Plasma Cell Leukemia: Clinical Guidelines

List of Abbreviations

CRAB – constellation of organ damage in symptomatic multiple myeloma: hypercalcemia, renal dysfunction, anemia, bone lesions

Dara-CVRd – an immunochemotherapy regimen including #daratumumab**, #cyclophosphamide**, #bortezomib**, #lenalidomide** and #dexamethasone**

Dara-KRd – an immunochemotherapy regimen including #daratumumab**, #carfilzomib**, #lenalidomide** and #dexamethasone**

Ig − immunoglobulin

IMWG – International Myeloma Working Group

Isa-KRd – an immunochemotherapy regimen including #isatuximab**, #carfilzomib**, #lenalidomide** and #dexamethasone**

ISS – International Staging System (ISS)

KRd – an immunochemotherapy regimen including #carfilzomib**, #lenalidomide** and #dexamethasone**

PAD – an immunochemotherapy regimen including #doxorubicin**, #bortezomib** and #dexamethasone**

Rd – an immunochemotherapy regimen including #lenalidomide** and #dexamethasone**

R-ISS – Revised International Staging System

R2-ISS – revised 2 International Staging System

SLiM – myeloma-defining biomarkers

VCD – an immunochemotherapy regimen including #cyclophosphamide**, #bortezomib** and #dexamethasone**

VRD – an immunochemotherapy regimen including #lenalidomide**, #bortezomib** and #dexamethasone**

allo-HSCT – allogeneic hematopoietic stem cell transplantation

Auto-HSCT – autologous hematopoietic stem cell transplantation

PFS – progression-free survival

IV – intravenous

TTP – time to progression

HDCT – high-dose chemotherapy

WHO – World Health Organization

VTE – venous thromboembolic events

GCs – glucocorticoids

rhG-CSF** – recombinant human granulocyte colony-stimulating factor** (L03AA Colony-stimulating factors according to the ATC classification)

HSCs – hematopoietic stem cells

BM – bone marrow

CT – computed tomography

LDH − lactate dehydrogenase

MM – multiple myeloma

INR – international normalized ratio

MRD – minimal residual disease

MRI – magnetic resonance imaging

OS – overall survival

VGPR – very good partial response

s.c. – subcutaneous

PCs – plasma cells

PCL – plasma cell leukemia

CR – complete remission

PET – positron emission tomography

HSC – hematopoietic stem cells

FLC – free light chains (of immunoglobulins)

ESR – erythrocyte sedimentation rate

HSCT – hematopoietic stem cell transplantation

CKD – chronic kidney disease

CNS – central nervous system

PR – partial response

ECG – electrocardiogram

** – vital and essential drugs

# – drug used off-label (not in accordance with the indications, contraindications, routes of administration, or dosages specified in the drug's package insert)

Terms and Definitions

Plasma cell leukemia – a B-cell malignancy whose morphological substrate consists of plasma cells circulating in the peripheral blood at 5% or more. According to the 5th edition of the WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, plasma cell leukemia is considered one of the clinical variants of multiple myeloma.

Multiple myeloma – a B-cell malignant tumor whose morphological substrate consists of plasma cells producing monoclonal immunoglobulin. According to the latest version of the World Health Organization (WHO) classification of 2017, the term "multiple myeloma" was replaced by "plasma cell myeloma", a disease characterized by multifocal proliferation of neoplastic plasma cells, in most cases associated with the secretion of monoclonal immunoglobulin.

Plasma cell – the final stage of B-lymphocyte differentiation. Functional activity includes participation in humoral immunity and antibody production.

Monoclonal immunoglobulin – an immunoglobulin of a single class synthesized in excess by a clonal plasma cell. The immunoglobulin structure remains normal, but the synthesis of the immunoglobulin or its individual components exceeds physiological requirements.

Monoclonal gammopathy – a condition characterized by the presence of an immunoglobulin of a single class.

M-protein spike – a narrow, distinct band on an electrophoretogram formed by monoclonal immunoglobulins.

Remission – a period of the disease course characterized by significant amelioration or complete disappearance of symptoms, including data from laboratory and instrumental diagnostic methods.

Relapse – the return of clinical manifestations of the disease, including based on laboratory and instrumental diagnostic methods.

Overall survival – calculated from the date of treatment initiation to death from any cause or the date of the patient's last follow-up.

Progression-free survival – calculated from the date of treatment initiation to disease progression or death from any cause.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Plasma cell leukemia – an aggressive B-cell lymphoproliferative disorder with extramedullary dissemination and an unfavorable prognosis. According to the 5th edition of the WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, plasma cell leukemia is considered one of the clinical variants of multiple myeloma [1]. At the same time, in the 10th and 11th revisions of the International Classification of Diseases, plasma cell leukemia is classified as a separate nosological entity.

In 2021, an expert consensus of the International Myeloma Working Group (IMWG) revised the diagnostic criteria for primary plasma cell leukemia. Currently, this term refers to a condition in which 5% or more circulating plasma cells are detected in the peripheral blood at the onset of the disease in MM patients, instead of the previously established 20%. It is important to note that patients with primary plasma cell leukemia should not have a prolonged history of MM, unlike patients with secondary plasma cell leukemia [2]. Secondary plasma cell leukemia develops in the terminal stage of the disease due to excessive tumor growth. Primary plasma cell leukemia is diagnosed 2–2.5 times more often than secondary plasma cell leukemia [3].

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

To date, the exact cause of plasma cell leukemia has not been determined. Like other types of malignant neoplasms, plasma cell leukemia develops due to a series of genetic events that form a pathological clone of plasma cells that grow and divide chaotically and uncontrollably. The biological and clinical features of PCL are associated with a wide range of genetic abnormalities, the most studied of which are hypodiploid karyotype, rearrangement of immunoglobulin heavy chain gene loci (most commonly t(11;14) and t(14;16)), as well as del(17p) [3–5].

1.3 Epidemiology of the Disease or Condition

The incidence of plasma cell leukemia accounts for approximately 0.5–2% of all MM cases annually and is more frequently diagnosed in young patients [4].

1.4 Features of Coding the Disease or Condition

C90.1 – Plasma cell leukemia

These clinical guidelines provide information on the diagnosis, treatment methods, and prognosis of primary plasma cell leukemia.

According to the expert community, secondary plasma cell leukemia should be considered a manifestation of terminal-stage MM resulting from excessive tumor growth. Therapy for secondary plasma cell leukemia is carried out in accordance with the principles of treatment for relapsed and refractory multiple myeloma.

1.5 Classification of the disease or condition

To date, classification criteria for staging primary plasma cell leukemia have not been developed.

Since PCL is considered by research groups as one of the clinical variants of MM, it is recommended to use the staging systems approved for assessing multiple myeloma.

A widely used staging system is the classification by B. Durie and S. Salmon proposed in 1975 (Table 1) [6], which was superseded by the International Staging System (ISS) [7], revised in 2014 [8].

Table 1. MM staging according to the B. Durie and S. Salmon system

An additional feature determining the substage is renal function:

• A − normal (serum creatinine <177 µmol/L or 2 mg/dL).

• B − impaired (serum creatinine ≥177 µmol/L or 2 mg/dL).

The ISS classification is based on the important prognostic significance of the combination of serum β2-microglobulin and albumin (Table 2) [7].

Table 2. Multiple myeloma staging according to the ISS

In 2014, the ISS was revised (revised ISS; R-ISS). In addition to serum β2-microglobulin and albumin levels, the R-ISS takes into account the presence of adverse chromosomal abnormalities and high lactate dehydrogenase (LDH) levels (Table 3) [8].

Table 3. Revised International Staging System for MM

The second revision of the International Staging System was conducted in 2022 (R2-ISS). Taking into account the results of a multicenter study, the authors identified the main risk factors, the combination of which affected the survival time of MM patients. The staging system is based on the evaluation of parameters such as ISS stage, LDH activity, cytogenetic abnormalities including del(17p), t(4;14), and 1q+ (Table 4). Each of the presented factors is assigned corresponding points, which are summed up to determine the disease stage or risk group [9].

1.6 Clinical presentation of the disease or condition

The clinical manifestations of PCL are extremely diverse, but are largely determined by bone marrow infiltration by plasma cells and organ damage. Clinical signs include symptoms caused by bone lesions (bone pain, skeletal fractures, spinal cord compression, radicular pain), hypercalcemia (polyuria, polydipsia, nausea, vomiting), renal failure (nausea, vomiting, malaise, weakness), bone marrow infiltration by myeloma cells (anemia, hemorrhagic syndrome), decreased normal immunoglobulin levels (frequent infections, pneumonia), cryoglobulinemia (Raynaud's syndrome, acrocyanosis), hyperviscosity syndrome (dyspnea, transient ischemic attacks, deep vein thrombosis, retinal hemorrhages, central retinal vein or branch occlusion, epistaxis), organomegaly (hepatomegaly and splenomegaly), and the presence of extramedullary tumors [3, 10, 11].

2. Diagnostics, medical indications and contraindications for diagnostic methods

Criteria for establishing the diagnosis/condition:

Currently, according to IMWG 2021 recommendations, the diagnosis of primary plasma cell leukemia is established in the presence of 5% or more circulating plasma cells in peripheral blood smears in patients with symptomatic MM [2].

A thorough examination of peripheral blood using conventional microscopy should be performed in all MM patients. At least 100–200 nucleated cells in a peripheral blood smear must be analyzed.

Upon establishing the diagnosis of symptomatic MM, there must be 10% or more plasma cells in the bone marrow and/or plasma cell infiltration in a biopsy specimen of the affected tissue, with the mandatory presence of at least one CRAB and/or SLiM criterion, including [12]:

1. One or more of the following signs of organ or tissue damage associated with plasma cell proliferation (CRAB criteria):

• hypercalcemia (serum calcium 0.25 mmol/L or 1 mg/dL above the upper limit of normal, or >2.75 mmol/L, or >11 mg/dL);

• renal failure (creatinine clearance <40 mL/min or serum creatinine >177 µmol/L, or >2 mg/dL);

• anemia (hemoglobin 20 g/L below normal values or below 100 g/L);

• bone lesions (one or more osteolytic lesions detected by radiography, CT, or PET/CT; with bone marrow plasma cell infiltration of less than 0.7%, more than 1 bone lesion must be detected for differential diagnosis with solitary plasmacytoma with minimal bone marrow involvement).

2. In the absence of symptoms of the “CRAB” complex – the presence of at least one marker of tumor activity (SLiM criteria):

• more than 60% plasma cells in the bone marrow;

• involved/uninvolved serum FLC ratio greater than 100;

• more than 1 bone marrow infiltration lesion according to MRI results: each lesion must be at least 5 mm in diameter.

2.1 Complaints and Anamnesis

• All patients with suspected or confirmed PCL at the initial appointment are recommended to undergo a thorough collection of complaints and medical history regarding blood and hematopoietic organ disorders to verify the diagnosis [3, 5, 13–18].

Recommendation grade − C (level of evidence − 5)

2.2 Physical Examination

• In all patients with suspected or confirmed plasma cell leukemia (PCL) at initial or follow-up visits, control examinations, and suspected disease recurrence, it is recommended to perform a general physical examination including therapeutic inspection, palpation, and auscultation, assess the general condition using the ECOG scale, and examine the tonsils and oral cavity to clarify the extent and severity of the disease [3, 5, 13–18].

Recommendation grade − C (level of evidence − 5)

Comment: during the examination, it is necessary to assess the patient's general condition using the ECOG scale (see Appendix G1), as well as to inspect the tonsils and oral cavity; palpation should include the assessment of accessible groups of peripheral lymph nodes, liver, and spleen.

2.3 Laboratory Diagnostics

• In all patients with suspected or confirmed PCL at initial or follow-up visits, control examinations, and suspected disease recurrence, it is recommended to perform the following laboratory tests to clarify the patient's condition, develop appropriate therapeutic tactics, and/or (in case of previously administered therapy) if treatment-related adverse events develop:

§ Complete blood count (CBC) with differential, including determination of hemoglobin, erythrocyte, platelet, and leukocyte levels, leukocyte count, reticulocyte count, and ESR [2, 3, 19, 5, 12–18];

§ urinalysis [3, 5, 12–19];

§ 24-hour urine protein quantification [3, 5, 12–19];

§ General clinical blood chemistry panel (total protein, albumin, LDH, urea, creatinine, bilirubin, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, calcium, potassium) [3, 5, 12–19];

§ Coagulogram (screening hemostasis assay) including the following parameters: prothrombin time, international normalized ratio (INR), activated partial thromboplastin time (APTT), fibrinogen, thrombin time [3, 5, 20, 12–19].

Recommendation grade − C (level of evidence − 5)

• In all patients with suspected or confirmed PCL at initial or follow-up visits, control examinations, and suspected disease recurrence, it is recommended to calculate the glomerular filtration rate (GFR) to assess renal function and determine the need for therapy or dosage modification in the presence of renal impairment and/or to determine indications for hemodialysis [3, 5, 12–19].

Recommendation grade − C (level of evidence − 5)

• In all patients with suspected or confirmed PCL at initial or follow-up visits, control examinations, and suspected disease recurrence, it is recommended to perform the following tests to clarify the activity of the underlying disease or to assess response to therapy:

§ determination of blood protein fractions (except in patients with non-secretory, smoldering, and light-chain myeloma) and urine protein electrophoresis with quantitative assessment of monoclonal immunoglobulins in the blood by immunofixation and polyclonal immunoglobulins [3, 5, 21, 22, 12–19];

§ serum beta-2-microglobulin testing at diagnosis for staging according to international classification and risk factor assessment [3, 5, 21, 22, 12–19];

§ assessment of immunoglobulin monoclonality in blood and 24-hour urine by immunofixation with quantitative determination of the M-spike concentration [3, 5, 22, 12–19].

Recommendation grade − C (level of evidence − 5)

• In all patients with non-secretory, oligosecretory myeloma, as well as dialysis-dependent renal failure, suspected disease, initial or follow-up visits for a diagnosed disease, control examinations, and suspected recurrence, it is recommended to determine the serum free light chain (FLC) kappa and lambda levels to clarify the activity of the underlying disease or to assess response to therapy [3, 5, 23, 12–19].

Recommendation grade − C (level of evidence − 5)

• In all patients with suspected or confirmed PCL at the initial visit, control examinations, and suspected disease recurrence, it is recommended to obtain a bone marrow (BM) cytologic specimen via puncture (sternal puncture), followed by a cytologic examination (myelogram), and, if necessary, flow cytometry of the biological material (bone marrow) to confirm and formulate the diagnosis [3, 5, 13–19, 24].

Recommendation Grade − C (Level of Evidence − 4)

• In all patients with suspected or confirmed PCL at the initial visit, as well as to assess bone marrow hematopoiesis before hematopoietic stem cell collection or upon suspicion of disease recurrence, it is recommended to obtain a bone marrow (BM) histologic specimen (trephine biopsy) and perform pathomorphological examination of the biopsy (surgical) material of the bone marrow (using immunohistochemical methods if necessary) to confirm and formulate the diagnosis [3, 5, 13–19, 24].

Recommendation Grade − C (Level of Evidence − 4)

• In all patients with newly diagnosed PCL, it is recommended to perform molecular cytogenetic testing (FISH method) for one pair of chromosomes to detect the most prognostically significant cytogenetic abnormalities: t(4;14), t(14;16), t(6;14), del 17p13, t(11;14), ploidy, and chromosome 1 alterations [3, 5, 8, 13–19].

Recommendation grade − C (level of evidence − 5)

• In all patients with newly diagnosed PCL, it is recommended to perform a lumbar puncture followed by cytological examination of cerebrospinal fluid cells [19, 25].

Recommendation grade − C (level of evidence − 5)

2.4 Instrumental Diagnostics

• In all patients at the time of PCL diagnosis / before starting therapy, when evaluating treatment response, and upon suspicion of disease recurrence, it is recommended to perform CT of all spinal segments, chest, and pelvis (low-dose whole-body CT is preferred) to clarify the presence and extent of bone lesions, and to detect bone and extramedullary plasmacytomas with measurement of their dimensions [18, 19, 26].

Recommendation grade − C (level of evidence − 5)

• In all patients at the time of PCL diagnosis before starting therapy, when evaluating treatment response, and upon suspicion of disease recurrence, as an alternative to whole-body CT, it is recommended to perform PET/CT to clarify the presence and extent of bone lesions, and to detect bone and extramedullary plasmacytomas with measurement of their dimensions [3, 5, 27, 12–19].

Recommendation grade − C (level of evidence − 5)

2.5 Other Procedures

Not used.

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

The prescription and use of medicinal products indicated in the clinical guidelines are aimed at providing the patient with clinically effective and safe medical care; therefore, their prescription and use in a specific clinical situation are determined in accordance with the instructions for use of specific medicinal products, implementing the precautions presented in the instructions, and dose adjustments are also possible taking into account the patient's condition.

Considering the low incidence of plasma cell leukemia, the revision of diagnostic criteria in 2021, data on the efficacy and safety of therapy based on the results of prospective clinical studies are limited. In the Russian Federation, among registered medicinal products with antitumor activity against plasma cells, PCL is absent from the approved indications section.

These clinical guidelines are based on the results of cohort studies, case reports, and expert consensus on optimal approaches to PCL therapy.

3.1 Indications for initiating therapy and defining treatment strategy

• In patients with primary PCL, the initiation of specific antitumor therapy is recommended [3–5, 10, 13–15, 19].

Recommendation Grade − C (Level of Evidence − 4)

Comment: Management tactics for patients under 65–70 years of age differ from those for elderly patients. For young patients without serious comorbidities, the treatment program should include high-dose chemotherapy (HDCT) with autologous hematopoietic stem cell transplantation (auto-HSCT); several study groups consider it appropriate to evaluate the feasibility of allogeneic hematopoietic stem cell transplantation (allo-HSCT), although consensus on this issue has not been reached.

Patients older than 65 years or young individuals with clinically significant comorbidities should be offered novel agent-based combinations without the HDCT with auto-HSCT or allo-HSCT phase.

When choosing an induction regimen, the patient's comorbidities and PCL complications must also be taken into account. In the presence of clinically significant cardiac pathology, it is advisable to exclude anthracyclines and related compounds from the therapy.

In the presence of life-threatening conditions (clinically significant bleeding, uncompensated severe diabetes mellitus), antitumor therapy is administered immediately after these complications are resolved.

3.2 Treatment of patients with newly diagnosed PCL

Recommendations for the treatment of primary plasma cell leukemia are based on the results of:

- several randomized trials including a small cohort of patients diagnosed based on 1974 or 2013 criteria;

- comparative cohort studies limited to dozens of observed cases, including both auto-HSCT candidates and older patients with comorbidities;

- descriptions of antitumor efficacy in individual clinical observations or case series;

- analysis of the mechanism of action of medicinal products on the tumor plasma cell, and expert community consensus.

3.2.1 Induction phase of therapy

• In patients with newly diagnosed PCL, as induction therapy, it is recommended to use one of the following #bortezomib**-based regimens (for regimen descriptions, see Appendix A3.1) [28–32]:

#bortezomib** / #lenalidomide** / #dexamethasone** (VRd) [19, 31, 33]

Level of recommendation — B (Level of evidence — 4)

#bortezomib** / #cyclophosphamide** / #dexamethasone** (VCd) [29]

Level of recommendation — B (Level of evidence — 4)

#bortezomib** / #doxorubicin** / #dexamethasone** (PAd) [29, 34]

Level of recommendation — B (Level of evidence — 4)

Comment: Subcutaneous administration of #bortezomib** is optimal in all presented regimens.

• Patients with newly diagnosed PCL are recommended therapy with #lenalidomide** and #dexamethasone** (for regimen descriptions, see Appendix A3.1.) [35]

Recommendation grade − B (level of evidence − 3)

• Patients with newly diagnosed PCL are recommended therapy with #carfilzomib**, #lenalidomide** and #dexamethasone** (for regimen descriptions, see Appendix A3.1.) [36]

Recommendation grade − B (level of evidence − 3)

• Patients with newly diagnosed PCL as induction therapy are recommended to use one of the following multi-agent regimens including at least two to three targeted drugs [31, 35, 36] (for regimen descriptions, see Appendix A3.1.):

#daratumumab**/ #cyclophosphamide**/ #bortezomib**/ #lenalidomide**/ #dexamethasone** (Dara-CVRd) [35, 37]

Recommendation grade − B (level of evidence − 3)•

#daratumumab**/ #carfilzomib**/ #lenalidomide**/ #dexamethasone** (Dara-KRd) [38, 39]

Recommendation grade − C (level of evidence − 5)

#isatuximab**/ #carfilzomib**/ #lenalidomide**/ #dexamethasone** (Isa-KRd) [41–43]

Recommendation grade − C (level of evidence − 5) Comment: In patients eligible for auto-HSCT, mobilization of hematopoietic stem cells is recommended after 4 cycles of therapy upon achieving remission.

• Patients with newly diagnosed PCL under the age of 65, as well as patients aged 65–70 years with a good performance status and no severe comorbidities, are recommended to undergo induction treatment followed by high-dose therapy including auto-HSCT [19, 31, 49, 50, 32, 33, 43–48]

Recommendation Grade − B (Level of Evidence − 3)

Comment: Age restrictions are due to the increased risk of transplant-related mortality in elderly patients.

• Patients with at least 1 adverse factor (age ≥75 years, comorbidities with impaired organ function) are recommended to be prescribed medications taking into account the presence of comorbidities (Table 5) [18, 19, 51].

Recommendation grade − C (level of evidence − 5)

3.2.2 Transplant phase

• Patients with newly diagnosed PCL under the age of 65, as well as patients aged 65–70 years with a good performance status and no severe comorbidities who have achieved CR, VGPR, or PR after induction therapy, are recommended to undergo mobilization and collection of blood HSCs under laboratory monitoring of the number of hematopoietic stem cells in peripheral blood and apheresis product by flow cytometry for subsequent auto-HSCT [19, 31, 49, 50, 32, 33, 43–48].

Recommendation Grade − B (Level of Evidence − 3)

If possible, it is recommended to harvest auto-HSCs in a quantity sufficient to perform two transplantations.

• Patients with newly diagnosed PCL under the age of 65, as well as patients aged 65–70 years with a good performance status and no severe comorbidities who have achieved CR, VGPR, or PR after induction therapy, in case of successful blood HSC collection, are recommended high-dose chemotherapy with #melphalan** followed by autologous HSC transplantation [19, 31, 49, 50, 32, 33, 43–48].

Recommendation Grade − B (Level of Evidence − 3)

Comment: patients who have achieved CR or VGPR after induction therapy should be considered candidates for auto-HSCT, since it is in these cases that the maximum effect from consolidation with high-dose #melphalan** (140-200 mg/m²) and an increase in progression-free survival can be achieved [19, 31, 49, 50, 32, 33, 43–48].

The interval from mobilization and HSC collection to the start of pre-transplant conditioning should be 2 to 4 weeks. In case of severe renal impairment (glomerular filtration rate <30 ml/min) not requiring hemodialysis, as well as in elderly patients (65–70 years), it is advisable to reduce the dose of #melphalan** to 140 mg/m². For patients undergoing regular hemodialysis, the recommended dose of melphalan** is 140 mg/m². Hemodialysis is performed on day -4, day -2 (before melphalan administration), and day 0 (before leukocyte concentrate transfusion) [19, 31, 49, 50, 32, 33, 43–48].

• Young patients with newly diagnosed PCL without severe comorbidities are recommended to consider the option of allo-HSCT [3, 13, 14, 36, 54–56]

Recommendation Grade − C (Level of Evidence − 4)

Comment: The results of a retrospective study analyzing data from 751 patients with primary PCL from 1998 to 2014 showed that performing allo-HSCT without prior auto-HSCT was characterized by a high rate of transplant-related mortality. When auto-HSCT was performed in CR, a subsequent second auto-HSCT (tandem approach) was characterized by improved PFS and OS rates, which is comparable to the results of sequential auto/allo-HSCT. In the absence of a complete response before the first auto-HSCT, it is advisable to recommend sequential allo-HSCT.

Researchers agree that young patients who have achieved a significant anti-tumor response after multi-agent therapy can be candidates for allo-HSCT. However, candidates for allo-HSCT should be carefully selected due to the high mortality associated with the early post-transplant period.

3.2.3 Consolidation treatment phase

• For patients with PCL under the age of 65, as well as patients aged 65–70 years with a good performance status and no severe comorbidities, following high-dose therapy and auto-HSCT, it is recommended to administer consolidation therapy to improve the quality of the anti-tumor response achieved at previous stages of treatment [34, 35, 38, 40–42, 56].

Recommendation Grade − B (Level of Evidence − 3)

Comment: consolidation therapy should advisablely be started 3 months after auto-HSCT, after receiving the results of follow-up examinations confirming the absence of disease progression.

3.3.4 Maintenance therapy stage

It is advisable to provide maintenance therapy to all PCL patients, regardless of the integration of auto-HSCT into the anti-tumor treatment program. Priority attention should be given to the possibility of prescribing multi-agent targeted maintenance therapy. However, there are no randomized trials demonstrating the significance of this recommendation.

• For PCL patients under the age of 65, as well as patients aged 65–70 years with a good performance status and no severe comorbidities, after completing high-dose therapy, single or tandem auto-HSCT and consolidation therapy (if administered), as well as for non-candidates for auto-HSCT after completing the induction phase of therapy, maintenance therapy is recommended [32, 38, 39][36][37][41–43]

Recommendation Grade − C (Level of Evidence − 4)

3.4 Treatment of relapsed PCL

Relapses in PCL inevitably occur in the majority of patients. The choice of relapse treatment program depends on the efficacy of prior therapy, duration of remission, patient's condition and age, concomitant pathology, and complications accompanying the initial therapy. In late relapses (more than 12 months after the end of prior treatment), resumption of initial therapy is possible. In early relapses and refractory PCL, a change of treatment program including drugs with a different mechanism of action is necessary. Repeated high-dose therapy with auto-HSCT in relapse should advisablely be performed only in cases where remission after the first auto-HSCT lasted more than 3 years.

• Patients with signs of clinical relapse, as well as rapid increase in paraprotein (doubling of M-spike within 2 months), are recommended anti-relapse therapy [18].

Recommendation grade − C (level of evidence − 5)

Comment: signs of clinical relapse include CRAB criteria:

- Hypercalcemia (blood calcium level >2.75 mmol/L)

- Renal insufficiency attributable to myeloma

- Anemia (hemoglobin <100 g/L)

- Bone lesions (lytic lesions or osteoporosis with compression fractures)

• Patients with relapsed PCL should receive anti-tumor therapy according to the principles of treatment for refractory and relapsed forms of multiple myeloma (see corresponding clinical guidelines) [13, 14, 47]

Recommendation grade − C (level of evidence − 5)

Comment: The treatment of primary PCL relapses should be carried out based on the efficacy of prior therapy, its duration, and the presence of adverse events. Planned clinical trials evaluating the efficacy of anti-tumor therapy for PCL relapses have not been conducted to date. Given the rarity of the pathology and the common tumor substrate in PCL and MM, the expert community agrees that the treatment of PCL, including relapses, should be carried out according to the principles of high-risk MM therapy, with a preference for multi-agent regimens integrating targeted drugs.

3.5 Supportive and concomitant therapy

Patients with PCL receive supportive and concomitant therapy in accordance with the clinical guidelines for the diagnosis and treatment of multiple myeloma [19]

Pain management

• In patients with PCL experiencing acute or chronic pain syndrome, it is recommended to determine the etiology of the pain; if an inflammatory focus is identified, to carry out necessary measures to treat the inflammatory focus in accordance with relevant clinical guidelines (including surgical treatment if necessary); if the infectious-inflammatory nature of the pain syndrome is ruled out, analgesic therapy is recommended in accordance with existing pain management protocols, taking into account potential contraindications associated with cytopenia and other clinical situations [19, 59, 61]

Recommendation grade − C (level of evidence − 5)

Diet therapy

Not applicable

3.7 Assessment of treatment efficacy

• Evaluation of the efficacy of antineoplastic therapy in patients with PCL is recommended to be performed according to the international criteria proposed in 2013 (see Section 7 of these guidelines) [58].

Recommendation grade − C (level of evidence − 5)

4. Medical Rehabilitation and Sanatorium-Resort Treatment

• All patients with PCL at all stages of disease therapy, as well as after completion of medical treatment, are recommended comprehensive rehabilitation [59].

Recommendation grade − C (level of evidence − 5)

Comment: there are no specific rehabilitation methods for PCL. Rehabilitation of patients with PCL should be comprehensive in nature, covering medical and socio-psychological aspects of the patient's adaptation to normal life. The scope of medical rehabilitation is developed individually for each patient by a rehabilitation specialist with the participation of a hematologist and depends on the course and manifestations of the disease (mobility disorders due to pathological fractures, anemia syndrome, pain syndrome, nutritional disorders, etc.) and performed interventions (HSCT, hemodialysis). In addition, the rehabilitation program must take into account the social and psychological problems of the patient and, in addition to medical care, requires the mandatory participation of social workers and psychologists. Rehabilitation in the event of complications during the course of the disease and treatment is carried out within the framework of the corresponding nosologies.

5. Prevention and Dispensary Observation

There are currently no methods for preventing PCL, as the etiological factor(s) leading to the development of the disease are unknown.

Patients with PCL throughout their lives, both during treatment and outside of PCL treatment, are under dispensary supervision by a hematologist.

Monitoring of the disease course and treatment efficacy should be performed regularly by a hematologist or oncologist at the patient's place of residence. During ongoing therapy, immunochemical testing of serum and urine proteins should be performed every 2–3 months. In patients with an oligo- or non-secretory form of the disease, testing for free immunoglobulin light chains should be performed. After completion of treatment, immunochemical blood and urine tests are performed every 3 months.

6. Organization of Medical Care

Medical care, with the exception of medical care provided as part of clinical trials, in accordance with Federal Law No. 323-FZ dated November 21, 2011 (as amended on May 25, 2019) "On the Fundamentals of Protecting Public Health in the Russian Federation", is organized and provided:

1. in accordance with the regulations on the organization of the provision of medical care by types of medical care, which is approved by the authorized federal executive body;

2. in accordance with the procedure for the provision of care for the profile "hematology", mandatory for execution on the territory of the Russian Federation by all medical organizations;

3. based on these clinical guidelines;

4. taking into account the standards of medical care approved by the authorized federal executive body.

Primary specialized health care is provided by a hematologist and other medical specialists at an ambulatory hematology/oncology care center, a primary hematology/oncology office, a primary hematology department, or an outpatient department of an oncological dispensary.

When PCL is detected or suspected in a patient, general practitioners, district general practitioners, general family physicians, medical specialists, and mid-level medical personnel shall refer the patient in the established manner for consultation to an ambulatory hematology/oncology care center or to a primary hematology office, primary hematology department of a medical organization to receive primary specialized health care.

An outpatient or inpatient hematologist organizes the diagnostic tests necessary to establish the diagnosis, including disease extent and stage.

If diagnostic tests cannot be performed, the attending physician refers the patient to a medical organization providing medical care to patients with hematological diseases to establish a diagnosis and provide specialized, including high-tech, medical care.

When PCL is detected or suspected during the provision of emergency medical care, the patient is transferred or referred to medical organizations providing medical care to patients with hematological diseases to determine management tactics and the need for additional methods of specialized antineoplastic treatment.

Specialized, including high-tech, medical care is provided by hematologists in medical organizations providing medical care to patients with PCL that have a license, the necessary material and technical base, certified specialists, in inpatient and day-hospital settings and includes prevention, diagnosis, and treatment of hematological diseases requiring the use of special methods and complex unique medical technologies, as well as medical rehabilitation.

In a medical organization providing medical care to patients with PCL, the tactics of medical examination and treatment are established by hematologists with the involvement, if necessary, of other medical specialists, and if necessary, by holding a medical concilium. The decision of the medical concilium is formalized in a protocol, signed by the participants of the medical concilium, and entered into the patient's medical documentation.

Indications for hospitalization in a 24-hour or day hospital of a medical organization providing specialized, including high-tech, medical care in the specialty "hematology" are determined by a hematologist/medical panel with the involvement of other medical specialists if necessary.

Indications for planned hospitalization:

The presence of a PCL diagnosis for performing:

1. a planned course of specific therapy, including chemotherapeutic drugs, targeted drugs with a biological mechanism of action, requiring round-the-clock patient monitoring (including in the presence of severe comorbidity, cytopenic syndrome),

2. a course of high-dose chemotherapy,

3. mobilization and collection of autologous blood hematopoietic stem cells,

4. transplantation of autologous (allogeneic) hematopoietic stem cells,

5. exfusion of autologous bone marrow for subsequent transplantation.

Indications for emergency hospitalization:

The presence of a PCL diagnosis complicated by:

1. acute kidney injury,

2. severe bone pain syndrome (including with the risk of fractures, spinal damage, spinal cord compression),

3. thrombotic/hemorrhagic complications against the background of specific therapy,

4. severe infectious complications against the background of specific therapy,

5. cardiac pathology against the background of specific therapy,

6. profound cytopenia.

Indications for patient discharge from the hospital:

1. Completion of a course of specific therapy.

2. Relief of complications that arose during specific therapy

The conclusion regarding the feasibility of transferring a patient to a specialized medical organization is made after a preliminary consultation based on submitted medical documents and/or a preliminary examination of the patient by medical specialists of the target organization.

7. Additional Information

Evaluation of the effectiveness of treatment for plasma cell leukemia

Evaluation of the effectiveness of PCL treatment is carried out according to the international criteria proposed in 2013 (presented in Table 6) [58].

During evaluation, any test must be performed at least twice to confirm the results.

Table 6. Criteria for antineoplastic response and relapse in plasma cell leukemia according to the 2013 IMWG consensus.

Assessment of the treatment effect based on serum and urine monoclonal protein levels is applicable to patients with "measurable" disease. The disease is considered "measurable" when the serum M-protein concentration is ≥10 g/L or in 24-hour urine ≥200 g [sic]. In the absence of monoclonal protein in serum and urine according to electrophoresis and immunofixation data (non-secretory myeloma), but when it is detected, the level of immunoglobulin "involved" FLCs ≥100 mg/L is considered "measurable". The immunoglobulin κ/λ FLC ratio must also be abnormal.

The normal κ/λ immunoglobulin free light chain ratio is 0.26–1.65. In patients with renal failure, a normal κ/λ immunoglobulin free light chain ratio is considered to be 0.37–3.1.

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Larisa P. Mendeleeva – MD, PhD, Professor, Head of the Department of Scientific and Educational Work, Head of the Department of Chemotherapy for Paraproteinemic Hemoblastosis, National Medical Research Center for Hematology of the Russian Ministry of Health, Member of the Supervisory Board of the Association for the Promotion of Hematology, Transfusion and Bone Marrow Transplantation "National Hematological Society", Member of the Russian Professional Society of Oncohematologists.

2. Maxim V. Solovyev – MD, PhD, Head of the Department of Hematology and Chemotherapy of Paraproteinemic Hemoblastosis with a Bone Marrow and Hematopoietic Stem Cell Transplantation Unit, Senior Researcher, National Medical Research Center for Hematology of the Russian Ministry of Health, Member of the Association for the Promotion of Hematology, Transfusion and Bone Marrow Transplantation "National Hematological Society".

3. Irina G. Rekhtina – MD, PhD, Head of the Department of Chemotherapy for Plasma Cell Dyscrasias, National Medical Research Center for Hematology of the Russian Ministry of Health, Member of the Association for the Promotion of Hematology, Transfusion and Bone Marrow Transplantation "National Hematological Society", Member of the Association of Nephrologists.

4. Maya V. Solovyova – MD, PhD, Senior Researcher at the Department of Chemotherapy for Paraproteinemic Hemoblastosis, National Medical Research Center for Hematology of the Russian Ministry of Health, Member of the Association for the Promotion of Hematology, Transfusion and Bone Marrow Transplantation "National Hematological Society".

5. Sergey V. Semochkin – MD, PhD, Chief Researcher at the Department of High-Dose Chemotherapy with Bone Marrow Transplantation Unit, A.Tsyb Medical Radiological Research Center – branch of the National Medical Research Center for Radiology of the Russian Ministry of Health, Professor at the Department of Oncology, Hematology, and Radiotherapy, Pirogov Russian National Research Medical University of the Russian Ministry of Health, Member of the Association for the Promotion of Hematology, Transfusion and Bone Marrow Transplantation "National Hematological Society", Russian Society of Oncohematologists, and European Association for Cancer Research (EACR).

6. Irina V. Poddubnaya – Academician of the Russian Academy of Sciences, MD, PhD, Professor, Head of the Department of Oncology and Palliative Medicine, Vice-Rector for Clinical Work and International Cooperation, Russian Medical Academy of Continuous Professional Education of the Russian Ministry of Health, Chairperson of the Russian Professional Society of Oncohematologists.

7. Tatyana I. Pospelova – MD, PhD, Professor, Vice-Rector for Research, Head of the Department of Therapy, Hematology, and Transfusion, Novosibirsk State Medical University of the Russian Ministry of Health, Member of the Association for the Promotion of Hematology, Transfusion and Bone Marrow Transplantation "National Hematological Society", Chairperson of the Regional Public Organization "Association of Hematologists of Siberia".

8. Alla M. Kovrigina – DSc, Professor at the Department of Pathological Anatomy, Cytology, and Molecular Pathology, Institute of Advanced Training of the Federal Medical-Biological Agency of Russia, Head of the Department of Pathology, National Medical Research Center for Hematology of the Russian Ministry of Health, Member of the Presidium of the Russian Society of Pathologists, Member of the Board of the Russian Society of Oncohematologists, Member of the Association for the Promotion of Hematology, Transfusion and Bone Marrow Transplantation "National Hematological Society".

There is no conflict of interest.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

• Hematologists.

• Oncologists.

• Medical students.

Methodology for evidence collection

Methods used for evidence collection/selection:

Search for publications in peer-reviewed journals with an impact factor >0.3;

Search in electronic databases

Databases used for evidence collection/selection:

The evidence base for the guidelines includes publications from the Cochrane Library, PubMed, and MEDLINE databases. The search depth was 30 years.

Methods used for analyzing evidence:

• reviews of published meta-analyses;

• systematic reviews with evidence tables.

Methods used for assessing the quality and strength of evidence:

• expert consensus;

• assessment of evidence significance in accordance with the evidence rating scheme (Tables A2.1. ‒ A2.3.).

These clinical guidelines present the levels of evidence for recommendations in accordance with the draft methodological guidelines for assessing the validity of evidence and the persuasiveness of recommendations from the Center for Expertise and Quality of Medical Care of the Russian Ministry of Health.

In accordance with this draft of recommendations, certain generally accepted diagnostic methods are assigned the level GPP (Good Practice Point) based on expert consensus.

Table A2.1. Scale for grading the levels of evidence (LE) for diagnostic methods (diagnostic interventions)

Table A2.2. Scale for grading the levels of evidence (LE) for prevention, treatment, and rehabilitation methods (preventive, therapeutic, and rehabilitative interventions)

Table A2.3. Scale for grading the grades of recommendation (GR) for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitative interventions)

Methodology for validation of guidelines

Methods for guideline validation:

• external expert review;

• internal expert review.

Description of the guideline validation methodology

The recommendations were discussed and approved by leading specialists from specialized Federal Centers of Russia and practicing physicians. The draft clinical guidelines were reviewed at working group meetings in 2024, the annual Russian Conference with international participation "Malignant Lymphomas 2024", and within the framework of the Congress of Hematologists of Russia.

Procedure for updating clinical guidelines

Updating is carried out at least once every two years or earlier, taking into account new information emerging on the diagnosis and management of patients suffering from PCD. The decision on updating is made by the Russian Ministry of Health based on proposals submitted by medical professional non-profit organizations. The formulated proposals must take into account the results of a comprehensive assessment of medicinal products, medical devices, and clinical approbation results.

Appendix A3. Reference Materials

Appendix A3.1 Drug therapy regimens for primary plasma cell leukemia

VRD  [19, 31, 33]

• #Bortezomib** 1.3 mg/m² s/c on days 1, 4, 8, and 11.

• #Lenalidomide** 25 mg orally, days 1 to 14.

• #Dexamethasone** 20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12 of each cycle.

Treatment is resumed on day 22.

VCD [29]#Bortezomib** 1.3 mg/m² SC or IV, days 1, 4, 8, 11

• #Cyclophosphamide** 300 mg/m² IV infusion, days 1, 8

• #Dexamethasone** 40 mg IV infusion or orally, days 1, 4, 8, 11. Treatment is resumed on day 22.

PAD   [29, 34]

• #Bortezomib** 1.3 mg/m² SC or IV, days 1, 4, 8, 11

• #Pegylated doxorubicin** 30 mg/m² on day 4

• #Dexamethasone** 40 mg IV infusion or orally, days 1, 4, 8, 11. Treatment is resumed on day 22.

Dara-CVRd [35, 37]

• #Daratumumab** 16 mg/kg IV on days 1, 8, 15 for the first 2 cycles, then on day 1 from cycles 3 to 6.

• #Cyclophosphamide** 500 mg orally on days 1, 8.

• #Bortezomib** 1.3 mg/m² s/c on days 1, 4, 8, and 11.

• #Lenalidomide** 25 mg orally, days 1 to 14.

• #Dexamethasone** 40 mg on days 1, 4, 8, 11.

Treatment is resumed on day 22.

Rd [35]

• #Lenalidomide** 25 mg orally, days 1–21

• #Dexamethasone** 40 mg orally, days 1, 8, 15, 22

Treatment is resumed on day 29.

KRd [36]

• #Carfilzomib** 36 mg/m² IV, days 1, 2, 8, 9, 15, 16.

• #Lenalidomide** 25 mg orally, days 1–21

• #Dexamethasone** 20 mg orally, days 1, 2, 8, 9, 15, 16, 22, 23

Treatment is resumed on day 29.

Dara-KRd [39,40]

• #Daratumumab** 16 mg/kg IV

- once a week in cycles 1 and 2

- once every 2 weeks from cycle 3 to 8

- once every 4 weeks from cycle 9 to 24

• #Carfilzomib** 20 mg/m² IV, days 1 and 2, then at a dose of 36 mg/m², days 8, 9, 15, 16 only in cycle 1, at a dose of 36 mg/m² on days 1, 2, 8, 9, 15, 16 in cycles 2–8, and starting from cycle 9 to 24 at a dose of 36 mg/m² on days 1, 2, 15, and 16.

• #Lenalidomide** 25 mg orally, days 1–21, for a total of 24 cycles.

• #Dexamethasone** 40 mg orally, days 1, 8, 15, 22 in cycles 1 to 8, then 20 mg on the same days in cycles 9–24.

Treatment is resumed on day 29.

Isa-KRd [41–43]

• #Isatuximab** 10 mg/kg IV

- on days 1, 8, 15, 22 of cycle 1

- on days 1 and 15 of subsequent cycles

• #Carfilzomib** administration option 1: 20 mg/m² IV, days 1 and 2, then at a dose of 36 mg/m², days 8, 9, 15, 16 only in cycle 1, at a dose of 36 mg/m² on days 1, 2, 8, 9, 15, 16 in subsequent cycles

• #Carfilzomib** administration option 2: 20 mg/m² IV, day 1, then at a dose of 56 mg/m² on days 8 and 15 only in cycle 1, at a dose of 56 mg/m² on days 1, 8, and 15 in subsequent cycles.

• #Lenalidomide** 25 mg orally, days 1–21.

• #Dexamethasone** 40 mg orally or IV, days 1, 8, 15, 22

Treatment is resumed on day 29.

Appendix A3.2. Guidelines for the treatment of PCL during pregnancy

Given the limited data on managing pregnancy upon the manifestation of plasma cell leukemia (PCL), the decision regarding the timing of initiation and treatment regimen is determined individually with the involvement of a multidisciplinary team and a telemedicine consultation with specialists from federal medical centers. If PCL is diagnosed in the first trimester (up to 12 weeks) of pregnancy, it is advisable to consider the option of its termination.

Appendix B. Physician Action Algorithms

Appendix C. Patient Information

PCL is a neoplastic disease and is currently incurable. However, modern innovative drugs and transplantation techniques make it possible to achieve a significant antitumor effect, known as remission.

Remission is a state in which the tumor burden is minimized, and the main clinical manifestations of the disease (bone pain, renal failure, infectious complications) are resolved. Modern treatment measures, including biological mechanism-based agents and traditional chemotherapy drugs, ensure control over the tumor process while preserving patients' quality of life.

Treatment for PCL is prolonged. Initial therapy is mostly performed in an inpatient setting. As clinical symptoms resolve, treatment can be continued in day care settings, outpatient clinics, or even at home.

However, it is well known that medications have side effects. Therefore, patients should promptly inform their attending physician about any adverse events occurring during treatment.

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

Appendix G1.1. ECOG scale for assessing the patient's general condition

Clinical assessment of the general condition of a patient with PCL is performed using the scale developed by the Eastern Cooperative Oncology Group [65]:

Original title: The ECOG Scale of Performance Status

Source: Oken M.M. et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group // Am. J. Clin. Oncol. 1982. Vol. 5, № 6. P. 649–65 [65]

Type: rating scale

Purpose: clinical assessment of the patient's general condition

Content and interpretation: