Clinical Presentation and Diagnosis in Multiple Myeloma

By Manni Mohyuddin, MD, Assistant Professor of Medicine at Huntsman Cancer Institute

Diagnostic Tests

There are numerous guidelines available for clinicians on the diagnosis and treatment of multiple myeloma (MM). Major societies that have released guidelines include International Myeloma Working Group¹, the National Comprehensive Cancer Network (NCCN)², and the European-Hematology-Association- European Society of Medical Oncology (EHA-ESMO)³.

Between these guidelines, there is considerable overlap in the diagnostic tests recommended.

The NCCN guidelines recommend the following tests for newly diagnosed MM⁴:

Complete blood count with differential, platelet count, peripheral blood smear
Serum blood urea nitrogen, creatinine, electrolytes, albumin, calcium, uric acid, lactate dehydrogenase, beta-2 microglobulin
Quantitative measurement of serum immunoglobulin, serum protein electrophoresis
24-hour urine total protein measurement, urine protein electrophoresis, urine immunofixation assay
Serum free light chain assay measurement
Imaging with either a PET/CT or low dose whole body CT Scan
Unilateral bone marrow aspirate and biopsy
Fluorescence in-situ hybridization panel on bone marrow, looking at the following abnormalities: del 13, del17p13, translocation (4;14), translocation (11;14), translocation (14;16), translocation (14;20) 1q21 gain/amplification, 1p deletion.

The European-Hematology-Association/European Society of Medical Oncology guidelines recommend a similar assortment of tests at diagnosis, although they also consider next generation sequencing or next generation flow (measurable residual disease assessment) to detect clonal plasma cells mandatory at the time of diagnosis³.

The International Myeloma Working Group guidelines also recommend a similar workup at the time of diagnosis.

Diagnostic Criteria

The diagnosis for MM is standardized based on criteria from the International Myeloma Working Group⁵.

Current diagnostic criteria for MM are as follows:

Presence of clonal bone marrow plasma cells ≥10% of the overall cellularity or bony or extramedullary plasmacytoma which is confirmed by a biopsy
One or more MM defining events.

MM-defining events include the traditional CRAB (hypercalcemia, renal failure, anemia, bone lesions) as well as the following features:

Hypercalcemia: Serum calcium level > 1 mg/dL greater than the upper limit of normal or > 11 mg/dL
Abnormal kidney function: Serum creatinine > 2 mg/dL or creatinine clearance < 40 mL/min
Anemia: Hemoglobin < 10 g/dL, or > 2 g/dL below lower limit of normal
Bone lesions: One or more osteolytic lesions seen on skeletal radiography, CT, or PET-CT
Clonal bone marrow plasma cells ≥60%
Involved/uninvolved serum free light chain ratio ≥100 (involved kappa) or < 0.01 (involved lambda)
One or more focal ≥5 mm lesions on MRI scans

As such, the aforementioned workup, including serum analysis, urine testing, a bone marrow biopsy, and advanced imaging (with either PET, low-dose whole body CT, or dedicated MRI scans), is necessary to fully establish the diagnosis of MM.

Staging

MM is a heterogenous disease, with tremendous variability in outcomes observed based on many known risk factors. The original Salmon-Durie staging system for MM, which is no longer in use, involved measurement of hemoglobin, calcium, bone damage and the amount of monoclonal protein⁶. As further information was gained on prognostic factors for the disease beyond measures of tumor burden, the International Staging System was formed, which has now been superseded by the Revised International Staging System⁷. The Revised International Staging System included serum albumin and beta2 microglobulin measurements from the original International Staging System measurements, but also incorporated florescence in situ hybridization (FISH) findings of high-risk cytogenetics and lactate dehydrogenase measurements.

The Revised International Staging System is listed below.

Stage I is as follows:

Beta-2 microglobulin ≤3.5 g/dL and albumin ≥3.5 g/dL
Standard risk cytogenetic/FISH findings.
Normal lactate dehydrogenase

Stage II comprises patients who do not meet criteria for stage I or stage III

Stage III consists of the following:

Beta-2 microglobulin of 5.5 g/dL or more, and either
High risk cytogenetic/FISH findings defined as presence of del(17p) and/or translocation t(4;14) and/or translocation t(14;16) or high lactate dehydrogenase

It is important to note that the R-ISS staging system does not incorporate all aspects of risk in MM prognostication. As an example, abnormalities of Gain 1q are increasingly recognized as a risk factor for poorer outcomes, but are not considered as high-risk cytogenetics within this system. Another example is the presence of circulating plasma cells at diagnosis, which is also an independent contributor to poor risk outcomes⁸.

Treatment Guidelines

NCCN Guidelines

The NCCN guidelines treatment recommendations are categorized based on whether patients are transplant eligible.

Transplant eligibility involves a thorough assessment based on many factors beyond just numerical age. In general, transplant centers in the United States routinely consider transplants for eligible patients well into their 70s.

The NCCN guidelines list the following regimens for transplant eligible patients:

Bortezomib/lenalidomide/dexamethasone (VRD) (category 1)

Other preferred regimens are as follows:

Carfilzomib/lenalidomide/dexamethasone
Ixazomib/lenalidomide/dexamethasone
Daratumumab/bortezomib/lenalidomide/dexamethasone.

NCCN guidelines also mention bortezomib/cyclophosphamide/dexamethasone, which is useful in patients with renal failure attributable to MM. Other regimens include daratumumab-based quadruplets, such as daratumumab/carfilzomib/lenalidomide/dexamethasone for very aggressive disease as well as daratumumab/ bortezomib/ thalidomide/dexamethasone.

For eligible patients, the NCCN guidelines recommend consolidation with a high-dose chemotherapy followed by single autologous stem cell transplant as the preferred approach in transplant-eligible patients.

Following autologous transplant, the preferred maintenance regimen with Category 1 evidence is lenalidomide. Ixazomib and bortezomib can be considered in other circumstances, and dual maintenance with both a proteasome inhibitor and lenalidomide is recommended for patients with high-risk disease.

For patients who are not transplant eligible, the NCCN guidelines recommend the following regimen as a Category 1 preferred regimen:

Daratumumab/lenalidomide/dexamethasone
Bortezomib/lenalidomide/dexamethasone

Other recommended regimens include:

Carfilzomib/lenalidomide/dexamethasone, daratumumab/bortezomib/melphalan/prednisone (which is a Category 1 regimen), ixazomib/lenalidomide/dexamethasone and daratumumab/cyclophosphamide/bortezomib/dexamethasone.

Regimens useful in certain situations include lenalidomide/dexamethasone (another regimen with Category 1 regimen) and low-dose bortezomib/lenalidomide/dexamethasone (VRD-lite). The maintenance therapy recommended in this setting is lenalidomide (Category 1 evidence). Dual maintenance (bortezomib/lenalidomide) is recommended for higher-risk patients.

For relapsed/refractory disease, the NCCN guidelines categorize regimens based on early relapse (patients treated with 1-3 prior regimens) or late relapse (those who have had greater than 3 prior relapses).

For patients with 1-3 prior regimens, a variety of regimens are recommended, with the following regimens having Category 1 evidence to guide them:

Carfilzomib/lenalidomide/dexamethasone
Daratumumab/bortezomib/dexamethasone
Daratumumab/carfilzomib/dexamethasone
Daratumumab/lenalidomide/dexamethasone
Ixazomib/lenalidomide/dexamethasone
Isatuximab/carfilzomib/dexamethasone

Important considerations mentioned by these guidelines are the following:

Patients who have progressed on lenalidomide should be placed on a lenalidomide-free triplet
Patients who have not previously received an autologous stem cell transplant should be considered for it, if they are appropriate candidates

For patients who have had two prior lines of therapy including a proteasome inhibitor and an immunomodulatory drug (IMiD), the following are listed by the NCCN as having Category 1 evidence:

Pomalidomide/bortezomib/dexamethasone
Isatuximab/pomalidomide/dexamethasone
Daratumumab/pomalidomide/dexamethasone

Various other regimens are recommended in the NCCN guidelines. Among these are regimens that previously utilized cytotoxic chemotherapy, such as bortezomib/liposomal doxorubicin/dexamethasone, or other regimens which have Category 1 evidence but their efficacy relative to other more commonly used regimens is in question such as selinexor/bortezomib/dexamethasone, or elotozumab/lenalidomide/dexamethasone.

Combinations listed as being useful in certain circumstances by the NCCN guidelines include venetoclax/dexamethasone for patients with the 11:14 translocation, bendamustine. Multi-agent chemotherapy combinations, such as dexamethasone/cyclophosphamide/etoposide/cisplatin or dexamethasone/thalidomide/cisplatin/doxorubicin/cyclophosphamide/eteposide, may be considered for patients with aggressive disease.

For patients who have had more than three prior lines of therapy, the following regimens are listed in the NCCN guidelines:

Belantamab
Idecabtagene vicleucel
Selinexor/dexamethasone

EHA-ESMO Guidelines

European Hematology Association and European Society for Medical Oncology (EHA-ESMO) guidelines have some similarities to the NCCN guidelines.

Like the NCCN guidelines, the EHA-ESMO guidelines recommend that autologous transplant be considered for fit, eligible patients. However, they mention that for patients less than 70 years of age without comorbidities, autologous stem cell transplant is the recommended treatment. The NCCN guidelines do not specify an age cut-off.

For induction therapy prior to ASCT, daratumumab/bortezomib/thalidomide/dexamethasone is recommended as the new standard of care. VRD is also considered as an alternate standard of care option. If these therapies are not available, triplets such as bortezomib/thalidomide/dexamethasone and bortezomib/cyclophosphamide/dexamethasone can be considered.

The EHA-ESMO guidelines recommend consolidation following ASCT. Although it is not universally considered as standard due to conflicting data, 2 cycles of bortezomib/lenalidomide/dexamethasone consolidation may be considered in patients who received induction bortezomib/cyclophosphamide/dexamethasone. They also recommend consideration of a tandem ASCT for patients with genetically defined high-risk disease.

As far as maintenance is concerned, the EHA-ESMO guidelines recommend lenalidomide for all patients. Bortezomib may be considered for high-risk disease. The guidelines state that although ixazomib maintenance offers PFS benefit over placebo, it has not yet been approved from a regulatory standpoint.

For patients ineligible for ASCT, the EHA-ESMO guidelines have the following treatment options as the recommended options:

Daratumumab/lenalidomide/dexamethasone
Daratumumab/bortezomib/melphalan/prednisone
Bortezomib/lenalidomide/dexamethasone

If any of the aforementioned options are not available or suitable for use, lenalidomide/dexamethasone and bortezomib/melphalan/prednisone may be considered.

For second-line treatment of MM, the EHA-ESMO guidelines categorize recommendations based on which first-line treatment patients received, as well as whether they are sensitive or refractory to lenalidomide. This allows for customization of treatment options based on a patient’s unique treatment history and sensitivity to drugs. A wide number of triplet options, as well as some doublets (such as carfilzomib/dexamethasone), are listed. As an example, pomalidomide/bortezomib/dexamethasone, daratumumab/carfilzomib/dexamethasone, and daratumumab/bortezomib dexamethasone, isatuximab/carfilzomib/dexamethasone are recommended therapies for patients who were previously exposed or are refractory to lenalidomide whereas daratumumab/carfilzomib/dexamethasone or isatuximab/carfilzomib/dexamethasone can also be given in patients who are refractory to bortezomib.

The EHA-ESMO guidelines also suggest that second-line ASCT be considered for patients who relapse after primary therapy that included an ASCT followed by lenalidomide maintenance and had an initial remission duration of 36 months or greater.

The guidelines also recommend consideration of venetoclax/bortezomib/dexamethasone for patients with t(11;14) MM in certain circumstances.

The EHA-ESMO guideline recommendations for third-line and subsequent therapy of MM include numerous options based on what drug/drug classes patients are refractory to. For triple-refractory patients, selinexor/dexamethasone or belantamab mafodotin monotherapy is recommended.

The EHA-ESMO guidelines also briefly address primary plasma cell leukemia, an aggressive variant of MM, the definition of which has changed in early 2021 to ≥5% circulating plasma cells in the bloodstream.⁹ Although no specific single treatment regimen is recommended, treatment is recommended to start immediately and should include bortezomib and/or lenalidomide based multi-phase approaches in combination with chemotherapy agents, with consideration of an allogenic transplant on a case-by-case basis.

Management of Complications

Multiple Myeloma–Related Bone Disease

The International Myeloma Working Group (IMWG) has released updated practice guidelines for the management of bone disease related to MM.¹⁰ The recommendations are summarized as follows:

Zolendronic acid is the preferred agent for patients, regardless of whether bone disease is present or not at the time of diagnosis.
Zolendronic acid is recommended monthly for at least twelve months, after which if patients have achieved at least a very good partial response, the physician can decrease the dosing frequency to either every 3 months, every 6 months, or even discontinued depending on a patient’s unique circumstances.
If a very good partial response is not achieved, zolendronic acid should be continued monthly until a very good partial response is achieved.
In patients with renal failure, denosumab can be considered. Denosumab use is only in the setting of MM bone disease, as opposed to zolendronic acid which has a recommendation for use regardless of presence of MM bone disease. Denosumab if given, has to be given monthly as there is a risk for rebound bone loss if discontinued. If discontinued, a dose of zolendronic acid should be given six months after last dose of denosumab to prevent bone loss.

The NCCN guidelines recommend either zolendronic acid or bisphosphonate for management of MM related bone disease. The NCCN guidelines state that the frequency (every month or every three months) should be dependent on the patient’s unique circumstances and response. Continuing beyond 2 years should be at the discretion of the individual physician.

Both the NCCN and the International Myeloma Working Group guidelines recommend a multi-disciplinary approach to management of bone complications, with the use of kyphoplasty for painful vertebral compression fractures, radiotherapy for uncontrolled pain, pathological fractures or impending compression, and surgery for prevention/restoration of long-bone fractures, vertebral instability, and spinal cord compression.

Vaccinations in Myeloma

A consensus statement from the European Myeloma Network provides clear recommendations for vaccinations in patients with MM.¹¹

The following vaccinations are clearly recommended for all patients:

Pneumococci – PCV13, PPV23, > 2 months, or 6–12 months, after PCV13
Haemophilus influenzae
Influenza
Herpes Zoster

For patients traveling to areas of high endemicity, Hepatitis A and Hepatitis B vaccinations are recommended. For patients on hemodialysis, or risk of behavioral/occupational exposure, Hepatitis B is recommended.

Patients with asplenia, complement deficiency, or recurrent episodes of bacterial infection are recommended to undertake the meningococci vaccine.

Patients who have not received the primary vaccination for diphtheria/tetanus/acellular pertussis are recommended to do so.

Infection Prevention

The EHA-ESMO guidelines recommend addition of prophylactic levofloxacin to MM for treatment during the first 12 weeks of therapy, especially in patients receiving lenalidomide or pomalidomide, or in patients who at high risk of infections. They also recommend acyclovir or valacyclovir for Herpes zoster virus prophylaxis for patients receiving proteasome inhibitor (PI)- based and daratumumab-based therapies. Intravenous immunoglobulin G (IgG) prophylaxis is not universally recommended but it can be used in patients with low IgG levels (less than 400-500 mg) who have had at least two infection related hospitalizations in the past year.

The NCCN guidelines offer similar recommendations regarding IVIG usage and anti-viral prophylaxis but recommend “consideration” of antibacterial prophylaxis with levofloxacin as opposed to the firmer recommendation by the EHA-ESMO guidelines.

Anemia

Both the NCCN and EHA-ESMO guidelines recommend consideration of erythropoietin in certain circumstances for anemia, but only after evaluation of other causes of anemia, and with close observation to prevent thromboembolic complications.

Renal Failure

Both the NCCN and EHA-ESMO guidelines recommend bortezomib based regimens as the mainstay of management for renal failure. Appropriate supportive care should include but not be limited to fluid status optimization, electrolyte observation, use of dialysis as indicated, and plasma exchange/high-cut off dialysis for mechanical removal of serum free light chains.

References

Dimopoulos MA, Sonneveld P, Leung N, Merlini G, Ludwig H, Kastritis E, et al. International Myeloma Working Group Recommendations for the Diagnosis and Management of Myeloma-Related Renal Impairment. J Clin Oncol 2016 May 1; 34(13): 1544-1557.
NCCN. NCCN Clinical Practice Guidelines in Oncology Multiple Myeloma 2021. 2021 [cited 2021 11/27/2021]; Available from: https://www.nccn.org/professionals/physician_gls/pdf/myeloma.pdf
Dimopoulos MA, Moreau P, Terpos E, Mateos MV, Zweegman S, Cook G, et al. Multiple myeloma: EHA-ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up(dagger). Ann Oncol 2021 Mar; 32(3): 309-322.
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Palumbo A, Avet-Loiseau H, Oliva S, Lokhorst HM, Goldschmidt H, Rosinol L, et al. Revised International Staging System for Multiple Myeloma: A Report From International Myeloma Working Group. J Clin Oncol 2015 Sep 10; 33(26): 2863-2869.
Derman BA, Kosuri S, Jakubowiak A. Knowing the unknowns in high risk multiple myeloma. Blood Rev 2021 Aug 28: 100887.
de Larrea CF, Kyle R, Rosiñol L, et al. Primary plasma cell leukemia: consensus definition by the International Myeloma Working Group according to peripheral blood plasma cell percentage. Blood Cancer J. 2021;11(12):192.
Terpos E, Zamagni E, Lentzsch S, Drake MT, Garcia-Sanz R, Abildgaard N, et al. Treatment of multiple myeloma-related bone disease: recommendations from the Bone Working Group of the International Myeloma Working Group. Lancet Oncol 2021 Mar; 22(3): e119-e130.
Ludwig H, Boccadoro M, Moreau P, San-Miguel J, Cavo M, Pawlyn C, et al. Recommendations for vaccination in multiple myeloma: a consensus of the European Myeloma Network. Leukemia 2021 Jan; 35(1): 31-44.