Month: November 2012

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.