Venetoclax

Venetoclax plus daratumumab and dexamethasone with or without bortezomib appeared to be safe and active in patients with relapsed or refractory multiple myeloma, according to the investigators of a phase I trial (NCT03314181).39 The overall response rates with and without the addition of bortezomib were 92% and 96%, respectively. Diarrhea (63% vs. 54%) and nausea (50% vs. 50%) were the most frequently reported adverse events; adverse events of grade 3 or higher were reported in 71% of patients who received bortezomib and 88% of those who did not. These findings seem to support the further assessment of venetoclax in combination with daratumumab in this clinical context, especially in patients harboring t(11;14) translocation.

These findings seem to support the further assessment of venetoclax in combination with daratumumab in this clinical context, especially in patients harboring t(11;14) translocation.

TRIMM-2

The two-part phase Ib TRIMM-2 trial was conducted to establish the recommended phase II dose and safety profile of each of the following daratumumab-based regimens: daratumumab plus teclistamab; daratumumab plus talquetamab; daratumumab plus talquetamab and pomalidomide; and daratumumab plus teclistamab and pomalidomide. The results may provide important insights into the use of this anti-CD38 monoclonal antibody in combination with bispecific T-cell redirection antibodies and inform the future treatment landscape for patients with relapsed or refractory multiple myeloma.

Daratumumab Plus Teclistamab

Initially, a total of 33 patients received 1,800 mg of subcutaneous daratumumab in combination with teclistamab at a dose of 1,500 µg/kg weekly (n = 21), 3,000 µg/kg weekly (n = 5), 300 mg biweekly starting on day 1 of the third cycle (n = 2), or 3,000 µg/kg biweekly (n = 5; none response-evaluable).40 With a median follow-up of 3.6 months across the cohorts, 13, 4, and 1 individuals achieved an overall response; 7, 3, and 0 achieved a very good partial response or better; and 3, 2, and 0 achieved a complete response or better, respectively. Daratumumab plus teclistamab demonstrated a manageable safety profile, which seemed to be consistent with those of the monotherapies. Adverse events were reported in 97.0% of patients; more than half of the population (66.7%) experienced an adverse event of grade 3 or 4.

At the time of an updated analysis, the population comprised 46 patients; the median duration of follow-up was 7.2 months.41 Overall responses, very good partial responses or better, and complete responses or better were reported in 15, 14, and 6 patients treated with 1,500 µg/kg weekly; 4, 4, and 2 with 3,000 µg/kg weekly; and 10, 9, and 1 with 300 mg biweekly, respectively. Adverse events of any grade occurred in 91% of patients; the incidence rate of grade 3 or 4 adverse events was 78%.

The ongoing phase III MajesTEC-3 trial will compare this combination with the investigator’s choice of daratumumab plus pomalidomide and dexamethasone (DPd) or DVd in patients with relapsed or refractory multiple myeloma (NCT05083169).

Daratumumab Plus Talquetamab

At the time of the initial data report, 23 patients received 1,800 mg of subcutaneous daratumumab in combination with talquetamab at a dose of 400 µg/kg weekly (n = 8), 400 µg/kg biweekly (n = 5), or 800 µg/kg biweekly (n = 10).42 With a median follow-up of 2.9 months across the cohorts, a total of three, three, and seven individuals achieved an overall response; three, three, and six achieved a very good partial response or better; and three, one, and one achieved a complete response or better, respectively. Any-grade adverse events were reported in 95.7% of patients; the incidence rate of adverse events of grade 3 or 4 was 78.3%.

Based on the aforementioned data, the recommended phase II doses were identified as 400 µg/kg weekly or 800 µg/kg biweekly. At the data cutoff of an updated analysis, a total of 46 patients were enrolled; the median duration of follow-up was 4 months.43 Overall responses, very good partial responses or better, and complete responses or better were reported in 9, 7, and 4 patients treated with 400 µg/kg weekly and 17, 15, and 6 of those who received 800 μg/kg biweekly, respectively. No new safety signals were observed. A total of 96% and 67% of patients experienced an any-grade or grade 3 or 4 adverse event, respectively.

Daratumumab for Special Populations

Several trials of daratumumab are underway in special populations, such as those with smoldering multiple myeloma or frailty. The findings have the potential to yield critical insights into the most effective treatments in these clinical contexts.

Smoldering Multiple Myeloma

In the phase II ASCENT trial, patients with high-risk smoldering myeloma received D-KRd for a fixed duration of 2 years. The best overall response rate at the end of maintenance therapy was 97%, including 37% of patients with a stringent complete response, 26% with a complete response, 29% with a very good partial response or better, 2% with a partial response, and 1% with stable disease.44

Ongoing research aims to further evaluate the potential of daratumumab to delay or prevent the progression of this premalignant condition. The phase III EAA173 trial (NCT03937635) will compare D-Rd and Rd in patients with high-risk smoldering myeloma.

Frail Populations

According to the investigators of the phase III IFM2017-03 trial, treatment with DR demonstrated “deep and rapid responses and a favorable safety profile” in frail patients with newly diagnosed multiple myeloma.45 The overall response rate was found to be significantly higher with this partially dexamethasone-sparing regimen versus Rd (89% vs. 77%); the 12-month rates of very good partial responses or better were 58% and 42%, respectively. During the first year of treatment, adverse events of grade 3 or higher were reported in 76% of patients treated with DR and 64% of those who received Rd.

In the phase II Hoven 143 trial, induction therapy with ixazomib, daratumumab, and low-dose dexamethasone resulted in an overall response rate of 78% in frail patients with newly diagnosed multiple myeloma; however, according to the investigators, premature treatment discontinuation remains a concern in this population.46 A total of 51% of patients prematurely discontinued induction therapy for reasons such as treatment noncompliance (6%), toxicity (9%), and death (9%).

Approvals Using Subcutaneous Administration

The intravenous administration of daratumumab may negatively impact quality of life because of its lengthy duration and frequency of infusion reactions. Multiple FDA approvals have been granted for the subcutaneous administration of this agent following its evaluation in the COLUMBA, PLEIADES, and APOLLO trials.

COLUMBA and PLEIADES

The results of the phase III COLUMBA and phase II PLEIADES trials served as the basis of the FDA’s May 2020 approval of daratumumab and hyaluronidase-fihj for adults with multiple myeloma.47 These trials demonstrated the safety and efficacy of this enzyme-assisted administration method, which was approved for use in multiple indications.

Findings from an analysis of the COLUMBA trial revealed subcutaneous daratumumab is not inferior to intravenous daratumumab in terms of efficacy and pharmacokinetics in patients with relapsed or refractory multiple myeloma; the overall response (41% vs. 37%) and maximum trough concentration (593 vs. 522 μg/mL) were found to have met the predefined noninferiority criteria at a median follow-up of 7.5 months.48 The efficacy of subcutaneous daratumumab in combination with either VMP or Rd was evaluated in two separate single-arm cohorts of the phase II PLEIADES trial. The objective response rates were 88% and 91%, respectively, in patients with newly diagnosed disease.

In November 2021, the FDA approved daratumumab and hyaluronidase in combination with Kd for adults with relapsed or refractory multiple myeloma who have received one to three prior lines of therapy.49 This approval was based on data from a single-arm cohort of the PLEIADES trial; in this population, the overall response rate was 84.8%.

APOLLO

The addition of subcutaneous daratumumab to Pd appeared to significantly reduce the risk of disease progression or death by 37% in patients with relapsed or refractory multiple myeloma who had received at least one prior line of therapy, based on the primary analysis of the phase III APOLLO trial.50 The median durations of progression-free survival were 12.4 and 6.9 months with DPd and Pd, respectively. The safety profile of DPd was found to be consistent with those of both subcutaneous daratumumab and Pd. Based on these data, in July 2021, the FDA granted approval to daratumumab and hyaluronidase in combination with Pd for adults with multiple myeloma who have received at least one prior line of therapy including lenalidomide and a proteasome inhibitor.51

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