Residency · Residency · Hematology Thrombosis

Multiple Myeloma

Introduction

Multiple myeloma is a malignant neoplasm characterized by the clonal proliferation of plasma cells in the bone marrow with the production of a monoclonal immunoglobulin (M protein). The incidence is approximately 7 per 100,000 per year, with a median age at diagnosis of 69 years and an approximately 2-fold higher incidence in Black Americans compared to White Americans. Myeloma develops along a well-defined disease continuum from the precursor states of monoclonal gammopathy of undetermined significance (MGUS) and smoldering myeloma to active (symptomatic) myeloma. The treatment paradigm has evolved dramatically, with quadruplet induction therapy, autologous stem cell transplantation, and continuous maintenance now constituting the standard approach, and median overall survival now exceeding 8 to 10 years for standard-risk disease.

Diagnostic Criteria

MGUS (Monoclonal Gammopathy of Undetermined Significance)

MGUS is defined by the presence of a serum M protein below 3 g/dL, bone marrow plasma cells below 10%, and the absence of CRAB criteria or myeloma-defining events. MGUS is remarkably common, present in 3 to 4% of adults over 50 years and approximately 5% of those over 70 years. The risk of progression to myeloma or a related malignancy is approximately 1% per year, and this risk persists indefinitely, making lifelong monitoring necessary. Risk factors for progression include non-IgG isotype, M protein above 1.5 g/dL, and an abnormal serum free light chain ratio.

Smoldering Myeloma (SMM)

Smoldering myeloma occupies an intermediate position on the disease continuum, defined by an M protein of 3 g/dL or greater, or bone marrow plasma cells between 10 and 60%, in the absence of CRAB criteria or myeloma-defining events. The 2/20/20 risk model stratifies progression risk based on three factors: M protein of 2 g/dL or greater, bone marrow plasma cells of 20% or greater, and free light chain ratio of 20 or greater. Patients with 0 risk factors are considered low risk (approximately 5% per year progression), 1 factor confers intermediate risk (approximately 10% per year), and 2 to 3 factors define high risk (approximately 20% per year progression). The standard of care remains observation with close monitoring every 3 to 6 months. Some evidence supports early intervention in high-risk smoldering myeloma, with the ECOG E3A06 trial demonstrating that lenalidomide delayed progression and the QuiRedex trial showing improved overall survival with lenalidomide-dexamethasone, but early treatment has not been universally accepted as standard practice.

Active (Symptomatic) Myeloma

Active myeloma requires clonal bone marrow plasma cells of 10% or greater (or a biopsy-proven plasmacytoma) plus evidence of end-organ damage or biomarkers of near-inevitable progression. The traditional CRAB criteria include hypercalcemia (calcium above 11 mg/dL), renal insufficiency (creatinine above 2 mg/dL or creatinine clearance below 40 mL/min), anemia (hemoglobin below 10 g/dL or 2 g/dL below the patient's normal), and bone lesions (lytic lesions on CT or PET-CT, or one or more lesions on skeletal survey). The 2014 IMWG update introduced additional myeloma-defining events (SLiM-CRAB criteria) that identify patients at such high risk of imminent progression that treatment should be initiated even in the absence of CRAB features: bone marrow plasma cells of 60% or greater, serum free light chain ratio of 100 or greater (with the involved light chain at 100 mg/L or greater), or more than 1 focal lesion of 5 mm or greater on MRI.

Workup at Diagnosis

The diagnostic workup for myeloma includes serum protein electrophoresis with immunofixation to identify and characterize the M protein, serum free light chain assay with kappa/lambda ratio, 24-hour urine protein electrophoresis with immunofixation, complete blood count, comprehensive metabolic panel (with particular attention to creatinine, calcium, and albumin), LDH, and beta-2-microglobulin. Bone marrow biopsy with plasma cell quantification and immunohistochemistry (CD138, kappa/lambda light chain restriction) is essential. Cytogenetic analysis including conventional karyotype and a FISH panel is critical for risk stratification. Skeletal imaging should employ whole-body low-dose CT or PET-CT, which have superior sensitivity compared to the conventional skeletal survey; MRI is indicated for equivocal findings or suspected spinal disease.

Risk Stratification (R-ISS)

Revised International Staging System (R-ISS)

The R-ISS integrates serum markers with cytogenetic and molecular data. R-ISS stage I is defined by beta-2-microglobulin below 3.5 mg/L, albumin of 3.5 g/dL or greater, standard-risk cytogenetics, and normal LDH, with a 5-year overall survival of approximately 82%. R-ISS stage II encompasses patients who do not meet criteria for stage I or III, with a 5-year OS of approximately 62%. R-ISS stage III requires beta-2-microglobulin above 5.5 mg/L combined with high-risk cytogenetics or elevated LDH, with a 5-year OS of approximately 40%.

Cytogenetic Risk Groups

Standard-risk cytogenetics include t(11;14), t(6;14), and hyperdiploidy (trisomies of odd-numbered chromosomes). High-risk cytogenetics include t(4;14), t(14;16), t(14;20), del(17p)/TP53, gain of 1q21, and complex karyotype. Ultra-high-risk or "double-hit" myeloma, defined by biallelic TP53 loss or mutation or the co-occurrence of 2 or more high-risk features, carries a particularly dismal prognosis with a 2-year overall survival of approximately 50%.

<image>A staging and risk stratification diagram for multiple myeloma. Show the disease continuum at the top: MGUS → Smoldering Myeloma → Active Myeloma, with diagnostic criteria for each stage and progression rates between stages. Below, display the R-ISS staging system as a table with three stages, showing the defining criteria (β2-microglobulin, albumin, cytogenetics, LDH) and associated 5-year overall survival for each stage. On the right, show the cytogenetic risk classification with specific FISH abnormalities listed under standard risk (t(11;14), hyperdiploidy), high risk (t(4;14), t(14;16), del(17p), gain(1q)), and ultra-high/double-hit risk. Include the updated R2-ISS if space permits. At the bottom, show the CRAB criteria and SLiM-CRAB myeloma-defining events as a visual checklist. Medical education poster format with color-coded risk categories.</image>

Treatment - Transplant-Eligible Patients

Induction (Quadruplet Preferred)

VRd (bortezomib, lenalidomide, and dexamethasone) has served as the standard triplet induction regimen for myeloma. However, the treatment paradigm has shifted to quadruplet induction with the addition of an anti-CD38 monoclonal antibody. The PERSEUS trial evaluated daratumumab combined with VRd (Dara-VRd) versus VRd alone in transplant-eligible patients and demonstrated a stringent complete response rate of 65% versus 47% and significantly improved PFS (hazard ratio 0.42). Dara-VRd is now considered the standard-of-care quadruplet induction for transplant-eligible patients. Daratumumab, an anti-CD38 monoclonal antibody, is preferably administered as the subcutaneous formulation (Darzalex Faspro) for improved patient convenience. Isatuximab combined with VRd (Isa-VRd), evaluated in the GMMG-HD7 trial, offers a similar benefit as an alternative anti-CD38-containing quadruplet. Induction typically consists of 4 to 6 cycles before proceeding to stem cell collection and autologous transplantation.

Autologous HSCT

Autologous HSCT following high-dose melphalan conditioning at 200 mg/m2 remains a central component of myeloma therapy. The IFM 2009 trial compared early autologous HSCT to delayed transplantation (at the time of relapse) and demonstrated that early ASCT improved PFS (50 versus 36 months) with a better quality of response and a longer treatment-free interval, though no overall survival difference was detected. The DETERMINATION trial produced similar findings, with PFS of 67.5 versus 46.2 months favoring early ASCT but no OS difference at 6 years. Early ASCT after induction remains the standard of care for fit patients up to age 70 to 75. Tandem ASCT was evaluated in the StaMIna trial, which showed no benefit of tandem over single ASCT when combined with lenalidomide maintenance.

Maintenance

Lenalidomide maintenance following ASCT is the established standard of care based on the CALGB 100104 and IFM 2005-02 trials, both of which demonstrated PFS and overall survival benefits with continuous post-transplant lenalidomide. The typical dose is 10 to 15 mg daily administered continuously until disease progression. For standard-risk disease, lenalidomide monotherapy maintenance is standard; for high-risk disease, the addition of bortezomib (VR maintenance) should be considered. The CASSIOPEIA trial (part 2) demonstrated a PFS benefit for daratumumab maintenance compared to observation after Dara-VTd induction and ASCT. The PERSEUS trial established daratumumab plus lenalidomide (Dara-R) maintenance as superior to lenalidomide alone, representing a new standard.

MRD Assessment

MRD negativity at a sensitivity threshold of 10^-5, assessed by next-generation flow cytometry or next-generation sequencing, is the strongest predictor of long-term PFS and overall survival in myeloma. MRD-negative patients have an approximately 75% lower risk of disease progression. MRD assessment is increasingly used as a surrogate endpoint in clinical trials but is not yet utilized to guide treatment discontinuation decisions outside of clinical trial protocols.

Treatment - Transplant-Ineligible Patients

Standard Regimens

Daratumumab plus lenalidomide and dexamethasone (Dara-Rd) is the standard first-line regimen for transplant-ineligible patients based on the MAIA trial, which demonstrated a median PFS of 61.9 months compared to 34.4 months with lenalidomide-dexamethasone alone, along with an overall survival benefit. Treatment is continued until disease progression. VRd in a modified schedule is an alternative, particularly for patients with contraindications to lenalidomide. Daratumumab plus bortezomib, melphalan, and prednisone (Dara-VMP), evaluated in the ALCYONE trial, demonstrated an OS benefit and is an option for patients unable to receive lenalidomide.

Relapsed/Refractory Myeloma

Key Regimens

The relapsed myeloma treatment landscape has expanded substantially. Carfilzomib-based regimens include carfilzomib-dexamethasone (Kd, ENDEAVOR trial) and carfilzomib-lenalidomide-dexamethasone (KRd, ASPIRE trial: PFS 26.3 versus 17.6 months compared to Rd). Pomalidomide-dexamethasone serves as a backbone that can be combined with proteasome inhibitors or anti-CD38 antibodies. Elotuzumab, an anti-SLAMF7 antibody, combined with Rd showed a modest PFS benefit in the ELOQUENT-2 trial. Selinexor, an XPO1 inhibitor evaluated in the STORM trial, provides an option for penta-refractory myeloma.

Belantamab mafodotin, an anti-BCMA antibody-drug conjugate, demonstrated impressive efficacy in the DREAMM-7 trial (belantamab plus VD versus DVd: PFS 37 versus 18 months) but requires ophthalmologic monitoring for keratopathy (corneal epithelial changes) with dose modifications as needed.

Teclistamab, a BCMA by CD3 bispecific antibody, achieved an ORR of 63% and CR rate of 39% in heavily pretreated patients in the MajesTEC-1 trial and is FDA-approved. CRS occurs in 72% of patients (mostly grade 1-2), ICANS in 3%, and infections in 76% including opportunistic infections. Step-up dosing mitigates CRS risk. Hypogammaglobulinemia is a significant concern, and IVIG replacement should be initiated when IgG falls below 400 mg/dL with recurrent infections. Elranatamab, another BCMA by CD3 bispecific, demonstrated an ORR of 61% in the MagnetisMM-3 trial and is FDA-approved. Talquetamab, a GPRC5D by CD3 bispecific, achieved an ORR of 74% in the RedirecTT-1 trial, with unique toxicities including skin changes (rash, nail dystrophy) and dysgeusia reflecting GPRC5D expression in skin and taste buds.

CAR T-Cell Therapy

Anti-BCMA CAR T-cell therapy has established a transformative role in relapsed myeloma. Idecabtagene vicleucel (Abecma/ide-cel), evaluated in the KarMMa-3 trial, demonstrated superior PFS compared to standard regimens in patients who had received 2 to 4 prior lines (13.3 versus 4.4 months, hazard ratio 0.49). Ciltacabtagene autoleucel (Carvykti/cilta-cel) produced remarkable results in the CARTITUDE-1 trial (ORR 98%, stringent CR 83% in heavily pretreated patients) and the practice-changing CARTITUDE-4 trial (cilta-cel versus standard regimens in patients with 1 to 3 prior lines: PFS markedly superior, hazard ratio 0.26). Based on CARTITUDE-4 and KarMMa-3, CAR T-cell therapy is moving to earlier lines in the treatment algorithm.

Supportive Care

Bone disease management requires bisphosphonate therapy with zoledronic acid at 4 mg intravenously every 3 to 4 weeks or denosumab at 120 mg subcutaneously monthly, administered for a minimum of 2 years. Dental screening for osteonecrosis of the jaw risk is essential before initiating antiresorptive therapy. Infection prophylaxis includes acyclovir or valacyclovir for varicella-zoster virus prevention in all patients receiving proteasome inhibitors, Pneumocystis jirovecii prophylaxis, and IVIG replacement for hypogammaglobulinemia with recurrent infections. Bortezomib-based regimens are preferred for patients with renal impairment because no dose adjustment is required. VTE prophylaxis is mandatory for patients receiving immunomodulatory agents: aspirin for standard-risk patients and low-molecular-weight heparin or a DOAC for those with high VTE risk.

<image>A comprehensive treatment landscape diagram for multiple myeloma organized by treatment setting. Show three columns: Transplant-Eligible, Transplant-Ineligible, and Relapsed/Refractory. For Transplant-Eligible: Dara-VRd induction x 4-6 cycles → ASCT (melphalan 200) → Dara-R maintenance (continuous). For Transplant-Ineligible: Dara-Rd (continuous until progression). For Relapsed/Refractory: show a hierarchical list of available agents organized by class - proteasome inhibitors (bortezomib, carfilzomib, ixazomib), IMiDs (lenalidomide, pomalidomide), anti-CD38 (daratumumab, isatuximab), BCMA-targeted (belantamab mafodotin, teclistamab, elranatamab, ide-cel, cilta-cel), anti-GPRC5D (talquetamab), and XPO1 inhibitor (selinexor). Include response rates for key agents. At the bottom, show the MRD assessment concept with the 10^-5 sensitivity threshold and its prognostic significance. Modern medical education infographic style.</image>

Key Clinical Pearls

• Quadruplet induction with Dara-VRd is now standard for transplant-eligible myeloma based on PERSEUS; the addition of daratumumab deepens response and improves PFS
• Dara-Rd (MAIA regimen) is standard first-line for transplant-ineligible patients; continuous treatment until progression
• BCMA-targeted therapies (bispecifics and CAR T) have transformed relapsed myeloma; CAR T (cilta-cel) is moving to earlier lines based on CARTITUDE-4
• MRD negativity at 10^-5 is the strongest predictor of long-term outcome and is being explored as a potential endpoint for treatment discontinuation
• Del(17p) and biallelic TP53 loss define ultra-high-risk disease requiring intensified approaches and clinical trial enrollment
• Teclistamab/elranatamab (BCMA bispecifics) cause significant infections and hypogammaglobulinemia; IVIG replacement and antimicrobial prophylaxis are essential components of care

References

1. Rajkumar SV. Multiple myeloma: 2024 update on diagnosis, risk-stratification, and management. Am J Hematol. 2024;99(6):1102-1122.
2. Sonneveld P, et al. Daratumumab, bortezomib, lenalidomide, and dexamethasone for transplant-eligible newly diagnosed myeloma (PERSEUS). N Engl J Med. 2024;390(4):301-313.
3. Facon T, et al. Daratumumab plus lenalidomide and dexamethasone for untreated myeloma (MAIA). N Engl J Med. 2019;380(22):2104-2115.
4. San-Miguel J, et al. Cilta-cel or standard care in lenalidomide-refractory myeloma (CARTITUDE-4). N Engl J Med. 2023;389(4):335-347.
5. Moreau P, et al. Teclistamab in relapsed or refractory multiple myeloma (MajesTEC-1). N Engl J Med. 2022;387(6):495-505.

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