Single-Arm phase 2 trial evaluating efficacy of incorporating Daratumumab to treatment of newly diagnosed primary plasma cell leukemia. Treatment will be based on Dara-VRd induction followed by first ASCT, Dara-VRd for first consolidation, second ASCT, Dara-VRd for 1 year as second consolidation and Lenalidomide for 1 year.

Inclusion Criteria:

1. Male or female patients 18 to 69 years old.

2. Patient with primary plasma cell leukemia disease as defined by the International Myeloma Working Group -IMWG (Annexe I)

3. Voluntary written consent must be given before performance of any study related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care

4. Eastern Cooperative Oncology Group (ECOG) performance status and/or other performance status 0, 1, or 2.

5. Eligible for high dose Melphalan therapy with ASCT

6. Total bilirubin <= 2 X the upper limit of the normal range (ULN).

7. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <= 3 ULN.

8. Calculated creatinine clearance >= 20 mL/min

9. Female patients who:

   • Have been postmenopausal for at least 2 years before the screening visit, OR
   • are surgically sterile, OR If they are of childbearing potential, agree to practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent form through 90 days after the last dose of study drug, OR
   • Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation, symptothermal and post-ovulation methods] and withdrawal are not acceptable methods of contraception.)

10. Male patients, even if surgically sterilized (i.e., status post-vasectomy), must agree to one of the following:

    • Agree to practice effective barrier contraception during the entire study treatment period and through 90 days after the last dose of study drug, OR
    • Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation, symptothermal and post-ovulation methods] and withdrawal are not acceptable methods of contraception.)

11. Patients agree

    • not to share study medication with any other person and to return all unused study drugs to the investigator.
    • to abstain from donating blood while taking the study drug therapy and for one week following discontinuation of the study drug therapy.

12. Must be able to adhere to the study visit schedule and other protocol requirements

13. Affiliated with an appropriate social security system

Exclusion Criteria:

1. Male or female patients <18 or > 69 years old
2. Prior history of malignancies, unless free of the disease for ≥ 5 years.
3. Prior history of symptomatic myeloma; did not received any previous chemotherapy for myeloma except corticotherapy (dexamethasone 40 mg/d for 4 days max).
4. Any other uncontrolled medical condition or comorbidity that might interfere with subject's participation.
5. Pregnant or breast feeding females
6. Known positive for HIV
7. Known seropositive for hepatitis C (except in the setting of a sustained virologic response [SVR], defined as a viremia at least 12 weeks after completion of antiviral therapy)
8. Seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen [HBsAg]). Subjects with resolved infection (ie, subjects who are HBsAg negative but positive for antibodies to hepatitis B core antigen [anti-HBc] and/or antibodies to hepatitis B surface antigen [anti-HBs]) must be screened using real-time polymerase chain reaction (PCR) measurement of hepatitis B virus (HBV) DNA levels. Those who are PCR positive will be excluded. EXCEPTION: Subjects with serologic findings suggestive of HBV vaccination (anti- HBs positivity as the only serologic marker) AND a known history of prior HBV vaccination, do not need to be tested for HBV DNA by PCR.
9. Patient with severe renal failure that require dialysis and clearance creatinine < 20 ml/min
10. Prior local irradiation within two weeks before first dose. However, an exception (that is patients allowed to remain in the treatment phase of the study) is made for radiation therapy to a pathological fracture site to enhance bone healing or to treat post-fracture pain that is refractory to narcotic analgesics because pathologic bone fractures do not by themselves fulfil a criterion for disease progression.)
11. Evidence of central nervous system (CNS) involvement
12. Unable to take corticosteroid therapy, daratumumab, bortezomib and or lenalidomide at study entry.
13. Ongoing active infection, especially ongoing pneumonitis
14. Ongoing Cardiac dysfunction: specify e.g. uncontrolled hypertension, MI within 6 months, unstable Angina pectoris, Cardiac arrhythmia Grade 2 or higher, NYHA class III/IV
15. Patients with a left ventricular ejection fraction under to 40 % (LVEF <40%).
16. Use of any other experimental drug or therapy within 15 days of screening.
17. Any >grade 2 toxicity unresolved
18. Inability or unwillingness to comply with birth control requirements
19. Unable to take antithrombotic medicines at study entry
20. Major surgery within 14 days before enrolment
21. Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol.
22. Known allergy to any of the study medications, their analogues, or excipients in the various formulations of any agent.
23. Known GI disease or GI procedure that could interfere with the oral absorption or tolerance of daratumumab and lenalidomide including difficulty swallowing