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Systemic therapy regimens for multiple myeloma: Daratumumab, lenalidomide, and dexamethasone (DRd)[1,2]

Systemic therapy regimens for multiple myeloma: Daratumumab, lenalidomide, and dexamethasone (DRd)[1,2]
Cycle length: 28 days.
Drug Dose and route Administration Given on days
Daratumumab-hyaluronidase* 1800 mg daratumumab plus 30,000 units hyaluronidase SC Infuse SC into the abdominal wall over approximately 3 to 5 minutes.

Cycles 1 to 2: Days 1, 8, 15, and 22

Cycles 3 to 6: Days 1 and 15

Cycles 7 and beyond: Day 1 only
Lenalidomide 25 mgΔ by mouth Administer with water. Swallow capsule whole; do not break, open, or chew. All cycles: Take once daily on days 1 through 21
Dexamethasone 20 mg IV (first dose of the first cycle only) or by mouth (all other doses)∆◊ Take with food (after meals or with food or milk) in the morning.

Cycles 1 to 2: Take once daily on days 1, 2, 8, 9, 15, 16, 22, and 23

Cycles 3 to 6: Take once daily on days 1, 2, 15, and 16

Cycle 7 and beyond: Take once daily on days 1 and 2
Dexamethasone 40 mg∆ by mouth Take with food (after meals or with food or milk) in the morning.

Cycles 3 to 6: Take once daily on days 8 and 22

Cycle 7 and beyond: Take once daily on days 8, 15, and 22
Pretreatment considerations:
Emesis risk
  • LOW.
  • Refer to UpToDate topics on prevention of chemotherapy-induced nausea and vomiting in adults.
Prophylaxis for infusion reactions
  • Premedicate with acetaminophen (650 to 1000 mg), diphenhydramine (25 to 50 mg), and dexamethasone (or equivalent glucocorticoid) one to three hours prior to each daratumumab infusion.[1,3] Observe all patients for at least six hours after the first infusion of daratumumab for evidence of infusion-related reactions.[2] To reduce the risk of delayed infusion reactions, administer oral glucocorticoids (eg, methylprednisolone 20 mg daily) to all patients for two days following each daratumumab infusion. If no major infusion reaction occurs during the first three infusions, may discontinue post-treatment glucocorticoids.[2,3] For patients with a history of asthma or COPD, one may add short- and long-acting bronchodilators and inhaled corticosteroids postinfusion. Discontinue these additional inhaled medications if no major infusion reactions occur during the first four infusions.[2,3]
  • Refer to UpToDate topics on infusion-related reactions to therapeutic monoclonal antibodies used for cancer therapy.
Infection prophylaxis
  • Daratumumab may be associated with an increased risk of herpes zoster. Antiviral prophylaxis (eg, acyclovir) is initiated within one week after starting daratumumab and continued for three months following treatment.[3] Primary prophylaxis with hematopoietic growth factors is not indicated. The risk of febrile neutropenia with this regimen was 5.7% in one clinical trial.[1]
Antithrombotic prophylaxis
  • Routine antithrombotic prophylaxis with aspirin or low-molecular heparin is warranted. Thromboembolism was reported in 1.8% of patients in a clinical trial despite antithrombotic prophylaxis.[1] The risk of thromboembolism was 10% with another lenalidomide and high-dose dexamethasone-containing (RD) regimen.[4]
  • Refer to UpToDate topics on thrombotic complications following treatment of multiple myeloma with immunomodulatory drugs (thalidomide, lenalidomide, and pomalidomide).
Dose adjustment for baseline liver or kidney dysfunction
  • Patients with kidney insufficiency experience more neutropenia with the use of lenalidomide.[5] Dose adjustment is recommended for patients with CrCl <60 mL/min.[6]
  • Refer to UpToDate topics on chemotherapy nephrotoxicity and dose modification in patients with kidney insufficiency, conventional cytotoxic agents.
  • Studies of lenalidomide have not been conducted in patients with hepatic impairment.
Blood bank issues
  • Notify blood transfusion centers of potential interference with cross-matching and red blood cell antibody screening and inform blood banks that a patient has received daratumumab. Type and screen patients prior to starting daratumumab.[3] Interference with testing may persist for up to six months after the last daratumumab infusion.
Monitoring parameters:
  • Assess CBC with differential, electrolytes, kidney function, liver function, and M-protein level prior to starting each new cycle.
Suggested dose modifications for toxicity:
Hematologic toxicity
  • A cycle of DRd should not be started unless the ANC is ≥1000/microL and the platelet count is ≥30,000/microL. DRd may be resumed following recovery. If a cycle of DRd is delayed because of neutropenia or thrombocytopenia, decrease the dose of lenalidomide to 15 mg when chemotherapy resumes. For subsequent cycles, reduce the lenalidomide dose by an additional 5 mg for each time the cycle is delayed by hematologic toxicity. There are no dose reductions for intracycle hematologic toxicity.
Other nonhematologic toxicity
  • For grade 3 or 4 nonhematologic toxicity thought to be due to lenalidomide alone, hold DRd and restart DRd with lenalidomide at a reduced dose (5 mg less than previous dose) when toxicity has resolved to grade 2 or less.[6]
Infusion reactions
  • In addition to more typical reactions, daratumumab-associated infusion reactions may mimic allergic rhinitis (eg, cough, wheezing, nasal congestion). Immediately interrupt daratumumab infusion for reaction of any severity. Manage symptoms as clinically appropriate.[3] For mild reactions that occur after the patient reaches home, acetaminophen or diphenhydramine are sufficient. Patients should contact their health care provider if shortness of breath or more significant reactions occur at home. For anaphylactic reaction or life-threatening administration-related reactions, immediately and permanently discontinue.[3]
If there is a change in body weight of at least 10%, doses should be recalculated.
This table is provided as an example of how to administer this regimen; there may be other acceptable methods. This regimen must be administered by a clinician trained in the use of chemotherapy, who should use independent medical judgment in the context of individual circumstances to make adjustments, as necessary.

ANC: absolute neutrophil count; CBC: complete blood count; COPD: chronic obstructive pulmonary disease; CrCl: creatinine clearance; IV: intravenous; REMS: Risk Evaluation and Mitigation Strategy; SC: subcutaneous.

* Daratumumab-hyaluronidase is a special formulation designed for subcutaneous administration. When compared with the intravenous daratumumab formulation, daratumumab-hyaluronidase appears to have similar efficacy and a more favorable toxicity profile, especially infusion-related reactions.[2] IV daratumumab is an acceptable alternative, but requires a prolonged infusion protocol.[3,7,8] Given the uncertainty of benefit, we consider discontinuation of daratumumab in the maintenance phase for patients who experience toxicity or significant administration burdens.

¶ In the United States, the use of lenalidomide is subject to the REVLIMID REMS program (www.REVLIMIDREMS.com), developed in an attempt to minimize the potential for pregnancy among patients taking this medication and associated birth defects.

Δ For frail, older adult patients, we decrease the starting doses of lenalidomide (to 15 mg) and dexamethasone (to 20 mg). For such patients, the total dose of dexamethasone given around the time of daratumumab infusion is not reduced. The 20-mg dose is given as a preinfusion medication, followed by low-dose methylprednisolone (eg, 20 mg or less) orally each day for two days following the infusion. Following 9 to 12 months of therapy in this population, we transition to maintenance with single agent lenalidomide.

◊ Administer IV prior to the first daratumumab infusion; oral administration may be used prior to subsequent infusions.

References:
  1. Dimopoulos MA, Oriol A, Nahi H, et al. Daratumumab, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med 2016; 375:1319.
  2. Mateos M-V, Nahi H, Legiec W, et al. Subcutaneous versus intravenous daratumumab in patients with relapsed or refractory multiple myeloma (COLUMBA): A multicentre, open-label, non-inferiority, randomised, phase 3 trial. Lancet Haematol 2020; 7:e370
  3. Daratumumab and hyaluronidase-fihj injection, for subcutaneous use. United States Prescribing Information. US National Library of Medicine. (Available online at dailymed.nlm.nih.gov, accessed on May 6, 2020).
  4. Rajkumar SV, Jacobus S, Callander NS, et al. Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: An open-label randomised controlled trial. Lancet Oncol 2010; 11:29.
  5. Niesvizky R, Naib T, Christos PJ, et al. Lenalidomide-induced myelosuppression is associated with renal dysfunction: Adverse events evaluation of treatment-naïve patients undergoing front-line lenalidomide and dexamethasone therapy. Br J Haematol 2007; 138:640.
  6. Lenalidomide capsule. United States Prescribing Information. US National Library of Medicine. (Available online at dailymed.nlm.nih.gov, accessed on May 6, 2020).
  7. Barr H, Dempsey J, Waller A, et al. Ninety-minute daratumumab infusion is safe in multiple myeloma. Leukemia 2018; 32:2495.
  8. Daratumumab injection. United States Prescribing Information. US National Library of Medicine. (Available online at dailymed.nlm.nih.gov, accessed on May 6, 2020).
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