Multiple myelomaC90.0

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The widespread classification of salmon and durie has now been replaced by the International Staging System (ISS).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. Thus, MM is often conspicuous as an incidental finding of serum protein electrophoresis. Skin lesions may also represent early diagnostic symptoms.

Initially, nonspecific disturbances 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 tubular bones. Several months usually elapse from the first symptoms of the disease to diagnosis.

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

• Hematology: Displacement of hematopoiesis findings, anemia (65%), leukopenia with tendency to infection, thrombocytopenia with petechial bleeding tendency.
• Immune system: antibody deficiency syndrome (the monoclonal antibodies produced are non-functional (clinical: atypical pyoderma, pyoderma gangrenosum, chronic candida disease of the skin and mucosa).
• Skeletal: osteolysis with bone pain (76%); a long asymptomatic course is also possible. If proliferating plasma cells displace bone marrow, anemia, tendency to infection and bleeding may occur.
• Skin: The dermatological symptomatology is defined on the one hand by the paraproteinemia (hyperviscosity syndrome with Raynaud's syndrome, urticarial vasculitis). On the other hand, the skin is involved by secondary sequelae 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 leukaemia cutis). Furthermore, secondary signs of disease develop in the skin, which are caused by paraproteinemia-induced organ changes (e.g. paraproteinemic renal changes).
• Kidney (33%): Foaming urine as a clinical correlate of Bence-Jones proteinuria. Late complicating finding is myeloma kidney (Cast nephropathy), a light chain disease of the kidney.
• Nephrocalcinosis in hypercalcemia (>2.75mmol/l).
• Vessels: If immunoglobulin polymers are formed at low temperatures, cryoglobulinemia occurs with corresponding clinical signs (see paraproteinemia and skin changes below).
• Coagulation: Monoclonal immunoglobulins can bind coagulation factors, resulting in haemorrhages (mostly in the skin) (see also Purpura, dysproteinemic).
• 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: mothlike osteolysis (Note: Myeloma cells have no osteolytic activities of their own; however, they stimulate osteolysis via various mechanisms. cytokines (RANKL =receptor activator of NF-kB-ligand, MIP-1 = macrophage inflammatory protein = CCL3) stimulate osteoclast and inhibit osteoblast activity.

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

Skeletal scintigraphy is less suitable because myeloma foci often do not save.

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

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

Inflammation parameters: BSG: extremely accelerated BSG, 1-h value:>100mm n.W., so-called fall reduction (often the first parameter of the disease. Note: In the Bence-Jones type of MM, BSG and immune electrophoresis are hardly changed!)

Detection of paraproteins; detection of cryoglobulins; high beta2-microglobulin (the detection has a negative prognostic significance).

Blood count: Anemia, leukopenia, in the course of pancytopenia

Eletrolytes: Serum calcium values ↑

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

Immunofixation electrophoresis: monoclonal gammopathy with M-gradients (antibodies without defence function - functional AK deficiency). Quantification of the immunoglobulins is useful for monitoring the course of the disease.

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

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

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

Epidemiology: prevalence between 45 and 75 years of age about 3%.

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

POEMS Syndrome

Severe 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, danger of paraplegia).

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

Myeloma kidneys (30%): see below: cast nephropathy (Clinic: nephrotic syndrome)

Cytopenia: especially anemia often macrocytic (72%)

Antibody deficiency syndrome with susceptibility to infection (90%) exacerbated by leukopenia.

Polyneuropathy: by 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: In newly diagnosed asymptomatic patients (NDMM: newly diagnosed MM), no acute therapy is required. In this case, a "watchful waiting" can be followed.

Symptomatic patients

First-line therapy in symptomatic NDMM patients: in newly diagnosed MM (Newly Diagnosed Multiple Myeloma), the goal is to achieve the highest possible remission rates with symptom control and minimal side effects or a very good partial response, as this will positively influence the overall course of the disease.

According to the criteria of the International Myeloma Working Group (IMWG), the indication for initiating therapy is given in the case of:

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

A distinction is made between:

• AutoSZT patients (autologous stem cell transplantation possible)
• and
• non-autoSCT patients.

AutoSZT patients: If the patient is to undergo autologous stem cell transplantation, 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), respectively (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 above combinations for induction (BCD, BLD, BAD, LAD, LD, BLCD, BD, BTD) with consecutive autologous stem cell transplantation.

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

Non-autoSCT patients: In non-autoSCT-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 followed by autoSZT should be given to prolong progression-free and overall survival in appropriate patients. Studies have included patients up to age 70 years.

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

Recurrences (RMM): Despite advances in treatment, > 90% of patients experience disease relapse or progression. Relapse therapy is significantly more difficult than first-line treatment. This relates to both the choice of drugs and the usually poorer response.

Primary progressive disease is present when the following criteria are present during therapy or within 60 days of completion of therapy:

• > 25 percent increase in serum monoclonal protein.
• > 25 percent increase in monoclonal light chains in 24-hour collection urine
• > 25 percent increase in bone marrow plasma cells
• Increase in size or new soft tissue plasmacytomas
• increase in number or size of osteolyses
• Increasing cytopenia that cannot otherwise be explained
• Development of hypercalcemia.

Indication for relapse therapy is given in symptomatic MM and at least one proven CRAB- criterion. Often, relapse can be detected by an increase in serum or urinary paraprotein before the appearance of a CRAB criterion. In case of an increase of paraprotein alone without recurrence of symptoms, therapy is usually not yet started outside of studies.

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

Alternative: If required, a combination of multiple agents may be required e.g. cyclophosphamide (C), thalidomide (T), doxorubicin(A): BCD, BTD, CAD or LCD.

Alternative: The combination of the 3-generation IMID pomalidomide (P) with dexamethasone (D) was also approved for RRMM (Relapsed/Refractory Multiple Myeloma) patients - after lenalidomide or bortezomib pretreatment (Kim Y et al 2015).

Alternatively: 3rd generation immunomodulatory agents (IMIDs). Generation such as pomalidomide, proteasome inhibitors such as carfilzomib, ixazomib and oprozomib or antibodies such as elotuzumab, daratumumab, siltuximab, tabalumab, denosumab, romosozumab, BTK, HSP inhibitors, tyrosine kinase inhibitors such as sorafenib, and other innovative phase I/II agents, repeat high-dose therapy is recommended in appropriate patients without significant comorbidity and a plateau phase of at least 12 to 24 months after initial high-dose therapy.

In RRMM patients, radiotherapy and osteoplastic procedures such as kyphoplasty/vertebroplasty may 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 autoSZT in selected RRMM patients can be considered if the ECOG index is good with an acceptable side effect profile.

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

Supportive therapy

• Osteolyses with fracture risk: radiatio of osteolytic foci (aim: remineralization).
• Osteolyses and osteoporosis in multiple myeloma: administration of bone-active substances: bisphosphonates or denosumab, always ensuring 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.

Course and prognosis very variable

Therapy objective: 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). Unfavourable prognostic factors are: high stage according to the International Staging System or Durie and Salmon, high age, β2-Mikroglobulin↑, Serumalbumin↓, CRP↑, LDH↑ etc. Some patients die after a few months, others have a life expectancy of >10 years.

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