Lymphoid Neoplasms

Phase 3, 1:1 randomized: DRd vs Rd x 2 years only

Key Eligibility Criteria:
1. Adults with newly diagnosed, high-risk SMM in past 12 months
2. High risk defined as 2 or more of the following
- t(4;14), del 17p, del 13q, 1q gain/amplification by cytogenetics or FISH
- FLC involved to uninvolved ratio between 100 and 20,
- Serum M-protein level > 2 gm/dL
- Bone marrow plasma cells > 20%
3. Measurable disease: SPEP ≥ 1 g/dL or UPEP ≥ 200 mg/24hr
4. No concomitant steroid use for MM, limit 10 mg/day for non-malignant comorbidities
5. Grade 2 peripheral neuropathy excluded
6. ECOG PS 0-2

Schedule: Arm A: weekly IV dosing Cycles 1 & 2, Q2W dosing Cycles 3-6, Q4W dosing Cycle 6+. For ASCT eligible patients, CD34+ collected between C4-6.

Phase 3, DRd Cycles 1-9, followed by 1:1 randomization DRd vs DRVd Cycles 10-18, and Dara + Len maintenance Cycles 19+ for all patients
- DRVd: Lenalidomide dose 15mg 21/28 C10-18.
- DR maintenance: Lenalidomide 10mg 21/28 C19+
- Patients can mobilize CD34+ any time after C4

Key Eligibility Criteria:

1. R-ISS Stage I or II NDMM ASCT-ineligible or prefers delayed ASCT
2. Measurable disease: SPEP ≥ 1 g/dL, UPEP ≥ 200 mg/24hr, or involved/uninvolved FLC ratio ≥ 10mg/dL
3. ECOG PS 0-2
4. Excludes prior Dex > 160mg cumulative or any prior MM treatment (incl. for SMM)
5. Grade 2 peripheral neuropathy excluded
6. Excludes severe/moderate persistent asthma in past two years

1. Must have a new diagnosis of symptomatic multiple myeloma according to IMWG criteria and have received 4 to 6 cycles of 3- or 4 drug-induction therapy that includes a proteasome inhibitor and/or an IMiD with or without anti-CD38 monoclonal antibody and a single or tandem ASCT. Post ASCT consolidation is permitted for up to 2 cycles as long as the total number of induction plus consolidation cycles does not exceed 6.
2. Must have received only one line of therapy and achieved at least a partial response (>/=PR) as per IMWG 2016 response criteria.
3. Must not be intolerant to the starting dose of lenalidomide (10 mg).
4. Must not have received any maintenance therapy.
5. ECOG performance status score of 0, 1, or 2.

Patient Eligibility Criteria:
- ECOG PS 0-1.
- ≥ 2 PLT (one PI, IMiD and/or anti-CD38 mAb).
- Measurable disease: M spike ≥ 0.5 g/dL, U-spike ≥ 200 mg/24 hours, sFLC) ≥ 10 mg/dL, plasmacytomas (≥ 2 cm).

Notable exclusion:
- ≥ 60% BM PCs or with multiple extramedullary disease sites or plasmacytomas, PCL, AL, WM, POEMS, active CNS+
- OPTec: excludes any prior BCMA
- OPTal: allows prior BCMA, but excludes prior GPRC5D

1. Documented diagnosis of MM as defined by the criteria below:
a. MM diagnosis according to the IMWG diagnostic criteria (Rajkumar 2014).
b. Measurable disease at screening as assessed by central laboratory, defined by any of the following:
i. Serum M-protein level ≥0.5 g/dL
ii. Serum immunoglobulin FLC ≥10 mg/dL and abnormal serum immunoglobulin kappa lambda FLC ratio
iii. Urine M-protein level ≥200 mg/24 hours
2. Received at least 3 prior lines of antimyeloma therapy including a PI, an IMiD, and an anti-CD38 antibody
3. Documented evidence of PD or failure to achieve a response (ie, PR or better) to the last line of therapy based on investigator’s determination of response by the IMWG criteria.
4. Have an ECOG performance status score of 0 to 2 at screening and immediately before the start of study treatment administration.

1. Has histologically confirmed newly diagnosed primary AL amyloidosis according to the following criteria:
-Presence of an amyloid-related systemic syndrome with 1 or more organs involved (e.g., renal, liver, heart, gastrointestinal tract, or peripheral nerve involvement, as per consensus guidelines
-Positive amyloid staining by Congo red stain with apple green birefringence on polarized light microscopy in any tissue (e.g., fat aspirate, BM, or organ biopsy), AND at least 1 of the following tests to confirm amyloid type as AL: Characteristic appearance by electron microscopy or confirmatory immunohistochemistry (see Section 8.1.4) or AL amyloidosis-typing by mass spectrometric proteomic analysis of the amyloid deposits or amyloid-typing by immunofluorescence
-Evidence of a monoclonal plasma cell proliferative disorder (serum or urine monoclonal protein, abnormal free light chain ratio, or clonal plasma cells in the BM).Measurable disease by RECIST 1.1

2. Measurable clonal disease as defined by at least 1 of the following:
-Serum monoclonal protein ≥0.5 g/dL by protein electrophoresis (routine serum protein electrophoresis and immunofixation performed at central laboratory)
-Involved serum FLC ≥5.0 mg/dL with an abnormal kappa:lambda ratio or the difference between involved and uninvolved light chain, dFLC ≥5 mg/dL.
NOTE: Measurable disease by urine Bence-Jones proteinuria is not sufficient for study enrollment.

3. Not considered candidate for high-dose chemotherapy with ASCT as part of first line of therapy, as per consensus guidelines.

4. Has an ECOG performance status of 0, 1 or 2, with no deterioration in the 2 weeks before enrollment.

1. Measurable disease of AL amyloidosis as defined by either dFLC ≥ 50 mg/L or meeting high riskdFLC progression to immediate prior line of therapy defined as meeting all of the following criteria:
-dFLC >20 mg/L
-dFLC >20% of baseline value before initiation of prior therapy
-dFLC >50% of nadir at best response to prior therapy
2. Diagnosis of primary systemic AL amyloidosis, according to consensus guidelines (Appendix H) or local standard of care.
-Diagnosis of systemic AL amyloidosis requires all of the following:
a. Presence of an amyloid-related systemic syndrome (e.g., renal, liver, heart, gastrointestinal tract, or peripheral nerve involvement)
b. Positive amyloid staining by Congo red in any tissue (e.g., fat aspirate, bone marrow, or organ biopsy)
c. Evidence that amyloid is light-chain-related established by direct examination of the amyloid using mass spectrometry-based proteomic analysis, or immune-electron microscopy, and
d. Evidence of a monoclonal plasma cell proliferative disorder (serum or urine monoclonal protein, abnormal free light-chain ratio, or clonal plasma cells in the bone marrow)
3. Considered AL amyloidosis cardiac risk stage 1, 2, or 3a, or considered cardiac risk stage 3b with stable cardiac function and biomarkers for 3 months prior to dosing with no cardiac related hospitalizations within 3 months and no changes to diuretic regimen within 21 days of first dose of study treatment (Appendix I).
4. ECOG performance status </=2.
5. At least 1 organ historically impacted by AL amyloidosis according to consensus guidelines.
6. Prior treatment with a PI and anti-CD38 monoclonal antibody.

1. Must have received a proteosome inhibitor, alkylator and anti-CD38 antibody (e.g. daratumumab --for patients who were eligible to receive in newly diagnosed AL Amyloidosis) and autologous stem cell transplant (for transplant eligible candidates).
Or
2. Failed treatment and/or intolerant/ineligible for above agents.
NOTE: Patients who fail to achieve Partial Hematological Response or better after 2 cycles of induction therapy for newly diagnosed AL Amyloidosis are also eligible.
3. Participant and Disease Characteristics: Patient must have primary systemic AL amyloidosis, histologically-confirmed at the initial diagnosis before initiation of 1st-line treatment 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).
4. Patient must have measurable disease within 28 days prior to registration; serum quantitative immunoglobulins (immunoglobulin IgG, IgA, and IgM), serum free kappa and lambda, and serum protein electrophoresis (SPEP) with M-protein quantification must be obtained within 28 days prior to registration.
• Measurable disease of amyloid light chain amyloidosis as defined by at least ONE of the following:
a. Serum M-protein ≥0.5 g/dL by protein electrophoresis (routine serum protein electrophoresis and immunofixation).
b. Serum free light chain ≥50 mg/L with an abnormal kappa:lambda ratio or the difference between the involved and uninvolved free light chains (dFLC) ≥50 mg/L.
6. New York Heart Association (NYHA) Class 1 to 3a which has been clinically stable for 56 days before registration.
7. ECOG performance score 0, 1 or 2.