Hematology & Oncology & Internal Medicine & Family Medicine
Multiple Myeloma | Omicron Clinic Quebec
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Multiple myeloma (MM) - also known as Kahler's disease - is a clonal plasma cell hematological malignancy, characterized by the uncontrolled proliferation of tumoral plasma cells in the bone marrow, secreting monoclonal immunoglobulin (M protein) and causing characteristic organ damage - summarized by the acronym CRAB: hyperCalcemia + Renal failure + Anemia + Bone lesions. MM accounts for around 10 % of hematological malignancies and 1-2 % of all cancers - with an incidence of 6-7/100,000/year in developed countries, mainly in adults over 60 (median age at diagnosis: 69). It is almost always preceded by monoclonal gammopathy of undetermined significance (MGUS) or smoldering myeloma (asymptomatic), before progressing to symptomatic MM. The therapeutic revolution of the last 20 years - with the introduction of proteasome inhibitors (bortezomib + carfilzomib + ixazomib), immunomodulatory agents (IMiDs - thalidomide + lenalidomide + pomalidomide), anti-CD38 antibodies (daratumumab + isatuximab), BCL-2 inhibitors (venetoclax for t(11;14)) and CAR-T therapies (cilta-cel + idecabtagene vicleucel) - has transformed prognosis: median survival has risen from 3 years in 2000 to over 8-10 years for patients eligible for autologous stem cell transplantation (ASCT) treated with modern protocols.
Pathophysiology, diagnostic criteria and initial workup
- Pathophysiology and 2014 IMWG criteria for multiple myeloma: pathogenesis : malignant plasma cells → massive production of monoclonal immunoglobulin (M protein - IgG > IgA > IgD + IgE + κ or λ light chains alone) + sequestration of bone marrow → inhibition of normal hematopoiesis → anemia + leukopenia + thrombocytopenia → activation of osteoclasts + inhibition of osteoblasts (via DKK1 + RANKL ++) → osteolytic lesions + osteoporosis + hypercalcemia → deposition of light chains in renal tubules (cylinder nephropathy or cast nephropathy) → renal failure → polyclonal immunoglobulin suppression → humoral immunosuppression → recurrent bacterial infections (pneumococcal ++) → hyperviscosity (if IgM or M protein very high) → IMWG 2014 (International Myeloma Working Group) diagnostic criteria: active myeloma (requires ≥1 CRAB criterion or biomarkers of malignancy): presence of clonal plasma cells ≥10 % in marrow + detectable M protein (except non-secreting MM) + PLUS at least one CRAB or SLiM criterion: S (Sixty - DFGe <60 mlmin) → non + l (light chain ratio κλ>100 or <0,01) + i (Imaging — ≥1 lésion focale PET-TDM ou IRM) → Ou CRAB : C (Calcium sérique >2.75 mmol/L) + R (creatinine >177 µmol/L or eGFR <40) + A (Hb <100 g/L or 20 g/L below normal) + B (osteolytic bone lesions on imaging) → monoclonal gammas of undetermined significance (MGUS): M protein <30 g/L + marrow plasma cells <10 % + no CRAB → risk of progression to MM: 1 %/year → smoldering myeloma (SMM): M protein ≥30 g/L or plasma cells ≥10 % + no CRAB → risk of progression 10 %/year
- Clinical presentation and initial diagnostic work-up : clinical manifestations of symptomatic MM : bone pain (osteolytic lesions → back + ribs + hips +++) + pathological fractures (vertebrae ++ - risk of spinal cord compression → emergency) + anemia (fatigue + dyspnea) + recurrent bacterial infections + fatigue + hypercalcemia (nausea + vomiting + constipation + confusion + polyuria - «stones + groans + bones + moans») + renal failure + hyperviscosity syndrome (dizziness + visual disturbances + consciousness disorders) → initial diagnostic workup: serum protein electrophoresis (SPE) + immunofixation → M protein detection and typing + immunoglobulin assay + serum free light chains (FLC) assay + κ/λ ratio + CBC + creatinine + calcium + albumin + β2-microglobulin + LDH + liver workup → bone marrow biopsy (BOM) + myelogram: percentage of clonal plasma cells + cytogenetics (FISH) - high-risk lesions: del(17p) + t(4;14) + t(14;16) + gain(1q) → imaging: low-dose whole-body CT (LDWBCT) or 18F-FDG PET-CT → bone lesions + extramedullary lesions → spinal MRI if spinal cord compression suspected.
Treatment and new therapies
| Treatment / appearance | Data, protocols and results | References and recommendations |
|---|---|---|
| Induction therapy and autologous transplantation VRd bortezomib lenalidomide dexamethasone - Dara-VRd - daratumumab - ASCT autologous transplant - G-CSF mobilization - complete response - lenalidomide maintenance - IFM - SWOG - high-risk cytogenetics - transplant eligibility criteria - age performance |
Induction therapy and autologous stem cell transplantation (ASCT): induction therapy - patient eligible for autologous transplantation (≤70 years + good performance status + no major comorbidities): triplet VRd (Bortezomib + Lenalidomide + Dexamethasone) × 4-6 cycles: standard North American therapy → overall response 80-90 % → SWOG S0777 (Durie 2017 - Lancet): VRd greater than Rd → reference + quadruplet Dara-VRd (Daratumumab + VRd): GRIFFIN trial (Voorhees 2020 - Blood) + PERSEUS trial 2023 - NEJM: Dara-VRd vs VRd → superior for strict complete response (sCR) + progression-free survival → new standard in 2024 in many centers → autologous hematopoietic stem cell transplantation (ASCT): mobilization of HSCs with G-CSF + mobilizing chemotherapy (cyclophosphamide + or plerixafor) → conditioning: high-dose melphalan 200 mg/m² (MEL200) → reinfusion of HSC → consolidation of response → improved progression-free survival (PFS) + IFM 2009 trial (Attal 2017 - NEJM): early ASCT vs late ASCT → early ASCT superior for PFS → lenalidomide maintenance after ASCT: MYELOMA XI (Jackson 2019 - Lancet Oncology) + IFM 2005-02: lenalidomide maintenance → 40-50 % reduction in risk of relapse → standard post-ASCT treatment → high cytogenetic risk: del(17p) + t(4;14) → intensified treatment → carfilzomib + or daratumumab → tandem ASCT discussed | Durie 2017 - Lancet (SWOG S0777): VRd + MM → superior Rd → reference + Attal 2017 - NEJM (IFM 2009): Early ASCT → superior PFS → reference + Voorhees 2020 - Blood (GRIFFIN): Dara-VRd → superior sCR + Sonneveld 2023 - NEJM (PERSEUS): Dara-VRd → superior PFS → new standard + Jackson 2019 - Lancet Oncology: lenalidomide maintenance → reference + AHOQ + INESSS Quebec + RAMQ: VRd + daratumumab + lenalidomide maintenance → reimbursed according to INESSS criteria |
| Treatment of ineligible patients and relapses DRd daratumumab lenalidomide dexamethasone - VMP bortezomib melphalan prednisone - MAIA trial - frail patient - pomalidomide - carfilzomib - isatuximab - venetoclax t(11;14) - belantamab mafodotin BCMA - cilta-cel idecabtagene CAR-T - bispecific antibodies - teclistamab - elranatamab - refractory relapse |
MM not eligible for transplantation and relapse treatments: patient not eligible for autologous transplantation (>70 years + comorbidities + frailty): DRd (Daratumumab + Lenalidomide + Dexamethasone): MAIA trial (Facon 2019 - NEJM n=737 new non-transplant-eligible patients): DRd vs Rd → median PFS not reached vs 31 months → 44 % reduction in progression risk → global reference for ineligible patients + VMP (Bortezomib + Melphalan + Prednisone) + or adapted VRd at reduced dose → frailty score (IMWG Frailty Score) to adapt treatment intensity → relapse treatments - successive progressions: relapse 1 → if lenalidomide maintenance → carfilzomib or bortezomib (KRd + or DVd) + or pomalidomide → relapse 2 → daratumumab + pomalidomide + dexamethasone (DPd) → or isatuximab-Pd → relapse 3+ → targeted therapies : venetoclax if t(11;14) (BCL-2 dependent) + belantamab mafodotin (anti-BCMA conjugated to a cytotoxic agent) + bispecific antibodies (FDA + Health Canada 2023-2024 approved) : teclistamab (Tecvayli - anti-BCMA × anti-CD3) + elranatamab (anti-BCMA × anti-CD3) + talquetamab (anti-GPRC5D × anti-CD3) → CAR-T therapies (Chimeric Antigen Receptor T cells) : cilta-cel (Carvykti - anti-BCMA): CARTITUDE-1 - Berdeja 2021 - Lancet: cilta-cel → response rate 97 % + CR 67 % → multiple relapses → idecabtagene vicleucel (ide-cel - bb2121 - anti-BCMA): KarMMa trial → response rate 73 % → supportive treatment: bisphosphonates (monthly IV zoledronate) for all bone lesions → reduction of bone events + prevention of fractures → palliative radiotherapy if bone pain + or verteboplasty | Facon 2019 - NEJM (MAIA trial n=737): DRd + MM not transplant eligible → higher PFS → reference + Berdeja 2021 - Lancet (CARTITUDE-1): cilta-cel → 97 % response + 67 % CR → CAR-T reference + Lonial 2020 - NEJM (KarMMa): ide-cel → 73 % response + Moreau 2019 - NEJM: isatuximab + pomalidomide → relapse + Gupta 2022 - NEJM: teclistamab → 63 % response multiple relapses → Health Canada: daratumumab + carfilzomib + pomalidomide + cilta-cel + ide-cel + teclistamab → approvals → AHOQ + INESSS Québec + RAMQ: DRd + pomalidomide + carfilzomib + bisphosphonates → reimbursed according to INESSS criteria |
| Complications and emergencies Spinal cord compression emergency - spinal MRI - decompressive radiotherapy - corticosteroids dexamethasone - vertebral fracture - vertebroplasty - hypercalcemia rehydration bisphosphonates - renal failure hydration - plasmapheresis - bacterial infections prophylaxis - IVIG - venous thrombosis prophylaxis aspirin lenalidomide |
Multiple myeloma complications and emergencies: spinal cord compression (oncological emergency): back pain + lower limb weakness + sphincter disorders + or paraplegia → emergency spinal MRI → high-dose dexamethasone 40 mg/d IV immediately (reduces peritumoral edema) → urgent decompressive radiotherapy + or decompressive surgery + stabilization → MM-specific treatment → neurological prognosis linked to speed of intervention + hypercalcemia: nausea + vomiting + constipation + confusion + polyuria + lethargy → severe if >3.5 mmol/L → treatment: hydration IV NaCl 0.9 % 2-3 L/d + zoledronate IV 4 mg over 15 min (bisphosphonate) + or denosumab SC if severe IR + or calcitonin + dialysis if refractory + corticosteroids → renal failure: cylinder nephropathy (cast nephropathy) → light chains → tubular obstruction → vigorous IV hydration → reduce M-protein load by anti-myeloma treatment as quickly as possible → avoid NSAIDs + IV iodine → high-dose dexamethasone (rapid antiproteinuric effect) → or bortezomib-based (rapid renal efficacy) → dialysis if severe AKI → recurrent bacterial infections: humoral immunodepression + neutropenia → anti-pneumococcal + anti-grip + anti-Haemophilus vaccination + anti-infective prophylaxis according to diet → IVIG if severe hypogammaglobulinemia + recurrent infections → antithrombotic prophylaxis: lenalidomide → high risk of DVT → aspirin 80-100 mg/d if standard risk → or LMWH if high risk → or oral anticoagulant if VTE ATCD + CMV infection (under bortezomib + corticoids) → acyclovir or valacyclovir prophylaxis. | Dimopoulos 2019 - NEJM: myeloma + renal failure + bortezomib → reference + Raje 2018 - NEJM: denosumab vs zoledronate + myeloma + bone lesions → + Attal 2017 - NEJM + Durie 2017 - Lancet + AHOQ + INESSS Quebec + RAMQ: bisphosphonates + dexamethasone + hydration + IVIG → reimbursed + denosumab → reimbursed depending on criteria + palliative radiotherapy → reimbursed + vertebroplasty → reimbursed |
ℹ️
Multiple myeloma must be suspected in the presence of persistent bone pain + unexplained anemia + renal failure + hypercalcemia + or proteinuria - the workup must include protein electrophoresis + immunofixation + serum free light chains: spinal cord compression is an oncological emergency requiring spinal MRI and immediate high-dose dexamethasone. Median survival now exceeds 8-10 years for patients eligible for autologous transplantation with modern protocols (Dara-VRd + ASCT + lenalidomide maintenance).
Situations requiring urgent oncology care
Patient with myeloma (known or suspected) + severe new back pain + or weakness of lower limbs + or urinary or fecal disorders (retention + incontinence) → spinal cord compression → MRI of spine urgently (within hours) → dexamethasone 40 mg IV immediately → urgent decompressive radiotherapy + or surgery → hematologist + neurosurgery + radiation oncology urgently → every hour of delay irreversibly worsens neurological prognosis.
Patient with myeloma + confusion + drowsiness + nausea + vomiting + polyuria + constipation + or serum calcium >3.0 mmol/L → severe hypercalcemia → emergencies → hydration IV 2-3 L NaCl 0.9 % + zoledronate IV 4 mg over 15 min + dexamethasone + calcitonin if severe → anti-myeloma treatment to be started as soon as possible to reduce tumor burden.
Patient with previously undiagnosed myeloma + anemia (Hb 200 µmol/L) + bone pain + M-protein on PES + or hypercalcemia → new symptomatic myeloma → urgent haematological referral (within 2-7 days) → full workup (FISH + BOM + imaging) + initiation of treatment without delay.
Consult at Clinique Omicron
Les médecins de Clinique Omicron suspecent le myélome multiple devant les signes cliniques évocateurs (douleurs osseuses + anémie + insuffisance rénale + hypercalcémie), prescrivent l'électrophorèse des protéines + immunofixation + chaînes légères libres sériques, orientent vers l'hématologue pour la biopsie et le traitement, gèrent les complications aiguës (hydratation + bisphosphonates + dexaméthasone), assurent la prophylaxie anti-infectieuse et antithrombotique, et participent au suivi multidisciplinaire. Des consultations sont disponibles dans plusieurs points de service au Québec et en télémédecine. Pour prendre rendez-vous, Choose your online service.
The content of this page is provided for information purposes only and does not replace the advice of a physician or hematologist-oncologist. Multiple myeloma is a complex disease requiring specialized multidisciplinary management. Spinal cord compression is an oncological emergency - any sudden back pain with neurological signs requires MRI and immediate management.
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