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.