A Phase III, Randomized Study of Daratumumab, Cyclophosphamide, Bortezomib and Dexamethasone (Dara-VCD) Induction Followed by Autologous Stem Cell Transplant or Dara-VCD Consolidation and Daratumumab Maintenance in Patients with Newly Diagnosed AL Amyloidosis

Registration Step 1 – Initial Enrollment to Study
a. Disease Related Criteria
1. Participants must have systemic AL amyloidosis which is biopsy proven and includes histologically-confirmed by positive Congo red stain with green birefringence on polarized light microscopy, OR characteristic appearance by electron microscopy AND confirmatory AL amyloid typing (mass spectrometry-based proteomic analysis or immunofluorescence). If there is question regarding diagnosis, consult Study Chairs prior to registration.
2. Participants must have measurable disease within 28 days prior to treatment if initiated prior to registration or within 28 days of registration as defined by at least one of the following:
i. Positive monoclonal serum immunofixation electrophoresis
ii. Positive monoclonal urine immunofixation electrophoresis
iii. Monoclonal plasma cells in bone marrow

In addition, participants must also have a difference between the involved and uninvolved free light chain (dFLC) greater than or equal to 2 mg/dL
b. Prior/Concurrent Therapy Criteria
1. Participants may receive up to one cycle(or 28 days) of therapy prior to enrollment. If a patient receives greater than or equal to 75% of 1 cycle of protocol identical Dara-VCD, this will be considered 1 cycle of protocol induction. Any patient who receives less than 75% of 1 cycle of Dara-VCD or non-protocol therapy will still be eligible but will be treated per protocol. If protocol identical therapy is initiated prior to enrollment, this treatment is not continued but rather treatment is dictated per protocol.
2. Participants may be receiving chronic corticosteroids if they are being given for disorders other than AL amyloidosis or myeloma.

c. Clinical/Laboratory Criteria
1. Participant must be greater than or equal to 18 years old.
2. Participant must have ECOG performance score (PS) of 0, 1, or 2 (PS = 3 may be allowed if secondary to neuropathy). (see Section 10).
3. Participant must have a complete medical history and physical exam within 28 DAYS prior to registration.
4. Participants must be willing to undergo high dose chemotherapy and autologous stem cell transplantation if they are randomized to the arm receiving high dose chemotherapy and autologous stem cell transplantation.
5. Participants must be eligible to receive high dose chemotherapy with melphalan at a dose of 200 mg/m2 or 140 mg/m2 (200 mg/m2 is highly encouraged but not mandated). Transplant eligibility criteria are included in the general eligibility criteria listed below:
a. Participant must have a supine systolic BP greater than or equal to 90 mmHg (at registration step-1, this may by supported by midodrine)
b. Participant must have non-severe cardiac AL (meeting all the below criteria) as defined by:

1. NT proBNP less than 5000 (if no NTproBNP, BNP must be available and less than 400)
2. TnT less than 0.06. If not available, one of the following two criteria must be met:
a. hsTnT less than 75 or Troponin I less than 0.1 ng/dL
3. NYHA I or II
4. Cardiac EF greater than or equal to 40 percent
6. Participants must have adequate organ and marrow function as defined below within 28 DAYS prior to registration (NOTE: Growth factor support (G-CSF) is permitted per institutional guidelines):
a. Hemoglobin Cell: greater than or equal to 8.0 g/dL (greater than or equal to 5 mmol/L); red blood transfusion allowed up to 7 day prior to registration
b. Leukocytes: greater than or equal to 2 x 10 to the 3rd / uL
c. Absolute neutrophil count: greater than or equal to 1.0 X 10 to the 3rd /uL
d. Platelets: greater than or equal to 50 X 10 to the 3rd / uL
e. Total bilirubin: less than or equal to 1.5 times the institutional upper limit of normal (ULN) unless history of Gilbert’s disease. Participants with history of Gilbert’s disease must have total bilirubin less than or equal to 5 X institutional ULN.
f. Direct bilirubin: less than or equal to 2.0 mg/dL
g. AST/ALT: less than or equal to 3X upper limit of normal (ULN) (except if secondary to hepatic involvement)
h. Alkaline phosphatase: less than or equal to 750 U/L (except if secondary to hepatic involvement)
7. Participants must have a serum creatinine less than or equal to the IULN OR measured OR calculated creatinine clearance greater than or equal to 30 mL/min using the following Cockcroft Gault Formula. This specimen must have been drawn and processed within 28 DAYS prior to registration:

Calculated Creatinine Clearance =
(140 - age) X (weight in kg) **
72 x serum creatinine *

Multiply this number by 0.85 if the participant is a female.
** The kilogram weight is the participant weight with an upper limit of 140% of the IBW.
*Actual lab serum creatinine value with a minimum of 0.7 mg/dL.
8. If peripheral neuropathy is present at diagnosis, participants must be grade 2 (moderate symptoms; limiting instrumental ADL) or less.
9. Participants must have adequate cardiac function. Participants with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, must have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification (see Section 18.) To be eligible for this trial, participants must be class 2 or better.
10. Participants must not be seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen [HBsAg]). Subjects with resolved infection (i.e., 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.
11. Participants with a history of hepatitis C virus (HCV) infection must have been treated and cured. Participants currently being treated for HCV infection must have undetectable HCV viral load test on the most recent test results obtained within 6 months prior to registration, if indicated.
12. Participants must not have concurrent multiple myeloma as defined by the presence of lytic bone disease, plasmacytomas, greater than or equal to 60% plasma cells in the bone marrow, or hypercalcemia. Participants will not be excluded solely based on the presence of plasma cells greater than 10% in the bone marrow unless the plasma cell percentage exceeds greater than 60%.
13. Participants must not have known allergies to any of the study drugs.
14. Participants must not have had a major surgery within 14 days prior to registration and be fully recovered from surgery completed within 14 days prior to registration.
15. Participants must not have a known chronic obstructive pulmonary disease with a forced expiratory volume in 1 second (FEV1) less than 50 percent of predicted normal.
16. Participants with known human immunodeficiency virus (HIV)-infection must be on effective anti-retroviral therapy at registration and have undetectable viral load test on the most recent test results obtained within 6 months prior to registration.
17. Participants must not have either moderate or severe persistent asthma within the past 2 years), or currently have uncontrolled asthma of any classification. (Note that subjects who currently have controlled intermittent asthma or controlled mild persistent asthma are allowed in the study).
18. Participants must not have uncontrolled diabetes within 28 days prior to registration. See Section 7. for definition of uncontrolled diabetes.
19. Participants must not have uncontrolled blood pressure and hypertension within 14 days prior to registration. Participants must have a supine systolic BP of greater than 90 mmHg See Section 5.1.c.5.a. for definition of uncontrolled blood pressure and hypertension.
20. Participants must not have a prior or concurrent malignancy whose natural history or treatment (in the opinion of the treating physician) has the potential to interfere with the safety or efficacy assessment of the investigational regimen.
21. Participants must not have received vaccination with live attenuated vaccines within 28 days prior to Registration to Step 1.
22. Participants must not have uncontrolled infection at the discretion of the enrolling physician and to be discussed with the study chair if the participant is on active anti-infectious therapy. Any patient on active anti-microbial therapy for chronic infectious issues should be discussed with the study chair prior to enrollment.
23. Participants must not be pregnant or nursing (nursing includes breast milk fed to an infant by any means, including from the breast, milk expressed by hand, or pumped). Individuals who are of reproductive potential must have agreed to use an effective contraceptive method with details provided as a part of the consent process. A person who has had menses at any time in the preceding 12 consecutive months or who has semen likely to contain sperm is considered to be of "reproductive potential." In addition to routine contraceptive methods, "effective contraception" also includes refraining from sexual activity that might result in pregnancy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) including hysterectomy, bilateral oophorectomy, bilateral tubal ligation/occlusion, and vasectomy with testing showing no sperm in the semen.
d. Additional Criteria
1. Participants must be offered the opportunity to participate in specimen banking as outlined in Section 15.With participant consent, specimens must be collected and submitted via the SWOG Specimen Tracking System as outlined in Section 15.
2. Participants must agree to have blood, bone marrow core biopsy and aspirate, and fat pad biopsy specimens submitted for minimal residual disease assessment and future exploratory studies as outlined in Section 15.
3. Participants who can complete PRO, QOL, PRO-CTCAE questionnaires, etc. forms in English and Spanish must participate in the patient-reported outcomes and quality of life as outlined in Section 15.
Registration Step 2 – Randomization Prior to Consolidation Therapy
a. Disease Related Criteria
1. Participants must have met all eligibility criteria for Step-1 registration as outlined in Section 5.1.
2. Participants must have achieved at least a partial response (see Section 10.3 and Section 18.9) to induction therapy.
3. Participants must continue receiving at least one of study drugs (bortezomib, cyclophosphamide, or daratumumab and hyaluronidase-fihj) if another study drug (daratumumab and hyaluronidase-fihj, cyclophosphamide, or bortezomib) has been discontinued due to adverse events. Note: daratumumab and hyaluronidase-fihj cannot be permanently discontinued.
b. Prior/Concurrent Therapy Criteria
1. Participants must have completed induction therapy as outlined in Section 7.3a.
2. Participants must be registered to Step 2 within 42 days of Cycle 3, Day 28 of induction therapy.
3. Participants must plan to initiate their assigned consolidation therapy within 8 weeks after randomization.
4. Participants must not have experienced a MOD-PFS event as defined in Section 10.1.
c. Clinical/Laboratory Criteria
1. Participants must have ECOG performance score (PS) of 0, 1, or 2 (PS equals 3 may be allowed if secondary to neuropathy). (see Section 10).
2. Participant must have a complete medical history and physical exam within 28 DAYS prior to registration.
3. Participants must be willing to undergo high dose chemotherapy and autologous stem cell transplantation if they are randomized to the arm receiving high dose chemotherapy and autologous stem cell transplantation.
4. Participants randomized to Arm 2 must be willing and able to return to a participating treatment center for their assigned treatment after transplant. Note that participants need not to have a direct relationship with the transplant center in order to register.
5. Participants must be eligible to receive high dose chemotherapy with melphalan at a dose of 200 mg/m2 or 140 mg/m2 (200 mg/m2 is highly encouraged but not mandated). Transplant eligibility criteria are included in the general eligibility criteria listed below:
a. Participant must have a supine systolic BP greater than or equal to 90 mmHg (at registration step-1, this may by supported by midodrine)
b. Participant must have non-severe cardiac AL (meeting all the below criteria) as defined by (within 14 days prior to registration step-2):
1. NT proBNP less than 5000 (if no NTproBNP, BNP must be available and less than 400)
2. TnT less than 0.06. If not available, one of the following two criteria must be met:
a. hsTnT less than 75 or Troponin I less than 0.1 ng/dL
3. NYHA I or II
4. Cardiac EF greater than or equal to 40 percent
6. Participants must have adequate organ and marrow function as defined below within 28 DAYS prior to registration (NOTE: Growth factor support (G-CSF) is permitted per institutional guidelines):
a. Hemoglobin Cell: greater than or equal to 8.0 g/dL (greater than or equal to 5 mmol/L); red blood transfusion allowed up to 7 day prior to registration
b. Leukocytes: greater than or equal to 2 x 10 to the 3rd / uL
c. Absolute neutrophil count: greater than or equal to 1.0 X 10 to the 3rd /uL
d. Platelets: greater than or equal to 50 X 10 to the 3rd / uL
e. Total bilirubin: less than or equal to 1.5 times the institutional upper limit of normal (ULN) unless history of Gilbert’s disease. Participants with history of Gilbert’s disease must have total bilirubin less than or equal to 5 X institutional ULN.
f. Direct bilirubin: less than or equal to 2.0 mg/dL
g. AST/ALT: less than or equal to 3X upper limit of normal (ULN) (except if secondary to hepatic involvement)
h. Alkaline phosphatase: less than or equal to 750 U/L (except if secondary to hepatic involvement)
7. Participants must have a serum creatinine less than or equal to the IULN OR measured OR calculated creatinine clearance greater than or equal to 30 mL/min using the following Cockcroft Gault Formula. This specimen must have been drawn and processed within 28 DAYS prior to registration:

Calculated Creatinine Clearance =
(140 - age) X (weight in kg) **
72 x serum creatinine *

Multiply this number by 0.85 if the participant is a female.
** The kilogram weight is the participant weight with an upper limit of 140% of the IBW.
*Actual lab serum creatinine value with a minimum of 0.7 mg/dL.
8. Participants must not have uncontrolled infection at the discretion of the enrolling physician and to be discussed with the study chair if the participant is on active anti-infectious therapy. Any patient on active anti-microbial therapy for chronic infectious issues should be discussed with the study chair prior to enrollment.
d. Additional Criteria
1. Participants randomized to the ASCT arm must be able to have at least 2.0 X 10 to the 6th CD34 cells/kg collected.
2. Participants who can complete PRO, QOL, PRO-CTCAE questionnaires, etc. forms in English and Spanish must participate in the patient-reported outcomes and quality of life as outlined in Section 15.5.
Registration Step 3 – Start of Maintenance Therapy
a. Disease Related Criteria
1. Participants must have completed induction and consolidation therapy as outlined in Section 7.3a.
2. Participants must not have had daratumumab and hyaluronidase-fihj permanently discontinued during induction or consolidation.
b. Prior/Concurrent Therapy Criteria
1. Participants must have completed induction and consolidation therapy as outlined in Section 7.3a.
2. Participants must be registered to Step 3 within the following time frames:
a. If randomized to Arm 1 Dara-VCD consolidation: within 28 days of completion of 3 cycles of consolidation therapy.
b. If randomized to Arm 2 high dose chemotherapy and autologous stem cell transplantation: within 180 days following initiation of stem cell transplantation.
3. Participants must not have experienced a MOD-PFS event as defined in Section 10.1.
c. Clinical/Laboratory Related Criteria
1. Participants must have ECOG performance score (PS) of 0, 1, or 2 (PS = 3 is allowed if secondary to neuropathy). (see Section 10).
2. Participants must have a complete medical history and physical exam within 28 DAYS prior to registration.
3. Participants must have adequate organ and marrow function as defined below within 28 DAYS prior to registration (NOTE: Growth factor support (G-CSF) is permitted per institutional guidelines):
i. Hemoglobin Cell: greater than or equal to 8.0 g/dL (greater than or equal to 5 mmol/L); red blood transfusion allowed up to 7 day prior to registration
j. Leukocytes: greater than or equal to 2 x 10 to the 3rd / uL
k. Absolute neutrophil count: greater than or equal to 1.0 X 10 to the 3rd /uL
l. Platelets: greater than or equal to 50 X 10 to the 3rd / uL
m. Total bilirubin: less than or equal to 1.5 times the institutional upper limit of normal (ULN) unless history of Gilbert’s disease. Participants with history of Gilbert’s disease must have total bilirubin less than or equal to 5 X institutional ULN.
n. Direct bilirubin: less than or equal to 2.0 mg/dL
o. AST/ALT: less than or equal to 3X upper limit of normal (ULN) (except if secondary to hepatic involvement)
p. Alkaline phosphatase: less than or equal to 750 U/L (except if secondary to hepatic involvement)
4. Participants must not have uncontrolled infection at the discretion of the enrolling physician and to be discussed with the study chair if the participant is on active anti-infectious therapy. Any patient on active anti-microbial therapy for chronic infectious issues should be discussed with the study chair prior to enrollment.
Regulatory Criteria
a. Participants must be informed of the investigational nature of this study and must sign and give informed consent in accordance with institutional and federal guidelines.
For participants with impaired decision-making capabilities, legally authorized representatives may sign and give informed consent on behalf of study participants in accordance with applicable federal, local, and CIRB regulations.