Bortezomib-Decp Alternating with Daratumumab-Vpd Plus Stem Cell Transplantation, Followed By Maintenance with VP in Ultra-High Risk (UHiR) Newly Diagnosed Multiple Myeloma (NDMM) and Primary Plasma Cell Leukemia (pPCL): A Multicenter, Prospective Phase 2 Pilot Trial (DRAGON CATCHER TRIAL)

Background: In the past 20 years, novel agents for the treatment of multiple myeloma have emerged one after another, especially with the application of proteasome inhibitors （PI）and immunomodulatory drugs（IMiDs）,the median overall survival (OS) of MM patients have been extended to nearly 10 years. However, outcomes for newly diagnosed patients with ultra-high-risk(UHiR) multiple myeloma(MM) and primary plasma cell leukemia（pPCL）remain very poor. A real-world study showed that the median PFS and OS for the patients with double/triple hit MM were 8 months and 13 months, respectively^[1]. Another study showed that the median PFS and OS of elderly patients with primary plasma cell leukemia were only 206.5 days and 282.5 days, respectively^[2]. Besides, most clinical trials underrepresent this group of patients.

The continuous therapy approach has been widely used for MM patients with poor prognosis. It generally consists of novel agents regimens and/or combined with chemotherapy, followed by hematopoietic stem cell transplantation（HSCT）and showed prolonged maintenance treatment.

In recent years, Daratumumab and pomalidomide demonstrated the great potential to overcome high risk cytogenetic factors. MRD negative can enable high-risk patients to obtain better survival benefits，a recent study supported undetectable MRD as treatment endpoint for MM patients with high cytogenetic risk^[3]. Preliminary results from the IFM2018-04 study demonstrated that a four-drug regimen with daratumumab plus tandem ASCT has good benefit in patients with high cytogenetic risk, overall response rate was 96%, including 92%≥very good partial response，among 37/46 evaluable patients post induction，Minimal Residual Disease negative rate（NGS, 10^-5）was 62%^[4]. OPTIMISMM study confirmed that pomalidomide can improve the poor prognosis of MM patients with high cytogenetic risk of first relapse, with an ORR of 94.4% ( Vd group 57.1%), the median PFS was 14.7 months, 4.8 months longer than Vd group^[5]. Therefore, we have designed an overall treatment regimen including V-DECP alternating with Dara-VPD as induction, tandem ASCT or allo-HSCT as consolidation, VP as maintenance for the UHiR MM and pPCL patients.

Aims: The aim of this study was to evaluate the efficacy and safety of an overall treatment regimen (V-DECP alternating with Dara-VPd plus tandem ASCT or allo-HSCT, followed by VP maintenance) in patients with newly diagnosed UHiR MM and pPCL.

Methods: This is a multicenter, prospective study (Figure 1). An estimated 39 patients will be enrolled. Eligible patients are aged 18 to 80 years with newly diagnosed ultra-high-risk multiple myeloma(≥2 high risk lesions: del(17p), t(4;14), t(14;16), t(14;20), amp(1q)) or pPCL(peripheral plasma cell ratio ≥5%, and/or peripheral plasma cell absolute value ≥0.5×10⁹/L.).

The study is divided into three phases: induction therapy, consolidation therapy and maintenance therapy. The specific drug regimens are as follows:

1) Induction therapy: Alternate treatment of V-DECP and Dara-VPD for 4 courses

V-DECP regimen (28 days/course)

Bortezomib 1.0 mg/m² SC/IV d1,4,8,11; Dexamethasone 40 mg PO d1-4; Etoposide 40 mg/m² IV d1-4; Cyclophosphamide 400 mg/m² IV d1-4; Cisplatin 10 mg/m² IV d1-4

Dara-VPD (21 days/course)

Daratumumab 16 mg/kg IV d1,8,15 or 1800 mg, SC d1,8,15; Bortezomib 1.3 mg/m² SC d1,4,8,11; Pomalidomide 4 mg PO d1-14; Dexamethasone 20 mg PO d1,2,8,9,15,16

Patients with ≥ SD after the fourth course of treatment underwent autologous stem cell mobilization and collection

2) Consolidation therapy: tandem ASCTs for UHiR MM and allo-HSCT for pPCL patients

3) Maintenance therapy: UHiR MM patients receive VP maintenance therapy (28d/course) until PD or intolerable toxicity (bortezomib 1.0 mg/m² /2w SC/IV, pomalidomide 2 mg PO 1-21d). pPCL patients do not undergo further maintenance.

The primary endpoint is ≥VGPR rate (after 4 cycles of induction therapy). Secondary endpoints include progression-free survival (PFS) rate and overall survival (OS) rate of 1 years and 3 years, ORR, MRD negative rate and safety. Enrollment for the study will begin in Q3 of 2022.

Results: Results for this study are not yet available.

Conclusion: Conclusion for this study is not yet available.

Keyword(s): Pomalidomide, Daratumumab, Ultra-high-risk multiple myeloma

No relevant conflicts of interest to declare.

Pomalidomide approved for relapsed and refractory multiple myeloma