Extended Post-Transplant Treatment With Revlimid, Velcade, And Dexamethasone Yields High Survival Rates In High-Risk Myeloma

A new retrospective study by Emory University researchers may stir debate about the best way to treat high-risk myeloma patients.
The researchers investigated treating high-risk myeloma patients for up to three years with a combination of Revlimid, Velcade, and dexamethasone.
The extended three-drug therapy, which the authors describe as a combined consolidation/maintenance regimen, was initiated after the patients had received a stem cell transplant. The patients' transplants were carried out soon after completion of the first (induction) treatment regimen following diagnosis.
Some, but not all, of the patients also received the Revlimid-Velcade-dexamethasone combination as induction therapy.
The researchers found that 100 percent of the patients in the study achieved at least a partial response during the extended post-transplant treatment.
In addition, most responses were deep responses. Just over half the patients achieved a stringent complete response, and nearly all the patients (96 percent) achieved at least a very good partial response.
Progression-free survival among the patients was 32 months from the time of diagnosis, and the estimated three-year overall survival rate is 93 percent.
“What is particularly intriguing about our data is not only the prolonged progression-free survival, but also the prolonged overall survival,” write the investigators in the journal article summarizing their findings. An earlier study involving extended dosing of Velcade alone, the researchers note, found a three-year overall survival rate of under 70 percent.
Significance Of The Study Results
The new study's findings are likely to draw attention because improving survival among high-risk myeloma patients has been a vexing challenge for myeloma specialists.
Researchers have generally assumed that, to improve survival among these patients, it is necessary to use regimens that generate the deepest possible responses, and then extend the responses as long as possible.
However, extended treatment with multi-drug regimens that achieve such responses – including the Total Therapy regimens pioneered at the University of Arkansas – have nevertheless failed to significantly improve survival among the approximately 20 percent of myeloma patients who have high-risk disease.
The Emory researchers believe that the results of their study may help explain why such previous approaches to treating high-risk myeloma have not been as successful as the regimen they investigated.
Prior approaches, they explain, often have relied on extended treatment with three- or four-drug combination regimens that include drugs known as alkylating agents. Melphalan (Alkeran) and cyclophosphamide (Cytoxan) are two alkylating agents commonly used in the treatment of myeloma.
There is evidence based on laboratory research, however, that alkylating agents may not be very effective in killing off the most aggressive myeloma cells found in high-risk patients, say the Emory researchers.
In fact, extended exposure to alkylating agents may actually contribute to the development of more aggressive forms of myeloma.
Thus, although extended treatment with combination regimens that include alkylating agents may wipe out many of the myeloma cells in high-risk patients, a sufficient number of aggressive myeloma cells may be left behind (or created) to cause early relapse.
This, the researchers explain, may be why the responses achieved by extended treatment regimens that include alkylating agents are not translated into prolonged survival in high-risk patients.
The study authors recognize that there is still scope for improving the progression-free survival seen in their study with the extended Revlimid-Velcade-dexamethasone treatment regimen.
Potential options for improving the regimen include using either Kyprolis (carfilzomib) or Pomalyst (pomalidomide, Imnovid) instead of Velcade and Revlimid (respectively), or adding drugs to the regimen from other classes of therapies, such as monoclonal antibodies or histone deacetylase inhibitors.
It also is worth noting that this study was retrospective, involved only a single treatment center, and included a somewhat limited number of patients (45).
The latter point is particularly important when interpreting the overall survival estimates, which currently are based on the experiences of a small number of patients.
Background
Although multiple myeloma remains a generally incurable disease, significant advances have been made in the treatment of the disease since the introduction of the novel agents thalidomide (Thalomid), Revlimid (lenalidomide), and Velcade (bortezomib).
The three-drug combination of Revlimid, Velcade, and dexamethasone (Decadron), commonly referred to as RVD or VRD, is particularly effective in controlling myeloma.
Findings from a Phase 1/2 study of RVD as initial therapy for newly diagnosed myeloma patients show that all patients responded to treatment (see related Beacon news).
In addition, results from a retrospective study indicate that the majority of patients with advanced myeloma respond to RVD therapy (see related Beacon news).
Yet, despite the progress made in recent years in the treatment of myeloma, the prognosis for high-risk patients remains poor (see related Beacon news for the current definition of high-risk, standard-risk, and low-risk myeloma).
According to the investigators, the use of novel agents in induction, consolidation, and maintenance therapies has improved response rates in high-risk patients. However, responses have typically been short lived.
The investigators therefore hypothesized that a prolonged post-transplant therapy combining the novel agents Revlimid and Velcade, as well as dexamethasone, might be a good solution for disease control in high-risk patients.
Study Design
Investigators from Emory University investigated the efficacy and safety of extended post-transplant therapy with RVD. The study included 45 high-risk myeloma patients who received extended treatment with RVD after undergoing an autologous (own) stem cell transplant soon after completion of initial therapy for myeloma.
The 45 patients in the study encompass all patients who were treated at Emory who met the study inclusion criteria – that is, diagnosis with high-risk myeloma, transplantation soon after completion of initial therapy, and extended RVD therapy after transplantation – and who started the RVD therapy between January 2008 and August 2012.
The median age of the patients at diagnosis was 55 years, and patients received their stem cell transplants a median of six months after diagnosis.
Around 65 percent of the patients received Velcade with either thalidomide or Revlimid as their initial induction therapy after diagnosis. A quarter of the patients were treated with the combination regimen known as VDT-PACE – Velcade, dexamethasone, and thalidomide plus cisplatin, doxorubicin (Adriamycin), cyclophosphamide, and etoposide – as induction therapy.
The investigators characterized patients as high-risk based on either the presence of certain chromosomal abnormalities or a diagnosis of (primary) plasma cell leukemia — a very advanced and aggressive form of multiple myeloma.
Chromosomal abnormalities considered high risk included del(17p) (42 percent of the patients), del(1p) (20 percent), t(14;16) (11 percent), and t(4;14) (5 percent). Three quarters of the patients had more than one chromosomal abnormality. One quarter of the patients had plasma cell leukemia.
The extended RVD treatment consisted of 10 mg of Revlimid per day on days 1 to 21 of a 28-day cycle, along with 1.3 mg/m2 of Velcade and 40 mg of dexamethasone per week for up to three years, followed by single-agent Revlimid maintenance therapy.
Study Results
Prior to transplantation, 96 percent of the study participants achieved at least a partial response to induction therapy, with 11 percent of patients achieving a stringent complete response, 9 percent a complete response, 33 percent a very good partial response, and 40 percent a partial response.
Transplantation deepened responses, such that two months after transplantation, all patients had achieved a partial response. Specifically, 22 percent of patients achieved a stringent complete response, 22 percent a complete response, 44 percent a very good partial response, and 11 percent a partial response.
After a median follow up of 26 months following the start of extended RVD therapy, responses deepened further, with 51 percent achieving a stringent complete response, 20 percent a complete response, 24 percent a very good partial response, and 4 percent a partial response.
The median time to best response was 11 months after diagnosis.
The median progression-free survival was 32 months.
Patients who had achieved at least a partial response or better prior to transplantation had longer progression-free survival (36 months) than patients who did not achieve a partial response (20 months).
The estimated three-year overall survival rate is currently 93 percent. The estimated four-year overall survival rate, however, is about 74 percent (based on results presented in a figure in the study).
There was no difference in the estimated three-year survival rate for all patients versus patients with the del(17p) chromosomal abnormality (93 percent versus 94 percent, respectively).
The researchers point out that none of the patients in the study developed severe peripheral neuropathy (pain, tingling, or loss of sensation in the extremities) during the extended RVD treatment, nor did any discontinue treatment due to side effects. However, 40 percent of patients required dose modifications.
For more information, please refer to the study in the journal Leukemia (abstract). The study response and survival rates quoted in this article reflect clarifications generously provided to The Beacon by Dr. Ajay Nooka of Emory University, one of the study authors.
Related Articles:
- Revlimid, Velcade, and Dexamethasone, Followed By Stem Cell Transplantation, Yields Deep Responses And Considerable Overall Survival In Newly Diagnosed Multiple Myeloma
- Nelfinavir Shows Only Limited Success In Overcoming Revlimid Resistance In Multiple Myeloma Patients
- Nelfinavir-Velcade Combination Very Active In Advanced, Velcade-Resistant Multiple Myeloma
- Adding Clarithromycin To Velcade-Based Myeloma Treatment Regimen Fails To Increase Efficacy While Markedly Increasing Side Effects
- Sustained Complete Response To Initial Treatment Associated With Substantial Survival Benefit In Multiple Myeloma
Wow..now that's a lot to digest!
I have high risk myeloma (p17 deletion and (14,16) trans)and I just underwent an allo transplant at Moffitt. I am receiving no followup treatment as doctors don't want to suppress the graft vs myeloma effect. Currently in remission and hoping to stay in remission for as long as possible. Disappointed by news from Myeloma Research that the pharmaceutical companies don't want to spend research money on the p17 subtype. Let's hope for a cure for all myeloma patients.
We hope your allo transplant works out well, Susan. Please keep us posted on how it's going. There are a lot of Beacon forum members interested in knowing more about allo transplants.
This will be one of best choices for MM. I It really works in control during its progresses. My family membership has VRD treatments for her Stage IV on Extramedular Plasmacytoma in Pancrea and Pelvic on March 2011.
Now, she only has Maintenance Chemotherapy by using Velcade twice a momth. So far, she has no blood transfusion and SCT. Doctors have not found tumors on both pelvic and pancrea in using CT scan since March 2012. Also, all of blood test are very fine except blood glucose. She does cook, walk, and shopping for our daily life.
Thank all doctors help her in best conditions under their treatments.