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by Dr. C.H. Weaver M.D. updated 2/2021

The U.S. Food and Drug Administration (FDA) has approved the precision cancer medicine Darzalex (daratumumab) to treat patients with multiple myeloma as part of initial therapy or for recurrent disease. Darzalex is the first monoclonal antibody approved for treating multiple myeloma and is typically administered in combination other anti-myeloma medications to achieve maximal effectiveness. In August 2020 the FDA approved Darzalex® in combination with Kyprolis® (carfilzomib) and dexamethasone (DKd) for the treatment of adult patients with relapsed/refractory multiple myeloma who have received one to three previous lines of therapy.

About Darzalex™ (daratumumab)

Darzalex™ is a monoclonal antibody that has been produced in a laboratory to bind to a protein often found on the surface of multiple myeloma cancer cells, called CD38. Administered by injection, the binding of Darzalex™ has direct killing effects on the myeloma cells, as well as stimulating the immune system to attack the cancer cells. Darzalex™ is approved for the treatment of multiple myeloma in combinations with different types of treatment regimens because it further improves survival and delays the time to cancer progression.(1-10) More about Darzalex...

Subcutaneous Administration Reduces Reactions - More Convenient

Doctors compared intravenous (IV) to subcutaneous (SC) administration of Darzalex and found that 34.5% of patients receiving IV experienced infusion reactions, compared to only 12.7% of those receiving SC. Injection-site reactions occurred in approximately 7% of patients receiving SC Darzalex. SC administration took 5 minutes compared with infusion times of 421 minutes, 255 minutes, and 205 minutes for patients receiving the first, second, and subsequent infusions of IV Darzalex.(8)

Newly Diagnosed Multiple Myeloma

Addition of Darzalex to Revlimid and Dexamethasone

The Phase III MAIA clinical study enrolled 737 newly diagnosed patients with multiple myeloma who were not candidates for high dose chemotherapy and ASCT to receive treatment with Revlimid (lenalidomide) and dexamethasone with or without Darzalex and directly compared.

  • On average Revlimid/Dexamethasone treated patients survived ~32 months without myeloma progression. Darzalex/Revlimid/Dexamethasone treated patients survive beyond 32 months with an average survival time not yet reached.
  • The estimated 30-month progression free survival was 71% for patients receiving Darzalex versus 56% for those treated only with Revlimid/Dexamethasone patients which is a 44% reduction in the risk of progression or death among patients receiving daratumumab
  • The study also showed a significantly higher response rate with the addition of Darzalex: complete response rates were 48% compared to and 25% for Revlimid/Dexamethasone.(2)

Darzalex- VRd in Transplant Eligible Patients

A phase 2 clinical trial referred to as “GRIFFIN” has demonstrated that the addition of Darzalex® to Velcade (bortezomib), Revlimid and dexamethasone (VRd) induces high response rates in newly diagnosed patients with multiple myeloma who were eligible for high-dose therapy and autologous stem cell transplantation (ASCT) compared with VRd alone.

Results from the 2 GRIFFIN clinical trial showed that by the end of six cycles of therapy and transplant, a 42% of patients receiving Darzalex®-VRd achieved a stringent complete response compared with 32% with VRd alone. (11)

D-VCd - An Alternative to single Immunomodulatory Based Treatment

The combination of Darzalex, Velcade, cyclophosphamide, and dexamethasone (D-VCd) induces very good partial responses and is a well-tolerated.

The multi-center, phase 2 LYRA study enrolled a total of 101 patients with previously untreated (n = 87) or relapsed after 1 line of therapy (n = 14. Eligible patients went on to undergo ASCT. After induction or aSCT, patients received ≤12 cycles of Darzalex maintenance.

After 4 induction cycles, the overall response to treatment among patients with newly-diagnosed MM was to 81%. At 12-month 87& of individuals had no evidence of myeloma progression.(3)

Addition of Darzalex™ to Velcade (bortezomib), Melphalan, and Prednisone (VMP)

Darzalex plus VMP reduces disease progression or death by 50%, among patients with newly diagnosed multiple myeloma who are not eligible to undergo a stem cell transplant.Researchers have reported the results of a clinical trial designed to evaluate the addition of Darzalex™ to VMP among patients who had not yet received prior treatment, and were not eligible for a stem cell transplant. Patients in the trial were at least 65 years of age and were divided into two groups: one group was treated with Darzalex™ plus VMP (D-VMP), and the other group was treated with VMP only. Data was retrieved at a median follow-up of 16.5 months following initiation of treatment.

  • Patients treated with D-VMP had a 50% reduction in their risk of death or disease progression, compared to those treated with VMP only.
  • Treatment benefit of D-VMP remained among all treatment groups: for patients 75 years of age and older; for patients with later-stage multiple myeloma; and for patients whose genetic analysis determined that they were at a high risk for a cancer recurrence.
  • At this time, overall survival data are too immature to determine true overall survival differences between the two groups of patients.

The addition of Darzalex™ to VMP or Revlimid/Dexamethasone for the treatment of newly diagnosed ASCT ineligible multiple myeloma patients significantly reduces their risk of death or disease progression and represents an effective treatment option.

Darzalex® Approved for Recurrent Multiple Myeloma

The FDA approved Darzalex for use in combination with Revlimid (lenalidomide) and dexamethasone, or in combination with Velcade (bortezomib) and dexamethasone.

Darzalex, Pomalyst, Dexamethasone in Refractory Myeloma

The phase 3 APOLLO clinical trial compared Darzalex in combination with Pomalyst (pomalidomide) and dexamethasone to Pomalyst and dexamethasone (Pd) alone in relapsed or refractory multiple myeloma. The three drug regimen did not appear to have worse side effects and it met the primary trial endpoint of delaying myeloma progression - final trial results will be released shortly. (12)

Darzalex Triple Combination Delays Disease Progression in R/R Multiple Myeloma

Adding Darzalex to Kyprolis and dexamethasone can significantly improve survival of relapsed or refractory multiple myeloma patients, suggesting that this three-drug combination may be an effective new regimen for this patient population, including those who were previously treated with Revlimid. (9,10)

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Treatment with Kyprolis, dexamethasone, and Darzalex resulted in a 37 percent reduction in the risk of progression or death versus Kyprolis and dexamethasone in patients with relapsed or refractory multiple myeloma. The progression-free survival (PFS) benefit of the triple combination was maintained in both Revlimid - exposed and refractory patients.

The CANDOR clinical trial enrolled 466 patients with relapsed or refractory multiple myeloma who have received one to three prior therapies at 102 sites worldwide to treatment with Kyprolis and low dose dexamethasone with or without Darzalex.

After a median follow-up of 17 months the average survival duration without myeloma progression was 16 months for Kyprolis and dexamethasone but had not been reached for the three-drug combination. The addition of Darzalex resulted in deeper responses compared with Kyprolis and dexamethasone alone, including superior overall response rates of 84% vs. 75%. The complete response rate with the triple combination was 28% as compared to 10% for the double combination.

The rate of undetectable minimal residual disease at 12 months was nearly 10-times higher in the three-drug group (12.5%) versus the two-drug group (1.3%). Median overall survival has not reached in either arm, and it is too early to be able to see any differences in survival.

Reported side effects were consistent with known safety profiles of the individual agents. The most common were thrombocytopenia, anemia, diarrhea, hypertension, upper respiratory tract infection, fatigue, and shortness of breath.

There was a high incidence of cardiac events, occurring in 5-8 percent of patients, which has been reported in prior studies. Rates of heart failure were lower in the three-drug combination group. There were five treatment-related deaths reported, all in the three-drug treatment group, due to pneumonia, sepsis, infection, and cardiac arrest.

Having a therapeutic option without Revlimid for patients who have been exposed to it or don't respond to it is a real clinical need.

The clinical trials prompting the initial approval are referred to as the CASTOR and POLLUX studies. The CASTOR trial included nearly 500 patients with multiple myeloma that had returned or stopped responding to prior therapy. One group of patients in the trial was treated with Darzalex plus Velcade and dexamethasone; a second group of patients was treated with Velcade and dexamethasone (a standard treatment regimen). Outcomes between the two treatment groups were directly compared.

  • Anti-cancer responses were achieved in 79% of patients treated with Darzalex/Velcade/dexamethasone, compared with 60% for patients treated with Velcade/dexamethasone only.
  • The median time to progression of cancer has not yet been reached among the group of patients treated with daratumumab/bortezomib/dexamethasone, compared with 7.2 months for those treated with bortezomib/dexamethasone only.

The POLLUX study included nearly 570 patients whose cancer had progressed or stopped responding to standard therapy. One group of patients in this trial was treated with daratumumab plus lenalidomide and dexamethasone; a second group of patients was treated with lenalidomide and dexamethasone (a standard treatment regimen). Outcomes between the two treatment groups were directly compared.

  • Anti-cancer responses were achieved in 91% of patients treated with daratumumab/lenalidomide/dexamethasone, compared with 75% for patients treated with lenalidomide/dexamethasone only.
  • Patients treated with daratumumab/lenalidomide/dexamethasone had a 63% reduced rate of cancer progression at the time of the last update of the trial, compared to those treated with lenalidomide/dexamethasone only.

Patients with multiple myeloma that have stopped responding to standard therapies now have additional treatment options available that continue to improve the outcomes of this disease.

Darzalex in Heavily Pretreated Patients

Darzalex produces long-lasting anti-cancer responses among patients with multiple myeloma that has stopped responding to several prior therapies. The trials included 148 patients who had received a median of 5 prior therapies, and 86.5% of patients had multiple myeloma that had stopped responding to treatment including both a PI and an IMiD.

  • 1% of patients achieved anti-cancer responses when treated with daratumumab.
  • The median duration of anti-cancer responses was 7.6 months.
  • The median time of survival without progression of disease was 4 months.
  • Median overall survival time was 20.1 months.
  • Survival benefit was achieved even among those patients whose cancer didn’t regress, but had stopped progressing and stabilized while receiving treatment with daratumumab.
  • No new safety issues regarding side effects of were noted.

The researchers concluded that “In this pooled data set, Darzalex 16 mg/kg monotherapy demonstrated rapid, deep, and durable responses, with a clinical benefit that extended to patients with stable disease or better.” Darzalex is an effective treatment option for patients with multiple myeloma that have stopped responding to several prior therapies.

About Multiple Myeloma

Multiple myeloma is a cancer of plasma cells, which are a special type of white blood cell that are part of the body’s immune system. In the U.S., approximately 70,000 people are living with multiple myeloma and approximately 24,000 new individuals are diagnosed annually. Patients with multiple myeloma have increased numbers of abnormal plasma cells that may produce increased quantities of dysfunctional antibodies detectable in the blood and/or urine.


  1. Genmab Announces Positive Topline Results in Phase III MAIA Study of Daratumumab in Front Line Multiple Myeloma
  2. Facon T, Kumar SK, Plesner T, et al. Phase 3 randomized study of daratumumab plus lenalidomide and dexamethasone (DRd) versus lenalidomide and dexamethasone (Rd) in patients with newly diagnosed multiple myeloma (NDMM) ineligible for transplant (MAIA). Oral presentation at: American Society of Hematology 60th Annual Meeting & Exposition; December 1-4, 2018; San Diego, CA. Abstract LBA-2.
  3. Br J Haematol. 2019 Mar 3. Epub ahead of print
  4. Mateos M-V, Dimopoulos M, Cavo M, et al. Phase 3 randomized study of Darzalex™ plus bortezomib, melphalan, and prednisone (D-VMP) versus bortezomib, melphalan, and prednisone (VMP) in newly diagnosed multiple myeloma (NDMM) patients (pts) ineligible for transplant (ALCYONE). Proceedings from the 59th annual meeting and exhibition of the American Society of Hematology; Atlanta, GA; December 9-12, 2017; Late-breaking abstract #4. Retrieved from here
  5. Genmab. Genmab News. Genmab Announces U.S. FDA Approval of DARZALEX® (daratumumab) for Relapsed Multiple Myeloma and Updates Financial Guidance. Available at: . Accessed November 22, 2016.
  6. Usmani S, Weiss B, Plesner T, et al. Clinical efficacy of daratumumab monotherapy in patients with heavily pretreated relapsed or refractory multiple myeloma. Blood. 2016; doi:10.1182/blood-2016-03-705210. Available here. Accessed June 29, 2016.
  7. Reference: Lokhohrst H, Plesner T, Laubach J, et al. Targeting CD38 with daratumumab monotherapy in multiple myeloma. New England Journal of Medicine. 2015; August 26, 2015DOI: 10.1056/NEJMoa1506348.
  8. Mateos M-V, Nahi H, Legiec W, et al. Efficacy and safety of the randomized, open-label, non-inferiority, phase 3 study of subcutaneous (SC) versus intravenous (IV) daratumumab (DARA) administration in patients (pts) with relapsed or refractory multiple myeloma (RRMM): COLUMBA. Presented at: 2019 American Society of Clinical Oncology (ASCO) Annual Meeting; May 31-June 4, 2019; Chicago, IL. Abstract 8005.
  9. Amgen Announces Phase 3 CANDOR Study Combining KYPROLIS (carfilzomib) And DARZALEX (daratumumab) Meets Primary Endpoint Of Progression-Free Survival [press release]. Thousand Oaks, CA: Amgen; September 13, 2019. Available here. Accessed September 16, 2019.
  10. Chari A, Martinez-Lopez J, Mateos MV, et al. Daratumumab plus carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma. Blood. 2019;134(5):421-431. doi: 10.1182/blood.2019000722.
  11. Voorhees P et al. Addition of Daratumumab (DARA) to Lenalidomide, Bortezomib, and Dexamethasone (RVd) Improves Depth of Response in Patients (pts) With Transplant-eligible Newly Diagnosed Multiple Myeloma (NDMM): Primary Efficacy Analysis of the GRIFFIN Study. 2019 International Myeloma Workshop meeting. September 2019.

Genmab Announces European Myeloma Network and Janssen Achieve Positive Topline Results from Phase 3 APOLLO Study of Daratumumab in Combination with Pomalidomide and Dexamethasone in Relapsed or Refractory Multiple Myeloma