New Therapy Options for Patients with Newly Diagnosed Multiple Myeloma who are Transplant-eligible 

The U.S. Food and Drug Administration (FDA) has approved daratumumab* and hyaluronidase-fihj (Darzalex Faspro®; Johnson & Johnson)**, a subcutaneous CD38-directed antibody approved to treat patients with multiple myeloma, in combination with bortezomib (Velcade®; Takeda), lenalidomide (Revlimid®; Celgene Corporation, a Bristol Myers Squibb company) and dexamethasone (VRd) for induction and consolidation in patients with newly diagnosed multiple myeloma (NDMM) who are eligible for autologous stem cell transplant (ASCT).[1]

Patients will have the opportunity to receive this daratumumab + hyaluronidase-based quadruplet therapy at initial diagnosis.  This new option may significantly improve the long-term treatment outcome. This news comes after the FDA granted  a priority review in March following the sBLA submission to the agency in January.

An Incurable disease
Multiple myeloma remains an incurable disease. [4] It is the second most common hematological malignancy worldwide that affects a type of white blood cell called plasma cells, which are found in the bone marrow. [2] In multiple myeloma, these malignant plasma cells proliferate and replace normal cells in the bone marrow. [3]

In 2024, it is estimated that more than 35,000 people will be diagnosed with multiple myeloma in the U.S. and more than 12,000 will die from the disease. [5] People with multiple myeloma have a 5-year survival rate of 59.8 percent.[5] While some people diagnosed with multiple myeloma initially have no symptoms, most patients are diagnosed due to symptoms that can include bone fracture or pain, low red blood cell counts, tiredness, high calcium levels, kidney problems or infections.[6][7]

Overall, multiple myeloma is responsible for about 10% of all hematological malignancies. The disease is more common in men than in women (the male:female ratio is 3:2), and is generally diagnosed in older people (the median age is 68 years for men and 70 yeras for women) and not in younger patients. Multiple myeloma is also more common in black and Hispanic people.

“Multiple myeloma has a highly varied clinical course among patients and in each individual patient, and there is a continued need for innovation and therapies that employ different targets and combinations to provide patients with treatment options at diagnosis and throughout the course of their disease,” said Amrita Y. Krishnan, M.D., Professor and Director of the Judy and Bernard Briskin Multiple Myeloma Center, City of Hope.*** ”

Phase 3 PERSEUS study
The approval is based on data from the pivotal Phase 3 PERSEUS study. The study results from this study demonstrated a significant clinical improvement in progression free survival (PFS) with daratumumab + hyaluronidase-based therapy, reducing the risk of disease progression or death by 60% for patients with NDMM who are transplant eligible (TE) compared to standard of care.

The PERSEUS study, an ongoing, randomized, open-label, Phase 3 clinical trial conducted in 14 countries in Europe and Australia in collaboration with the European Myeloma Network as the sponsor, evaluated daratumumab + hyaluronidase-based therapy  in a regimen that included D-VRd induction and consolidation therapy compared to bortezomib, lenalidomide and dexamethasone (VRd) during induction and consolidation in patients with NDMM eligible for ASCT.[1]  Following consolidation, patients received an investigational treatment regimen for maintenance that included daratumumab + hyaluronidase-based therapy  in combination with lenalidomide or lenalidomide alone.[1]

The approval allows patients to maximize their optimal treatment regimen as early as possible, further cementing daratumumab + hyaluronidase-based therapy as a frontline standard of care for all patients with NDMM, with five hundred thousand patients treated worldwide.

Study results
Findings from the PERSEUS study demonstrated a significant improvement in the primary endpoint of progression-free survival (PFS), with D-VRd reducing the risk of disease progression or death by 60 percent compared to VRd (HR [95% CI]: 0.40 [0.29, 0.57]; p-value < 0.0001). [1]

Treatment with D-VRd induction and consolidation resulted in deeper responses at the end of consolidation compared to VRd: minimal residual disease (MRD) negativity rates of 57.5 percent vs. 32.5 percent, and MRD-negativity rates in patients with complete response (CR) or better of 76.6 percent vs. 58.5 percent, respectively.[1]

The secondary endpoints include overall CR or better rate, and overall MRD-negativity (in patients with CR or better). The median age is 61.0 (range, 32-70) years for patients in the D-VRd arm and 59.0 (range, 31-70) years for patients in the VRd arm. [1]

“The efficacy data supporting this new quadruplet regimen, combined with its established safety and tolerability profile, provide compelling evidence that adding D-VRd upon initial diagnosis as compared to VRd can deepen responses and prolong remissions in the context of autologous stem cell transplantation,” Krishnan added.

Clinically significant
“This latest indication for daratumumab + hyaluronidase-based quadruplet therapy demonstrated a clinically significant reduction in disease progression or death during first-line treatment when patients are likely to experience their deepest responses,” said Jordan Schecter, M.D., Vice President, Disease Area Leader, Multiple Myeloma, Johnson & Johnson.

“Today’s approval embodies our commitment to setting new standards of care for patients newly diagnosed with multiple myeloma who are transplant eligible,” Schecter concluded.

The overall safety profile of D-VRd was consistent with the known safety profiles for daratumumab and hyaluronidase-fihj and VRd. [1] The most common adverse reactions (≥20%) in patients with multiple myeloma who received D-VRd are peripheral neuropathy, fatigue, edema, pyrexia, upper respiratory infection, constipation, diarrhea, musculoskeletal pain, insomnia, and rash. [1]

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Note: * In August 2012, Janssen Biotech and Genmab entered a worldwide agreement, which granted Janssen an exclusive license to develop, manufacture and commercialize daratumumab.
** daratumumab and hyaluronidase-fihj  is co-formulated with recombinant human hyaluronidase PH20 (rHuPH20), Halozyme’s ENHANZE^® drug delivery technology.
*** Amrita Y. Krishnan, MD, has provided consulting, advisory, and speaking services to Johnson & Johnson; she has not been paid for any media work.

Clinical trials
Daratumumab, VELCADE (Bortezomib), Lenalidomide and Dexamethasone Compared to VELCADE, Lenalidomide and Dexamethasone in Subjects With Previously Untreated Multiple Myeloma (Perseus) – ClinicalTrials.gov ID NCT03710603

Highlights of Prescribing Information
Daratumumab and hyaluronidase-fihj (Darzalex Faspro®; Johnson & Johnson)[Prescribing Information]
Bortezomib (Velcade®; Takeda)[Prescribing Information]
Lenalidomide (Revlimid®; Celgene Corporation, a Bristol Myers Squibb company)[Prescribing Information]
Dexamethasone [Prescribing information]

References
[1] Sonneveld P, Dimopoulos MA, Boccadoro M, Quach H, Ho PJ, Beksac M, Hulin C, Antonioli E, Leleu X, Mangiacavalli S, Perrot A, Cavo M, Belotti A, Broijl A, Gay F, Mina R, Nijhof IS, van de Donk NWCJ, Katodritou E, Schjesvold F, Sureda Balari A, Rosiñol L, Delforge M, Roeloffzen W, Silzle T, Vangsted A, Einsele H, Spencer A, Hajek R, Jurczyszyn A, Lonergan S, Ahmadi T, Liu Y, Wang J, Vieyra D, van Brummelen EMJ, Vanquickelberghe V, Sitthi-Amorn A, de Boer CJ, Carson R, Rodriguez-Otero P, Bladé J, Moreau P; PERSEUS Trial Investigators. Daratumumab, Bortezomib, Lenalidomide, and Dexamethasone for Multiple Myeloma. N Engl J Med. 2024 Jan 25;390(4):301-313. doi: 10.1056/NEJMoa2312054. Epub 2023 Dec 12. PMID: 38084760. [Article].
[2] Rajkumar SV. Multiple myeloma: 2020 update on diagnosis, risk-stratification and management. Am J Hematol. 2020 May;95(5):548-567. doi: 10.1002/ajh.25791. Erratum in: Am J Hematol. 2020 Nov;95(11):1444. doi: 10.1002/ajh.25876. PMID: 32212178.
[3] National Cancer Institute. Plasma Cell Neoplasms. Online. Last accessed in July 2024.
[4] Multiple Myeloma. City of Hope, 2022. Multiple Myeloma: Causes, Symptoms & Treatments. Online. Last accessed in July 2024.
[5] American Cancer Society. Myeloma Cancer Statistics. Online. Last accessed in July 2024.
[6] American Cancer Society. What is Multiple Myeloma? Online. Last accessed in July 2024.
[7] American Cancer Society. Multiple Myeloma Early Detection, Diagnosis, and Staging. Online. Last accessed in July 2024.

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