Summary

This phase III trial compares the effect of usual treatment (lenalidomide) to using daratumumab/rHuPH20 plus the usual treatment after stem cell transplantation in patients with multiple myeloma. This drug combination may help patients live longer after their stem cell transplant. Another purpose of this study is to learn if the presence and amount of minimal residual disease (MRD) can help doctors predict when a patient’s multiple myeloma will get worse. MRD is the name for the small number of cancer cells that remain in the patient even after their multiple myeloma has been treated and they have no symptoms of the disease. Drugs used in chemotherapy, such as lenalidomide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Immunotherapy with daratumumab/rHuPH20, may induce changes in body’s immune system and may interfere with the ability of tumor cells to grow and spread. Giving lenalidomide and daratumumab/rHuPH20 may work better in treating patients with multiple myeloma compared to lenalidomide alone.

Objectives

PRIMARY OBJECTIVE:
I. To compare overall survival (OS) between the two treatment arms with lenalidomide as the comparator arm and lenalidomide + daratumumab/rHuPH20 as the experimental arm in post-autologous transplant multiple myeloma (MM) patients.

SECONDARY OBJECTIVES OF FIRST RANDOMIZATION:
I. To compare the best overall response rate (ORR), including partial remission (PR), very good partial remission (VGPR), and complete remission (CR, stringent [s]CR) in the subset of patients not in PR at randomization to lenalidomide versus lenalidomide + daratumumab/rHuPH20 in this patient population.
II. To compare progression-free survival (PFS) between the study arms in this patient population.
III. To evaluate MRD-negativity (<10*-6 by next-generation sequencing [NGS]) on the two treatment arms at randomization (Registration Step 2), and to compare MRD-negativity rate at 12, 24 (second randomization), 36, and 48 months after first randomization between lenalidomide and lenalidomide + daratumumab/rHuPH20 in this patient population.
IV. To compare toxicities and tolerability of long term therapy between the study arms.

OBJECTIVES OF SECOND RANDOMIZATION:
I. To compare overall survival (OS) between MRD negative (<10^-6 by NGS) patients randomized to continued lenalidomide versus (vs.) discontinued lenalidomide from the time of second randomization in this patient population.
II. To compare overall survival (OS) between MRD negative (<10^-6 by NGS) patients randomized to continued lenalidomide + daratumumab/rHuPH20 vs. discontinued lenalidomide + daratumumab/rHuPH20 from time of second randomization in this patient population.

ADDITIONAL OBJECTIVES:
I. To report the findings of the 24-month MRD analysis as early as 24 months after all patients have been accrued.
II. To compare patient-reported health-related quality of life at 24 months after first randomization (approximately 2 years post-transplant) and at 48 months after first randomization (4 years post-transplant and 2 years after second randomization) in patients with multiple myeloma randomized to Daratumumab/rHuPH20 (NSC- 810307) + Lenalidomide versus Lenalidomide post-autologous stem cell transplantation (ASCT) using the Patient-Reported Outcomes Measurement Information System (PROMIS) 29.
III. To compare select patient-reported outcomes using the Common Terminology Criteria for Adverse Events (PRO-CTCAE) by arm.
IV. Among patients with conclusive MRD results at 24 months after first randomization, to compare responses to the Intolerance of Uncertainty Scale Short Form (IUS) and the PROMIS-29 by MRD status.
V. To explore whether PROMIS-29 scores at baseline (Registration Step 2) and 24 months (both first and second randomizations) are associated with PFS, and whether the effect of randomized assignment on PFS differs according to baseline PROMIS-29 levels

OUTLINE: Patients are randomized to 1 of 2 arms after undergoing autologous stem cell transplantation.

ARM I: Patients receive lenalidomide orally (PO) once daily (QD) on days 1-28. Cycles repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients who achieve MRD negativity (< 10^-6 by NGS) are then randomized to continue lenalidomide treatment for 5 years or stop treatment. Patients who are MRD positive continue lenalidomide treatment for 5 years in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive lenalidomide PO QD on days 1-28. Patients also receive daratumumab/rHuPH20 subcutaneously (SC) over 3-5 minutes on days 1, 8, 15 and 22 of cycles 1-2, days 1 and 15 for cycles 3-6, and day 1 for subsequent cycles. Cycles repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients who achieve MRD negativity (< 10^-6 by NGS) are then randomized to continue lenalidomide and daratumumab/rHuPH20 treatment for 5 years or stop treatment. Patients who are MRD positive continue lenalidomide and daratumumab/rHuPH20 treatment for 5 years in the absence of disease progression or unacceptable toxicity.

Patients undergo bone marrow aspirate and/or biopsy, bone scan, computed tomography (CT) scan, magnetic resonance imaging (MRI), or positron emission tomography (PET) scan throughout the study.

After completion of study treatment, patients are followed up every 2 or 6 months for 7 years, and then annually for up to 15 years after Registration Step 2.

Eligibility

1. Except where otherwise indicated below that test is required in a shorter timeframe, all tests for establishing baseline disease status must be completed prior to registration. All diagnostic test results must be documented on the Baseline Tumor Assessment Form for Multiple Myeloma and the Onstudy Form. (REGISTRATION STEP 1 - STUDY ENTRY)
2. Patients must have had a confirmed diagnosis of symptomatic multiple myeloma with measurable disease at the time of myeloma diagnosis that required systemic induction therapy prior to autologous stem cell transplantation (ASCT). Measurable disease is defined as measurable M protein in the serum (>= 0.5 g/dL) or urine (>= 200 mg/24h) or serum free light chain assay (defined as >= 10 mg/dL [>= 100 mg/L] on involved light chain) at the time of diagnosis. Patients with smoldering myeloma are not eligible until they have progressed to active myeloma. Patients with purely non-secretory MM at the time of diagnosis are not eligible. Patients with plasma cell leukemia are not eligible. (REGISTRATION STEP 1 - STUDY ENTRY)
3. Patients must not have any organ involvement by amyloidosis or evidence of amyloidosis related organ dysfunction (REGISTRATION STEP 1 - STUDY ENTRY)
4. Patients must not have progressive disease at any time prior to registration (REGISTRATION STEP 1 - STUDY ENTRY)
5. Patients must not be refractory to either lenalidomide or daratumumab/rHuPH20 (REGISTRATION STEP 1 - STUDY ENTRY)
6. Patients must not be intolerant to the starting dose of either lenalidomide (10 mg or 5 mg in patients with renal insufficiency) or daratumumab/rHuPH20. Patients intolerant to the 25 mg starting dose of lenalidomide are eligible (REGISTRATION STEP 1 - STUDY ENTRY)
7. Patients who have already received transplant must have initiated induction therapy within 18 months prior to transplant and received at least two cycles of induction therapy before transplant. Patients who have not already received transplant must have begun induction therapy within 18 months prior to the planned date of transplant and must receive at least two cycles of induction therapy before transplant. Note that patients who receive tandem transplant will not be eligible for step 2 registration (REGISTRATION STEP 1 - STUDY ENTRY)
8. Patients must be registered to step 1 prior to registration to step 2. Registration to step 1 may take place prior to or after autologous stem cell transplant (ASCT), but after completion of induction therapy. Patients who have completed ASCT may be registered to step 1 and step 2 on the same day, provided all eligibility criteria are met. (REGISTRATION STEP 1 - STUDY ENTRY)
9. Patients must not have received any investigational agents within 14 days prior to registration (REGISTRATION STEP 1 - STUDY ENTRY)
10. Patients must be willing and able to take deep vein thrombosis (DVT) prophylaxis (aspirin, low molecular weight heparin, warfarin, or equivalent oral anticoagulation) (REGISTRATION STEP 1 - STUDY ENTRY)
11. Patients must have a history and physical exam within 28 days prior to registration (REGISTRATION STEP 1 - STUDY ENTRY)
12. Patients must be >= 18 and =< 75 years of age at time of registration to step 1 (REGISTRATION STEP 1 - STUDY ENTRY)
13. Patients must have Zubrod performance status =< 2 (REGISTRATION STEP 1 - STUDY ENTRY)
14. Creatinine clearance (CrCl) >= 30 mL/min., as measured by a 24-hour urine collection, or estimated by the Cockcroft and Gault formula, or serum creatinine < 2.5 mg/dL. Values must be obtained within 28 days prior to registration (REGISTRATION STEP 1 - STUDY ENTRY)
15. Total bilirubin =< 1.5 x IULN (institutional upper limit of the normal [norm]) (within 42 days prior to registration) (REGISTRATION STEP 1 - STUDY ENTRY) * Note: Patients with Gilbert Syndrome and elevated baseline bilirubin up to 3.0 mg/dL are eligible for registration to Step 1 and registration Step 2
16. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3.0 x IULN (within 42 days prior to registration) (REGISTRATION STEP 1 - STUDY ENTRY)
17. Patients with a known history of asthma or chronic obstructive pulmonary disease must not have had forced expiratory volume in 1 second (FEV1) < 50% of predicted normal (REGISTRATION STEP 1 - STUDY ENTRY)
18. Patients must not have moderate or severe persistent asthma within the past 2 years and must not have currently uncontrolled asthma of any classification (REGISTRATION STEP 1 - STUDY ENTRY)
19. Patients must meet one of the following criteria: * Be acceptable for transplant per institutional guidelines and the criteria evidencing this must be documented on the S1803 on study form OR * Have completed autologous stem cell transplant within 180 days prior to registration (REGISTRATION STEP 1 - STUDY ENTRY)
20. Patients must not have had prior autograft or allograft, or prior organ transplant requiring immunosuppressive therapy (REGISTRATION STEP 1 - STUDY ENTRY)
21. Patients with human immunodeficiency virus (HIV) are eligible providing they are on effective antiretroviral therapy and have undetectable viral load at their most previous viral load test and within 6 months prior to registration (REGISTRATION STEP 1 - STUDY ENTRY)
22. Patients must not have known allergy to any of the study drugs (REGISTRATION STEP 1 - STUDY ENTRY)
23. Patients with uncontrolled bacterial, viral or fungal infections (currently taking medication and with progression or no clinical improvement) at time of enrollment are not eligible (REGISTRATION STEP 1 - STUDY ENTRY)
24. Patients must not have known central nervous system (CNS) involvement with multiple myeloma, defined as cerebrospinal fluid (CSF) positivity for plasma cells at any time or a parenchymal CNS plasmacytoma at time of enrollment. Lumbar puncture is not required (REGISTRATION STEP 1 - STUDY ENTRY)
25. Patients must not be seropositive for hepatitis C (except in the setting of sustained virologic response, defined as undetectable viral load at least 12 weeks after completion of antiviral therapy). Hepatitis C virus (HCV) testing is only required if clinically indicated or if the patient has a history of HCV (REGISTRATION STEP 1 - STUDY ENTRY)
26. Patients must be able to take and swallow oral medication (capsules) whole. Patients may not have any known impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of study drug (e.g. ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection) (REGISTRATION STEP 1 - STUDY ENTRY)
27. No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease free for three years (REGISTRATION STEP 1 - STUDY ENTRY)
28. Patients must not have any uncontrolled intercurrent illness including (not limited to): symptomatic congestive heart failure (CHF) (New York Heart Association [NYHA] III/IV), unstable angina pectoris or coronary angioplasty, or stenting within 6 months prior to registration, unstable cardiac arrhythmia (ongoing cardiac dysrhythmias of National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] version [v]5.0 grade >= 2), intra-cardiac defibrillators, known cardiac metastases, or abnormal cardiac valve morphology (>= grade 3), or known psychiatric illness that would limit study compliance (REGISTRATION STEP 1 - STUDY ENTRY)
29. Patients 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) deoxyribonucleic acid (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 (REGISTRATION STEP 1 - STUDY ENTRY)
30. For patients who have not yet received transplant: Patients must be willing and able to return to a participating treatment center for their assigned treatment after randomization. Note that patients need not have a direct relationship with the transplant center in order to register (REGISTRATION STEP 1 - STUDY ENTRY)
31. Patients who can complete patient-reported outcomes instruments in English, Spanish or French must agree to complete the assessments at the protocol-specified time points. (REGISTRATION STEP 1 - STUDY ENTRY)
32. Patients must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines. Note: For patients registering to step 1 prior to transplant or who are not planning to begin treatment at the time of registration, the observation consent will be used to obtain consent. For patients concurrently enrolling to steps 1 and 2, sites need not utilize the observation consent and may utilize the treatment consent for both registration steps. Note: As a part of the Oncology Patient Enrollment Network (OPEN) registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system (REGISTRATION STEP 1 - STUDY ENTRY)
33. Patients must have completed ASCT within 180 days prior to registering to step 2. Patients who enroll after ASCT may be registered to step 1 and step 2 concurrently (REGISTRATION STEP 2 - FIRST RANDOMIZATION)
34. Patients must not have received tandem transplant (REGISTRATION STEP 2 - FIRST RANDOMIZATION)
35. Patients must not have received any maintenance therapy post-ASCT and prior to Step 2 registration. (REGISTRATION STEP 2)
36. Patients must not have had progressive disease between induction and registration step 2 (REGISTRATION STEP 2 - FIRST RANDOMIZATION)
37. Patients must have the following performed within 60 days prior to registration step 2 for disease assessment: * Myeloma-specific tests for establishing baseline disease status (serum protein electrophoresis [SPEP], serum immunofixation, serum free light chains, 24-hour urine protein electrophoresis [UPEP], urine immunofixation, bone marrow aspirate/biopsy, and quantitative immunoglobulins) AND * One of the following: diagnostic quality skeletal survey, whole body computed tomography (CT) scan, magnetic resonance imaging (MRI), or positron emission tomography (PET) (REGISTRATION STEP 2 - FIRST RANDOMIZATION)
38. Patients must have Zubrod performance status =< 2 (REGISTRATION STEP 2 - FIRST RANDOMIZATION)
39. Platelets >= 75,000/mm^3 within 28 days prior to first randomization (REGISTRATION STEP 2 - FIRST RANDOMIZATION)
40. Absolute neutrophil count (ANC) >= 1,000/mm^3 within 28 days prior to first randomization (REGISTRATION STEP 2 - FIRST RANDOMIZATION)
41. Total bilirubin =< 1.5 x IULN (institutional upper limit of the norm) (within 28 days prior to first randomization) (REGISTRATION STEP 2 - FIRST RANDOMIZATION)
42. AST and ALT =< 3.0 x IULN (within 28 days prior to first randomization) (REGISTRATION STEP 2 - FIRST RANDOMIZATION)
43. Patients must have evidence of adequate renal function, as defined by creatinine clearance (CrCl) >= 30 mL/min., as measured by a 24-hour urine collection, or estimated by the Cockcroft and Gault formula, or have a serum creatinine < 2.5 mg/dL within 28 days prior to first randomization (REGISTRATION STEP 2 - FIRST RANDOMIZATION) * Note: Patients with creatinine clearance (measured or estimated) of < 30 mL/minute may be eligible for registration step 1 and step 2 if their serum creatinine is < 2.5 mg/dL within 28 days prior to registration and first randomization, respectively
44. All ASCT-related toxicities must have recovered to = grade 1 (except for alopecia, fatigue and amenorrhea) prior to first randomization (REGISTRATION STEP 2 - FIRST RANDOMIZATION)
45. ASCT-related mucositis and gastrointestinal symptoms must have resolved to =< grade 1 (REGISTRATION STEP 2 - FIRST RANDOMIZATION)
46. Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL within 10-14 days prior to registration. FCBP must agree to have a second pregnancy test within 24 hours prior to starting cycle 1. Further, FCBP must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control: one highly effective method and one additional effective method AT THE SAME TIME, at least 28 days before starting lenalidomide. FCBP must also agree to ongoing pregnancy testing and must agree to not become pregnant for at least 3 months after the last dose of study treatment. A FCBP is a female who: 1) has achieved menarche (first menstrual cycle) at some point, 2) has not undergone a hysterectomy (the surgical removal of the uterus) or bilateral oophorectomy (the surgical removal of both ovaries) or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time during the preceding 24 consecutive months). Men must agree to use a latex condom during sexual contact with a FCBP, even if they have had a successful vasectomy, during the study treatment and for 3 months after the last dose of study treatment (REGISTRATION STEP 2 - FIRST RANDOMIZATION)
47. Patients must have archival specimens for MRD by NGS or a linkable commercial sequencing to provide ID clonality. Submission must include 3-5 diagnostic bone marrow aspirate smear or formalin-fixed paraffin-embedded (FFPE) re-cuts from bone marrow aspirate clot (bone marrow biopsy core specimens are not accepted) * Note: Plasmacytoma slides can be submitted when diagnostic bone marrow slides are not available
48. Patients must be offered participation in specimen banking for future research. With patient’s consent, specimens must be submitted (REGISTRATION STEP 2 - FIRST RANDOMIZATION)
49. Patients must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines. (REGISTRATION STEP 2 - FIRST RANDOMIZATION)
50. Note: For patients concurrently enrolling to steps 1 and 2, sites need not utilize the observation consent and may utilize the treatment consent for both registration steps (REGISTRATION STEP 2 - FIRST RANDOMIZATION)
51. NOTE: Participants are not to be registered to step 3 without notification from the SDMC via the 24 Month MRD and Response form, or via email specified in the SWOG Specimen Tracking System when shipping 24 month MRD sample. Confirmation of eligibility can be obtained by contacting myelomaquestion@crab.org (REGISTRATION STEP 3 - SECOND RANDOMIZATION)
52. Patients must have been enrolled on Registration Step 2, must have 24-month MRD by next generation sequencing (NGS) test results available and must be MRD negative (< 10^-6 by NGS) as determined by results provided by Adaptive Biotechnologies). Patients whose MRD results are indeterminable will be considered to have positive results (REGISTRATION STEP 3 - SECOND RANDOMIZATION)
53. Patients must be in very good partial remission (VGPR) or better by International Myeloma Working Group (IMWG) response criteria (REGISTRATION STEP 3 - SECOND RANDOMIZATION)

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