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The Management of Multiple Myeloma in Younger Patients

September 19, 2013 Chemotherapy, Cytogenetics, Hematology, Therapeutics, Transplantation No comments , , , , , , , , , ,

Therapy for multiple myeloma (MM) has advanced with gratifying speed over the past 5 to 7 years and with this progress, a degree of uncertainty has arisen about optimal approaches to therapy, particularly in the newly diagnosed patients. Indeed, using mordern therapeutic strategies, living with MM for a decade or longer has now become a reality for a significant proportion of patients.

Pathophysiology

MM is characterized by neoplastic proliferation of plasma cells involving more than 10% of the bone marrow. Increasing evidence suggests that the bone marrow microenvironment of tumor cells plays a pivotal role in the pathogenesis of myelomas.

The malignant cells of MM, plasma cells, and plasmacytoid lymphocytes are the most mature cells of B-lymphocytes. B-cell maturation is associated with a programmed rearrangement of DNA sequences in the process of encoding the structure of mature immunoglobulins. It is characterized by overproduction of monoclonal immunoglobulin G (IgG), immunoglobulin A (IgA), and/or light chains, which may be identified with serum protein electrophoresis (SPEP) or urine protein electrophoresis (UPEP).

The role of cytokines in the pathogenesis of MM is an important area of research. Interleukin (IL)–6 is also an important factor promoting the in vitro growth of myeloma cells. Other cytokines are tumor necrosis factor and IL-1b.

The pathophysiologic basis for the clinical sequelae of MM involves the skeletal, hematologic, renal, and nervous systems, as well as general processes.

Development Progresses

Skeletal processes

Plasma-cell proliferation causes extensive skeletal destruction with osteolytic lesions, anemia, and hypercalcemia. Mechanisms for hypercalcemia include bony involvement and, possibly, humoral mechanisms. Isolated plasmacytomas (which affect 2-10% of patients) lead to hypercalcemia through production of the osteoclast-activating factor.

Destruction of bone and its replacement by tumor may lead to pain, spinal cord compression, and pathologic fracture. The mechanism of spinal cord compression symptoms may be the development of an epidural mass with compression, a compression fracture of a vertebral body destroyed by multiple myeloma, or, rarely, an extradural mass. With pathologic fracture, bony involvement is typically lytic in nature.

Hematologic processes

Bone marrow infiltration by plasma cells results in neutropeniaanemia, andthrombocytopenia. In terms of bleeding, M components may interact specifically with clotting factors, leading to defective aggregation.

Renal processes

The most common mechanisms of renal injury in MM are direct tubular injury, amyloidosis, or involvement by plasmacytoma.[14, 15] Renal conditions that may be observed include hypercalcemic nephropathy, hyperuricemia due to renal infiltration of plasma cells resulting in myeloma, light-chain nephropathy,amyloidosis, and glomerulosclerosis.

Neurologic processes

The nervous system may be involved as a result of radiculopathy and/or cord compression due to nerve compression and skeletal destruction (amyloid infiltration of nerves).

General processes

General pathophysiologic processes include hyperviscosity syndrome. This syndrome is infrequent in MM and occurs with IgG1, IgG3, or IgA. MM may involve sludging in the capillaries, which results in purpura, retinal hemorrhage, papilledema, coronary ischemia, or central nervous system (CNS) symptoms (eg, confusion, vertigo, seizure). Cryoglobulinemia causes Raynaud phenomenon, thrombosis, and gangrene in the extremities.

Workup

Some tests can afford important prognostic information and the subtypes of myeloma. These tests include classic CRAB measurements (calcium level, renal function, amemia, bone damage) , β2-microglobulin, albumin, lactate dehydrogenase (LDH), serum and urine monoclonal protein (24-hour) such as serum protein electrophoresis (SPEP), serum immunofixation electrophoresis (SIFE), 24 h urine protein electrophoresis (UPEP), urine immunofixation electrophoresis (UIFE), and so on, serum-free light chain assay.

Bone marrow examinations such as morphology, FISH (fluorescent in situ hybridization) analysis of key genetic events, metaphase cytogenetics are also mandatory at present.

Table 1. Genetic Tests to Be Performed in Myeloma Patients at Diagnosis.

With these tests, multiple myeloma can be divided into three subtypes, which are solitary plasmacytoma, smoldering myeloma (asymptomatic myeloma) and active myeloma (symptomatic myeloma).

Subtypes of Multiple Myeloma

According to the latest NCCN guideline MM can be categorized into three subgroups including solitary plasmacytoma, smoldering myeloma (asymptomatic), and active myeloma (symptomatic).

Solitary plasmacytoma

Solitary plasmacytoma is a large solitary focus of plasma cell proliferation. To simplify, solitary plasmacytomas can be divided into 2 groups according to location: Plasmacytoma of the skeletal system (SBP) or Extramedullary plasmacytoma (EMP). Similarly, the latest NCCN guideline for MM categorizes solitary plasmacytoma into solitary osseous or solitary extraosseous.

Criteria for identifying solitary bone plasmacytoma (SBP) vary among authors. Some include patients with more than one lesion and elevated levels of myeloma protein and exclude patients whose disease progressed within 2 years or whose abnormal protein persisted after radiotherapy. With the use of magnetic resonance imaging (MRI), flow cytometry, and polymerase chain reaction (PCR), the currently accepted criteria are as follows:

  • Single area of bone destruction due to clonal plasma cells
  • Bone marrow plasma cell infiltration not exceeding 5% of all nucleated cells
  • Absence of osteolytic bone lesions or other tissue involvement (no evidence of myeloma)
  • Absence of anemia, hypercalcemia, or renal impairment attributable to myeloma
  • Low, if present, concentrations of serum or urine monoclonal protein
  • Preserved levels of uninvolved immunoglobulins

Diagnostic criteria for extramedullary plasmacytoma (EMP) are as follows:

  • Tissue biopsy showing monoclonal plasma cell histology
  • Bone marrow plasma cell infiltration not exceeding 5% of all nucleated cells
  • Absence of osteolytic bone lesions or other tissue involvement (no evidence of myeloma)
  • Absence of hypercalcemia or renal failure
  • Low serum M protein concentration, if present

Smoldering myeloma

Smoldering myeloma describes a stage of disease of MM with no symptoms and no related organ or tissue impairment. According to the latest version of NCCN guideline for MM, criteria for the definition of smoldering myeloma are as follows:

  • M-protein in serum ≥30 g/L and/or
  • Bone marrow clonal plasma cells ≥10%
  • No related organ or tissue impairment (no end organ damage, including bone lesions) or symptoms.

Note that the M-protein refers to the monoclonal protein produced by MM cells.

Active/symptomatic myeloma

Criteria for the definition of active/symptomatic myeloma requires one or more of the following:

  • Calcium elevation (>11.5 mg/dL) [>2.65 mmol/L]
  • Renal insufficiency (creatinine >2 mg/dL) [177 µmol/L or more]
  • Anemia (hemoglobin <10 g/dL or 2 g/dL < normal)
  • Bone disease (lytic or osteopenic)

In the section of management of MM we will discuss the specific therapeutic approaches for these three subtypes of MM.

Prognosis and Genetics

Several factors can afford important prognostic information for multiple myeloma. They are β2-microglobulin, lactate dehydrogenase (LDH), cytogenetics, and plasma cell-specific FISH analysis (hyperdiploidy, t(4;14)(p16;q32), t(14;16)(q32;q23), 17p13, t (11;14)(q13;q32), 1q amplifications, 1p deletions, loss of 12p, gains of Cr5).

Table 2. Risk Classification Based on Baseline Testing

Of note that in the latest NCCN guideline about multiple myeloma several high-risk chromosomal aberrations in MM locates at 14q32, including three main ones that are t(11;14)(q13;q32), t(4;14)(p16;q32) and t(14;16)(q32;q23). Thus the risk incidence of t(11;14) is inconsistent with what was decribed in Table 2.

For this inconsistent two view I have sent an inquiry to NCCN and their answer was “We have reviewed your inquiry with the NCCN Guidelines Panel Chair, Dr. Kenneth Anderson. NCCN does not classify t(11;14) as high risk, it is only listed as a major group containing the 14q32 translocation. ”

And pay attention that patients with t(4;14), β2 microglobulin <4 mg/L and hemoglobin ≥10 g/dL may have intermediate risk disease.

Although the genetics can afford the prognosis of multiple myeloma, this approach still needs more evidence. At present the method is still the Durie-Salmon criteria or ISS criteria.

Table 3. Stage of Multiple Myeloma

As shown in the table 2 at left, the stage of multiple myeloma can be divided into three periods: stage I, stage II, and stage III.

The Management of Solitary Plasmacytoma

For those patients with osseous plasmacytoma, primary radiation therapy (45 Gy or more) to the involved field is the initial treatment and is potentially curative. Extraosseous plasmacytomas are treated initially with radiation therapy (45 Gy or more) to the involved field followed by surgery if necessary.

After radiation thearpy, patients with solitary plasmacytoma need follow-up. Blood and urine tests performed every 4 weeks initially to monitor response to the primary radiation therapy. If the patient achieves complete disappearance of the paraprotein then the frequency could be reduced to every 3-6 months or as indicated clinically. If the protein persists, then the monitoring should continue every 4 weeks. These tests include CBC, serum chemistry and those listed in the section of workup.

If progressive disease emerges, then the patient should be re-evaluated for recurrent plasmacytoma or myeloma, and systemic therapy administered as indicated.

The Management of Smoldering Myeloma

Although the activity of novel agents has advanced to the point that early interventions are now being explored in clinical trials for smoldering myeloma, there is still no evidence that early treatment will improve survival in asymptomatic and biochemically stable patients. A critical point is that up to 25% of smoldering myeloma patients will not require active treatment for 10 to 15 years. However, the majority will indeed progress during that time.

Once diagnosed, smoldering myeloma patients require frequent monitoring to allow treatment to begin before end-organ damage is evident. These tests are similar with solitary plasmacytoma, which are listed in the section of workup. If the disease progresses to symptomatic myeloma, these patients should be managed as active/symptomatic myeloma. We will discuss the management of active/symptomatic myeloma below.

The Management of Active/Symptomatic Myeloma

If the patients with MM progresse to active/symptomatic myeloma. Treatment should be initiated. Generally, we divide the treatment strategy into initial drug therapy, hematopoietic cell transplantation, and consolidation and maintenance thearpy after transplantation.

Therapeutic goal

There is a growing body of evidence showing an association between depth of response to therapy and improved long-term outcomes, including progressive-free survival (PFS) and overall survival (OS), in MM patients. Using conventional chemotherapy, it has been shown that there is a correlation between response before and after transplantation and that the quality of response after transplantation has a marked impact on outcome.

Importantly, studies suggest that if a patient achieves a complete response (CR), this must be durable and that the duration of CR is the best predictor of OS. However, some special cases makes the view that initially obtaining a CR in predicting long-term outcome questionable, for instance, group of rapidly responding but early relapsing patients, group of more indolent myelomas that revert to an “monoclonal gammopathy of uncertain significance like” profile after therapy, and group of myeloma patients with stable nonprogressive disease after induction therapy.

Initial drug therapy

Although success and long-term remission have been achieved in many transplantation-eligible patients using limited treatment regimens, such as thalidomide/dexamethasone, bortezomib/dexamethasone, and lenalidomide/dexamethasone, complete and very good partial response (VGPR) rates can be substantially increased by combining these various drugs in triplets or even using 4 drugs together.

On the right is the data of several clinical trials. I list all the detail of regimens below:

VAD: vincristine, adriamycin, and dexamethasone;

TD: thalidomide and dexamethasone;

RD: lenalidomide and dexamethasone;

PAD: bortezomib, doxorubicin, and dexamethasone;

VTD: bortezomib, thalidomide, and dexamethasone;

CVD: cyclophosphamide, bortezomib, and dexamethasone;

RVD: lenalidomide, bortezomib, and dexamethasone;

CVRD: cyclosphamide, bortezomib, lenalidomide, and dexamethasone.

A note of caution is that many of these studies are based on relatively small numbers of patients at single, or limited numbers, of centers, but cumulatively the message is consistent, with frequent, rapid, and deep responses seen.

Althought response rates are clearly improved with new drug cocktails, proving a consequent OS advantage is difficult and especially challenging given the large numbers of patients and the long duration of follow-up required. However, based upon response rates, depth of response achieved, and PFS as surrogates, 3-drug cocktails are currently the modality of choice in clinical practice, with use of RVD, CVD, or VTD as the most commonly chosen regimens outside of clinical trials.

Transplantation

Transplantation is a useful modality helping achieve or consolidating CR. But is it necessary to provide any consolidation chemotherapy before transplantation? If the patient is going to proceed to  transplantation, when do we implement the transplantation. However, because the goal of therapy is to maximize the depth and duration of remission, induction therapy can be continued in some patients for as long as the patient is responding and tolerating therapy, which might be instead of transplantation.

Generally ASCT is the primarily way of transplantation. Allo-SCT should infrequently be performed outside of clinical trials, as the risk of morbidity and early mortality of even nonmyeloablative transplantations is considerable.

Question one is whether to offer any consolidation chemotherapy before transplantation.

After initial induction thrapy, the subsequent approach is to provide further 4 to 6 cycles of induction threapy, then proceed eligible patients to ASCT. The reason to use stem cell transplantation is to provide a consolidation of remission after obtaining the best possible response to frontline treatment.

But a controversial area is what to do if the patient has already achieved a CR before transplantation. In this decision, the role of continued chemotherapy treatment versus proceeding to transplantation is less clear and an are of active research. Generally, in practice we prefer to proceed patients to transplantation without any further induction chemotherapy.

The reason to proceed to transplantation even achieving CR before transplantation is that current measures of CR are insufficiently sensitive and residual disease is in many, if not all, patients present but below the level of detection.

Question two is when do we offer stem cell transplantation to our patients who are eligible to this procedure. The timing of ASCT is also an area of active research. Patients are usually more fit for intensive therapy early in the course of the disease, but prior studies using conventional chemotherapy as induction demonstrated this a delayed ASCT had no adverse impact on OS and is feasible as part of salvage therapy in first relapse.

Maintenance therapy

Clinical studies found thalidomide maintenance to improve overall survival. Lenalidomide may offer the same advantages with less toxicity. Generally, it has become our practice to use maintenance routinely when patients have not achieved a CR after stem cell transplantation or when genetic risk markers suggest a very high risk of early relapse.

Figure 1. Respond Criteria for Multiple Myeloma

Current Standards of The Care of Multiple Myeloma

November 22, 2012 Chemotherapy, Hematology, Pharmacotherapy, Therapeutics No comments , , , , , , , ,

Introduction to Multiple Myeloma

As a clinical pharmacist, you should always know the pharmacotherapy information. Recent days I read some articles about multiple myeloma. Today we’re going to talk about the standards care of multiple myeloma. Think this information will benefits all pharmacists around the world. OK, let’s get start.

Multiple myeloma (MM) is characterized by the malignant proliferation of plasma cells in bone marrow, which may result in skeletal manifestations hematologic complications and renal failure. The secretion of monoclonal immunoglobulin by plasma cells into urine, serum, or both, may result in hyperviscosity syndrome. The diagnostic criteria for MM include bone marrow containing at least 10% plasma cells and a characteristic pattern of end-organ damage, which is defined by the CRAB criteria: hyperCalcemia, Renal failure, Anemia, and Bone disease.

Multiple myeloma is staged using serum β2 microglobulin and albumin concentrations. The median survival decreases from 62 months for patients diagnosed with Stage I MM to 29 months for those diagnosed with Stage III disease.

Multiply Myeloma Staging and Median Survival.

In the 1970s, treatment with traditional chemotherapy was associated with a 5-year survival rate of approximately 25%. By 2003, autologous stem cell transplantation (ASCT) increased 5-year survival rate to 34%. Now due to some novel immunomodulatory drugs the 5-year survival rate is increasing over 40%.

Treatment Selection

The first treatment decision following a diagnosis of MM is to determine whether or not the patient is a candidate for transplantation. Transplant-eligible patients receive induction chemotherapy and ASCT, which may be followed by maintenance chemotherapy. Patients who are not eligible for ASCT receive chemotherapy. A variety of chemotherapy options are available, including regimens that combine 2, 3, 4 different drugs.

Transplant-Eligible Patients

Two-drug combinations include:

  1. Bortezomib plus dexamethasone (the VD regimen);
  2. Lenalidomide plus high-dose dexamethasone (the RD regimen): Lenalidomide 25 mg daily on d1-d21, Dexamethasone 40 mg daily on d1-d4, d9-d12, and d17-d20;
  3. Lenalidomide plus lower-dose dexamethasone (the Rd regimen): Lenalidomide 25 mg daily on d1-d21, Dexamethasone 40 mg daily on d1, d8, d15, and d22.

The researchers found that compared with the traditional chemotherapy VAD regimen (vincristine/doxorubicin/dexamethasone) alone, the CR or nCR was noted for significantly more patients who received VD regimen. The ORR (overall response rate) with VD regimen was significantly higher than with VAD regimen (78.5% vs 62.8%). This study showed that the VD regimen should be considered first-line therapy for transplant-eligible patients with MM. After the induction chemotherapy, 2 cycles of consolidation therapy of DCEP regimen (dexamethasone/cyclophosphamide/etoposide/cisplatin) were added, but the consolidation therapy was considered by the investigators to be of only marginal benefit.

The RD or Rd regimen are the alternative plans, but there is no data in this article which compared RD or Rd regimen with VD regimen. Study primary end point of ORR (overall response rate) after the first 4 cycles was higher with the RD regimen than with Rd regimen (81% vs 70%; P = .04). However, the 1-year overall survival was significantly higher in the Rd group than RD group. From the study it can be concluded that lenalidomide in combination with reduced-dose dexamethasone is an effective and well-tolerated first-line therapy for patients with MM.

Three-drug and four-drug combinations include:

  1. Lenalidomide plus bortezomib pluse dexamethasone (the RVD regimen): Lenalidomide 25mg daily on d1-d14, Bortezomib 1.3 mg/m2 on d1, d4, d8 and d11, Dexamethasone 20 mg on d1, d2, d4, d5, d8, d9, d11, and d12 (MTD: maximum tolerated dose);
  2. Bortezomib plus dexamethasone plus cyclophosphamide (the VDC regimen);
  3. Bortezomib plus dexamethasone plus cyclophosphamide plus an additional dose of cyclophosphamide on d15 (the VDC-modified regimen);
  4. Bortezomib plus dexamethasone plus cyclophosphamide plus lenalidomide (the VDCR regimen).

Preliminary results of clinical trial demonstrated that all 4 regimens above were highly active, with overall respone rates of 86% with VDCR, 83% with RVD, 75% with VDC, and 100% with VDC0modified. However, four-drug regimen was associated with higher rates of severe adverse reactions than three-drug regimens. Although the data from the study are not yet fully mature, they suggest that the additional toxicity may outweigh the potential benefits of the four-drug combination.

Induction Therapy for Transplant-Ineligible Patients

For these patients the MP regimen (Melphalan and Prednisone) has been used for over 40 years, but the benefit of this regimen is smaller than new chemotherapy regimens. The new chemotherapy regimen for transplant-ineligible patients are MPT (Melphalan plus Prednisone plus Thalidomide) regimen and VMP (Bortezomib plus Melphalan plus Prednison) regimen. Compared with MP regimen, the MPT has significantly longer median progression-free survival (24.1 vs 18.5 months; P = .001) and OS (44 months vs 29.1 months; P = 0.028). MPT is also associated with a higher CRR (7% vs 1%) and a greater number of patients who attained PR or better (62% vs 31%).

However, toxicity is more common with MPT regimen, including a higher rate of grade 3/4 neutropenia (23% vs 9%) and grade 2-4 peripheral neuropathy (21% vs 5%). No difference was noted in the incidence of grade 3/4 DVT. Myelosuppression was not associated with an increased risk of infections.

The research of VISTA trial examined the addition of bortezomib to MP, VMP regimen. CR was noted for 33% of patients with VMP versus 4% with MP (P < .001). PR was noted for 33% versus 31% (not statistically), and  a PR or better was attained by 74% versus 39% (P < .001). The primary end point, time to progression, was significantly longer for patients in the bortezomib group (2 years vs 16.6 months;P < .001). However the addition of bortezomib was associated with an increased likelihood of neutropenia, thrombocytopenia, gastrointestinal toxicity, peripheral neuropathy, and herpes zoster infection.

So these results show that MP chemotherapy alone can no longer be considered the standard of care in transplant-ineligible patients.

Role of ASCT (Autologous Stem Cell Transplantation)

ASCT is considered the gold standard for transplant-eligible patients who are younger than 65 years of age, and improves OS by approximately 12 months compared with standard chemotherapy alone. Now transplantation remains an important tool to further decrease myeloma disease burden after induction therapy. In addition, higher CR rates before tansplantation are associated with better posttransplantation outcomes, suggesting that the combination of ASCT with these newer antitumor agents may produce even better clinical outcomes.

It has also been reported that OS after ASCT as salvage therapy after first relapse is identical to OS for patients who receive early ASCT, whereas a study conducted that patients who responded to induction therapy did not derive additional benefit from ASCT. These observation suggest that the greatest benefit of early ASCT may be in patients who have primary refractory disease. In standard-risk patients who are responding well to therapy, it may be reasonable to consider delaying ASCT until first relapse.