Among Velcade-Based Combinations, Four-Drug Combo Is Not More Effective Than Similar Three-Drug Combos For Newly Diagnosed Multiple Myeloma
The results of a recent Phase 2 clinical trial comparing four Velcade-based combination therapies in newly diagnosed multiple myeloma patients show that a four-drug combination containing Velcade, Revlimid, cyclophosphamide, and dexamethasone led to similarly high response rates as the three-drug regimens, but resulted in a higher rate of side effects.
“We were hoping to see more activity at the same level of toxicity as the three-drug combination, but the result was similar efficacy at higher toxicity,” said Dr. Shaji Kumar of the Mayo Clinic in Rochester, Minnesota, and lead investigator of the study. “Clearly, as the study showed, more is not necessarily better.”
However, Dr. Kumar added, “I think we should continue to work on novel combinations of drugs working through different mechanisms in order to identify better ways to treat these patients.”
Based on their findings, Dr. Kumar and his colleagues concluded that the combinations of Revlimid (lenalidomide), Velcade (bortezomib), and dexamethasone (Decadron) (commonly referred to as RVD or VRD) as well as Velcade, cyclophosphamide (Cytoxan), and dexamethasone (commonly referred to as VCD or CyBorD) are preferred in clinical settings and should be further assessed in larger Phase 3 trials.
“The trial reinforces prior observations that these two regimens are very effective and should be considered as part of the treatment armamentarium,” said Dr. Kumar.
Previous clinical studies have demonstrated the strong anti-myeloma activity of RVD and CyBorD, which have overall response rates of up to 100 percent, and complete response rates of about 40 percent. Additionally, a recent retrospective study comparing multiple initial therapies in newly diagnosed patients showed CyBorD to be slightly more effective than Revlimid-dexamethasone and Revlimid-cyclophosphamide-dexamethasone (see related Beacon news).
Based on these findings, the researchers sought to evaluate a four-drug regimen involving Revlimid, Velcade, cyclophosphamide, and dexamethasone (abbreviated as RVCD) in newly diagnosed myeloma patients and compare the response rates and survival outcomes to those for RVD and CyBorD.
According to Dr. Shaji, “This [four-drug regimen] was a logical combination to study given that patients continue to relapse with either of the three-drug regimens. The question was whether we could achieve a deeper remission state that would translate to a better outcome.”
A total of 140 newly diagnosed myeloma patients with a median age of 61 years were enrolled in the study between June 2008 and September 2009. The participants were initially randomly divided into three treatment groups receiving RVCD, RVD, or CyBorD. Following an interim analysis, a fourth treatment arm was introduced with a modified dosing of CyBorD.
All patients could receive a maximum of eight three-week cycles of induction (initial) therapy and could opt to receive a stem cell transplant after four cycles.
Every patient received 1.3 mg/m m2 of Velcade on days 1, 4, 5, and 11 and 40 mg of dexamethasone on days 1, 8, and 15. Patients on the RVCD regimen also received 15 mg of Revlimid on days 1 through 14 and 500 mg/m2 of cyclophosphamide on days 1 and 8. Those in the RVD group received 25 mg of Revlimid on days 1 through 15. Lastly, patients in the CyBorD group received 500 mg/m2 of cyclophosphamide on days 1 and 8. Patients in the modified-CyBorD group received an additional dose of 500 mg/m2 cyclophosphamide on day 15.
Following induction therapy, patients received a maintenance regimen of 1.3 mg/m2 of Velcade on days 1, 8, 15, and 22 of four six-week cycles.
Patients received a median of six treatment cycles. Eighty-seven percent of patients completed four or more cycles of initial treatment and were evaluated for response. Of these patients who were eligible for a stem cell transplant, 45 percent from the RVCD group, 44 percent from the RVD group, 28 percent from the CyBorD group, and 53 percent from the modified-CyBorD group underwent a transplant.
Across all treatment cycles, the overall response rate (partial response or better) was 88 percent in the RVCD group, 85 percent in the RVD group, 75 percent in the CyBorD group, and 100 percent in the modified-CyBorD group. According to the researchers, the response rates for the three-drug combinations are comparable to those from prior studies.
The one-year progression-free survival rate was 86 percent in the RVCD group, 83 percent in the RVD group, 93 percent in the CyBorD group, and 100 percent for the modified-CyBorD group.
The one-year overall survival rate was 92 percent for the RVCD group and 100 percent for all three of the groups that received a three-drug combination.
More RVCD patients (79 percent) experienced at least one drug-related severe or life-threatening side effect than patients receiving RVD (60 percent), CyBorD (71 percent), or modified CyBorD (61 percent).
In addition, the RVCD group experienced a higher rate of blood-related side effects, including low white blood cell counts (44 percent for RVCD, 10 percent for RVD, 30 percent for CyBorD, and 24 percent for modified CyBorD) and low platelet counts (15 percent for RVCD, 12 percent for RVD, 12 percent for CyBorD, and 0 percent for modified CyBorD).
Other common side effects affecting all treatment groups included fatigue, diarrhea, pneumonia, and peripheral neuropathy (pain or tingling in the extremities).
The share of patients who discontinued treatment due to side effects was highest in the RVCD group (21 percent, compared to 19 percent in the RVD group, 12 percent in the CyBorD group, and 6 percent in the modified-CyBorD group).
For more information, please see the study in the journal Blood (abstract).
Related Articles:
- Adding Clarithromycin To Velcade-Based Myeloma Treatment Regimen Fails To Increase Efficacy While Markedly Increasing Side Effects
- Nelfinavir-Velcade Combination Very Active In Advanced, Velcade-Resistant Multiple Myeloma
- Nelfinavir Shows Only Limited Success In Overcoming Revlimid Resistance In Multiple Myeloma Patients
- Revlimid, Velcade, and Dexamethasone, Followed By Stem Cell Transplantation, Yields Deep Responses And Considerable Overall Survival In Newly Diagnosed Multiple Myeloma
- Once-Weekly High-Dose Kyprolis Yields Deeper Responses And Longer Remissions Than Twice-Weekly Kyprolis (ASCO & EHA 2018)
I hope that Dr. Kumar is not surprised that a four drug combo has more side effects than a three drug combo WHEN HE DID NOT REDUCE THE DOSE of the agents. How much chemo can the body handle? Does it not make sense to capture the positive synergies of the combo by using lower doses of each component without without overwhelming the ability or the body to fight these poisons? Let's start thinking about the dosing regimens instead of the number of drugs in the combo.
It seems the modified CyBorD arm has the best response rate and the lowest relative side effects. I am curious why the summary did not highlight this important finding, even though it is not the main purpose of the trial. Does that mean a shift can be made now to turn away from the standard RVD combination?
Thanks, Gary and Ben, for your comments.
Gary - The four-drug combination used a lower Revlimid dose (15 mg) than the standard dose (25 mg) that was used in the three-drug combination.
Ben S. - Yes, you are right that in this trial, the modified CyBorD was the most effective and safest among the four investigated combinations. As is mentioned at the beginning of the article, the study investigators recommend the use of CyborD and RVD and suggest further investigation of the two combinations.
"The cell-kill caused by antineoplastic agents follows first-order kinetics, that is, a constant percentage, rather than a constant number, of cells is killed by a given therapeutic maneuver, This finding has had a profound impact on clinical cancer chemotherapy. For example, a patient with myeloma might harbor 10 to the negative 12 or about 1 kg of malignant cells. A drug killing 99.99% of these cells would reduce the tumor mass to about 100mg, and this would be apparent as a complete clinical remission. However, 10 to the negative 8 malignant cells would remain, any of which could cause a relapse in the disease. The logical outgrowth of these concepts has been the attempt to achieve total cell-kill by the use of several chemotherapeutic agents concurrently or in rational sequences."
In 2006-2008 Kumar also did this trial in newly dx MM pts:
"The trial was initiated in July 2006 and completed the initial target accrual of 33 patients by July 2007 (Cohort 1). Due to high rate of dose reductions in cohort 1, between July 2007 and May 2008 an additional 20 patients were enrolled with lower doses of cyclophosphamide (Cohort 2). The treatment protocol consisted of lenalidomide given orally at a dose of 25 mg daily on days 1–21 of a 28-day cycle. Dex was given orally at a dose of 40 mg on days 1, 8, 15, and 22 of each cycle.
Cyclophosphamide at a dose of 300 mg/m2 was given on days 1, 8, and 15 of each cycle in cohort 1 and 300 mg on days1, 8, and 15 of each cycle in cohort 2. Patients also received an aspirin once daily as thromboprophylaxis. Response was defined as a decrease in serum monoclonal (M) protein by 50% or higher and a decrease in urine M protein by at least 90% or to a level less than 200 mg/24 hours"
http://www.cancereducation.com/CancerSysPagesNB/abstracts/mmrf/113/abdz14.pdf
So based on the above trial, Kumar knew, giving 2 major toxic myelosuppressive agents concomittantly resulted in higher AE's.
As a result there needed to be a second cohort in 2006 with reduced doing?...how utterly unpredictable...that Kumar did not have a lower dose cyBorD to begin with.
Despite the conclusion in 2008:
"Myelosuppression was a significant toxicity leading to dose reductions and cycle delays, and is lower with decreased dose of CTX in cohort 2 without any apparent loss of responses."
Ben, I suspect, the modified dose of CyBorD was not highlighted because it was already known from a previous trial Kumar did.
CyBorD has less AE's RELATIVE to the combination of Cy with lenalidomide. However, both drugs are myelosuppressive and when used in combination they cause major myelosupression toxicity, a known fact.
Kumar wanted to focus on using 4 chemoagents simultaneously in this trial, vs. what he had already demonstrated in prior trials.
Quote:
“This [four-drug regimen] was a logical combination to study given that patients continue to relapse with either of the three-drug regimens. The question was whether we could achieve a deeper remission state that would translate to a better outcome.”
Am I reading the study results correctly to assume that the extra cyclophosphamide in the modified CyBorD group produced the best results? That's interesting...that is the same drug given before a stem cell harvest, isn't it?
Wow, Suzierose, imagine one's having 1 kg. of malignant cells, and then having it reduced to 100 mg. That in itself is a big success, but of course there can always be more to be done. i appreciate that...thanks everybody for the information!
Hi Nancy,
If we want to compare whether the modified (high dose) CyBorD group is we have to compare it with high dose lenalidimide. That was not done here. So the only real conclusion is that a higher dose of cyclophosphamide beats a lower dose of lenalidamide in a 3 drug regimen with bortezomib/dex.
The modified CyBorD arm in this trial is not comparable to the lenalidamide arm.
Maximum dose cyclophosaphimde is used but only 15mg lenalidamide is used in the three drug regimen arm. The higher dose of cyclophosphamide was able to be used because lenalidamide was not in the 3 drug regimen and that reduced the likelihood of major myelosuppressive toxicities.
If we want to compare apples to apples then it is the EVOLUTION trials that have comparable arms. This trial was run by Kumar as well.
At 2010 ASH:
"Shaji Kumar from the Mayo Clinic Rochester provided an update of the randomized phase II EVOLUTION trial.4 Approximately 140 previously untreated symptomatic patients with myeloma were randomized to 1 of 4 regimens: bortezomib, dexamethasone, and lenalidomide (VDR), VDR plus cyclophosphamide (VDCR), bortezomib, dexamethasone, and cyclophosphamide (VDC), or VDC-modified, which added an additional cyclophosphamide dose on day 15. Baseline characteristics were similar. A median of 5-6 cycles was administered in each arm of the studyAll 4 arms appeared highly active, but the 4-drug VDCR arm did not result in a substantial increase in response rates compared to the VDR arm. Safety profiles were similar and quite acceptable although there was a higher rate of adverse event–related treatment discontinuation in the VDCR arm"
It was already a known fact that the AE's from combining lenal/cyclo were not only highly toxic but letha1 as well.
Regarding reduction in cells, if we do not eradicate the cancerous population, it results in relapse. So going from 1kg to 100mg simply means the patient is in remission and will relapse as the cancerous cells that remain repopulate and the patient becomes refractory to different chemotherapies.
Thanks Suzie, I appreciate your getting back to me. You are right, lowering the tumour burden , but not eliminating the cancer cells will probably lead to relapse. One can't assume that one is clear of the cancer indefinitely just because it is not measurable after the treatments given. That has to be why patients are checked often for problems in the blood..every three months in my case!
Hi, Suzierose:
“The cell-kill caused by antineoplastic agents follows first-order kinetics, that is, a constant percentage, rather than a constant number, of cells is killed by a given therapeutic maneuver, This finding has had a profound impact on clinical cancer chemotherapy."
This clarified quite a few confusions that I had. It answered the question quite a few participants on this forum have asked regarding why an SCT is till needed even after induction therapies enable a patient to achieve CR.
It also seems to provide some rationales for seemingly over-aggressive treatments that use multiple agents all for the elimination of the small "percentage" of myolama cells that could have survived a smaller number of agents. Is that also what you think?
Ben
Hi Ben,
Absolutely!
The first order kinetics is why we have 4-6 drug combo therapies used as 'standard of care' in many types of cancers.
It is also why there are trials like the one Kumar did here with bortezomib along with lenalidomide/cyclophosamide and dexamethsone, despite the combination having greater myelosuppressive toxicity, AE's as well as deaths.
Also, a CR, does not mean that all cancer cells have been eradicated (only a percentage), it simply means that the tests which are used to measure/assay level of cancer cells remaining are not sensitive enough to pick up the diminished percent level of cells remaining, NOT, that there are no longer any cancer cells remaining.
I think this is a critical point in understanding why cancer is basically a chronic disease and why words like remission/relapse can be somewhat misleading as patients believe their cancer is gone when in actuality it is merely undetectable by the tests, not that it is gone, thus the need for ongoing follow-up. Remission/relapse are medical terms and specific parameters set up to facilitate FDA approval and decide if trial met the outcomes RESPONSE criteria. Rather than remission/relapse cancer has periods of exacerbation/abatement.
Which is why my hope is for more effective/less toxic chemo agents that help us manage the disease better just as we can manage other chronic diseases like diabetes, hypertension, arthritis etc.
Thanks, Suzierose. Your comment made me think back of an article I read a few weeks ago about the childhood leukemia cure rate that has reached 90-95%. Granted, it is measured as a 5-year survival rate. But since that rate flats out after the 5-year mark, it is commonly regarded as the cure rate. Just for comparison, I looked into the treatment protocols for childhood ALL. They include induction, consolidation and maintenance therapies that could last for three years, almost identical to what some of the MM centers practice nowadays with the exception of SCT. It is also known that UAMS models its MM treatments after the successful treatments for childhood ALL.
I wonder what the differences are between the two closely related blood diseases. Aren't all theories that negate the possibility of an MM cure would equally negate that of the childhood ALL cure? They would include what you stated above and the myeloma stem cell theory. This is crucially important to those patients who are still contemplating which area of the treament spectrum to land on - conservative or aggressive.
Ben
Just to add to this subject. Dr. Rajkumar of Mayo didn't object directly to the curability of the disease during his debate with Dr. Barlogie of UAMS. All their arguments, as I recall, seemed to center on the subject of whether the UAMS curves actually flatten out after a certain number of years, compared to the similar curves for childhood ALL. I did, however, remember the mentioning of differences between childhood ALL and MM. I just don't know what those differences are and would welcome any knowledge or insights Suzierose or other readers can provide. Thanks!
Ben S.,
I do not think UAMS survival curves have anything to do with the issue of if Myeloma is curable. Dr. Rajkumar does think Myeloma is curable, he just does not think the path to it is worthwhile for most patients.
"Third, in most cases, it is probably impossible (with the possible exception of allogeneic transplantation where true complete eradication is possible for a minority of patients), unnecessary, and prohibitively toxic to attempt to eradicate all clonal plasma cells. Unlike other cancers where benign clonal expansion can be distinguished histopathologically from malignant cells, such discrimination is not currently possible in MM."
"Although CR defined using molecular methods with patient-specific primers after allogeneic transplantation is more prolonged, it cannot predict cure with certainty."
"For example, younger patients may opt for early intensive strategies, such as allogeneic transplantation, accepting high treatment-related mortality in exchange for a chance at long-term survival."
http://bloodjournal.hematologylibrary.org/content/118/12/3205.full
One of the big reasons Myeloma is different from other blood cancers is this:
"The researchers found that immune-system cells known as plasmacytoid dendritic cells (pDCs) essentially assume a new identity in the presence of myeloma – promoting the growth and survival of malignant myeloma cells, helping them fend off drugs, and depleting the overall strength of the immune system."
""This is the first time that immune system cells have been found to be converted to another function," says Chauhan, who is also a principal associate in medicine at Harvard Medical School. Investigators don't yet know how the conversion occurs, but they suspect the proteins cause a different set of genes to be activated within the pDCs."
http://www.sciencedaily.com/releases/2009/10/091005123043.htm
Mark
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