(2019 UPDATE) Daratumumab (Darzalex®) (Multiple Myeloma)

From its introduction as monotherapy for multiple myeloma to its increasing utilization as a combination agent for relapsed or refractory multiple myeloma, daratumumab continues to be a major tool in the hematologist’s treatment armamentarium (See original Daratumumab Spotlight). Its indications in multiple myeloma include use as a single agent and as part of several combination regimens: with bortezomib, melphalan, and prednisone; with lenalidomide and dexamethasone, or bortezomib and dexamethasone; and with pomalidomide and dexamethasone.

In fact, daratumumab appears to be the “gift that keeps on giving” to the myeloma community. “It seems we can add daratumumab to almost anything and make the regimen better. It’s got good activity and a good safety profile,” said Kenneth Shain, MD, PhD, Director of the Myeloma Working Group at Moffitt Cancer Center, Tampa, who commented on the benefit observed by adding the monoclonal antibody to doublets and triplets in clinical trials.¹

And yet its portfolio of indications was recently further enhanced, with daratumumab being approved on June 27, 2019, for use in combination with lenalidomide and dexamethasone (Rd) in the treatment of patients newly diagnosed with multiple myeloma who are ineligible for autologous stem cell transplantation (ASCT).² The approval was supported by data from the phase III MAIA (MMY3008) study.³ The study showed that at a median follow-up of 28 months, daratumumab-Rd significantly reduced the risk of disease progression or death by 44% in this patient population compared with treatment with Rd alone. No new safety signals were observed with this regimen.

ASCO 2019: COLUMBA and CASSIOPEIA Trials

In addition, as reported at the 2019 ASCO Annual Meeting, the phase III COLUMBA trial reported that a new formulation of daratumumab specifically engineered with recombinant human hyaluronidase PH20 for subcutaneous administration had adequate pharmacokinetics, low rates of infusion-related reactions, and similar efficacy to intravenous daratumumab in patients with relapsed or refractory multiple myeloma.⁴ The subcutaneous version of daratumumab showed noninferior efficacy with a reduction in the treatment burden compared with the original intravenous formulation.

Also reported at the 2019 ASCO Annual Meeting, daratumumab in combination with bortezomib/thalidomide/dexamethasone (VTd) as induction therapy before and consolidation therapy after ASCT improved the rate and depth of response and progression-free survival, with acceptable safety.⁵ The favorable benefit-risk profile supports the use of daratumumab in transplant-eligible newly diagnosed patients with multiple myeloma. The study, CASSIOPEIA, is the first study to demonstrate the clinical benefit of daratumumab plus the standard-of-care VTd in transplant-eligible newly diagnosed patients with multiple myeloma.⁵ Based on the CASSIOPEIA study, the U.S. Food and Drug Administration (FDA) granted a Priority Review designation to a supplemental biologics license application for daratumumab in combination with bortezomib/thalidomide/dexamethasone.⁶

In patients with newly diagnosed multiple myeloma who are eligible for ASCT, the addition of daratumumab to a regimen of bortezomib, lenalidomide, and dexamethasone (D-VRd) was found to be safe and effective, with no additional safety concerns or negative effects on stem cell mobilization.⁷ The overall safety profile of D-VRd was consistent with those previously reported for daratumumab and the VRd combination, with manageable toxicity and no new safety findings with longer therapy.

After the earlier phase III SWOG S0777 trial showed a survival benefit with the three-drug induction regimen VRd over the two-drug regimen Rd among newly diagnosed patients, there was greater enthusiasm for exploring the use of quadruplet therapies among newly diagnosed transplant-eligible patients. It was at this point that daratumumab seemed to fit as the placeholder in the quadruplet induction therapies for multiple myeloma. A higher minimal residual disease–negativity rate and an acceptable nonoverlapping toxicity profile have made daratumumab an ideal partner to the existing backbone three-drug induction regimens.⁸

In Relapsed or Refractory Disease

Given the chronic nature of multiple myeloma today, patients continue to require repeated lines of therapy to maintain adequate disease control over long periods. As a result, the sequential use of the different available therapies has taken on more significance. The uniform adoption of proteasome inhibitors and immunomodulatory drugs in the setting of newly diagnosed disease and the increasing use of continuous therapy in the initial treatment setting have a major impact on subsequent therapeutic choices at the time of relapse.⁹

In the setting of relapsed and/or refractory disease, further treatment is guided by two major factors: (1) the presence of aggressive disease; and (2) the depth and duration of response to prior treatment. Aggressive, “high-risk” disease, which is less likely to respond well to treatment, is characterized by cytogenetic abnormalities (eg, del[17p13]), the presence of plasma cell leukemia in addition to multiple myeloma, extramedullary disease, and other factors.¹⁰

Perhaps the most challenging clinical scenario is a patient whose disease is refractory to both lenalidomide and bortezomib. The combination of daratumumab/pomalidomide/dexamethasone is approved for this indication.¹¹

Split-Dosing Regimen Approved

On February 12, 2019, the FDA approved a split-dosing regimen for daratumumab, providing health-care professionals and patients with multiple myeloma an option to split the first infusion over 2 consecutive days. The approval is based on data from the phase Ib EQUULEUS clinical study (ClinicalTrials.gov identifier NCT01998971), which evaluated daratumumab in combination with various treatment regimens. Splitting the first dose of daratumumab over 2 consecutive days effectively reduced the duration of the first infusion, with a similar rate and pattern of infusion reactions. Data from the study demonstrated that daratumumab concentrations were comparable at the end of weekly dosing, regardless of whether the first 16-mg/kg dose was administered as a split infusion or a single first infusion.^12,13

Rapid Infusion Protocol

The prolonged infusion duration with daratumumab has created logistical challenges for both patients and infusion therapy centers. Attempts to reduce the infusion time have resulted in the development of an accelerated infusion approach. In a single-center study,¹⁴ patients who had received at least two prior doses of daratumumab received daratumumab at a customized starting rate (infusion rate was calculated to deliver 20% of the dose over 30 minutes [200 mL/h]); the rate was then increased to deliver the remaining 80% over 60 minutes (450 mL/h). This resulted in a 90-minute estimated infusion time (total volume = 550 mL). The premedication for the first dose consisted of oral acetaminophen at 650 mg, intravenous or oral diphenhydramine at 50 mg, intravenous dexamethasone at 20 mg, oral montelukast at 10 mg, and intravenous famotidine at 20 mg. This infusion strategy was well tolerated and is increasingly being adopted.

Screening Implications

That CD38 is highly expressed in more than three-quarters of cases of multiple myeloma is widely known.⁹ Daratumumab can bind to CD38 present on red blood cells and interfere with routine testing for clinically significant antibodies. Treatment of the antibody panel cells with dithiothreitol and repeating testing will effectively negate the binding of daratumumab to CD38.¹⁵

It is advisable to perform a baseline antibody screen and Rh & Kell phenotyping (type and screen) before starting therapy with daratumumab. This agent can also interfere with flow cytometric evaluation of multiple myeloma, causing an apparent lack of plasma cells.¹⁶

Several methods have been proposed to overcome anti‐CD38 interference in immunohematology testing and to facilitate alloantibody screening, thus reducing the risk of incompatible transfusions and the possibility of transfusion reactions.⁷ They include testing the patient’s plasma against a panel of reagent red blood cells treated with dithiothreitol or trypsin. In addition, extended red blood cell phenotyping or genotyping of the patient before the first dose of daratumumab enables transfusion laboratories to provide red blood cells with a phenotype that matches the patient’s red blood cell phenotype, with the aim of preventing or at least minimizing the risk of incompatibility, particularly when daratumumab interference cannot be immediately resolved and/or the red blood cell transfusion is urgent.

Managing Grade 3 or 4 Adverse Events

According to the MAIA trial, the most common grade 3 or 4 treatment-emergent adverse events for daratumumab-Rd (at least 10%) included neutropenia (50%), lymphopenia (15%), pneumonia (14%), and anemia (12%).¹⁷ Infusion-related reactions occurred in 41% of patients receiving daratumumab-Rd, 3% of which were grade 3 or 4.² Potential severe infusion reactions include bronchospasm, hypoxia, dyspnea, and hypertension. They usually occur during the first infusion but can also occur in subsequent infusions. Nearly all reactions seem to happen during infusion or within 4 hours of completing the infusion.

Premedication with antihistamines, antipyretics, and corticosteroids is required. The infusion should be halted for any infusion reactions and then managed as appropriate. For grade 4 infusion reactions, therapy should be discontinued permanently. The drug should be administered in a facility with immediate access to resuscitative measures (eg, glucocorticoids, epinephrine, bronchodilators, and/or oxygen). Oral corticosteroids should be administered on the first and second days after infusion to reduce the risk of delayed infusion reactions. Short- and long-acting bronchodilators and inhaled corticosteroids may be considered for patients with obstructive pulmonary disorders.¹⁷

References

1. Helwick C. ASH reports show benefit of adding daratumumab to initial therapy in multiple myeloma. The ASCO Post, March 25, 2019. Available at https://www.ascopost.com/issues/march-25-2019/benefit-of-adding-daratumumab-to-initial-therapy-in-multiple-myeloma/. Accessed July 12, 2019.

2. U.S Food & Drug Administration. FDA approves daratumumab for multiple myeloma ineligible for autologous stem cell transplant. Available at https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-daratumumab-multiple-myeloma-ineligible-autologous-stem-cell-transplant. Accessed June 28, 2019.

3. Facon T, Kumar SK, Plesner T, et al. Phase 3 randomized study of daratumumab plus lenalidomide and dexamethasone (D-Rd) versus lenalidomide and dexamethasone (Rd) in patients with newly diagnosed multiple myeloma (NDMM) ineligible for transplant (MAIA). Blood 2018;132:LBA2.

4. Mateos MV, Nahi H, Leggier W, et al. Efficacy and safety of the randomized, open-label, non-inferiority, phase 3 study of subcutaneous versus intravenous daratumumab administration in patients with relapsed or refractory multiple myeloma: COLUMBA. J Clin Oncol 2019;37(suppl); Abstract 8005).

5. Moreau P, Attal M, Hulin C, et al. Phase 3 randomized study of daratumumab (DARA) + bortezomib/thalidomide/dexamethasone (D-VTd) vs VTd in transplant-eligible (TE) newly diagnosed multiple myeloma (NDMM): CASSIOPEIA Part 1 results. J Clin Oncol. 2019;37(suppl); Abstract 8003.

6. FDA Pipeline: Reviews and designations in multiple myeloma, lymphoma, prostate cancer. The ASCO Post, June 10, 2019. Available at https://www.ascopost.com/News/60125. Accessed July 12, 2019.

7. Voorhees PM, Rodriguez C, Reeves B, et al. Efficacy and updated safety analysis of a safety run-in cohort from Griffin, a phase 2 randomized study of daratumumab, bortezomib, lenalidomide, and dexamethasone (D; Dara‐Vrd) vs. Vrd in patients with newly diagnosed multiple myeloma eligible for high‐dose therapy and autologous stem cell transplantation. Blood 2018;132:151.

8. Durie BG, Hoering A, Abidi MH, 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;389:519–527.

9. Kumar SK. Reshaping the treatment landscape in refractory multiple myeloma. The ASCO Post, March 10, 2019. Available at https://www.ascopost.com/issues/march-10-2019/reshaping-the-treatment-landscape-in-refractory-multiple-myeloma/. Accessed July 12, 2019.

10. Institute for Clinical and Economic Review. Treatment options for relapsed or refractory multiple myeloma: effectiveness and value. April 2016. Available at https://icer-review.org/wp-content/uploads/2016/04/MWCEPAC_MM_Draft_Evidence_Report_040716.pdf. Accessed May 3, 2019.

11. Kumar SK: Emerging options and sequencing therapies for relapsed multiple myeloma. Presented at the 2018 NCCN Annual Congress: Hematologic Malignancies; September 21–22, 2018; New York, New York.

12. FDA approves split-dosing regimen of therapy for multiple myeloma. The ASCO Post, February 25, 2019. Available at https://www.ascopost.com/issues/february-25-2019/fda-approves-split-dosing-regimen-of-therapy-for-multiple-myeloma/. Accessed July 12, 2019.

13. Chari A, Suvannasankha A, Fay JW, et al. Daratumumab plus pomalidomide and dexamethasone in relapsed and/or refractory multiple myeloma. Blood 2017;130:974–981.

14. Barr H, Dempsey J, Waller A, et al. Ninety-minute daratumumab infusion is safe in multiple myeloma. Blood 2017;130:1889.

15. Chapuy CI, Nicholson RT, Aguad MD, et al. Resolving the daratumumab interference with blood compatibility testing. Transfusion 2015;55:1545–1554.

16. Perincheri S, Torres R, Tormey CA, et al. Daratumumab interferes with flow cytometric evaluation of multiple myeloma. Blood 2016;128:5630.

17. Darzalex (daratumumab). Prescribing information. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/761036s016lbl.pdf. Accessed May 3, 2019.

Commentary by Multiple Myeloma Site Editor for JNCCN 360

Shaji K. Kumar, MD

Professor of Medicine, Mayo Clinic, Rochester, Minnesota

Since its introduction, the use of daratumumab has increased exponentially, with its utilization in a variety of combinations and in newly diagnosed myeloma as well as in relapsed disease. Ongoing trials are examining its potential role as an early intervention in smoldering myeloma, as well as in related plasma cell disorders such as amyloidosis. Clearly, the targeting of CD38 appears to be a strategy that is paying off in myeloma.

DISCLOSURES

Dr. Kumar has received clinical research support/data safety monitoring board from Abbott Laboratories, Amgen, Inc., Bristol-Myers Squibb Company, Janssen Pharmaceutical Products, LP, Kite Pharma, MedImmune Inc., Merck & Co., Inc., Roche Laboratories, Inc., sanofi-aventis U.S., and Takeda Pharmaceuticals North America, Inc. He also has served on a scientific advisory board or as a consultant or expert witness for Abbott Laboratories, Amgen Inc., Celgene Corporation, Janssen Pharmaceutical Products, LP, Karyopharm, Kite, Merck & Co., Inc., Oncopeptides, Reddy’s Laboratory, and Takeda Pharmaceuticals North America, Inc.