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.

Many patients will require dose modification based on the severity of bortezomib-induced peripheral neuropathy (the table above). The incidence of neuropathy may be reduced by the use of subcutaneous rather than intravenous (IV) administration. In a recent randomized, phase III noninferiority clinical trial of patients with relapsed or refractory MM with evidence of disease progression, subcutaneous bortezomib was statistically noninferior to conventional IV bortezomib for overall complete response and for other clinical outcomes. Subcutaneous dosing significantly reduced the incidence of peripheral neuropathy of any grade (53% vs 38% for IV and subcutaneous bortezomib, respectively;P = .044), as well as neuropathy of at least grade 2 (41% vs 24%;P = .012) or at least grade 3 (16% vs 6%;P = .026). We have a online neurological toxicity scale for the evaluation of peripheral neuropathy here.

Below is the dose adjustment of bortezomib in patients with peripheral neuropathy.

Renal Impairment, Osteonecrosis of The Jaw During The Treatment for Skeletal Complications

Multiple Myeloma paitents are commonly have skeletal complications. Bisphosphonates can prevent the skeletal events effectively. However one problem is the impairment of renal function. As we know the MM itself will cause renal impairment due to the precipitate of monoclone protein. The bisphosphonates are associated with a risk of worsening renal function. In these patients I recommend monitor the renal function, serum creatine level is a good goal to monitor. We can adjust the dose of bisphosphonates on the basis of the serum creatine level.

Osteonecrosis of the jaw (ONJ) is another potential cause for concern in patients receiving bisphosphonate therapy, especially in patients receiving treatment for longer periods of time (> 2 y) or those with history of poor oral care or more invasive dental procedures. Before beginning treatment of bisphosphonates we shoud assess the patient’s level of risk by a thorough dental evaluation.

Denosumab is a monoclonal antibody against the RANK ligand, a protein that is involved in osteoclast survival and function. Denosumab prevents RANKL from activating its receptor, RANK, on the surface of osteoclasts and their precursors. Prevention of the RANKL/RANK interaction inhibits osteoclast formation, function, and survival, thereby decreasing bone resorption and increasing bone mass and strength in both cortical and trabecular bone. The main adverse reactions of denosumab are similar to bisphosphonates, renal impairment and osteonecrosis of jaw.