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 plasma cell leukemia 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, and neurologic deficits due to central nervous system involvement [2]. In addition, laboratory evaluation frequently demonstrates elevated levels of lactate dehydrogenase (LDH) 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 [8]. (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 [9-11]:

●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 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 [1,12,13]. Other chromosomal abnormalities that have been identified in primary PCL include the loss of chromosomes 16 (80 percent) [14], 7 (11 percent) [14], and X (25 percent) [15], and trisomy of chromosome 8 (43 percent) [9].

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]:

●IgG – 33 percent

●IgA – 20 percent

●IgD – 3 percent

●IgE – 1 percent

Approximately 35 percent of patients will have light chain only disease and less than 10 percent will be non-secretors. (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 [8]. Flow cytometry of the peripheral blood is also performed to confirm clonality and further classify the circulating cells. 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 [8]:

●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 a conventional peripheral blood smear examination and not on flow cytometry. 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 [16,17].

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 [18]. In 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 [8,19-21].

The original diagnostic criteria required both an absolute plasma cell count exceeding 2000/microL and 20 percent of the peripheral blood white cells [19,21]. 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 [2,8,16,17,22,23].

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 absence 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 dying within the first month after diagnosis [1,5,12,19]. Survival was even shorter (two to seven months) when PCL occurred in the context of refractory or relapsed MM (ie, secondary PCL) [1].

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 1973-1995, 1996-2000, 2001-2005, and 2006-2009, respectively [24].

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 [25]:

●Age ≥60 years

●Platelet count ≤100 x 10⁹/L

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

The median OS in patients with 0, 1, or 2 to 3 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 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) [26].

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

TREATMENT

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 exam.

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, albumin, lactate dehydrogenase, uric acid, phosphorus, and beta-2 microglobulin. (See "Multiple myeloma: Staging and prognostic studies".)

●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 electrophoresis (UPEP) and immunofixation. (See "Laboratory methods for analyzing monoclonal proteins".)

●Bone marrow aspiration and biopsy with 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, and trisomies of odd numbered chromosomes. FISH for del1p32 can provide additional prognostic information, if available. (See "Multiple myeloma: Staging and prognostic studies", section on 'Other cytogenetic lesions'.)

●Cross sectional imaging (eg, computed tomography [CT], positron emission tomography with computed tomography [PET/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 MUGA) should be performed prior to treatment with potentially cardiotoxic agents (eg, doxorubicin, cyclophosphamide).

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. Preventative 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 insure 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".)

Initial 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 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 (www.clinicaltrials.gov).

Our approach is generally consistent with that of the European Myeloma Network [27]. Treatment begins as soon as possible after the diagnosis is confirmed and 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 autologous HCT and 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 maintenance until progression or unacceptable toxicity.

There have been no prospective randomized trials investigating the treatment of PCL, and the vast majority of 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. Most experts offer regimens that incorporate the proteasome inhibitor bortezomib [27]. While initial data regarding other proteasome inhibitors (eg, carfilzomib) are promising, we do not use them off-label for the initial treatment of PCL.

For patients with PCL, we suggest induction therapy with one of the following bortezomib-based regimens [28,29]:

●VDT-PACE (bortezomib, dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, and etoposide). (See "Multiple myeloma: Treatment of third or later relapse", section on 'VDT-PACE'.)

●Dara-VRd (daratumumab, bortezomib, lenalidomide, and dexamethasone). (See "Multiple myeloma: Initial treatment", section on 'Daratumumab, bortezomib, lenalidomide, dexamethasone'.)

●VCd (bortezomib, cyclophosphamide, dexamethasone, also known as CyBorD) (table 2).

●VTd (bortezomib, thalidomide, dexamethasone) (table 3).

●VRd (bortezomib, lenalidomide, dexamethasone) (table 4).

A choice among these depends on the patient's general health, comorbidities, and presentation. Of these, VDT-PACE is the most aggressive regimen; it may be preferred in younger, fit patients who require a rapid response. Options for patients with acute kidney failure due to cast nephropathy include VDT-PACE, VCd, and VTd; lenalidomide is typically avoided in this population. Escalation of care to a four-drug regimen that incorporates an anti-CD38 monoclonal antibody (eg, daratumumab-VTd or daratumumab-VRd) is a reasonable option for selected patients with a suboptimal response after the first cycle.

As described in more detail below, one nonrandomized trial and several retrospective series suggest bortezomib-based combinations are active in PCL. Additional support comes from extrapolation of data from prospective trials in MM that suggest proteasome inhibitors, such as bortezomib, are one of our most active therapies in patients with high-risk MM as defined by genetic abnormalities. Since patients with PCL often demonstrate these same genetic abnormalities, bortezomib has been tested in PCL, and it appears to be active. Responses have also been seen in patients treated with lenalidomide-based regimens [30-33]. In contrast, patients with PCL have had poor OS with older treatments for MM [1,9,15].

The following is a survey of studies that have investigated bortezomib in the treatment of PCL:

●In a phase II trial, 40 patients with PCL underwent induction with four cycles of bortezomib-based chemotherapy [34]. Bortezomib, dexamethasone, and doxorubicin (PAD) was given for cycles 1 and 3, and VCD was given for cycles 2 and 4. Responding patients underwent high-dose melphalan plus autologous HCT followed by either a second autologous HCT and maintenance therapy or a reduced-intensity allogeneic HCT. The overall response rate was 69 percent (10 percent complete). Median progression-free survival (PFS) and OS were 15 and 36 months, respectively.

●A multicenter retrospective study of 73 patients with PCL included 14 patients initially treated with a regimen that contained bortezomib [7]. Of these, 10 (71 percent) demonstrated an at least partial response (four complete responses). Among patients initially treated with bortezomib, thalidomide, or a combination of the two drugs, the median survival was 12.6 months, but among patients responding to bortezomib, approximately half were alive without relapse at 26 months from diagnosis. In this study, the choice of initial therapy did not affect survival, but the sample size does not permit adequate comparisons, and no conclusions can be made.

●In another multicenter retrospective study of 42 patients with primary or secondary PCL, bortezomib-based therapy was associated with higher response rates (69 versus 31 percent) and longer median survival (13 versus 2 months) [35]. When treated with a bortezomib-based therapy, the median survival times of patients with primary and secondary PCL were 18 and 7 months, respectively.

The above reports and smaller case reports show the safety and feasibility of bortezomib-based initial therapy [33,36-45].

Carfilzomib has not been directly compared with bortezomib in this setting. A nonrandomized, phase 2 multicenter trial (EMN 12/HOVON129) evaluated carfilzomib plus lenalidomide and dexamethasone as induction in primary PCL followed by tandem autologous HCT (if eligible) and consolidation and maintenance with carfilzomib and lenalidomide [46]. The transplant-ineligible population will receive 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, the median PFS was 15.5 months, and the 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, the median PFS was 13.8 months, and the median OS was 24.8 months. There were 18 deaths: 12 from disease progression, 3 from infection, 2 from other causes, and 1 unknown cause.

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

Transplantation — 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. A minority of patients will be eligible for allogeneic HCT. As the role of allogeneic HCT remains investigational, such transplants should ideally be conducted in the context of a clinical trial.

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 [7,34,47-50]. However, most of these data are based on patients who were treated with non-bortezomib-based induction regimens.

Due to the poor prognosis with chemotherapy alone in these patients, we offer high-dose chemotherapy followed by autologous stem cell rescue to eligible patients with PCL. This approach follows bortezomib-based induction therapy as discussed above. Following HCT, consideration should be given to some form of maintenance therapy to prevent relapse.

At present, the data suggest that HCT may be of value in PCL, although no definite conclusions can be made due to lack of randomized data. Further, there are no data on whether allogeneic approaches offer any additional benefit compared with autologous HCT. 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 (nine patients), a double autologous HCT (eight patients), an allogeneic HCT (two patients), or a tandem autologous/allogeneic HCT (four patients) [7]. Among patients who underwent HCT, the 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 [25]. 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 – The largest retrospective study was conducted by the European Group for Blood and Marrow Transplantation and included 272 patients with primary PCL and 20,844 patients with MM who had undergone autologous HCT from 1980 to 2006 [51]. While patients with PCL were more likely to enter complete remission after transplantation, their median PFS (14 versus 27 months) and OS (26 versus 62 months) were inferior to that of patients with MM.

●Inferior outcomes following allogeneic HCT when compared with autologous HCT – A retrospective study from the Center for International Blood and Marrow Transplant Research 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 reported inferior outcomes with allogeneic compared with autologous transplantation in this patient population [49]:

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

•Following allogeneic HCT – estimated three-year PFS (20 percent), relapse (38 percent), non-relapse 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) [34]. 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. Ongoing clinical trials (eg, EMN12/HOVON 129) are evaluating maintenance with lenalidomide plus carfilzomib, and we consider this combination investigational.

There have been no randomized studies of maintenance therapy in patients with PCL. However, since virtually all patients with PCL who attain a complete remission 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 for MM (table 5) [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 complete response or better

●The 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 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 a monoclonal protein, the 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.

Treatment of 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 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 or second relapse" and "Multiple myeloma: Treatment of third or later relapse".)

The following treatments are of particular interest in relapsed PCL:

●Daratumumab-based regimens – As PCL expresses CD38, regimens that include an anti-CD38 monoclonal antibody (eg, daratumumab, lenalidomide, and dexamethasone (table 6)) 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 [52]. Among the 14 patients with primary PCL (four previously untreated), 11 patients (79 percent) achieved an at least partial response and the median PFS was 20 months. Among the 14 patients with secondary PCL, 8 patients (57 percent) achieved a partial response or better and the median PFS was 5 months. Daratumumab-containing regimens used for MM are discussed separately. (See "Multiple myeloma: Treatment of first or second relapse".)

●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 cases reports have described responses to venetoclax or venetoclax-containing therapy [53-59]. Further data are needed to better understand the efficacy and toxicity of this agent in PCL. Use in MM is discussed separately. (See "Multiple myeloma: Treatment of third 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. Patients who have undergone allogeneic HCT may respond to withdrawal of immunosuppression or immunotherapy with donor lymphocyte infusion. (See 'Transplantation' 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, two of whom had primary PCL [60]. 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 third or later relapse", section on 'Chimeric antigen receptor T cells'.)

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 (www.clinicaltrials.gov).

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 (LDH)

•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 'Treatment' above.)

Treatment begins as soon as possible after diagnosis, and choice of therapy 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 autologous HCT and 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 maintenance until progression or unacceptable toxicity.

For most patients with PCL we suggest a multidrug induction regimen that includes bortezomib (Grade 2C). For young, fit patients, we suggest VDT-PACE (bortezomib, dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, and etoposide) (Grade 2C). Alternatives for less-fit patients are discussed above. (See 'Induction therapy' above.)

For patients who are candidates for transplantation, we suggest proceeding after induction therapy to high-dose therapy plus autologous HCT rather than delaying HCT until the time of relapse (Grade 2C). (See 'Transplantation' above.)

For most patients, we suggest maintenance with lenalidomide and bortezomib rather than single-drug maintenance or observation until relapse (Grade 2C). However, if not tolerated, single-drug maintenance is an acceptable alternative. (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 'Treatment of recurrent or refractory disease' above.)