Plasma cell leukemia

INTRODUCTION — 

Plasma cell leukemia (PCL) is a rare, yet aggressive form of multiple myeloma (MM) characterized by plasma cells circulating in the peripheral blood that can be detected on conventional peripheral blood smear examination. PCL can either originate de novo (primary PCL) or as a secondary leukemic transformation of MM (secondary PCL).

The epidemiology, clinical presentation, diagnosis, prognosis, and treatment of PCL are discussed here. The related disorders of MM and plasmacytoma are presented separately.

●(See "Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis".)

●(See "Solitary extramedullary plasmacytoma".)

●(See "Solitary plasmacytoma of bone".)

EPIDEMIOLOGY — 

PCL is a rare plasma cell disorder characterized by circulating plasma cells on conventional peripheral blood smear in patients otherwise meeting the criteria for multiple myeloma (MM) (table 1). (See 'Diagnostic criteria' below.)

PCL is subclassified based on clinical presentation:

●Primary PCL – PCL as the initial manifestation of MM

●Secondary PCL – PCL as a leukemic transformation of previously diagnosed MM

Historically, most cases have been primary PCL (60 to 70 percent), although the distribution of disease is now more evenly split, perhaps due to an increased incidence of secondary PCL reflecting improved survival of patients with MM with treatment advances [1,2]. An estimated 1 to 4 percent of patients with MM progress to secondary PCL [1,3,4]. When compared with secondary PCL, primary PCL presents at a slightly younger age (median age 55 versus 66 years).

PCL occurs in all geographic locations and in patients of all backgrounds. The reported incidence of PCL in the United States and Europe is approximately 4 cases per 10,000,000 persons per year [5,6]. The true incidence is likely higher as these data were collected before a change in the diagnostic criteria that decreased the required plasma cell percentage. As with MM, PCL is more common in Black Americans than in White populations [5].

The most extensive data on the epidemiology of PCL come from a series of 291 patients identified in the Surveillance, Epidemiology, and End Results (SEER) database between 1973 and 2004 [5]. During this period, approximately 49,000 patients with MM were identified for a relative incidence of 0.6 percent. In this series, there were no significant differences based on sex, age, or race when compared with patients with MM. This SEER study did not distinguish between primary and secondary PCL.

CLINICAL PRESENTATION — 

Presenting signs and symptoms can include those seen in multiple myeloma (MM; eg, kidney dysfunction, hypercalcemia, lytic bone lesions, bone pain, anemia) and in other leukemias (eg, leukocytosis, anemia, thrombocytopenia, infections, hepatomegaly, splenomegaly). Approximately 40 to 50 percent of patients will have already been diagnosed with MM [7].

As an example, a retrospective analysis reported the following clinical features in patients presenting with PCL [1]:

●Median white blood cell count – 18.6 cells/microL

●Median hemoglobin – 9.2 g/dL

●Median platelet count – 75 platelets/microL

●Osteolytic lesions – 44 percent

●Extramedullary plasmacytoma – 14 percent

●Hepatomegaly – 21 percent

●Splenomegaly – 13 percent

Other findings that may be present on physical examination include lymphadenopathy, pulmonary findings related to pleural effusions, skin or soft tissue lesions, and neurologic deficits due to central nervous system involvement [2,8]. In addition, laboratory evaluation frequently demonstrates elevated levels of lactate dehydrogenase and beta-2 microglobulin.

PATHOLOGIC FEATURES

Peripheral blood

Morphology — The peripheral blood smear of patients with PCL demonstrates circulating plasma cells. To meet criteria for PCL, the proportion of plasma cells detected on conventional peripheral smear of the blood (manual white blood cell differential count) should be ≥5 percent [9]. (See 'Diagnostic criteria' below.)

The morphologic features of plasma cells can differ depending on their maturity and, at times, may be indistinguishable from myeloblasts.

●Mature plasma cells – Mature plasma cells are oval with abundant basophilic cytoplasm (picture 1 and picture 2). The nucleus is round and eccentrically located with a marked perinuclear hof, or cytoplasmic clearing. The nucleus contains "clock-face" or "spoke wheel" chromatin without nucleoli.

●Immature plasma cells – Immature plasma cells have dispersed nuclear chromatin, prominent nucleoli, and a high nuclear to cytoplasmic ratio.

Pathologic features of multiple myeloma (MM) are discussed in detail separately. (See "Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis", section on 'Peripheral smear' and "Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis", section on 'Bone marrow'.)

Immunophenotype — The cytoplasm of the neoplastic plasma cells contains either kappa or lambda light chains, but not both, indicating that the cells are clonal.

The immunophenotype of PCL differs from that of MM. While both PCL and MM express the two common plasma cell markers CD38 and CD138, PCL demonstrates a more immature phenotype as reflected in [10-12]:

●More frequent expression of CD20, CD23, CD28, CD44, and CD45

●Less frequent expression of CD9, CD56, CD71, CD117, and HLA-DR antigens

Genetic features — There is no single cytogenetic abnormality that is typical or diagnostic of PCL. Most cases will have complex cytogenetic abnormalities with a high frequency of abnormalities known to be associated with rapidly progressive, or high-risk, MM.

Hypodiploid or diploid cells are present in more than 80 percent of cases [2]. The most common abnormalities are deletion of chromosome 13q and monosomy 13. Deletion 17p, resulting in loss of TP53, has been detected in almost one-half of primary PCL and three-quarters of secondary PCL. In addition, PCL frequently has abnormalities in chromosome 1, in particular 1q21 amplification and del(1p21).

In one retrospective study, patients with PCL were noted to have the following high-risk abnormalities [1]:

●del13 – 67 to 85 percent

●t(4;14) – 16 percent

●t(14;16) – 16 percent

●del17p13 – 50 to 75 percent

This and other studies suggest that, when compared with MM, PCL has a higher incidence of t(11;14), t(14;16), and monosomy 13, with a similar incidence of t(4;14).

MYC rearrangements have also been found in PCL, although the reported incidence varies between 13 and 40 percent [1,13,14]. Other chromosomal abnormalities that have been identified in primary PCL include the loss of chromosomes 16 (80 percent) [15], 7 (11 percent) [15], and X (25 percent) [16], and trisomy of chromosome 8 (43 percent) [10].

Bone marrow aspiration and biopsy — The findings on bone marrow aspiration and biopsy are similar to those seen in MM without PCL and demonstrate an increased number of monoclonal plasma cells (picture 3). The bone marrow infiltration is usually extensive and consists of plasma cells with a high proliferative index and anaplastic or plasmablastic morphology [2]. (See "Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis", section on 'Bone marrow'.)

Protein electrophoresis and immunofixation — Protein electrophoresis of the serum and an aliquot from a 24-hour urine collection usually demonstrates monoclonal immunoglobulin production (figure 1). (See "Laboratory methods for analyzing monoclonal proteins", section on 'Serum protein electrophoresis (SPEP)'.)

Serum immunofixation will reveal production of one of the following immunoglobulins (figure 2) [1]:

●Immunoglobulin G (IgG) – 33 percent

●Immunoglobulin A (IgA) – 20 percent

●Immunoglobulin D (IgD) – 3 percent

●Immunoglobulin E (IgE) – 1 percent

Rare cases of immunoglobulin M (IgM) primary PCL have been reported [17,18].

Approximately 35 percent of patients will have light chain only disease, and less than 10 percent will be nonsecretors. (See "Laboratory methods for analyzing monoclonal proteins", section on 'Serum immunofixation'.)

DIAGNOSIS

Diagnostic evaluation — The diagnosis of PCL should be suspected in patients with confirmed or suspected multiple myeloma (MM) who present with or develop any of the following:

●Circulating plasma cells on conventional leukocyte differential count/peripheral smear evaluation

●Elevated lactate dehydrogenase (LDH)

●Hepatosplenomegaly

●Pleural effusion

Patients suspected of having PCL should be referred urgently for expert evaluation and management. Careful examination of the peripheral blood smear is key. Guidelines from the International Myeloma Working Group recommend that an experienced clinician (eg, pathologist, hematologist) systematically analyze a minimum of 100 to 200 nucleated cells per smear [9]. Flow cytometry of the peripheral blood is also performed to confirm clonality and further classify and count the circulating cells. This can be particularly helpful in cases with atypical morphology (eg, lymphoplasmacytoid features in those with t(11;14)) [19]. Further evaluation is identical to that for suspected MM (algorithm 1). (See "Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis", section on 'Evaluation'.)

Diagnostic criteria — The diagnosis of PCL requires both of the following [9]:

●Confirmed diagnosis of MM (table 1).

Bone marrow aspiration and biopsy will demonstrate a monoclonal population of plasma cells. Monoclonal protein on serum protein electrophoresis (SPEP) or urine protein electrophoresis (UPEP) supports, but is not necessary for, making the diagnosis.

●Plasma cells ≥5 percent of white blood cells on conventional peripheral blood smear (manual white blood cell differential count).

The cytoplasm of the neoplastic plasma cells must contain either kappa or lambda light chains, but not both, indicating that the cells are clonal.

Importantly, these diagnostic criteria use the plasma cells detected by manual differential count on conventional peripheral blood smear examination and not on flow cytometry. Although flow cytometry is not routinely used for this purpose, it may be a helpful adjunct in diagnostically challenging cases with atypical morphology or with borderline values (ie, approximately 5 percent circulating plasma cells on conventional peripheral blood smear). While a 5 percent cutoff is used to define PCL, lower levels of circulating plasma cells (eg, 3 to 4 percent) on conventional peripheral smear may be associated with highly proliferative and aggressive MM [20,21].

Almost all patients with MM have circulating plasma cells on flow cytometry due to the high sensitivity of the assay, and thus, their detection cannot be used to differentiate MM from PCL [22]. By contrast, the presence of ≥5 percent plasma cells on conventional white blood cell differential count indicates a very high level of circulating plasma cells. It is this level that gives PCL a unique clinical phenotype and the need to differentiate from MM, including high-risk MM. In general, median survival of PCL is much lower than that of high-risk MM, and the classification of these patients into a unique disease entity allows for better prognostication, counseling, treatment planning, and research. (See 'Prognosis' below.)

Previously, the plasma cell cutoff used to diagnose PCL was ≥20 percent, but the International Myeloma Working Group revised the cutoff to ≥5 percent based on studies indicating that the prognosis is similar for patients meeting the lower threshold [9,23-25].

The original diagnostic criteria required both an absolute plasma cell count exceeding 2000/microL and 20 percent of the peripheral blood white cells [23,25]. However, many of the older published case series required only one of these criteria for the diagnosis. There were concerns that these stringent diagnostic criteria missed many patients with PCL. Subsequent studies have found that lower plasma cell levels (eg, 5 percent and/or absolute peripheral blood plasma cell count ≥0.5 x 10⁹/L) have the same prognostic impact, leading to the revised disease definition for PCL [2,9,20,21,26,27].

Differential diagnosis — The differential diagnosis of PCL includes MM as well as other leukemias and lymphomas with abnormal cells circulating in the peripheral blood. It also includes reactive polyclonal plasmacytosis that can be related to infectious or autoimmune disorders.

Most cases will be easily distinguished from other forms of leukemia and lymphoma by morphology, with confirmation by flow cytometry or immunohistochemistry.

Patients with PCL are distinguished from those with MM or other plasma cell dyscrasias based on the detection of ≥5 percent plasma cells on white blood cell differential count examination in the peripheral blood.

A diagnosis of reactive polyclonal plasmacytosis can be excluded based on the presence of kappa or lambda light chain restriction.

PROGNOSIS — 

The prognosis of PCL is poor, and it is worse than that of high-risk multiple myeloma (MM). While the prognosis has improved with the development of new therapies, it is difficult to accurately estimate expected survival.

Historically, the median overall survival (OS) was only 6 to 11 months, with up to 28 percent of patients dying within the first month after diagnosis [1,5,13,23]. Survival was even shorter (two to seven months) when PCL occurred in the context of refractory or relapsed MM (ie, secondary PCL) [1,28].

While still suboptimal, OS has improved modestly with the widespread use of high-dose therapy with autologous hematopoietic cell transplantation (rescue) and the availability of novel agents. This was best illustrated in an analysis of the Surveillance, Epidemiology, and End Results (SEER) database of 445 patients with primary PCL diagnosed between 1973 and 2009 that reported median OS of 5, 6, 4, and 12 months for those patients diagnosed during 1973 through 1995, 1996 through 2000, 2001 through 2005, and 2006 through 2009, respectively [29]. Treatment options have improved further since this last cohort, and it is difficult to predict the expected OS of patients treated with modern regimens.

Prognostic models are under development. As an example, a multicenter retrospective study of 117 patients with primary PCL between 2006 and 2016 identified the following independent predictors of worse OS [30]:

●Age ≥60 years

●Platelet count ≤100 x 10⁹/L

●Peripheral blood plasma cell count ≥20 x 10⁹/L

The median OS in patients with zero, one, or two to three of these risk factors was 46, 27, and 12 months, respectively.

It is likely that the poor outcome in PCL is related to a high proliferative rate and the frequent presence of cytogenetic abnormalities known to be associated with rapidly progressive, or high-risk, MM. In one retrospective study, patients with PCL were noted to have the following high-risk abnormalities [1]:

●del13 – 67 to 85 percent

●t(4;14) – 16 percent

●t(14;16) – 16 percent

●del17p13 – 50 to 75 percent

More research is needed to better understand the impact of specific genetic findings on the prognosis of primary PCL and secondary PCL. As an example, primary PCL with t(11;14) may have a better prognosis than primary PCL without t(11;14). In a study of 128 patients with primary PCL diagnosed between 2014 and 2020, the 62 cases with t(11;14) had fewer adverse cytogenetic abnormalities, a different gene expression profile, and longer median OS (39 versus 18 months) when compared with those without t(11;14) [31].

Genetic markers of high-risk MM are discussed in more detail separately. (See "Multiple myeloma: Pathobiology", section on 'Cytogenetic abnormalities'.)

PRETREATMENT CONSIDERATIONS

Pretreatment evaluation — Because of the rigorous nature of the chemotherapy required for the treatment of PCL, particular attention should be paid in the history and physical examination to the presence of comorbid conditions in the patient that could complicate overall management. The history should pay specific attention to complaints of bone pain, constitutional symptoms, neurologic symptoms, and infections. The physical examination should include a detailed neurologic examination.

Our pretreatment evaluation also includes the following studies, some of which are performed as part of the diagnostic evaluation:

●A complete blood count and differential with examination of the peripheral blood smear. Flow cytometry of the peripheral blood.

●A chemistry screen that includes measurements of serum calcium, creatinine, and albumin; lactate dehydrogenase; uric acid; phosphorus; and beta-2 microglobulin. (See "Multiple myeloma: Staging and prognostic studies".)

●Prothrombin time (PT)/international normalized ratio (INR), activated partial thromboplastin time (aPTT), and fibrinogen. PCL has been associated with a disseminated intravascular coagulation (DIC)-like clinical picture, especially in the setting of a very high white blood cell count and rapid tumor lysis. In addition, patients with PCL are at increased risk for thrombosis due to circulating tumor cells, proinflammatory and prothrombotic cytokine release, and some treatments (eg, lenalidomide, thalidomide).

●Serum-free monoclonal light chain (FLC) measurement.

●A serum protein electrophoresis (SPEP) with immunofixation and quantitation of immunoglobulins. A routine urinalysis and a 24-hour urine collection for urine protein electrophoresis (UPEP) and immunofixation. (See "Laboratory methods for analyzing monoclonal proteins".)

●Bone marrow aspiration and biopsy with morphologic evaluation, immunophenotyping, and fluorescence in situ hybridization (FISH). FISH should include probes that identify t(11;14), t(4;14), t(6;14), t(14;16), t(14;20), del17p13, gain 1q, deletion of chromosome 13, and trisomies of odd-numbered chromosomes. FISH for del1p32 can provide additional prognostic information, if available. Testing for TP53 mutation can provide additional prognostic information in those without del(17p). (See "Multiple myeloma: Staging and prognostic studies", section on 'Other cytogenetic lesions'.)

●Cross-sectional imaging (eg, computed tomography [CT], positron emission tomography [PET] with CT, or magnetic resonance imaging [MRI]) for the detection of bone involvement. The choice of imaging modality is discussed separately. (See "Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis", section on 'Choice of modality'.)

●A study of cardiac ejection fraction (eg, echocardiogram or multigated acquisition [MUGA]) should be performed prior to treatment with potentially cardiotoxic agents (eg, doxorubicin, cyclophosphamide).

●A diagnostic lumbar puncture should be performed in patients with neurologic symptoms suspicious for central nervous system involvement.

Prevention and management of complications — In addition to therapy directed at the malignant clone, the management of PCL includes careful monitoring for and management of tumor lysis syndrome and hypercalcemia. Preventive measures to reduce the incidence of skeletal events, kidney damage, infections, neuropathy, and thrombosis are required for all patients with multiple myeloma (MM), as discussed separately. (See "Multiple myeloma: Overview of management", section on 'Prevention and management of complications'.)

●Tumor lysis syndrome – Given the high tumor burden and aggressiveness of the disease, patients with PCL are at risk for developing tumor lysis syndrome. This syndrome is best prevented via appropriate treatment with aggressive intravenous fluid hydration, prophylactic rasburicase or allopurinol, correction of any prior electrolyte disturbances and elements of reversible kidney failure, as well as the provision of sufficient fluids to ensure a high urine output. Patients should be monitored with serum uric acid, calcium, phosphorus, and serum creatinine (algorithm 2). This is most appropriately performed in a continuously monitored inpatient setting. (See "Tumor lysis syndrome: Prevention and treatment".)

●Hypercalcemia – Patients with hypercalcemia may be asymptomatic or present with anorexia, nausea, vomiting, polyuria, polydipsia, constipation, weakness, confusion, or stupor. The treatment of hypercalcemia depends on the calcium level, the rapidity with which it developed, and the patient's symptoms. Emergency treatment with hydration, glucocorticoids, bisphosphonates, and/or hemodialysis/calcitonin is indicated for symptomatic patients. (See "Treatment of hypercalcemia".)

TREATMENT

Goals of care and overall strategy — Patients with PCL are not cured with conventional therapy. Treatment alleviates symptoms, reverses cytopenias, and decreases end-organ damage, and it is given with the overall goals of achieving and maintaining a response, improving quality of life, and prolonging overall survival (OS).

There is no standard of care, and the approach used by experts varies. When available, we encourage patients to enroll on clinical trials. Additional information and instructions for referring a patient to an appropriate research center can be obtained from the United States National Institutes of Health.

Our approach is generally consistent with that of the European Myeloma Network [32]. Treatment begins as soon as possible after the diagnosis is confirmed, and the choice of therapy depends on eligibility for autologous hematopoietic cell transplantation (HCT) (see "Determining eligibility for autologous hematopoietic cell transplantation"):

●Eligible for HCT – For most patients eligible for HCT, we suggest three to six cycles of induction therapy, followed by tandem HCT, consolidation cycles based on response, and then two-drug maintenance until progression or unacceptable toxicity.

●Ineligible for HCT – Those ineligible for HCT are treated with 8 to 12 cycles of induction therapy, followed by two-drug maintenance until progression or unacceptable toxicity.

There have been no randomized trials investigating the treatment of PCL, and most multiple myeloma (MM) trials have excluded patients with active PCL. Recommendations are primarily based on data from small uncontrolled prospective studies, retrospective series, case reports, and extrapolation of data from patients with MM.

Induction therapy — The best induction regimen for PCL is not known, and there is great variability in clinical practice. We encourage enrollment on clinical trials when available. Most experts offer three- or four-drug regimens that include an anti-CD38 monoclonal antibody, a proteasome inhibitor and/or immunomodulator, and dexamethasone [32]. A choice among regimens depends on the patient's general health, comorbidities, presentation, and access to medications.

DVRd or IsaVRd for most patients — For most patients with PCL, we suggest induction with a four-drug regimen plus low-dose cyclophosphamide rather than a three-drug regimen. The cyclophosphamide can be omitted if tolerance is an issue. Options for the four-drug regimen include:

●DVRd (daratumumab, bortezomib, lenalidomide, and dexamethasone) (see "Multiple myeloma: Initial treatment", section on 'Daratumumab, bortezomib, lenalidomide, dexamethasone')

●IsaVRd (isatuximab, bortezomib, lenalidomide, and dexamethasone) (see "Multiple myeloma: Initial treatment", section on 'Isatuximab-based four-drug regimens')

This preference is based on extrapolation of data that demonstrate better outcomes with four-drug, rather than three-drug, regimens in patients with MM; data that suggest that proteasome inhibitors and anti-CD38 monoclonal antibodies are among our most active therapies in patients with MM and high-risk genetic abnormalities also seen in PCL; and retrospective studies that suggest the activity of these drugs in PCL. We have a low threshold to incorporate low-dose cyclophosphamide based on the OPTIMUM trial in ultra-high-risk MM described below. A three-drug regimen is an alternative for patients who cannot tolerate a four-drug regimen. (See 'Triplet regimens as an alternative' below.)

We also suggest induction with DVRd or IsaVRd rather than VDT-PACE (bortezomib, dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, and etoposide). VDT-PACE is an older, aggressive regimen that had been commonly used in younger, fit patients who required a rapid response prior to the development of four-drug regimens in MM. Although DVRd and IsaVRd have not been directly compared with VDT-PACE, they also produce rapid responses and are well tolerated. (See "Multiple myeloma: Treatment of second or later relapse", section on 'VDT-PACE'.)

While there are several randomized trials demonstrating the benefit of four-drug regimens in MM, there is a paucity of data specifically evaluating DVRd and IsaVRd in PCL. Nonrandomized, prospective trials of other intensive protocols that included proteasome inhibitor-containing induction, autologous HCT, and maintenance in the treatment of PCL have reported high response rates, median progression-free survival (PFS) of approximately 15 months, and median overall survival (OS) as long as three years [33,34]. Although cross-trial comparisons have significant limitations, these results are better than the median PFS of 2 months and OS of 12 months reported in a trial of induction with lenalidomide plus dexamethasone with or without autologous HCT [35]. Retrospective studies have also reported superior outcomes in patients with PCL treated with multidrug regimens that included a proteasome inhibitor and/or daratumumab [7,36-50]. In addition, a small number of patients with PCL were included in the OPTIMUM phase 2 trial of ultra-high-risk MM that reported relatively good outcomes following an intensive induction with daratumumab, low-dose cyclophosphamide, lenalidomide, bortezomib, and dexamethasone, followed by autologous HCT, extended consolidation, and two-drug maintenance with daratumumab and lenalidomide [51]. Specific outcomes in the PCL population are not available for this trial.

Triplet regimens as an alternative — Three-drug regimens are an alternative for patients with PCL who are ineligible for four-drug regimens due to frailty, comorbidities, or access. We prefer triplets that contain the anti-CD38 monoclonal antibody daratumumab because this drug is effective and well tolerated.

●Daratumumab-containing triplets:

•DRd (daratumumab, lenalidomide, and dexamethasone) (table 2) (see "Multiple myeloma: Initial treatment", section on 'Daratumumab, lenalidomide, dexamethasone')

•DVd (daratumumab, bortezomib, and dexamethasone) (see "Multiple myeloma: Treatment of first relapse", section on 'Daratumumab, bortezomib, dexamethasone (DVd)')

●Other proteasome inhibitor-containing triplets:

•KRd (carfilzomib, lenalidomide, and dexamethasone) (see "Multiple myeloma: Treatment of first relapse", section on 'Carfilzomib, lenalidomide, dexamethasone (KRd)')

•VRd (bortezomib, lenalidomide, and dexamethasone) (table 3) (see "Multiple myeloma: Initial treatment", section on 'Bortezomib, lenalidomide, dexamethasone')

Adjustments and dose modifications may be needed. For frail adults, we use lower doses of lenalidomide (15 mg instead of 25 mg) and dexamethasone (20 mg once a week instead of 40 mg once a week). Lenalidomide is usually avoided in patients with kidney dysfunction, especially those with acute kidney failure due to cast nephropathy. DVd can be used in patients with kidney impairment and acute kidney failure.

There are limited data regarding the use of these regimens in PCL. Support largely comes from extrapolation of data from patients with MM, some of which included a small number of patients with PCL. A nonrandomized, phase 2 multicenter trial (EMN 12/HOVON129) evaluated KRd as induction in primary PCL, followed by tandem autologous HCT (if eligible) and consolidation and maintenance with carfilzomib and lenalidomide [34]. The transplant-ineligible population received the same approach but without autologous HCT. Those eligible for allogeneic HCT could receive autologous HCT followed by reduced-intensity allogeneic HCT instead of the tandem autologous HCT. Results included:

●Among the 36 patients ≤65 years, most patients had a measurable response (86 percent partial response or better, 50 percent complete response, 28 percent minimal residual disease negative). After a median follow-up of 44 months, median PFS was 15.5 months, and median OS was 28.4 months. There were 20 deaths: 19 from progressive disease and 1 from infection after allogeneic HCT. Early mortality was uncommon (8.3 percent at six months).

●Among the 25 patients ≥66 years, most patients had a measurable response (80 percent partial response or better, 36 percent complete response). After a median follow-up of 32 months, median PFS was 13.8 months, and median OS was 24.8 months. There were 18 deaths: 12 from disease progression, 3 from infection, 2 from other causes, and 1 from an unknown cause.

These results suggest that carfilzomib is also effective, although with moderate toxicity, especially among the older group.

Transplantation and consolidation — High-dose chemotherapy followed by autologous HCT improves OS in patients with MM and has become part of the standard of care for eligible patients. For HCT-eligible patients with PCL, we suggest induction therapy followed by immediate autologous HCT rather than delaying HCT until the time of relapse. For most patients, we suggest a second autologous HCT (tandem auto-auto), ideally within three to six months of the first HCT, based on retrospective studies that suggest improved PFS with this approach. A minority of patients will be eligible for allogeneic HCT and have an appropriate donor; our approach to such patients is highly individualized and influenced by the response to initial therapy. Such patients who did not achieve a complete remission (CR) after induction therapy may elect to proceed with autologous HCT followed by reduced-intensity conditioning and allogeneic HCT (tandem auto-allo) rather than a second autologous HCT.

Following HCT, our use of consolidation is individualized based on response. For those who have not achieved a CR after tandem HCT, we offer up to four cycles of consolidation chemotherapy with the same regimen used for induction therapy prior to proceeding with maintenance therapy. Those who achieved a CR with tandem HCT may reasonably proceed directly to maintenance.

Prospective randomized trials of autologous or allogeneic HCT versus nontransplant strategies have not included patients with PCL. Case reports and case series have recorded some long-term responses to autologous or allogeneic HCT in PCL [7,33,52-56]. However, most of these data are based on patients who were treated with induction regimens that did not include bortezomib or anti-CD38 monoclonal antibodies.

Due to the poor prognosis with chemotherapy alone in these patients, we offer high-dose chemotherapy followed by autologous stem cell rescue and a second (tandem) autologous or allogeneic HCT. Following HCT, maintenance therapy is offered to delay relapse. (See 'Maintenance' below.)

Available data suggest that HCT may be of value in PCL, although no definite conclusions can be made due to a lack of randomized data. The following is a compilation of reports on the use of HCT in PCL along with corresponding key conclusions:

●Superior outcomes with HCT when compared with nontransplant strategies – A multicenter retrospective analysis of 73 patients with primary PCL included 23 patients who had undergone a single autologous HCT (9 patients), a double autologous HCT (8 patients), an allogeneic HCT (2 patients), or a tandem autologous/allogeneic HCT (4 patients) [7]. Among patients who underwent HCT, median OS and duration of response were 38 and 27 months, respectively. In this highly selected group, patients who survived initial therapy and received HCT had superior survival and response durations when compared with those who did not receive HCT.

In another multicenter retrospective study that included 117 patients with primary PCL, 98 patients were treated with novel agents, with an overall response rate of 78 percent [30]. Of these, 55 patients (64 percent) underwent upfront autologous HCT. After a median follow-up of 50 months (95% CI 33-76), median OS for the group as a whole was 23 months (95% CI 15-34). Those who underwent upfront autologous HCT had longer median OS than those who did not receive autologous HCT (35 months [95% CI 24.3-46] versus 13 months [95% CI 6.3-35.8]).

●Inferior outcomes following HCT for PCL when compared with MM – A retrospective study conducted by the European Society for Blood and Marrow Transplantation (EBMT) included 272 patients with primary PCL and 20,844 patients with MM who had undergone autologous HCT from 1980 to 2006 [57]. While patients with PCL were more likely to enter CR after transplantation, their median PFS (14 versus 27 months) and OS (26 versus 62 months) were inferior to those of patients with MM.

●Impact of tandem HCT and role for allogeneic HCT in select patients – Although outcomes appear to be improved with autologous HCT, relapse rates remain high. A meta-analysis that included 1535 patients with primary PCL who underwent autologous HCT reported pooled estimates for three-year OS (51 percent), PFS (36 percent), and relapse (68 percent) [58]. Tandem transplant has been offered in an attempt to delay relapse. A retrospective analysis from the EBMT included 751 patients with primary PCL who underwent HCT between 1998 and 2014 using one of four strategies: single autologous HCT; single allogeneic HCT; tandem auto-auto HCT; or tandem auto-allo HCT [56]. With a median follow-up of 49 months, median OS and PFS were 33 and 14 months, respectively. When compared with initial autologous HCT (with or without subsequent HCT), initial allogeneic HCT was associated with better disease control and a lower relapse rate (46 versus 68 percent at 36 months) but higher nonrelapse mortality (27 versus 7 percent at 36 months), especially early mortality, which translated into inferior OS (median 18 versus 34 months). By contrast, when compared with those undergoing a single autologous HCT, those who underwent tandem auto-allo HCT had similar early mortality and improved PFS (hazard ratio [HR] 0.69). Tandem auto-auto HCT appeared to be similarly effective to tandem auto-allo HCT in those who achieved a CR prior to first transplant, but inferior to auto-allo HCT in those who did not achieve a CR prior to transplant. This provides support for initial autologous HCT followed by a tandem autologous or allogeneic HCT, depending on initial disease control.

Careful patient selection and choice of conditioning regimen are important to minimize nonrelapse mortality in this setting. The risk of substantial nonrelapse mortality with allogeneic HCT was highlighted in a retrospective study from the Center for International Blood and Marrow Transplant Research that analyzed the outcomes of patients with PCL who underwent autologous (97 patients, median age 56 years) or allogeneic (50 patients, median age 48 years) HCT within 18 months of diagnosis between 1995 and 2006 [54]:

•Following autologous HCT – Estimated three-year PFS (34 percent), relapse (61 percent), nonrelapse mortality (5 percent), and OS (64 percent).

•Following allogeneic HCT – Estimated three-year PFS (20 percent), relapse (38 percent), nonrelapse mortality (41 percent), and OS (39 percent).

In a phase II trial of 40 patients with PCL treated with bortezomib-based induction, responding patients underwent autologous HCT followed by either a second autologous HCT (6 patients) or reduced-intensity allogeneic HCT (16 patients) [33]. For the entire cohort, median PFS and OS were 15 and 36 months, respectively. The median OS was not reached for those undergoing autologous HCT and was 36 months for those undergoing allogeneic HCT. Part of this survival benefit may reflect selection bias with younger patients who survived initial therapy proceeding to HCT.

Maintenance — For all patients with PCL, we suggest maintenance with lenalidomide and/or bortezomib rather than observation until relapse. Two-drug maintenance is preferable, if tolerated. This preference is based on the short remission durations (14 months) seen in these patients and the relatively mild toxicity of maintenance. For most patients, we offer two-drug maintenance with bortezomib plus lenalidomide. Lenalidomide plus carfilzomib is an acceptable alternative for patients unable to tolerate standard-dose bortezomib due to neuropathy. Daratumumab plus lenalidomide is an acceptable alternative, especially for patients who cannot tolerate bortezomib or carfilzomib.

There have been no randomized studies of maintenance therapy in patients with PCL. However, since virtually all patients with PCL who attain a CR develop relapsed disease, consideration should be given to some form of maintenance therapy.

Maintenance can prolong PFS in patients with MM. The benefits of improved PFS must be balanced against an increased rate of severe (grade 3/4) neutropenia, risk of second cancers and other toxicities, the cost, and the possibility that the PFS advantage may be neutralized by the use of lenalidomide at time of first relapse.

Studies evaluating the use of maintenance therapy in patients with MM are presented separately. (See "Multiple myeloma: Initial treatment", section on 'Maintenance for patients who are ineligible for or defer HCT' and "Multiple myeloma: Use of hematopoietic cell transplantation", section on 'High-risk disease'.)

RESPONSE ASSESSMENT — 

Patients should be evaluated before each treatment cycle to determine how their disease is responding to therapy. Response is evaluated using specific criteria from the International Myeloma Working Group that incorporate response features used for acute leukemia and multiple myeloma (table 4) [2].

This assessment includes the following:

●Quantitation of peripheral blood plasma cells by morphologic review of the peripheral smear.

●Measurement of monoclonal (M) protein in the serum and urine (SPEP, UPEP).

●Evaluation of previously identified or suspected extramedullary disease.

●Bone marrow evaluation is incorporated to identify a complete response or better.

●The free monoclonal light chain (FLC) assay and flow cytometry or immunohistochemistry of the bone marrow are incorporated to identify stringent complete remission.

The goal of therapy in PCL is to achieve and maintain a complete response, as much as possible; this goal therefore influences the choice of the initial treatment options. However, since the disease is not considered curable, failure to achieve a complete response should not be construed as a reason to change or intensify therapy. There are no data that such an approach leads to superior survival. In selected patients with good performance status who respond but fail to achieve a complete response, after a full discussion of the pros and cons, consideration can be given to allogeneic HCT and other options used for patients with relapsed/refractory disease. (See "Multiple myeloma: Use of hematopoietic cell transplantation", section on 'Allogeneic HCT'.)

Relapse from complete remission is identified by the reappearance of an M protein, development of extramedullary disease, reappearance of circulating plasma cells, or an increase in the bone marrow plasma cells to >10 percent [2]. Therapy should be reinstated at the time of relapse.

RECURRENT OR REFRACTORY DISEASE — 

There is limited information to guide the treatment of recurrent or refractory PCL, and care is individualized.

Options include a trial of another regimen active in multiple myeloma (MM), retreatment with previously effective regimens (if the relapse occurred off-therapy), and transplantation. Options for relapsed or refractory MM are discussed separately. (See "Multiple myeloma: Treatment of first relapse" and "Multiple myeloma: Treatment of second or later relapse".)

The following treatments are of particular interest in relapsed PCL:

●Regimens that include an anti-CD38 monoclonal antibody – Regimens that include an anti-CD38 monoclonal antibody (eg, daratumumab, isatuximab) are an option for patients who have not been exposed to these agents or have progressed more than 60 days after their last dose. As PCL expresses CD38, regimens that include an anti-CD38 monoclonal antibody are an attractive option, and initial reports suggest that they are active. Efficacy data are primarily from case reports. A retrospective study reported outcomes in 28 patients with PCL treated with daratumumab-based combinations [48]. Among the 14 patients with primary PCL (4 previously untreated), 11 patients (79 percent) achieved an at least partial response, and median PFS was 20 months. Among the 14 patients with secondary PCL, 8 patients (57 percent) achieved a partial response or better, and median PFS was 5 months. The use of anti-CD38 monoclonal antibodies for induction as part of quadruplet and triplet regimens is discussed in detail separately. (See 'Induction therapy' above.)

●Venetoclax for t(11;14)-positive disease – There is also interest in venetoclax because the t(11;14) has been reported in 45 to 70 percent of patients with PCL. Several case reports have described responses to venetoclax or venetoclax-containing therapy [59-66]. Further data are needed to better understand the efficacy and toxicity of this agent in PCL. Its use in MM is discussed separately. (See "Multiple myeloma: Treatment of second or later relapse", section on 'Venetoclax for MM with t(11;14)'.)

●Transplantation and other cellular therapies – Patients who are eligible may be considered for allogeneic HCT or an autologous HCT followed by an allogeneic HCT, if they have not received these options as part of initial therapy. Patients who have undergone allogeneic HCT may respond to the withdrawal of immunosuppression or immunotherapy with donor lymphocyte infusion. (See 'Transplantation and consolidation' above.)

Data regarding BCMA-directed chimeric antigen receptor (CAR)-T cell therapies are limited. PCL was an exclusion criterion in the trials conducted for the approval of idecabtagene vicleucel and ciltacabtagene autoleucel. A study conducted in China evaluated the efficacy and safety of a BCMA-CAR-T in 30 patients with relapsed/refractory MM, 2 of whom had primary PCL [67]. One patient achieved a complete response with a PFS of 307 days, and the other patient achieved a very good partial response with a PFS of 117 days. (See "Multiple myeloma: Treatment of second or later relapse", section on 'Chimeric antigen receptor T cells'.)

●Other options – There are limited data on the use of bispecific antibodies in PCL. A case report illustrated disease response to the anti-BCMA/CD3 bispecific antibody elranatamab and to the anti-GPRC5D/CD3 bispecific antibody talquetamab [68]. Similarly, case reports described a response to the combination of selinexor, pomalidomide, and dexamethasone [69].

Often, there is no better therapy to offer a patient than enrollment onto a well-designed, scientifically valid, peer-reviewed clinical trial. Additional information and instructions for referring a patient to an appropriate research center can be obtained from the United States National Institutes of Health.

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Multiple myeloma".)

SUMMARY AND RECOMMENDATIONS

●Clinical presentation – Plasma cell leukemia (PCL) is a rare, yet aggressive variant of multiple myeloma (MM) characterized by plasma cells circulating in the peripheral blood. PCL can either originate de novo (primary PCL) or as a secondary leukemic transformation of MM (secondary PCL).

Presenting signs and symptoms can include those seen in MM (eg, kidney dysfunction, hypercalcemia, lytic bone lesions, anemia) and in other leukemias (eg, anemia, thrombocytopenia, infections, hepatomegaly, splenomegaly). (See 'Clinical presentation' above.)

●Diagnostic evaluation – The diagnosis of PCL should be suspected in patients with confirmed or suspected MM who present with or develop any of the following:

•Circulating plasma cells on conventional leukocyte differential count/peripheral smear evaluation

•Elevated lactate dehydrogenase

•Hepatosplenomegaly

•Pleural effusion

Patients suspected of having PCL should be referred urgently for expert evaluation, which includes careful examination of the peripheral blood smear, flow cytometry of the peripheral blood, and evaluation for suspected MM (algorithm 1). (See 'Pathologic features' above.)

Diagnosis of PCL requires both a confirmed diagnosis of MM (table 1) and ≥5 percent plasma cells on white blood cell differential count on conventional peripheral blood smear evaluation. (See 'Diagnostic criteria' above and 'Differential diagnosis' above.)

●Initial treatment – While not curative, treatment aims to improve quality of life and extend survival. There is no standard of care, and the approach used by experts varies. (See 'Induction therapy' above.)

Treatment begins as soon as possible after diagnosis, and our strategy depends on eligibility for autologous hematopoietic cell transplantation (HCT):

•Eligible for HCT – For most patients eligible for HCT, we administer three to six cycles of induction therapy, followed by tandem HCT, consolidation based on response, and two-drug maintenance until progression or unacceptable toxicity.

•Ineligible for HCT – Those ineligible for HCT are treated with 8 to 12 cycles of induction therapy, followed by two-drug maintenance until progression or unacceptable toxicity.

For most patients with PCL, we suggest induction with a four-drug regimen that includes an anti-CD38 monoclonal antibody (daratumumab or isatuximab) plus bortezomib, lenalidomide, and dexamethasone plus low-dose cyclophosphamide (Grade 2C). The cyclophosphamide can be omitted if tolerance is an issue. A three-drug regimen is an alternative for patients who cannot tolerate a four-drug regimen. (See 'Induction therapy' above.)

For patients who are candidates for HCT, we suggest proceeding after induction therapy to high-dose therapy plus autologous HCT rather than delaying HCT until the time of relapse (Grade 2C). For most patients, we suggest a second autologous HCT rather than a single HCT (Grade 2C). A minority of patients will be eligible for allogeneic HCT and have an appropriate donor. Such patients who did not achieve a complete remission (CR) after induction therapy may elect to proceed with autologous HCT followed by reduced-intensity conditioning and allogeneic HCT instead of a second autologous HCT. (See 'Transplantation and consolidation' above.)

For those who have not achieved a CR after tandem HCT, we suggest consolidation chemotherapy with the same regimen used for induction therapy (Grade 2C), administered for up to four cycles prior to proceeding with maintenance therapy. Those who achieved a CR with tandem HCT may reasonably proceed directly to maintenance. (See 'Transplantation and consolidation' above.)

For most patients, we suggest maintenance with lenalidomide and bortezomib rather than single-drug maintenance or observation until relapse (Grade 2C). Lenalidomide plus carfilzomib is an acceptable alternative for patients unable to tolerate standard-dose bortezomib due to neuropathy. Daratumumab plus lenalidomide is an acceptable alternative for patients who cannot tolerate bortezomib or carfilzomib. (See 'Maintenance' above.)

●Relapsed or refractory disease – There is limited information to guide the treatment of recurrent or refractory PCL, and care is individualized. Options include a trial of another regimen active in MM, retreatment with previously effective regimens (if the relapse occurred off-therapy), and transplantation. (See 'Recurrent or refractory disease' above.)