Multiple Myeloma

• Definition:

  • ≥10% clonal BM plasma cells + ≥1 myeloma-defining event

  • Biopsy-proven plasmacytoma + ≥1 myeloma-defining event

• Myeloma-defining events → CRAB-SLiM

  • Calcium >11 or >1 above ULN

  • Renal insufficiency: Cr >2 or CrCl <40 

  • Anemia: Hb <10 or 2< below LLN

  • Bone: ≥1 osteolytic lesion

  • ≥Sixty/60% clonal plasma cells in BM

  • Free Light chains (FLC): involved FLC/uninvolved FLC ≥100 AND involved FLC ≥100 mg/L

  • MRI >1 focal lesion, each ≥5 mm

• Risk Stratification:

  • High risk MM:

    • High risk cytogenetics:

      • del(17p) and/or TP53 mutation

      • t(4;14), t(14;16), or t(14;20) co-occurring with 1q+ and/or del(1p32)

      • Monoallelic del(1p32) with 1q+, or biallelic del(1p32)

      • high β2M (>5.5 mg/dL) with normal creatinine (<1.2 mg/dL)

    • R-ISS III

    • Extramedullary disease

  • Standard risk MM:

    • Favorable cytogenetics: t(6;14), t(11;14), Hyperdiploid karyotype

International Staging System:

• Stage I:   B2 microglobulin <3.5 or Alb >3.5

• Stage II:  Not stage I or III

• Stage III: B2 microglobulin ≥5.5

Revised- International Staging System:

• Stage I:   ISS stage I + no high-risk chromosomal abnormality AND normal LDH

• Stage II:  Not stage I or III

• Stage III: ISS stage III + high-risk chromosomal abnormality OR high LDH

Revised 2- International Staging System:

• Low risk: 0 point

  • Not stage II or III AND normal LDH AND no high risk chromosomal abnormality

• Low intermediate: 0.5-1 points

  • Stage II OR high LDH OR high risk chromosomal abnormality

• High intermediate risk: 1.5-2.5 points 

  • Any combination of high risk features with score of 1.5-2.5

• High risk: 3-5 points

  • Any combination of high risk features with score of 3-5

Medications:

Lenalidomide: 

• Dosage:

  • If CrCl >60: No adjustment

  • If CrCl 30-60: 10-15 mg daily

  • If CrCl <30: 15 mg every other day

  • If patient is on HD: 5 mg daily

• Multiple myeloma and (Lenalidomide + Dexa): increases risk of thrombotic events → patients may need Aspirin or AC based on IMPEDE or SAVED scoring system. (You can search and memorize them or simply ignore them as I did)

Bortezomib:

• Does not need dose adjustment in renal failure

• Causes peripheral neuropathy

             - SQ causes less neuropathy compared to IV

• Particularly effective in patients with high risk chromosomal abnormalities

• If T.bili >1.5 xULN: dose  0.7 mg/m2 per injection

• Needs prophylaxis for shingles: Valacyclovir 500 mg po BID

Daratumumab:

• CD 38 antibody

Pomalidomide:

• For patients who:

• received at least one prior therapies including lenalidomide and Bortezomib

• disease progressed within 60 days after the last treatment

• Should not be given to patient if T.bili >2 and AST/ALT >3 xULN 

• Reduce the dose 25% in patients on HD

Ixazomib:

• For patients who received at least one prior therapies

• 46% improvement in PFS in patients with high risk cytogenetics

Elotuzumab:

• Targets SLAMF7 (on myeloma and NK cells)

Talquetamab:

• Targets CD3 and GPRC5D

Zoledronic acid:

• Side effects: myalgia, hypocalcemia, jaw osteonecrosis and renal failure

• Dosage:

- CrCl >60: 4.0 mg daily

- CrCl 50-60: 3.5 mg daily

- CrCl 40-50: 3.3 mg daily

- CrCl 30-40: 3.0 mg daily

- CrCl <30: Zoledronic acid is contraindicated

Denosumab:

• Can be offered to patients with kidney failure

Treatment regimens:

• Non-transplant eligible patients:

  • DRd (MAIA):

    • Daratumumab + Lenalidomide (Revlimid) + dexamethasone 

  • VRd (SWOG S0777):

    • Bortezomib (Velcade) + Lenalidomide (Revlimid) + dexamethasone 

  • Dara-VRd

    • Daratumumab + Bortezomib (Velcade) + Lenalidomide (Revlimid) + dexamethasone 

    • Restricted to patients <80 years old who are not frail

  • Isa-VRd

    • Isatuximab + Bortezomib (Velcade) + Lenalidomide (Revlimid) + dexamethasone 

    • Restricted to patients <80 years old who are not frail

• Transplant eligible patients:

  • Renal dysfunction and advanced age are not contraindications to transplant.

  • Regimens:

    • RVD

    • Dara-VRd

    • RVD + Daratumumab (GRIFFIN)

    • restricted to patients <80 years old who are not frail

    • Isa-VRd

    • RVD + Isatuximab

    • restricted to patients <80 years old who are not frail

  • Avoid myelotoxic agents like Melphalan

  • Maintenance:

    • Lenalidomide (preferred)

    • Carfilzomib/Lenalidomide

    • Daratumumab/Lenalidomide

      • Two-drug maintenance is recommended for high-risk MM.

• If myeloma kidney/renal failure:

  • Cyclophosphamide + Bortezomib + Dexa (CyBorD) 

  • These patients should not be treated with Lenalidomide initially. When the kidney function improves, treatment can be transitioned from CyBorD to RVD ± Daratumumab.

• Refractory MM (failed at least two prior treatments):

  • Pomalidomide + Dexa

  • Ixazomib + Lenalidomide + Dexa (TOURMALINE-MM1)

  • Elotuzumab + Lenalidomide + Dexa 

  • Elotuzumab + Pomalidomide + Dexa

• Patients with significant neuropathy at baseline:

  • Daratumumab

  • Melphalan + Dexa (transplant ineligible)

• Systemic Amyloidosis:

  • CyBorD + Daratumumab and hyaluronidase 

  • CyBorD

  • Daratumumab

  • Bortezomib + Melphalan + Dexa (transplant ineligible)