Multiple myeloma C90.0

Multiple myeloma (MM) is a malignant tumor disease that belongs to the B-cell non-Hodgkin's lymphomas according to the current WHO criteria. MM is characterized by a diffuse or multilocular, monoclonal plasma cell proliferation (myeloma cells) in the bone marrow. It is the most common tumor of bone marrow and bone.

The "plasmocytoma" is characterized by a solitary plasma cell proliferation at one localization and is considered a special form of multiple myeloma in the true sense. In this respect, the term "plasmocytoma" should only be used for a solitary plasmocytoma.

Plasma cell leukaemia is characterised by a leukaemic course.

About 85 g of monoclonal light chains are produced per day in patients with multiple myeloma, whereas healthy individuals, for example, produce only about 0.9 g of polyclonal light chains per day. Several myeloma types can be defined by characterising the paraprotein type:

• MM type IgG: 50% of all multiple myelomas
• MM type IgA: 25% of all multiple myeloma
• MM type Bence-Jones myeloma (light chains): 20% of all multiple myelomas
• Rare: MM type IgD (secretory myeloma): <1% of all multiple myeloma

An abnormal production of monoclonal IgM antibodies does not indicate multiple myeloma, but rather Waldenstrom's disease!

Staging according to Durie and Salmon. This classification is internationally accepted. By determining various clinical parameters, conclusions can be drawn about the tumour mass. Depending on the tumour cell mass and various disease factors, myeloma is divided into 3 stages:

• Stage I
  • Haemoglobin normal: >10 g/dl <8.5 g/dl
  • Serum Ca2+normal (<2.65 mmol/l)
  • X-ray: skeleton normal or maximum 1 solitary osteolytic focus
  • Low concentration of monoclonal immunoglobulins (IgG<5g/dl; IgA<3g/dl; Bence-Jones protein in urine: <4g/ low concentration
• Stage II: Neither stage I nor stage III
• Stage III
  • Haemoglobin <8.5 g/dl
  • Serum Ca2+ increased (>2.65 mmol/l)
  • X-ray skeleton: numerous advanced osteolyses
  • High concentration of monoclonal immunoglobulins (IgG>7g/dl; IgA>5g/dl; Bence-Jones
  • Protein in urine: >12g/24h
• Prognostically, kidney function is also of particular relevance. The classification is therefore additionally divided into:
  • A: Creatinine <2 mg/dl;
  • B: Creatinine ≥2 mg/dl

The widespread classification of salmon and durie has now been replaced by the International Staging System (ISS). This system is based on different staging systems. serum values. The parameters albumin and ß2-microglobulin reflect the tumor burden and nutritional status as well as the presence of a deterioration of renal function. The Revised ISS (R-ISS) was published in 2015.

Staging according to the International Myeloma Working Group (International Staging System = ISS)

• Stage I: β2-Microglobulin <3,5 mg/l and albumin ≥3,5 g/dl
• Stage II: β2 microglobulin 3.5-5.5 mg/l or β2 microglobulin <3.5 mg/l and albumin <3.5 g/dl
• Stage III: β2-Microglobulin >5.5 mg/l

Median survival: stage I: >5 years, stage II: 3-4 years, stage III: 2-3 years

The ISS classification is suitable for estimating the prognosis and is independent of the subjective assessment of the radiological findings.

Revised International Staging System (R- ISS; Palumbo A 2015)

• Stage I: ISS stage I and no risk iFISH- cytogenetics and normal LDH
• Stage II: Neither ISS stage I nor III
• Stage III: ISS stage III and either high risk iFISH cytogenetics or high LDH

Multiple myeloma is rare, but is one of the most common tumors of bone and bone marrow. The worldwide incidence is 1-5/100,000 per year. In Europe it is about 5/100,000 (Swan D et al. 2019); higher incidences are observed in Africans(Acquah ME et al. ); m>w.

Unknown; in contrast to the other non-Hodgkin's lymphomas , no association with infectious diseases (e.g. viral infections) has yet been established. After malignant transformation of a plasma cell and its clonal proliferation in the bone marrow, the pathological cells produce immunoglobulins with a uniform structure (monoclonal immunoglobulins = paraproteins of the classes IgG, IgA or IgD) or only light chains (kappa or lambda). Various environmental factors such as radioactive radiation or pesticides are discussed as possible contributors to multiple myeloma. Familial clusters are known, indicating a hereditary component. Risk factors are ionizing radiation, pesticides.

Genetic and genomic aberrations in the following genes have been reported: KRAS, NRAS, TP53, FAM46C, BRAF, DIS3, ATM, and CCND1 (Weaver CJ et al 2017). Known and prognostically significant are chromosomal aberrations such as translocations t (14;16), t (4;14) or t (14;20), as well as deletions 1p, 17p or 13q (detection is associated with a significantly worse prognosis)

Frequency peaks between the ages of 50 and 70; in a Ghanaian population the average age of onset of the disease was 58 years (Acquah ME et al. 2019)

Initial symptoms: 20% of patients are asymptomatic at diagnosis. For example, MM is often conspicuous as an incidental finding on serum protein electrophoresis. Skin changes can also be early diagnostic symptoms.

Initially, non-specific disorders of the general condition such as fatigue, night sweats, weight loss (50%) and elevated temperatures predominate. Many (>90%) patients complain of bone pain, especially in the back, ribs and long bones. It usually takes several months from the first symptoms of the disease to diagnosis.

Specific symptoms: The specific symptoms of MM are derived from the pattern of myeloma (Jagosky MH et al. 2020):

• Hematology: Suppression of hematopoiesis, anemia (65%), leukopenia with tendency to infection, thrombocytopenia with petechial bleeding tendency.
• Immune system: antibody deficiency syndrome (the monoclonal antibodies produced are not functional (clinical: atypical pyoderma, pyoderma gangrenosum, chronic candida diseases of the skin and mucous membranes)
• Skeleton: osteolysis with bone pain (76%); a long asymptomatic course is also possible. If the proliferating plasma cells displace the bone marrow, anemia, a tendency to infection and bleeding may occur.
• Skin: The dermatological symptoms are defined on the one hand by the monoclonal gammopathy (hyperviscosity syndrome with Raynaud's syndrome, urticarial vasculitis, occluding vasculopathy of small to medium-sized vessels). On the other hand, the skin is involved due to secondary consequences such as AL amyloidosis and antibody deficiency syndrome (infections and atypical skin infections).
• Specific infiltrates of the skin: In 5-10% of cases, specific infiltrates develop in the skin and subcutis (see also plasmocytoma of the skin; see also leukemia cutis). Furthermore, secondary disease symptoms develop on the skin, which are caused by paraproteinemia-induced organ changes (e.g. paraproteinemic kidney changes).
• Kidney (33%): Foaming urine as a clinical correlate of Bence-Jones proteinuria. A late complication is the finding of myeloma kidney (cast nephropathy), a light chain disease of the kidney.
• Nephrocalcinosis with hypercalcemia (>2.75mmol/l).
• Vessels: If immunoglobulin polymers form at low temperatures, cryoglobulinemia occurs with corresponding clinical symptoms (see below paraproteinemia and skin changes).
• Coagulation: Monoclonal immunoglobulins can bind coagulation factors so that bleeding (usually into the skin) can occur (see also purpura, dysproteinemia)
• Consecutive development of AL amyloidosis with all the consequences of amyloid deposition in the various organs (heart, kidney, blood vessels). organs (heart, kidney, liver, spleen, skin).
• Other:
  • Polyneuropathy due to paraproteins
  • Osteolysis: bone pain and spontaneous fractures; hypercalcemia
  • Although multiple myeloma is a B-cell non-Hodgkin's lymphoma, enlargement of the lymph nodes is rather atypical!

X-ray skull: moth-eaten osteolysis (Note: myeloma cells have no osteolytic activity of their own; however, they stimulate the osteoclasts via various cytokines (RANKL = receptor activator of NF-κB ligand). Cytokines (RANKL = receptor activator of NF-κB ligand, MIP-1= macrophage inflammatory protein = CCL3) stimulate osteoclast activity and at the same time inhibit osteoblast activity.

Low-dose CT is recommended as the most sensitive imaging method.

Skeletal scintigraphy is less suitable, as myeloma foci often do not store.

MRI and PET are suitable for the detection of extramedullary foci.

The following parameters are only diagnostically relevant in the case of systemic involvement (multiple myeloma):

Inflammatory parameters: ESR; extremely accelerated ESR, 1-h value >100 mm n. W., so-called fall reduction (often the first parameter of the disease; however, in the Bence-Jones type of MM, BSG and immunoelectrophoresis are hardly changed!)

Detection of paraproteins; detection of cryoglobulins; high β2-microglobulin (the detection has a negative prognostic significance).

Blood count: anemia, leukopenia, in the course pancytopenia

Eletrolytes: serum calcium values ↑

Urine: proteinuria with L-chain excretion = (Bence-Jones proteins; Bence-Jones proteins are found in about 60 % of all multiple myelomas from IgG or IgA light chain myeloma). Possibly also cryoglobulins.

Immunofixation electrophoresis: monoclonal gammopathy with M-gradients (antibodies without defense function - functional AK deficiency). Quantification of immunoglobulins as a follow-up is useful.

Bone marrow cytology: Detection of bone marrow infiltration with loose clusters of monoclonal tumor cells with a typical wheel-spoke structure of the cell nuclei. Individual chromatin clumps in the periphery of the cell nucleus are detectable. Perinuclear whitening. Detection of chromosomal aberrations(FISH analysis) such as translocations t (14;16), t (4;14) or t (14;20) as well as deletions 1p, 17p or 13q are associated with a significantly poorer prognosis.

Monoclonal gammopathy of undetermined significance (MGUS): In monoclonal gammopathy of undetermined significance (MGUS), complete or incomplete monoclonal immunoglobulins are detectable in the serum by laboratory analysis, but there are no clinical symptoms.

Secondary monoclonal gammopathy: reactive in other malignant hematologic diseases (CLL; NHL), autoimmune diseases

Epidemiology: Prevalence between the ages of 45 and 75 approx. 3 %

Smoldering myeloma (C90.0): Plasma cells 10-60 % in the bone marrow; paraprotein > 30 g/l. No end organ damage.

POEMS syndrome

Heavy or light chain disease or Al amyloidosis

Osteolytic foci in the bone (e.g. shotgun skull), osteoporosis with pain and spontaneous fractures (pathological fracture without adequate trauma in 80 % of vertebral body fractures, risk of paraplegia).

Hypercalcemic crises: mostly due to osteolysis (clinical picture: polyuria, vomiting, somnolence, deterioration of renal function). Rarely: nephrocalcinosis.

Myeloma kidney (30 %): see below cast nephropathy (clinical picture: nephrotic syndrome)

Cytopenia: mainly anemia, often macrocytic (72 %)

Antibody deficiency syndrome with susceptibility to infections (90 %) aggravated by leukopenia

Polyneuropathy: due to deposition of free light chains

Hyperviscosity syndrome: increase in blood viscosity; with possible cerebral circulatory disorders

Cryoglobulinemia: Raynaud's symptoms; see also cryoglobulinemic purpura

Al-amyloidosis (up to 10 % of cases): Heart, kidney, liver, nervous system

Increased risk of secondary neoplasia

Asymptomatic patients

No acute therapy is required for newly diagnosed asymptomatic patients (NDMM: newly diagnosed MM). A "watchful waiting" approach can be adopted here.

Symptomatic patients

First-line therapy for symptomatic NDMM patients: In newly diagnosed MM, the aim is to achieve the highest possible remission rates with symptom control and minimal side effects or a very good partial response, as this has a positive influence on the overall course of the disease.

According to the criteria of the International Myeloma Working Group (IMWG), the indication for the initiation of therapy is given when:

• Detection of clonal plasma cells in the bone marrow ≥ 10 % and/or
• monoclonal protein in the serum and/or
• monoclonal protein in the urine and
• Detection of CRAB criteria

A distinction is made between:

• auto-SZT patients (autologous stem cell transplantation possible) and
• non-auto-SZT patients.

Auto-SSCT patients: If an autologous stem cell transplant is to be performed in the patient, a combination of bortezomib (Bo), lenalidomide (L), doxorubicin (A) and dexamethasone (D) is recommended for induction in the presence of a deletion 17p or translocation t (4;14) (BCD, BLD, BAD, BD; Tabchi S et al. 2019). Followed by autologous stem cell transplantation (ACT) or inclusion in clinical trial protocols. ASCT is the treatment of choice for young, symptomatic patients (NDMM). For older NDMM patients (> 75 years), the value (overall survival-based outcome) of the procedure is still unclear (Mian H et al.2019).

Alternative: For other genetic risk constellations, lenalidomide (L), thalidomide (T) and cyclophosphamide (C) can be added to the combinations listed above for induction (BCD, BLD, BAD, LAD, LD, BLCD, BD, BTD), with consecutive autologous stem cell transplantation.

Note: With regard to minimal residual disease (MRD) after auto-SCT, MRD could be detected by PCR or flow cytometry even in patients in complete remission, so that MRD determination is currently not part of standard diagnostics due to uncertain data (Chan HSH et al. 2017; Martin T et al 2019).

Non-auto-SZT patients: In non-auto-SZT-eligible patients, the following combinations can also be used with melphalan (M) for induction: BCD, BT, BAD, BD, LD, MPT, MPL. A final maintenance therapy can be continued with bortezomib (B) and lenalidomide (L), but a wait-and-watch strategy is also possible.

High-dose chemotherapy with melphalan and subsequent auto-SZT should be used to prolong progression-free and overall survival in suitable patients. Patients up to the age of 70 were included in studies.

Alternative: "DCR" (dexamethasone (D), cyclophosphamide (C), anti-CD20 antibody rituximab (R)).

Relapses (RMM): Despite advances in treatment, > 90 % of patients suffer a relapse or progression of the disease. Recurrence therapy is significantly more difficult than first-line treatment. This applies both to the choice of medication and the generally poorer response.

Primary progressive disease is present if the following criteria are met during therapy or within 60 days of the end of therapy:

• > 25 % increase in the monoclonal protein in the serum
• > 25 % increase in monoclonal light chains in the 24-hour urine collection
• > 25 % increase in bone marrow plasma cells
• Increase in size or new soft tissue plasmacytomas
• Increase in the number or size of osteolyses
• Increasing, otherwise unexplained cytopenia
• Development of hypercalcemia

The indication for relapse therapy is given in the case of symptomatic MM and at least one proven CRAB criterion. A relapse can often be recognized by an increase in paraprotein in the serum or urine even before a CRAB criterion occurs. If the paraprotein alone rises without renewed symptoms, treatment is not usually started outside of studies.

Patients should be treated (outside of studies) with lenalidomide (L), bortezomib/proteasome inhibitor(B) in combination with dexamethasone (D) (e.g. LD, BD). (Richardson PG et al. 2019).

Alternative: If necessary, a combination of several substances, e.g. cyclophosphamide (C), thalidomide (T) or doxorubicin (A) can be given: BCD, BTD, CAD or LCD.

Alternative: The combination of the third-generation IMiD pomalidomide (P) with dexamethasone (D) was also approved for RRMM patients (Relapsed/Refractory Multiple Myeloma) - after lenalidomide or bortezomib pre-treatment (Kim Y et al. 2015).

Alternatively, third-generation immunomodulatory drugs (IMiDs; imide-based derivatives such as pomalidomide), proteasome inhibitors such as carfilzomib, ixazomib and oprozomib, monoclonal antibodies such as elotuzumab, daratumumab, siltuximab and tabalumab as well as other targeted substances, including BTK and HSP inhibitors, tyrosine kinase inhibitors (e.g. sorafenib) and other targeted substances, can be used. (e.g. sorafenib) and other innovative phase I/II substances. In suitable patients without significant comorbidities and with a plateau phase of at least 12-24 months after initial high-dose therapy, renewed high-dose therapy may also be recommended.

In RRMM patients, radiotherapy and osteoplastic procedures such as kyphoplasty/vertebroplasty can be part of the therapy in special situations, especially in cases of local pain due to osteolytic bone destruction.

Tandem high-dose therapy: A second high-dose therapy with auto-SZT in selected RRMM patients can be considered if the ECOG index is good and the side effect profile is acceptable.

In young patients and those with an unfavorable prognosis such as early recurrence (< 12 months) after initial high-dose therapy, chromosomal aberrations such as del17p or t (6;18), an extramedullary manifestation or with plasma cell leukemia, allogeneic SCT should be considered as a potentially curative therapy (preferably in the context of clinical trials). Cave: therapy-associated mortality of 10-15 % Tabchi S et al.2019; - Kim Y et al. 2015).

Supportive therapy

• Osteolysis with risk of fracture: radiotherapy of osteolytic foci (aim: remineralization)
• Osteolysis and osteoporosis in multiple myeloma: administration of bone-active substances: bisphosphonates or denosumab, always ensuring an adequate supply of calcium and vitamin D.
• Pancytopenia with anemia and tendency to infection: blood transfusion; G-CSF and EPO as growth factors for the bone marrow

Very variable course and prognosis

Therapeutic goal: prolongation of life with the highest possible quality of life

Despite significantly better therapeutic options, a cure is only possible in a few cases (Castaneda O et al.2019) Unfavorable prognostic factors are: high stage according to the International Staging System or Durie and Salmon, advanced age, β2-microglobulin↑, serum albumin↓, CRP↑, LDH↑, etc. Some patients die after just a few months, others have a life expectancy of > 10 years.

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