Multiple Myeloma

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

Complications of The Care of Multiple Myeloma

November 29, 2012 Adverse Drug Reactions, Chemotherapy, Hematology, Infectious Diseases, Pharmacology, Pharmacotherapy 2 comments , , , , , ,

As a clinical pharmacist you should always know the adverse effect of the pharmacotherapy. That is why we are trained again and again. That is we are educated for. This is more important for oncology pharmacists because the chemotherapy always is relevant to adverse reactions which are commonly grade 3/4.

Last post we talked about the care of multiple myeloma (MM). Today let’s talk about the comlications and toxicities of the treatement of MM.

Infectious Complications of Myeloma Treatment

As we talked before, bortezomib is a novel agent which reversibly inhibits the chymotrypsin-like activity of the 26S proteasome in mammalian cells. While the clinical outcome is improved, side effects accompany. In one study it was found that infection rate of herpes zoster was higher in bortzeomib group than the dexamethasone group (13% vs 5%;P = .0002). However the incidence of grade 3/4 herpes zoster infection was not significantly different for the 2 groups, nor was the incidence of serious infections. One thing to emphasize is that patients in this study didn’t recevie prophylaxis against herpes simplex virus (HSV) reactivation.

At least 4 different mechanisms have been proposed to explain the increased risk of HSV reactivation in patients receiving bortezomib: (1) bortezomib is thought to produce its therapeutic effect at least partly as a result of decreased cell-mediated immunity,3 which could promote viral replication; (2) bortezomib may specifically inhibit the immunoproteasome that is responsible for the suppression of latent varicella zoster virus (VZV)4; (3) bortezomib may alter the function and viability of dendritic cells, which are important antigen-presenting cells involved in the initiation of an antiviral response5,6; and (4) bortezomib is known to affect the dorsal root ganglia, which is where latent VZV resides.7,8

Recent retrospective studies have demonstrated that patients who receive acyclovir prophylaxis are less likely to experience bortezomib-related HSV reactivation. In a study performed at the Roswell Park Cancer Center, investigators reviewed medical charts for 100 consecutive patients who were treated with bortezomib-based therapy for MM, including 59 patients treated as initial therapy and 41 patients for recurrent or refractory disease; and 87 patients receiving bortezomib as part of a combination regimen and 13 patients receiving bortezomib monotherapy.9 All patients received acyclovir, which was initiated before bortezomib and continued until 4 weeks after the last bortezomib dose. All patients but 1 received a fixed dose of acyclovir 400 mg twice daily regardless of renal function. Compliance was evaluated by review of the medical record. Of the 100 patients enrolled in the study, none developed VZV reactivation. In another study patients receiving steroids, no episodes of VZV were observed in patients who received antiviral prophylaxis.

These studies demonstrate that antiviral prophylaxis reduces the incidence of herpes zoster-related complications;the specific antiviral agent is less important.

Venous Thromboembolism (VTE) Complication 

Factor that are associated with increased risk include:

The use of thalidomide or lenalidomide;

Steroid use (especially high-dose steroids);

Concomitant chemotherapy (especially anthracycline-based therapy);

The use of erythropoiesis-stimulating agents (ESAs).

A review of VTE risk factors and prophylaxis for patients receiving thalidomide or lenalidomide for MM recommended aspirin prophylaxis for patients with no more than 1 VTE risk factor. LMWH (equivalent to enoxaparin 40 mg/d) was recommended for patients with 2 or more risk factors, and for patients receiving high-dose dexamethasone or doxorubicin. Full-dose warfarin targeting an INR of 2 to 3 was recommended as an alternative to LMWH.

In a phase III, randomized clinical trial that compared lenalidomide plus standard-dose or low-dose dexamethasone in patients with newly diagnosed MM, high-dose dexamethasone was associated with higher rates of a number of adverse event which included deep vein thrombosis/pulmonary embolism (DVT/PE) (26% vs 12%). For patients who received antithrombotic prophylaxis with aspirin, the incidence of DVT/PE decreased to 14% for the high-dose dexamethasone group and 5% for low-dose dexamethasone group.

Hematologic Toxicity in Renal Insufficiency Patients

In patients receiving lenalidomide for MM, renal insufficiency has been associated with significantly shorter time to the onset of myelosuppression such as thrombocytopenia. In one study of 72 patients with MM, 8 of 14 patients with myelosuppression of grade 3 or worse had baseline creatinine clearance (CrCl) values of 40 mL/min or lower.

The elimination of lenalidomide is primarily renal. Follow a single oral administration of [14C]-lenalidomide (25 mg) to healthy subjects, approximately 90% and 4% of the radioactive doseis eliminated within ten days in urine and feces, respectively. Approximately 82% of the radioactive dose is excreted as lenalidomide in the urine within 24 hours. Hydroxy-lenalidomide and N-acetyl-lenalidomide represent 4.59% and 1.83% of the excreted dose, respectively.

Above describes the reason why the hematologic toxicity of lenalidomide is enhanced is patients with renal insufficiency. So dose adjustment is needed. Recommendations for dose adjustment are shown in table below.

The Complication of Neuropathy in MM patients

Nearly all patients receiving bortezomib develop some degree of neuropathy. (more…)

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.

Systemic Therapy for Bone Metastases

August 24, 2012 Adverse Drug Reactions, Drug Informatics, Hematology, Pharmacology, Therapeutics No comments , , ,

zoledronic acid

Accelerated bone loss in patients with cancer is a frequent problem that may result from [1]invasion of the cancer to bone, [2]paraneoplastic tumor proteins, and/or [3]hormonal therapies utilized for cancer treatment.

  • Invasion of the cancer to bone;
  • Paraneoplastic tumor proteins;
  • Hormonal therapies utilized for cancer treatmen.

Invasion of cancer to bone is common complication in patients. The proportion of cancer invading to bone is 20% to 25% in kidney cancers, 65% to 75% in breast and prostate cancers, and almost all patients (70% to 95%) with multiple myeloma.

Mechanism of Bone Metastases

  1. Metabolically active tumor cells invade and populate bone and secrete growth factors that affect bone resorption and formation by stimulation of osteoclasts, cells that destroy bone by attacking the mineralized bone matrix.
  2. On the other hand osteoclasts also secrete growth factors that induce tumor cells in the bone to grow, spread, and stimulate the activity of osteoblasts, cells responsible for the formation of bone. However, osteoblastic activity creates new bone formation away from the sites of osteolytic bone resorption. So weakened areas are not strengthened by osteoblastic activity.
  3. Also, osteoblasts release receptor activator of nuclear factor κB ligand (RANKL), a key mediator of osteoclast formation, function, and survival, which is one of the mechanisms of metastatic bone disease.

Patients with osteolytic bone disease from multiple myeloma and bone metastases from solid tumors may develop a vicious cycle of bone destruction involving both ostelytic and osteoblastic effects. Consequently, a variety of skeletal-related events (SREs) may occur, including pathological fractures, hypercalcemia, spinal cord compression, and the need for surgical intervention and radiation therapy.

  • Pathological fractures;
  • Hypercalcemia;
  • Spinal cord compression;
  • The need for surgical intervention and radiation therapy.

Untreated patients with bone metastases are at risk for multiple SREs within a single year, ranging from 1.5 events for prostate cancer to 4.0 for breast cancer.

Treatment Agents

Now two types of agents are used to treat bone metastases – bisphosphonates and denosumab.

Bisphosphonates

Bisphosphonates are unique drugs with an affinity for bone mineral matrix with the ability to inhibit bone resorption. Bisphosphonates decrease bone resorption and increase mineralization by entering osteoclasts and inhibiting farnesyl diphosphate synthase, a key enzyme in the biosynthetic mevalonate pathway.

Bisphosphonates may also affect bone resorption through the inhibition of osteoclast precursor maturation, induction of apoptosis in mature osteoclasts, inhibition of tumor cell adhesion to bone, and inhibition of inflammatory cytokine production.

Nitrogencontaining bisphosphonates (N-BPs) have the greatest antiresorptive activity. Based on in vitro studies, zoledronic acid is the most potent aminobisphosphonate and is the only intravenous bisphosphonate found to be effective in all types of metastatic bone lesions.

Bisphosphonates also have a potential antitumor effect. Data from multiple studies suggest that bisphosphonates may directly or indirectly impair multiple processes required for cancer growth and metastases. Bisphosphonates have demonstrated an ability to induce apoptosis in a variety of cancer cell lines. These agents may also inhibit metastases by decreasing tumor cell adhesion, migration, and invasion. Inhibition of angiogenesis is another property associated with bisphosphonates. Furthermore, these pharmacologic agents may modulate the immune system with subsequent antitumor activity. Recent research also found that zoledronic acid may exert its antitumor activity by inhibiting mesenchymal stem cell migration and blocking mesenchymal stem cell secretion of factors involved in breast cancer progression.

However data from the FDA and the United Kingdom showed the issue of potential risk of esophageal cancer with oral bisphosphonate use was raised. The FDA recently announced plans to continue review of the conflicting studies.

Safety and efficacy data of intravenous bisphosphonates in the metastatic setting are predominantly limited to 24 months of treatment. The most frequently reported side effects from intravenous bisphosphonates are fever and myalgias, which may occur in up to 55% of patients, typically within 12 hours of the initial infusion. Antiinflammatory agents may easily provide relief. Diarrhea and gastric irritation may develop with the oral bisphosphonates ibandronate and clodronate, which are not approved in the management of bone metastases in the United States. Electrolyte abnormalities, including hypophosphatemia, hypocalcemia, hypomagnesemia, and hypermagnesemia, are rarely reported with intravenous bisphosphonates. Other condition such as  vitamin D deficiency, hypoparathyroidism, hypomagnesemia, or use of medication such as interferon, aminoglycosides, or loop diuretics may provoke these abnormalities. (more…)

Recent Advances in Multiple Myeloma Therapy

August 10, 2012 Chemotherapy, Hematology, Therapeutics No comments , , ,

Lenalidomide Maintenance in Elderly Patients?

Alway lenalidomide maintenance therayp is not approved, but researchers now have the final results of the melphalan, prednisone, and lenalidomide followed by lenalidomide maintenance study.

According to their study, this will probably translate into routine practice in the next year because it is probable that this therapy will be approved by the European Medicines Agency.

This regimen will be approved only in patients aged 65-75 years, on the basis of the results of that particular study.

Adding Bortezomib: The VISTA Trial

In a large randomized trial, melphalan/prednisone (MP) regimen was compared with the regimen bortezomib plus melphalan/prednisone (VPM). With a median follow-up of 5 years (4.5 years from the last patient enrolled), there was a significant overall survival benefit of more than 1 year (13.3 months) in favor of the experimental arm (VMP group). This benefit was observed across group analyses.

In addition, this study has shown something that is very important about the paradigm of using a more conventional approach (MP up front) and reserving the other drugs until the time of relapse. This study has clearly shown that it is better to use an optimized treatment up front.

The third message of the study was that for the first time, in the analysis of risk for second primary malignancies with the use of bortezomib (in this case, in combination with MP), it showed that the incidence is the same as in the control arm.

The study was not sufficiently powered to analyze the role of cytogenetics because the number of patients with high-risk cytogenetics was very small (22 patients in 1 group and 24 in the other). Initially, we saw an advantage for the experimental arm vs the MP group, but now with longer follow-up, the incidence of second primary malignancies was exactly the same. One could argue that at the time of relapse, fewer patients were receiving bortezomib, but this is not the right answer. The right answer is that no difference in risk for second primary malignancies was seen in this study.

In the VISTA study, we used biweekly dose of bortezomib. Now we have the once-a-week regimen of bortezomib. We had an update of the weekly administration of bortezomib.[3] This clearly indicated (especially in older patients) that not only is weekly bortezomib associated with better tolerance, but at the end of the day, the cumulative dose of bortezomib is higher. The complete response (CR) rate is the same, and there might even be a trend toward a better CR rate, especially with a maintenance phase in these trials. So, clearly, weekly administration of bortezomib is the way to go in older patients, and discussions are occurring about treating even older and frailer patients with weekly doses of bortezomib.

 Early vs Late Autologous Stem Cell Transplant

In younger patients who are eligible for high-dose therapy and autologous stem cell transplantation. A prospective comparison of melphalan/prednisone/lenalidomide vs melphalan (200 mg/mgMEL200 ) in tandem with autologous stem cell transplantation following an induction phase with lenalidomide-dexamethasone (len-dex) was also reported.

Today, early transplant should be considered the standard because the study that compared the conventional approach (a novel agent vs an autologous transplant approach including a novel agent) clearly showed that the use of the autologous transplant significantly improves progression-free survival (PFS). We do not yet have data in terms of overall survival, but there is a clear advantage in terms of PFS. For the younger patient, a strategy including a novel agent as induction, consolidation with high-dose melphalan in tandem with stem cell support, and maintenance should be introduced as quickly as possible. (more…)